MS news and research
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The Cognitive Rehabilitation for Attention and Memory trial (CRAMMS), a major study to be conducted on patients with multiple sclerosis, was recently awarded £1,167,000 by the National Health Service (NHS), through its Health Technology Assessment (HTA) Program.
The study, which is expected to be the largest trial of its kind in the United Kingdom, is designed to examine MS patients’ cognitive rehabilitation capacities and determine if a group of cognitive rehabilitation programs is able to improve patients’ quality of life.
This symptom management clinical trial for MS is being conducted because so many patients experience difficulties in cognitive processes, including loss in memory, decision making, and concentration, and there are currently few effective treatments available for the management of these symptoms. Therefore, the CRAMMS trial is expected to be able to advance the development of new therapies to improve the lives of patients with these problems.
The trial, which is expected to occur between September of 2014 and August of 2018 at four centres in Nottingham, Sheffield, Liverpool, and Birmingham, is currently enrolling patients, who must be diagnosed with MS and between the ages of 18 and 70 years old. During the trial, participants will be enrolled over the course of 16 months and will participate in either weekly group cognitive rehabilitation sessions with a psychologist and their usual care, or just their usual care. The investigators will then evaluate and compare the effects on the two groups.
“We do not know whether taking part in the study will help but we expect that some people will find the intervention helps them cope with memory and attention problems,” the website of the trial states. “However, the information we get from this study may help us to treat people with MS and attention and memory problems better in future. There are no particular risks involved in taking part in this study.”
In addition, the trial is also expected to raise particular attention and investment into other research focused to the disease.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (21/11/14)
Researchers presented a new mouse model for fatigue at the 2014 Society for Neuroscience meeting. The model is the first of its kind and works by manipulating the pro-inflammatory cytokine interleukin-1β.
There’s a new animal model coming down the pike that may be of use to multiple sclerosis researchers. At the Society for Neuroscience (SfN) annual meeting in Washington, D.C., researchers announced that they have developed a new mouse model for fatigue. This is the first mouse model to isolate fatigue from other symptoms.
Fatigue is said to be the most common and debilitating symptom of multiple sclerosis. It’s characterised less as sleepiness and more as an inability to function normally, even if the motivation is there.
“Surprisingly, this is an underrepresented area of research,” Mary Harrington, Ph.D., of Smith College said at an SfN press conference. “There is little to no understanding of what is the underlying neurobiology of fatigue.”
The researchers began by activating the pro-inflammatory cytokine interleukin-1β (IL-1β) in young, middle-aged, and aged female mice. The animals demonstrated signs of fatigue, without any other signs of sickness (Bonsall et al, 2014). Middle-aged (6 to 12 months old) and aged mice (18 to 24 months old) almost completely stopped voluntary wheel-running compared to their baseline activity. They did not, however, show signs of fever, muscle ache, or anhedonia (decreased pleasure-seeking activity). The researchers saw no significant change in the young (3- to 5-month-old) mice.
The researchers also found that the treatment did not seem to act upon the neurotransmitter orexin to induce fatigue. Orexin is thought to mediate arousal and wakefulness. Unsurprisingly, the mice also did not respond well to medications that work on the arousal system, such as modafinil (Provigil, Teva Pharmaceuticals) or methylphenidate (Ritalin, Concerta, and others), a drug commonly prescribed to treat attention deficit hyperactivity disorder.
In an interview with MSDF, Harrington, whose background is in studying circadian rhythms, said that patients often don’t report fatigue to their physician because it seems hopeless. Currently, no effective treatments exist for fatigue.
One possible reason that it’s been so difficult to get a handle on the biology of fatigue is that researchers may have been looking in the wrong place. It could be that fatigue originates in the immune system, not in the nervous system. Harrington pointed out that the diseases characterized by fatigue have one major common denominator: inflammation. Harrington said that she decided to target IL-1β after reviewing the literature and work done in a model for fatigue used in rats.
In the rat model, researchers give the rats a compound called PolyIC. “It’s a viral mimic so your body thinks you’re having a viral infection,” Harrington said to MSDF. “When researchers tried to reverse the effects of PolyIC they realised that they could do it with a blocker of interleukin-1β.”
Harrington said that more work needs to be done to verify her work. But she hopes the model can help illuminate key players in generating fatigue and can be used for drug screening. She said she hopes that MS researchers will use it to help defeat the most debilitating symptom of MS.
Key open questions
How can this model be used to best serve MS research? Can it be combined with experimental autoimmune encephalomyelitis (EAE)? Why does fatigue result from inflammation, and how can it be best treated?
Disclosures and sources of funding
Harrington’s work was supported by NIH grant R21NR012845. She reported no conflicts of interest.
Inflammation-induced fatigue: Exploring neurobiological mechanisms and potential treatments BONSALL D, Kim H, PETRONZIO AM, MOLYNEUX PC, SCAMMELL TE, HARRINGTON ME Society for Neuroscience 2014. 11/18/2014.
Source: Multiple Sclerosis Discovery Forum Copyright © 2014 MGH and ACP (21/11/14)
A study by Dr. Anna Karin Hedström and a team of researchers from Sweden's Karolinska Intstitute have discovered a possible link between alcohol consumption and a reduction in the risk of having multiple sclerosis, the degenerative disease of the central nervous system.
According to the abstract of the study published in the Journal of the American Medical Association, the researchers' goal was to “investigate the possible association of alcohol consumption with the risk of developing MS and to relate the influence of alcohol to the effect of smoking.”
The team conducted two case-control studies in which researchers followed more than 6,500 participants from Sweden aged between 16 and 70 years old. The studies took place from April 2005 to November 2011.
In an interview with medical website Medscape, Hedström said the researchers conducted the large-scale study because previous research showed alcohol can have an anti-inflammatory effect.
“The current case-control studies are the largest to look at this association. We wanted to study this as experimental studies and clinical observations have suggested that alcohol has an effect on the immune system and may have anti-inflammatory actions,” she said in the interview. “As MS is an inflammatory condition, we thought alcohol may have a protective effect.”
The results of the test showed a 50 percent reduction in the risk of MS for frequent alcohol drinkers.
The study defined frequent drinkers as men who drank 14 drinks a week and women who drank 9 drinks a week. According to a press release by the National Multiple Sclerosis Society, the results of Hedström's research conflict with earlier studies done by the Harvard School of Public Health (HSPH).
“In a previous study, researchers at (HSPH) examined the association between alcohol and caffeine intake and risk of developing MS in two large groups of women and found no connection between either and the development of MS,” the release stated.
The results of the Karolinska study, however, are encouraging, the society said in the release.
“Unlike a previous study in MS, this study shows some evidence that alcohol consumption is associated with a decrease risk of developing MS,” the release said.
The study did not observe the effect of alcohol on patients who already have MS, Hedström said in her Medscape interview.
“We didn't look at patients who already had MS, so we cannot make firm recommendations on this, but previous research has shown an anti-inflammatory effect of moderate intake,” she said. “I would say that if an MS patient wants to drink alcohol that is absolutely fine.”
Her recommendation comes with the implicit rule that patients should consult their doctors before making a lifestyle change of this sort.
As for MS patients who are concerned about their children's risk for having MS, Hedström say her team's findings aren't a license to begin heavy drinking.
“Whilst we wouldn't recommend them drinking large quantities of alcohol because of other negative consequences, we can probably say that alcohol in moderation will not increase risk and may reduce it somewhat,” she told Medscape. “So I wouldn't advise people to start drinking alcohol specifically to reduce their risk of developing MS, but I would say that you don't need to avoid alcohol or stop drinking alcohol.”
Source: Snooth Copyright © 2014 Snooth, Inc (21/11/14)
Tongue shocks hasten healing(20/11/14)
A little-known fact: the tongue is directly connected to the brain stem. This anatomical feature is now being harnessed by scientists to improve rehabilitation.
A team at the University of Wisconsin–Madison recently found that electrically stimulating the tongue can help patients with multiple sclerosis (MS) improve their gait. MS is an incurable disease in which the insulation around the nerves becomes damaged, disrupting the communication between body and brain. One symptom is loss of muscle control.
In a study published in the Journal of Neuro-Engineering and Rehabilitation, Wisconsin neuroscientist Yuri Danilov and his team applied painless electrical impulses to the tip of the tongue of MS patients during physical therapy. Over a 14-week trial, patients who got tongue stimulation improved twice as much on variables such as balance and fluidity as did a control group who did the same regimen without stimulation.
The tongue has extensive motor and sensory integration with the brain, Danilov explains. The nerves on the tip of the tongue are directly connected to the brain stem, a crucial hub that directs basic bodily processes. Previous research showed that sending electrical pulses through the tongue activated the neural network for balance; such activation may shore up the circuitry weakened by MS.
The team is also using tongue stimulation to treat patients with vision loss, stroke damage and Parkinson's. “We have probably discovered a new way for the neurorehabilitation of many neurological disorders,” Danilov says.
Source: Scientific American 16/10/14
Although the drug development pipeline still contains numerous products intended for patients with relapsing-remitting multiple sclerosis (RRMS), the consensus among clinicians is that relapses can be effectively squelched in nearly all RRMS patients with the dozen or so currently approved therapies.
Patients now have a choice between injectables and oral drugs, and within the injectable class there is a range of dosing intervals and delivery types -- expanded just this week with the approval of alemtuzumab (Lemtrada) that requires just two brief courses of therapy a year apart.
The more pressing clinical need now, researchers told MedPage Today, is for treatments that stop or reverse the progressive forms of MS. This has been a tougher nut to crack because the mechanisms underlying progressive MS are less well understood than the acute demyelinating attacks that characterise RRMS. A particularly important aspect that remains mysterious is the switch that occurs in many patients from RRMS to the secondary progressive form or SPMS.
Currently the sole FDA-approved treatment for SPMS is the chemotherapeutic agent mitoxantrone, which has only been tested in two small trials of questionable design that showed relatively modest efficacy. The drug also has significant toxicities that earned a lengthy boxed warning on its label.
But that doesn't mean MS researchers haven't made any progress -- in fact, enough knowledge about progressive MS has accumulated that rational approaches to therapy are now in clinical development. The following is a rundown, aided by Jeffrey Cohen, MD, who spoke at length recently with MedPage Today. Cohen is director of the experimental therapeutics program in the Cleveland Clinic's Mellen Center for Multiple Sclerosis.
He summarised the field's current status in progressive MS this way: "There are now a lot of candidate approaches being considered and we're finally starting to test them."
Jumpstarting Oligodendrocyte Activity
One firmly established feature of advanced MS is that the physical disability results from destruction of nerve axons following demyelination -- the process that defines MS in all its forms, stripping away the protective myelin sheaths from axons.
There is a class of cells called oligodendrocytes whose job is to maintain the myelin coatings. A problem in MS is that these cells stop functioning and/or are simply killed off. If their activity could be restarted -- thereby promoting remyelination -- it may prevent and even possibly reverse disability progression.
Several avenues are now being pursued to promote oligodendrocyte activity:
Anti-LINGO. About 10 years ago, a protein called LINGO-1 found in the central nervous system was revealed to be an inhibitor of oligodendrocyte generation from precursor cells. Subsequent animal studies confirmed that blocking this protein could promote oligodendrocyte proliferation and lead to remyelination in models of MS. A monoclonal antibody called BIIB033 targeting LINGO-1 is now in phase II clinical studies, sponsored by Biogen Idec, following favorable safety results in the first phase.
Antihistamines and other small-molecule drugs to boost oligodendrocytes. By mechanisms that are still not fully understood, it appears that certain histamine pathways also inhibit differentiation of oligodendrocyte precursor cells (OPCs) into the mature remyelination-capable types, raising the possibility that antihistamines can have the same effect as anti-LINGO-1. A histamine H3 antagonist (or inverse agonist) developed by GlaxoSmithKline called GSK239512 is now in phase II studies, although at this point the trials are testing it in RRMS patients with relatively narrow outcome measures intended to prove the concept.
Separately, researchers at the University of California San Francisco (UCSF), using a high-throughput screening approach to find drugs that promote oligodendrocyte-driven remyelination, found that their best hit was an over-the-counter antihistamine, clemastine (sold as Tavist).
The antihistamine approaches may help in MS by preventing demyelination as well as by promoting remyelination, Cohen told MedPage Today.
Groups elsewhere have programs in place to identify other small-molecule agents that promote OPC differentiation into remyelination-capable oligodendrocytes, such as this one at the Scripps Research Institute in San Diego that reported benztropine was one such candidate.
OPC-based cell therapies. A number of groups have been looking at the possibility of implanting OPCs to jumpstart remyelination -- perhaps collected autologously and expanded ex vivo, or developed in vitro from pluripotent stem cells or other sources. None of these have yet moved into clinical testing, said Cohen, who predicted it would be at least several years before human trials could begin.
Mesenchymal stem cells. Another type of cell therapy in development involves autologous mesenchymal stem cells, which are usually extracted from patients' bone marrow (although other sources are possible) and then coaxed either ex vivo or in vivo to mature into oligodendrocytes. Several groups have conducted phase I trials and the treatment's safety has been fairly well established. Cohen has led one such trial and said the efficacy data are necessarily sparse at this point but have shown "encouraging hints" that this is a viable approach, including signs of "repair of demyelination." He added that other groups are expected to report results next year.
However, he stressed, much work remains to be done on cell therapies, including optimising the cell types, the dosing regimens (numbers of cells, routes of delivery), and the manipulations the cells undergo before implantation.
Protecting the Demyelinated Axon
Another way to prevent nerve degradation is to interfere with the cellulo-chemical attacks on the exposed axon. In a recent paper appearing in The Neurohospitalist, Bruce Cree, MD, PhD, of UCSF, noted that microglia mediate one type of this attack. An inhibitor of microglial activity called NT-KO-003 has completed an early efficacy/safety study although results have not been released. However, mouse studies indicated that the agent was neuroprotective in a variety of degeneration models.
Mast cells are believed to participate in the axonal attacks as well. Now in a phase IIb/III trial in patients with SPMS and PPMS -- after favourable results in earlier studies -- is masitinib, an oral tyrosine kinase inhibitor targeting mast cell activity. Masitinib is currently a veterinary drug, which is also in human testing in a variety of other oncologic and inflammatory conditions. This is a full-scale, placebo-controlled trial structured like those normally conducted for RRMS drugs, lasting 2 years with a target enrollment of 450 and with a functional outcome measure as the primary endpoint.
In a phase II trial currently is a familiar neurology drug, phenytoin. The rationale is that it blocks sodium entry into cells; in the nervous system, this is a key mechanism of neuronal damage. The trial, which is sponsored by MS-related nonprofits in the U.S. and the U.K., is actually testing the drug in optic neuritis, which is a common manifestation of MS (but can have other causes also).
RRMS Drugs for Progressive Disease
Trials are now underway with several currently approved RRMS drugs in primary and/or secondary progressive MS, including natalizumab (Tysabri) and fingolimod (Gilenya). Cohen told MedPage Today that a trial in this area is now being planned as well for dimethyl fumarate (Tecfidera).
Earlier RRMS drugs including the interferon-beta class have also been studied for an effect on progressive MS, with mostly negative results. Because the mechanisms of those drugs and of the disease process were not well understood at the time, the trials could be regarded mainly as expressions of hope.
But for the newer agents, Cohen said, there are mechanistic reasons to think they may be effective. "The aspects of MS that those drugs have been shown to be effective for [e.g., lymphocyte trafficking for fingolimod] do carry over, to some extent, into progressive MS," he said, noting that SPMS patients often still show gadolinium-enhancing lesions on MRI, for example. "At least in a subset of patients, those drugs might be helpful."
Cohen added that fingolimod and dimethyl fumarate also have activity involving glia and neuronal function that may make them especially suited to neuroprotection in the purely progressive state.
Another drug that could be included in the "current drug" group is ocrelizumab, a follow-on drug to rituximab (Rituxan) that depletes B cells but in a more targeted way. It has not yet been approved but is well along in development for RRMS. A trial in PPMS is now underway as well, in the wake of mixed results with rituximab in an earlier PPMS trial. Its manufacturer and some independent researchers believe that the more selective action of ocrelizumab boost its chances for success for this indication.
Vitamin D Supplements?
Deficiencies or insufficiencies in vitamin D have been linked to many disorders, but perhaps none so closely as in MS. Many studies have found associations between serum levels as well as in risk factors for low vitamin D, such as latitude.
But these association studies, by virtue of their design, fall short of proving that low vitamin D is causative. The counter-hypothesis, which has yet to be disproven, is that low vitamin D merely reflects other factors that correlate with increased risk of diagnosis and/or increased risk of more severe or aggressive disease after diagnosis. It may simply be that people more likely to develop or progress with MS spend less time outdoors where they would be exposed to vitamin D-producing sunlight.
Cohen said a causal connection is supported by lab studies finding that vitamin D (increasingly called a hormone rather than a nutrient) affects a number of immune functions "that one would think would be involved in relapses and lesion formation, but also effects on cells that one would think would be involved in demyelination." He added that the substance is "a neurotrophic factor" as well.
Randomised trials of vitamin D supplementation are considered the key test of the so-called vitamin D hypothesis for MS, or any other condition, for that matter. The record in other conditions thus far has been largely negative. But those negative studies are often criticized for using inadequate vitamin D doses or the wrong type of vitamin D (D2 instead of the more bioactive D3, for example).
Several supplement trials are now underway in RRMS, some involving doses of 50,000 IU weekly or more, which should satisfy most adherents of the vitamin D hypothesis on the dosage score. Of course, the results -- whether positive or not -- may not translate directly to progressive forms of MS. But the hypothesis has been developed to apply to the entire disease course of MS, so results in the RRMS setting will probably be interpreted more generally by the MS community.
One problem, Cohen predicted, is that any benefit is likely to be relatively modest, meaning that a relatively large trial will be needed to detect it. The studies now underway are enrolling no more than a few hundred patients each, which may make a positive finding hard to come by.
Cohen said that another important target for intervention is comorbid conditions that serve as risk factors shown to be associated with aggressive forms of MS, such as smoking and cholesterol. As with vitamin D, whether addressing these factors in patients with established disease will affect the risk or speed of progression is not yet known and needs to be tested. On the other hand, as is commonly stated, these comorbid conditions are worthy of intervention irrespective of their relationship to MS.
In fact, with respect to cholesterol, one study has already shown that a statin drug, simvastatin (Zocor), slowed brain atrophy in SPMS patients. It's unclear, though, whether this was related to the drug's cholesterol-lowering function or to a more general anti-inflammatory action that is also a known statin effect -- or to some other mechanism not yet known.
Cohen noted that a longer-term challenge in developing progressive MS treatments lies in trial design -- "For outcome measures, specifically which MRI measures are the best and, secondly, what is the best study design." For example, he said, some groups have chosen to test therapies in optic neuritis instead of MS per se, and other trials have used a variety of MRI outcomes, a marked contrast with trials of RRMS drugs for which there is an almost immutable formula in terms of outcome measures and trial duration.
"We're testing unknown agents with not fully worked-out study designs," Cohen said.
Cohen disclosed relevant relationships with EMD Serono, Genentech, Innate Immunotherapeutics, Novartis, Vaccinex, Genzyme, Receptos, Synthon, and Teva.
Cree disclosed relevant relationships with AbbVie, Biogen Idec, EMD Serono, Genzyme/Sanofi, Medimmune, Novartis, Teva Neurosciences, and Hoffmann-La Roche.
Primary source: The Neurohospitalist
Source reference: Cree B "2014 Multiple sclerosis therapeutic update" Neurohospitalist 2014; DOI: 0.1177/1941874414525410.
Source: Medpage Today © 2014 MedPage Today, LLC. (20/11/14)
The Irish Health Service Executive has said its drugs committee will meet to reconsider a decision not to fund a life-changing drug for multiple sclerosis patients.
Fampyra, or Fampridine, which is made by Biogen Idec, costs between €220 and €500 for a monthly dose.
Patients were receiving the drug for free until July of this year, but since then they have had to start paying for it themselves.
The drug helps MS patients to walk and walk faster.
It does not work for everyone, but some of the thousand or so patients taking the drug have claimed it has meant the difference between whether they could leave their homes unaided or not.
In May 2013, the HSE decided not to approve the reimbursement of the drug under any of its free schemes as the manufacturer had failed to formally justify the high price it was charging.
Earlier this year, patients stopped getting the drug for free and now have to pay up to €500 for a monthly dose.
The HSE has since had further contact with the makers of the drug.
It has said its drugs committee will reconsider the outcome of its commercial discussions with the manufacturer before the end of next month.
Independent TD Denis Naughten, who raised the plight of MS patients on a number of occasions in the Dáil, has called on the HSE to ensure that the drug is provided under one of its free schemes.
Source: RTÉ News © RTÉ 2014-RTÉ Commercial Enterprises Ltd (19/11/14)
ENDECE Neural announced the presentation of new, pre-clinical evidence that the company’s lead compound, NDC-1308, induces remyelination and increases forelimb grip strength in a validated animal model of demyelination. As presented in a poster session at the 2014 annual meeting of the Society for Neuroscience in Washington, D.C., the improvements with NDC-1308 therapy are linked to the drug’s unique ability to repair the myelin sheath of demyelinated axons (nerve fibres).
The data, presented by Steven H. Nye, Ph.D., Vice President of Discovery at ENDECE Neural, suggest that the remyelinating properties of NDC-1308 may benefit patients with secondary progressive multiple sclerosis (SPMS). ENDECE Neural has announced plans to initiate non-clinical investigational new drug (IND)-enabling studies of NDC-1308 and a first-in-humans Phase 1 clinical trial in 2015.
“We continue to be encouraged by the reproducible pre-clinical data generated for NDC-1308,” said Dr. Nye. “In addition to our previous knowledge about its mechanism of action, we now conclusively demonstrate the ability of NDC-1308 to repair the damaged myelin sheath in a cuprizone mouse model of demyelination. The grip-strength findings are especially encouraging, as this test may be translated to the clinic for measuring functional improvement in MS patients. We look forward to initiating clinical trials of this promising compound.”
Dr. Nye and colleagues reported that NDC-1308 induced significant remyelination in several brain regions using the cuprizone model of demyelination, in which the neurotoxicant cuprizone was used to remove the myelin sheath from the axons of mice. In addition, prophylactic treatment with NDC-1308 delayed the onset of clinical symptoms of MS in an experimental autoimmune encephalomyelitis (EAE) mouse model of brain inflammation while preserving neuronal cells, suggesting that it also exerts a neuroprotective activity. Chronic treatment with NDC-1308 was well-tolerated by the studied animals, suggesting it can be safely administered.
“All research to date indicates that NDC-1308 is ready to advance to IND-enabling and clinical studies,” commented James G. Yarger, Ph.D., Chief Executive Officer of ENDECE Neural. “The IND-enabling program has been designed to determine the safety and toxicity of NDC-1308 and appropriate starting doses for initiating Phase 1 studies in humans. We look forward to continuing the momentum from the pre-clinical studies as we enter the clinic with NDC-1308.”
NDC-1308 is a novel chemical entity designed to address the damage to the myelin sheath that occurs in patients with secondary progressive MS (SPMS), a common later phase of the disease that follows relapsing-remitting MS (RRMS). NDC-1308 is being developed for potential use either alone or in combination with other MS therapeutics that slow the progression of the disease. By dramatically up-regulating key genes in pathways leading to oligodendrocyte progenitor cell (OPC) differentiation and myelin synthesis, NDC-1308 appears to induce restoration of the lost myelin sheath that is believed to cause the devastating symptoms of MS. NDC-1308 is a small molecule that readily crosses the blood-brain barrier, allowing it to reach the tissues in the brain and spinal cord where promoting myelin production is needed. NDC-1308 works by inducing differentiation of OPCs into mature oligodendrocytes, cells that synthesize and maintain the myelin sheath. ENDECE Neural discovered NDC-1308, and owns the intellectual property surrounding the compound.
Source: Business Wire © 2014 Business Wire (19/11/14)
Azathioprine versus Beta Interferons for Relapsing-Remitting Multiple Sclerosis: A Multicentre Randomized Non-Inferiority Trial
Luca Massacesi, Irene Tramacere, Salvatore Amoroso, Mario A. Battaglia, Maria Donata Benedetti, Graziella Filippini, Loredana La Mantia, Anna Repice, Alessandra Solari, Gioacchino Tedeschi, Clara Milanese
For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists.
To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers.
Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions.
Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons).
Annualised relapse rate was 0.26 (95% Confidence Interval, CI, 0.19–0.37) in the azathioprine and 0.39 (95% CI 0.30–0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01).
MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61–0.95) in the azathioprine and 0.69 (95% CI 0.54–0.88) in the interferon group.
Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year.
The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.
Source: PLOS One (18/11/14)
Upper limb spasticity and lower leg cramps and spasms, two conditions that affect patients with multiple sclerosis, are being treated in separate clinical trials with results from both showing positive benefits. Dysport (abobotulinumtoxinA), from Ipsen Biopharmaceuticals, Inc., and transient receptor potential (TRP) activators, from Flex Pharma, are proving to be effective in alleviating patients’ symptoms in novel ways.
“To our knowledge, no marketed products have been shown to be safe and effective in treating leg cramps in well-designed, blinded human clinical studies, said Rod MacKinnon, MD, Co-Founder of Flex Pharma, in a news release from the company. “These study results support the belief that our proprietary treatment has significant potential as a solution for people suffering from muscle cramping and spasms resulting from a broad range of neuromuscular disorders, including nocturnal leg cramps, multiple sclerosis, spinal spasticity, and cervical dystonia.”
A representative from Flex Pharma presented data during the Cell Symposium on Translational Neuroscience that demonstrated efficacy for preventing muscle cramps, the study’s primary endpoint. Study participants experienced significantly fewer electrically-induced muscle cramps when taking the TRP activators, and the effect lasted for six to eight hours. Cramp intensity was reduced three-fold compared to cramps experienced by participants receiving a control treatment.
“With these positive results in healthy normal volunteers, we plan to initiate at least one proof-of-concept efficacy study in patients with nocturnal leg cramps in the second quarter of 2015,” said Christoph Westphal, MD, PhD, Chairman and Chief Executive Officer of Flex Pharma. “Nocturnal leg cramps can cause distress, interrupted sleep, reduced quality of life, and interference with activities of daily living.”
Moving on to upper limb spasticity, representatives will present five posters at the Annual Assembly of the Academy of Physical Medicine and Rehabilitation (AAPM&R) concerning the use of Dysport during clinical trials for cervical dystonia, a condition of neck muscle contractions and spasms. “We are very encouraged by this new research, confirming the use of Dysport as an effective treatment option for cervical dystonia, while continuing to pursue its potential use in other investigational indications, including upper limb spasticity,” said Cynthia Schwalm, Chief Executive Officer of Ipsen Biopharmaceuticals, in a news release.
When used to treat upper limb spasticity in a phase 3 study, Dysport was shown to be safe for treated patients, with no reported safety events. Muscle tone, spasticity, and active range of motion in spastic upper limbs were improved after four weeks of treatment with 500 or 1,000 IU of Dysport. Outside of the United States, Dysport is approved to treat upper limb spasticity. However, in the United States, it is approved only for treating adults with cervical dystonia. Ipsen’s supplemental Biologics License Application for Dysport to treat upper limb spasticity in adults has been accepted by the FDA.
Although both TRP activators and Dysport are in the clinical trial stages of development, they may be future treatments for muscle spasms in the upper and lower extremities, giving relief to multiple sclerosis patients afflicted by these symptoms.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (17/11/14)
Almost two years ago, Julius Lukes sat down to a meal of raw fish riddled with tapeworm eggs. “I did not enjoy it,” he recalls. Happily, it took just a second or two: “You put it on your spoon and shovel it down.”
Today, his intestines are home to three tapeworms with a total length of about 20 metres – all because Mr. Lukes, a senior fellow at the Canadian Institute for Advanced Research (CIFAR) and a professor at the University of South Bohemia in the Czech Republic, belongs to a small but growing group of scientists who maintain that some parasites may actually be good for us. In other words, the dictionary isn’t completely accurate when it says that a parasite “obtains nourishment” from its host, “which does not benefit from the association, and is often harmed by it.”
The researchers are exploring whether parasites could be used to treat a raft of autoimmune disorders, such as inflammatory bowel disease, multiple sclerosis and arthritis – chronic and often painful conditions in which the body’s immune system produces antibodies that attack its own tissues. Studies have repeatedly shown that the incidence of such disorders is highest in the developed world, where people live in relatively sterile environments.
Inflammatory bowel disease – Crohn’s disease and ulcerative colitis – affects about a quarter-million Canadians. An estimated 100,000 in this country have multiple sclerosis, one of the highest rates in the world. And arthritis affects no fewer than 4.5 million of us. There is no cure for any of these illnesses – only treatments that provide inconsistent relief.
But what if there is a cure, and we’ve been too squeamish to take it seriously? Scientists are beginning to investigate a theory that parasites can prime the immune system so that, when faced with a minor insult such as gluten or cheese, for example, it does not overreact and cause a serious disorder.
In a recent review in Trends in Parasitology, Mr. Lukes and his colleagues go so far as to call some parasites “old friends” who have evolved along with us over millions of years. Today’s overly hygienic lifestyle, however, has reduced our contact with these friends, perhaps sparking the rising rates of autoimmune disorders.
Not that every one gets a pass. “There is no good parasite in human blood or in the brain,” says Mr. Lukes, who is also a researcher at the Czech Academy of Sciences. “The argument is for intestinal parasites only.”
Experiments with rodents already suggest that infection with worm-like intestinal parasites called helminths can provide relief from autoimmune disorders. As well as his one-man study of tapeworms, Mr. Lukes plans to add to the helminth research with a rodent study of his own. He is collaborating with University of British Columbia microbial ecologist Laura Wegener Parfrey on a CIFAR-sponsored study of two parasites: a species of tapeworm called hymenolepis and a single-celled parasite called a blastocystis. Working with rats suffering from a form of inflammatory bowel disease, they will see what impact both parasites have on the illness, and hope to have results next fall.
Ms. Wegener Parfrey’s previous research suggests parasites are a normal part of a healthy gut. In a study published in June in Frontiers in Microbiology, she found that a greater variety of parasites live in the guts of healthy people in remote areas of Malawi than in those of North Americans. “The ubiquity of parasites in healthy people in developing countries and high abundance even in westernized countries shaped my thinking that parasites are likely good, at least some of the time,” she says.
According to Ms. Wegener Parfrey, the critical time for infection is probably in childhood, when our immune system is still developing. But small clinical trials in Europe and North America involving adults suggest that infection with worms in particular can reduce symptoms of some autoimmune diseases. Biopharmaceutical companies Ovamed GmbH in Germany and Coronado Biosciences in Massachusetts are conducting trials involving T. suis, a pig whipworm that sometimes infects humans and may be effective against inflammatory bowel disease, multiple sclerosis and arthritis.
T. suis is a good candidate for therapeutic infection because it can’t complete its life cycle in humans: To survive, it must find its way into a pig at some point, meaning it can’t stick around in the human gut long enough to cause serious problems. Other good candidates include parasites that don’t migrate to the blood or brain, and those that aren’t infectious when excreted from the body.
Mr. Lukes’s tapeworms – a species called Diphyllobothrium latum – fit the bill on all counts. He does not suffer from an autoimmune disorder; the point of his experiment is to see whether the worms can do him any harm. And so far, so good, he says – despite the fact that his tenants are not all that much shorter than the newly named Dreadnoughtus, the biggest dinosaur. He has experienced none of the diarrhea or vomiting typically considered symptoms of infestation.
Medical textbooks suggest he should be suffering a vitamin B12 deficiency by now, but tests show that he is healthy. “I feel wonderful,” he says.
As a guinea pig, Mr. Lukes is not alone. Last year, James Logan, a parasitologist at the London School of Hygiene and Tropical Medicine, infected himself with hookworms, providing detailed online video documentation of his body’s reaction. Mr. Logan did not feel wonderful. He suffered stabbing abdominal pains that kept him up at night. On the other hand, he found relief from a long-standing allergy to bread products – an immune-system overreaction to something normally harmless. After two months, he swallowed a pill to get rid of his parasite along with his new-found ability to eat bread.
Mr. Lukes could do the same for his tapeworms, but says he won’t. In fact, last month he tried to infect himself with giardia, a microscopic parasite known among North American backpackers as the cause of “beaver fever.” It is most often transmitted through contaminated water and is widely believed to cause violent diarrhea, nausea and cramping that can last weeks without treatment. “Everybody freaks out about giardia,” says Mr. Lukes, whose first dose didn’t take – although he plans to down another one soon. “But in most cases, it doesn’t do anything. So that’s my testable hypothesis. That can be a follow-up story in a year.”
Source: The Globe and Mail © Copyright 2014 The Globe and Mail Inc. (17/11/14)
The U.S. Agency for Healthcare Research and Quality (AHRQ) recently released a draft review on the evidence on discontinuation of disease-modifying therapies. Shocked by the apparent lack of expertise in the first draft, MS researchers and advocacy groups sent in a wave of comments chastising the AHRQ for the perceived shoddiness of the report.
A draft review of the evidence surrounding discontinuation of disease-modifying therapies (DMTs) has sparked a firestorm within the MS research community.
The draft, released in October 2014 by the U.S. Agency for Healthcare Research and Quality (AHRQ), remained open for comment for the standard four weeks. During that time, the MS research community appeared to unite to express its collective disapproval of the study.
The extensive AHRQ review, titled “Discontinuation of Disease-Modifying Treatment for Multiple Sclerosis,” is 126 pages long and lists nearly 150 references. Its authors, whose names the agency has withheld, examined only long-term studies (longer than three years) related to two key questions: “What are the consequences of discontinuing disease-modifying treatments in adult patients?” and “What are individual values, beliefs, and preferences regarding discontinuing disease-modifying treatments?”
The review concluded that meager information exists to guide patients and their physicians in making decisions about discontinuing DMTs. The authors stated that there’s little evidence suggesting long-term harms are any greater than short-term harms for patients taking DMTs. Similarly, they stated that there’s little evidence supporting long-term benefits from DMTs for patients with relapsing-remitting MS (RRMS).
“It galvanized the MS community”
Despite the ostensibly neutral tone of the review, the MS research community reacted quickly and forcefully.
By the November 10 deadline, the National Multiple Sclerosis Society, Medical Partnership 4 Multiple Sclerosis (MP4MS), the Multiple Sclerosis Coalition, and several other patient-centered and researcher-centered organizations submitted highly critical comments. Their main concerns centered on the potential for healthcare providers and patients to misinterpret the document as justification to go off of treatment when they should not. The commenters were also concerned that insurance companies would use the document to guide their decisions about which medications to cover, and for how long.
“It galvanized the MS community in a way that’s never been galvanized before. We’ve never had such a unified response,” Daniel Kantor, M.D., of MP4MS said in an interview with MSDF. “It’s scary that we need a near-crisis to bring us together.”
The MP4MS letter was highly critical of the study design. Kantor and his fellow signatories suspected that the authors involved in conducting the study were not experts, citing the fact that his group as well as the MS Coalition, the National MS Society, and others were not approached to aid in this study.
Leadership within the Evidence-based Practice Centers (EPC)—the branch of the AHRQ that develops these reviews—appears to have been taken aback by the vehement response. Stephanie Chang, M.D., M.P.H., director of the EPC, expressed surprise at the response from the MS community.
“A lot of [the MP4MS] concerns seemed to be about the process, about which we make every effort to be very open and transparent,” Chang said in an interview with MSDF.
She said the EPC began the research when some people submitted questions to the AHRQ asking that a review look into early diagnosis and clinical signs of MS. The AHRQ then consulted a panel of end-point users of medicine, such as physicians and patients, to see what research should be done in this area.
“We had a stakeholder group that represents people from patients, physicians, and various MS groups,” Chang said. “They together weighed in on the fact that a review of the evidence on discontinuation of therapy would be of interest and had not been addressed by any other review.”
“They leave out a lot of good data”
In addition to questions about the genesis of the study, MP4MS criticised the trials the EPC chose to include in its review and, more importantly, the ones they didn’t include. “They leave out a lot of good data,” said David Jones, M.D., of the University of Virginia. “Any study that was 3 years or less was excluded, and—because of cost—most good studies are 2 to 3 years. The studies that were left had a high risk of bias.” Jones was also a signatory on the MP4MS response.
“It seems like the authors had a conclusion in mind and rejected evidence that didn’t fit with that,” Kantor said.
When MSDF asked about this concern, EPC Task Order Officer Suchitra Iyer, Ph.D., defended the study, saying, “Because the EPC was interested in long-term patient-centered health outcomes and not just short-term outcomes, EPC chose to look at long-duration studies.”
Chang clarified that the document is not intended as a clinical guideline, and that everything about the way the study was conducted was in line with standard operating procedure for the AHRQ, including redacting the names of the authors and key informants in the draft. She said that once the draft is finalized in the spring of 2015, all the names of those involved in the study will be published along with all the comments received during the four-week comment period.
“The EPC is not recommending that patients should discontinue disease-modifying therapies,” Chang said. “The report does not make clinical recommendations.” But instead, she said, it is a review of the evidence.
“It’s not that anyone is saying anything bad, but I think it’s very easy for people to make the wrong assumption that the absence of positive data is the same as negative data, which is what’s happening in this paper. We shouldn’t confuse those two things,” said Rosalind Kalb, Ph.D., vice president of clinical care at the National MS Society, in an interview with MSDF.
“Too easy to be misused or misconstrued”
“It’s just too easy for the paper to be misused or misconstrued as evidence that continuing treatment isn’t helpful,” Kalb continued. “We just don’t know yet. We should be just saying we don’t know this. They say it, it’s embedded in the paper, but the structure of the paper and the title of the paper don’t go along with that conclusion.”
The question of taking people with MS off DMTs often comes up once they enter the progressive phase of the disease. According to Jonathan Carter, M.D., of the Mayo Clinic in Arizona, secondary progressive MS comes with many nuances that are difficult to navigate when making therapeutic decisions. Some patients continue to have relapses and disease activity, while others have low activity.
Carter told MSDF about another situation that occurred in 2013. A seeming lack of understanding of the nuances of progressive MS stirred up similar concerns when the American Academy of Neurology published a list titled “Five Things Physicians and Patients Should Question.” Number four on that list stated that patients in progressive phases of multiple sclerosis should not be given glatiramer acetate or interferon beta because they do not protect against disability and are therefore not cost-effective. Many in the MS community were worried that this list would influence patients against using DMTs and insurance companies against covering them, Carter said.
Carter, who was not a signatory on any of the comments submitted to the AHRQ, told MSDF, “I understand the concern people would have because this [draft] is a government document purporting that this will help develop policy and reimbursement decisions. That always kind of raises a red flag.”
He said that the document also didn’t address his questions as a neurologist. The major question for him is, what are the road signs in a patient’s disease course that suggest that it would be safe to take him or her off therapy?
“They are not able to find any studies because I don’t think any exist of a randomised, placebo-controlled withdrawal of therapy in people who have been on MS therapies for a long period of time,” Carter said. He noted that one abstract was presented at the American Academy of Neurology 2014 annual meeting in Philadelphia, PA, that outlined a prospective study looking at the discontinuation of DMTs in people with progressive MS (Birnbaum, 2014).
All parties agree that more work must be done in this area. AHRQ’s Iyer noted that one of the strengths of the report may be that it underlines the lack of information in this area and hence will inspire more research: “Our report highlights research gaps, and funding agencies can use it to set their research agenda.”
At the end of her interview with MSDF, the AHRQ’s Chang stressed that the EPC takes comments very seriously and will carefully consider all the feedback received on this draft document.
Key open questions
What research is needed to better answer questions surrounding discontinuation of DMTs?
How likely is it that this document, if adopted in its present form, will have the far-reaching consequences feared by some groups? How does this AHRQ study stack up against others?
Disclosures and sources of funding
MSDF’s parent organization, the Accelerated Cure Project, submitted its own comment suggesting that its clinical research program, OPT-UP (Optimizing Treatment, Understanding Progression), may help answer questions surrounding the discontinuation of disease-modifying therapies.
MP4MS as an organization receives no financial support from pharmaceutical companies. However, Kantor does receive compensation from Acorda, Avanir, Biogen, Genzyme, Novartis, and Questcor.
Carter is a member of a safety and monitoring committee sponsored by EMD Serono.
Jones has received compensation for consulting with Novartis, Genzyme, and Biogen, the latter two through an institutional contract. Jones is also about to start a research project with Biogen, for which he will be the primary investigator.
Source: Multiple Sclerosis Discovery Forum Copyright © 2014 MGH and ACP (17/11/14)
The U.S. Food and Drug Administration has approved Sanofi's multiple sclerosis treatment Lemtrada, Sanofi said in a statement on Saturday.
Lemtrada is already sold in Europe but last December U.S. regulators rejected it on security concerns, prompting analysts to slash their global sales forecasts for the drug.
Sanofi said in its statement that "because of its safety profile" the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.
Lemtrada is given in two courses via an intravenous drip for five days and for three days one year later.
It is designed to re-program the immune system, but in doing so can make the body more vulnerable to other diseases. FDA staff had last year flagged risks of autoimmune diseases including blood disorders, infections and cancer.
Lemtrada was at the core of Sanofi's $20 billion 2011 takeover of U.S. biotech Genzyme, which developed the drug.
Sanofi's chief executive at the time, Chris Viehbacher, who was sacked by Sanofi's board last month, had championed the move into rare diseases as he sought new areas of growth to offset the impact of patent losses on big-selling drugs.
Multiple sclerosis is a chronic, autoimmune condition which affects more than 2 million people worldwide and up to 500,000 in the United States. It attacks the central nervous system and can cause muscle weakness, pain and cognitive difficulties.
The multiple sclerosis market is increasingly moving away from injectable treatments in favour of pills such as Novartis' Gilenya and Biogen Idec's Tecfidera.
But Genzyme hopes Lemtrada's ability to reduce the risk of relapse of the disease will win it market share.
Industry observers however expect it will be reserved for patients for whom other treatments are ineffective. Analysts on average expect the drug to generate sales of just $141 million next year and just under $400 million by 2018, according to Thomson Reuters Cortellis data.
Germany's Bayer has an option to co-promote Lemtrada in the United States.
Source: Rueters © Thomson Reuters 2014 (17/11/14)
A multifaceted team of researchers developed a new mathematical formula to scour existing DNA databases in order to determine why inherited DNA variations contribute to disease. The sequencing techniques they developed examined epigenetic characteristics of specialised immune cells.
Previously, the researchers had used a similar tool to study 21 different autoimmune diseases, and they were able to apply that method to the current project.
The researchers probed 39 genome-wide association studies (GWAS) – which each enlist thousands of participants – to identify DNA blocks implicated in genetic factors for diseases. GWAS rarely point to altered proteins, however. The researchers believe this is because only a few protein-encoding gene variants with these DNA codes have been investigated, let alone associated with autoimmune disease.
Investigators found the presence of specific gene variants differ among autoimmune diseases, which can further alter the functional ability of the immune system. This remained true even though the genetic variants are not within genes.
The majority of DNA changes related to autoimmune diseases occurred in the section of DNA known as “enhancers.” The enhancers of DNA – which is typically shaped in stringy molecules – allow DNA to fold so the various proteins can interact with each other. The enhancers also allow the bending of DNA to activate switches that can turn on specific genes. The enhancers the researchers identified as essential to DNA interaction had not been previously thought to have any functional role.
“Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology,” Alex Marson, MD, PhD, the corresponding author for the study, said in a press release.
After combing through data collected about DNA patterns, the researchers determined T helpers, a type of immune cell, may be a response to stimuli that increase the risk of autoimmune diseases. The researchers believe MS therefore stems from the immune system, and not from genetic variants associated with the nervous system.
“This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” David A. Hafler, MD, co-first author of the study, continued in the press release. He went on to explain that the immune system plays a primary role in MS, and is almost certainly an autoimmune disease.
The researchers hope these findings can ultimately lead to better diagnosis and improved treatments.
Source: HCPLive © Health Care Professionals 2014 (14/11/14)
New Zealand and Australia-based Innate Immunotherapeutics Limited, a medical biotechnology company with offices in Sydney and Auckland, has issued an update regarding its Phase 2B trial for secondary progressive multiple sclerosis (SPMS) and other recent activities.
The Phase 2B MIS416 trial Patient dosing with MIS416 is now underway at the West Australian Neuroscience Institute (WANRI) in Perth and at Nucleus Network’s AMREP Centre for Clinical Studies in Melbourne. Each site has dosed their first two patients with several more patients due to commence treatment this month. A Brisbane site, the Wesley-St. Andrew’s Research Institute (WSARI), will be initiated on November 12th and will start recruiting patients shortly thereafter.
Following on from the commencement of the Phase 2B trial, the Company has made a key new appointment to its scientific staff. Dr Claudia Mansell has joined the Innate team as Senior Research Scientist to lead the analysis of trial subjects’ blood samples. The goal of this work is to develop tests that could be used to help monitor patients’ responses to treatment with MIS416. Developing such a test would be a significant achievement as there are currently no blood tests available to monitor the effects of disease or treatment in patients with SPMS.
Dr Mansell obtained her Ph.D. in Immunology at the Heinrich Heine Universität (Düsseldorf, Germany) and the Harvard Medical School (Boston, U.S.A) and has joined the Company from the School of Biological Sciences, University of Auckland (Auckland, NZ).
Innate Immunotherapeutics has designed and manufactured a unique immunomodulator microparticle pharmaceutical technology. This technology can be used to induce the human immune system designed to fight certain cancers and infections, or modulate certain immune mechanisms implicated in autoimmune diseases such as Multiple Sclerosis (MS). They say the same technology can be used in designing better vaccines to potentially treat or prevent diseases such as influenza, cancer, malaria, or tuberculosis.
The two main forms of MS are an early “relapsing-remitting” stage of disease and a later, more disabling “secondary-progressive” stage of disease (SPMS). Thirty percent of the estimated 2.5 million MS sufferers worldwide have SPMS, and there are currently no approved disease modifying drugs for the safe and effective ongoing treatment of this disabling form of the disease, which causes walking, hand, eyesight, and cognitive function disabilities.
Innate Immunotherapeutics’ MIS416 experimental therapy for Secondary Progressive Multiple Sclerosis (SPMS) is a biologically derived novel immune modulator that can target both regulatory functions and the defensive (pathogenic) functions of the innate immune system. MIS416 targets myeloid cells, a sub-set of innate immune cells not currently targeted by existing or other ‘in-trial’ MS drugs.
Myeloid cells have only recently been recognised as a significant potential therapeutic target in SPMS. Myeloid cells have the capacity to remodel the deregulated immune activity, which is an important part of the disease process in SPMS. These same cells, remodeled in the correct fashion, can also promote neuro repair pathways critical to slowing or reversing disability in SPMS.
The primary goal of the current trial is to determine the efficacy and safety of MIS416 compared to patients treated with the placebo. As part of the study, patients will also report their own health status quarterly, as previous study results have shown significant and sustained reductions in pain and fatigue. Innate says previous non-placebo controlled MIS416 studies found that 80% of patients with SPMS had shown a 30 percent or greater improvement in at least one measure of their MS-related symptoms. Patient stakeholder groups such as Multiple Sclerosis Research Australia (MSRA) and the United States National Multiple Sclerosis Society (US MS Society) have expressed strong support of Innate’s pursuit of an effective treatment for SPMS. The experimental medication has been studied and used as part of the ongoing compassionate use program in Australia, and revealed promising results in studies led by researchers at Victoria University of Wellington in which researchers demonstrated that MIS416, developed originally to treat the relapsing-remitting form of MS, is efficient in the treatment of secondary progressive multiple sclerosis as well. However, the research team has not fully understood what makes the therapy effective.
How MIS416 Works in Treating SPMS
The microparticle at the core of Innate Immunotherapeutics’ technology provides a unique delivery system for a suite of both known and novel immune system triggers or modulators. By attaching selected modulators to the microparticle, these triggers can be delivered reliably to specific cells of the immune system.
Target diseases or applications for drugs developed using this approach include:
• Auto-immune diseases such as Multiple Sclerosis;
• Certain cancers that are known to be immune-sensitive, such as prostate, colon, & renal cancer; and
• Preventive vaccines for malaria and tuberculosis, and therapeutics vaccines for cancers.
In vitro studies have shown that MIS416 has specific immunomodulatory effects on dendritic cell, monocyte / macrophage, Natural Killer (NK) and NKT-cell cytokine secretion patterns, in parallel with enhancement of a broad range of soluble and cellular tumouricidal mechanisms such as granule, Fas, TRAIL and TNF-a. Due to the significant degree of unmet medical needs, Secondary Progressive Multiple Sclerosis has been selected as the initial clinical target for MIS416.
Unlike most pharmaceutical agents (drugs or monoclonal antibodies), immunomodulators like MIS416 do not act directly on the target (cancer tumor, infectious agent, damaged nerve), but instead switch on powerful disease fighting mechanisms that form part of the human immune system. The immune system is a collection of biological barriers and processes that protects against disease by identifying and killing external threats such as infectious agents (bacteria, viruses, parasites, other pathogens) and internal threats such as cancer tumor cells. To function properly, the immune system needs to distinguish between threats and the body’s own healthy cells. When this ability to distinguish between non-self and self breaks down, the immune system can attack healthy cells resulting in one of several autoimmune diseases.
When administered as a distinct agent, Innate Immunotherapeutics says MIS416 is a potent activator of broad but well characterized innate immune responses. The immune system comprises several layers of defense. The first line of defense consists of physical barriers, such as the skin and mucous membranes that line the digestive, respiratory, and reproductive tracts. For infection to occur, pathogens must first breach this physical barrier. When such a breach does occur, the innate immune system is the next line of defense — ‘innate’ because all animals naturally possess it from birth. The surveillance cells of the innate immune system firstly recognize the signature (or pattern) of an invading pathogen and then activate appropriate attack cells or mechanisms to clean out the invader. This same surveillance and response process also works for cells that go bad, e.g. early stage cancer cells. If the innate system is overwhelmed, the adaptive immune system is triggered, providing the last, but often the most potent layer of immune defense. The cells that form part of the adaptive response (antibodies and killer T-cells) must be custom-made to match the pathogen and so the process is relatively slow, but once designed, these cells can be made in huge quantities to overwhelm the threat. Once the system is adapted to recognize and destroy a particular invader, it remembers that invader, and can then react more quickly next time the invader is encountered.
The innate system is pivotal to the successful operation of the entire human immune system. It recognizes trouble, provides an immediate general (or non-specific) defense and if required, gives permission to the adaptive system to respond. Importantly, it also regulates the overall reaction to ensure that the level of response is appropriate to the degree of the threat. By activating and/or regulating important innate system mechanisms, Innate Immunotherapeutics’ microparticle immunomodulator technology presents a new and effective way to safely fight infections, certain cancers, and to treat select autoimmune diseases.
Source: Multiple Sclerosis News Today © Copyright 2014, BioNews Services, LLC (13/11/14)
Teva Pharmaceutical Industries Ltd. multiple sclerosis treatment Copaxone is progressing toward regulatory approval in Japan. At the end of 2013, Teva reported a development and marketing agreement with Japan's Takeda Pharmaceutical Co. Ltd. for the Japanese market.
At the time, Teva said that regulatory approval was expected to be received in less than a year. However, nearly a year has passed and no approval has been received.
The annual market potential for Copaxone in Japan is estimated at $700-900 million. Sales of the rug in the first nine months of 2014 totaled $3.1 billion. But in North America and Europe, such high sales of the treatment (in its smaller dosage) are nearing the end of their cycle due to the expiration of patents, and the Japanese market is expected to provide a welcome boost for Copaxone.
Teva said, "Our agreement with Takeda to bring this important medicine to patients in Japan is progressing positively. Together with Takeda, we are working through the remaining aspects of the process in order to meet the requirements of the Japanese authorities. We are hopeful to be in a position to complete the filing in the near future."
Estimates are that Copaxone is responsible for more than half of Teva's profits.
Source: Globes © Globes 2014. (13/11/14)
While yoga seems to be effective in a number of neuropsychiatric disorders, the evidence of efficacy in multiple sclerosis remains unclear.
The aim of this review was to systematically assess and meta-analyze the available data on efficacy and safety of yoga in patients with multiple sclerosis.
Medline/PubMed, Scopus, the Cochrane Central Register of Controlled Trials, PsycINFO, CAM-Quest, CAMbase, and IndMED were searched through March 2014.
Randomized controlled trials (RCTs) of yoga for patients with multiple sclerosis were included if they assessed health-related quality of life, fatigue, and/or mobility. Mood, cognitive function, and safety were defined as secondary outcome measures.
Risk of bias was assessed using the Cochrane tool. Seven RCTs with a total of 670 patients were included.
Evidence for short-term effects of yoga compared to usual care were found for fatigue (standardized mean difference [SMD] = −0.52; 95% confidence intervals (CI) = −1.02 to −0.02; p = 0.04; heterogeneity: I2 = 60%; Chi2 = 7.43; p = 0.06) and mood (SMD = −0.55; 95%CI = −0.96 to −0.13; p = 0.01; heterogeneity: I2 = 0%; Chi2 = 1.25; p = 0.53), but not for health-related quality of life, muscle function, or cognitive function.
The effects on fatigue and mood were not robust against bias. No short-term or longer term effects of yoga compared to exercise were found. Yoga was not associated with serious adverse events. In conclusion, since no methodological sound evidence was found, no recommendation can be made regarding yoga as a routine intervention for patients with multiple sclerosis.
Yoga might be considered a treatment option for patients who are not adherent to recommended exercise regimens.
Source: PLOS | One (13/11/14)
What may be overlooked in relating to and caring for patients with multiple sclerosis is the fact that the neurodegenerative disease sometimes affects a person’s ability to properly convey and perceive emotion. According to the National Multiple Sclerosis Society (NMSS), while there is not enough conclusive evidence to suggest the disease directly affects emotion, it is important to consider that MS patients may either be struggling to cope with the disease, or are physiologically affected by it, making perception and expression beyond their control.
Aside from the loss of the ability to recognise the appropriate emotion behind certain expressions, a new study from the International School of Advanced Studies (Scuola Internazionale Superiore di Studi Avanzati or SISSA) in Italy now suggests MS patients have an increased difficulty interpreting emotions expressed through one’s posture, countenance, and comportment. Additionally, the study suggests these issues are caused by the patient’s inability to identify his or her own emotions, which is a phenomenon termed as alexithymia, and is observed in some MS patients.
“The finding on posture is new, and even though this symptom is less pronounced than the inability to read facial expressions, it is nonetheless important. Studies on the identification of expressions in neurological disorders such as multiple sclerosis are important,” said Marilena Aiello, researcher, Scuola Internazionale Superiore di Studi Avanzati. ”In this type of disease the relationship between patients and carers is crucial to guarantee the patient the best quality of life. It’s thus vital to identify the factors that may influence and improve this relationship.”
Lead author Cinzia Cecchetto, and SISSA neuroscientist and coordinator, Raffaella Rumiati are fellow SISSA researchers who assisted Aiello in conducting this study and bringing it to completion and publication in the Journal of the International Neuropsychological Society.
Qualitative studies underscore the importance of comprehensive healthcare that focuses not merely on treating the disease, but on patients’ overall wellness. A study from the Kessler Foundation suggests a 10-week wellness program led to several improvements in MS patients, notably in their mood, mental health, perceived stress, and pain. The study is published online as “Development and effectiveness of a psychoeducational wellness group for individuals living with MS: Description and outcomes” in the International Journal of MS Care.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (12/11/14)
In multiple sclerosis, the immune system goes rogue, improperly attacking the body's own central nervous system. Mobility problems and cognitive impairments may arise as the nerve cells become damaged.
In a new study, researchers from the University of Pennsylvania and co-investigators have identified a key protein that is able to reduce the severity of a disease equivalent to MS in mice. This molecule, Del-1, is the same regulatory protein that has been found to prevent inflammation and bone loss in a mouse model of gum disease.
"We see that two completely different disease entities share a common pathogenic mechanism," said George Hajishengallis, a professor of microbiology in Penn's School of Dental Medicine and an author on the study. "And in this case that means that they can even share therapeutic targets, namely Del-1."
Because Del-1 has been found to be associated with susceptibility to not only multiple sclerosis, but also Alzheimer's, it's possible that a properly functioning version of this protein might help guard again that disease's effects as well.
Penn contributors to the study included Hajishengallis, Penn Dental Medicine postdoctoral researcher Kavita Hosur and Khalil Bdeir, a research associate professor at Penn's Perelman School of Medicine. They collaborated with senior author Triantafyllos Chavakis of Germany's Technical University Dresden and researchers from South Korea's University of Ulsan College of Medicine and other institutions. The work appears online in the journal Molecular Psychiatry.
In earlier studies, Hajishengallis, Chavakis and colleagues found that Del-1 acts as a gatekeeper that thwarts the movement and accumulation of immune cells like neutrophils, reducing inflammation. While neutrophils are needed to effectively respond to infection or injury, when too many of them accumulate in a tissue, the resulting inflammation can itself be damaging. Hajishengallis has found that gum tissue affected by periodontitis, a severe form of gum disease associated with inflammation and bone loss— had lower levels of Del-1 than healthy tissue.
While researching Del-1 in other tissues, such as gums and lungs, Hajishengallis and Chavakis found that Del-1 was also highly expressed in the brain. In addition, genome-wide screens indicate that the Del-1 gene may contribute to multiple sclerosis risk. For these reasons, the scientists hypothesized that Del-1 might prevent inflammation in the central nervous system just as it does in the gum tissue.
To test their theory, the researchers examined Del-1 expression in brain tissue from people who had died from MS. In MS patients with chronic active MS lesions, Del-1 was reduced compared to both healthy brain tissue and brain tissue from MS patients who were in remission at the time of their death. Similarly, Del-1 expression was reduced in the spinal cords of mice with the rodent equivalent of MS, experimental autoimmune encephalomyelitis (EAE).
Having confirmed this association between reduced Del-1 and MS and EAE, the scientists wanted to see if the reduction itself played a causal role in the disease.
Hajishengallis's and Chavakis's labs had previously utilized mice that lack Del-1 alone or Del-1 together with other molecules of the immune system. The researchers found that mutant mice lacking Del-1 had more severe attacks of the EAE than normal mice, with more damage to myelin, the fatty sheath that coats neurons and helps in the transmission of signals along the cell. Loss of this substance is the hallmark of MS and other neurodegenerative diseases.
Mice without Del-1 that had been induced to get EAE also had significantly higher numbers of inflammatory cells in their spinal cords at the disease's peak, a fact that further experiments revealed was due to increased levels of the signaling molecule IL-17.
Mice that were induced to get EAE that lacked both Del-1 and the receptor for IL-17 had a much milder form of the disease compared to mice that lacked only Del-1. These doubly depleted mice also had fewer neutrophils and inflammation in their spinal cords.
With a greater understanding of how Del-1 acts in EAE, the researchers were curious whether simply replacing Del-1 might act as a therapy for the disease. They waited until mice had had an EAE attack, akin to a flare-up of MS in human patients, and then administered Del-1. They were pleased to find that these mice did not experience further episodes of the disease.
"This treatment prevented further disease relapse," Chavakis said. "Thus, administration of soluble Del-1 may provide the platform for developing novel therapeutic approaches for neuroinflammatory and demyelinating diseases, especially multiple sclerosis."
The team is pursuing further work on Del-1 to see if they can identify a subunit of the protein that could have the same therapeutic effect.
"It's amazing that our work in periodontitis have found application in a central nervous system disease," Hajishengallis said. "This shows that periodontitis can be a paradigm for other medically important inflammatory diseases."
Source: Medical Xpress © Medical Xpress 2011-2014,Science X network (12/11/14)
Patients who have progressive conditions, such as multiple sclerosis (MS), are submitted to unnecessary evaluations for disability benefits and often denied the full payment of their out-of-work benefits or deemed as fit to work when they are in fact not able. This new perspective was highlighted by a group of health-related charities which recently released data about Multiple Sclerosis, employment, and disability in order to call attention to how patients with progressive conditions are largely misunderstood by benefits assessors.
More than a third (36%) of patients with MS, Parkinson’s, motor neuron disease, cystic fibrosis, and rheumatoid arthritis were evaluated as fit for work-related activity, a level of the Employment and Support Allowance (ESA) granted to people who are expected to recover enough and be able to work again. That means that 8,000 people suffering from those diseases are supposed to attend regular interviews with advisers, as well as apply for jobs and prepare for a role in the workforce.
The ESA is a benefit design to support people who cannot work due to illnesses or disability, and most beneficiaries are evaluated through a Work Capability Assessment. According to the results, people are placed either on the work-related activity group, or in the support group, in which they do not have to attend interviews. Also, depending on the group, the benefit is different. The first group is paid at a lower rate than the second one, and people who are in the work-related activity ESA may suffer sanctions and see their benefit payment reduced if they don’t attend interviews or other activities.
In addition, the data revealed that 5,000 from the total of people assessed as fit to work were placed in that group despite the fact that the Work Capability Assessment stated that their return to employment was “unlikely in the longer term.” The five charities who joined forces to disclose the data are now asking assessors to show medical evidence that justifies placing patients suffering from progressive conditions in the work-related activity group.
“It is unfathomable that people with progressive conditions who are deemed by assessors to be unlikely to return to work in the longer term are still being told to seek employment,” said the Senior Policy and Campaigns Officer at the MS Society, Claire Nurden. “It is vital that additional safeguards are introduced into the assessment process to stop people with MS slipping through the net.”
In addition to the MS Society, Parkinson’s UK, the Motor Neurone Disease Association, National Rheumatoid Arthritis Society, and The Cystic Fibrosis Trust, are all asking assessors to reconsider and place progressive diseases patients in the support group, where they wouldn’t be required to attend meetings and would receive the highest payment possible.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (11/11/14)
Autoimmune diseases like Crohn’s Disease and multiple sclerosis, in which the immune system attacks its own body rather than predatory invaders, affect 5-20% of the global community. A study published recently in Autoimmunity Reviews by Prof. Yehuda Shoenfeld, the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel Aviv University’s Sackler Faculty of Medicine and Head of Zabludowicz Center for Autoimmune Diseases at Chaim Sheba Medical Center, Tel Hashomer, points to the major role obesity plays in triggering and prolonging these autoimmune diseases.
According to the research, obesity leads to a breakdown of the body’s protective self-tolerance, creating the optimal environment for autoimmune diseases, and generates a pro-inflammatory environment likely to worsen the disease’s progression and hinder its treatment.
“We’ve been aware of a long list of causes of autoimmune disorders — infections, smoking, pesticides, lack of vitamins, and so forth. But in last five years, a new factor has emerged that cannot be ignored: obesity,” said Prof. Shoenfeld. “According to the World Health Organization, approximately 35% of the global community is overweight or obese, and more than ten autoimmune diseases are known to be associated with increased weight. So it’s critical to investigate obesity’s involvement in the pathology of such diseases.”
In addition to their own research, Prof. Shoenfeld and his team from Tel Hashomer hospital conducted a systematic review of 329 studies from around the world on the relationship between obesity, adipokines (compounds secreted by fat tissue and involved in numerous physiological functions, including the immune response), and immune-related conditions like rheumatoid arthritis, multiple sclerosis, type-1 diabetes, psoriasis, inflammatory bowel disease, psoriatic arthritis, and Hashimoto thyroiditis.
“According to our study and the clinical and experimental data reviewed, the involvement of adipokines in the pathogenesis of these autoimmune diseases is clear,” said Prof. Shoenfeld. “We were able to detail the metabolic and immunological activities of the main adipokines featured in the development and prognosis of several immune-related conditions.”
Prof. Shoenfeld conducted a study on mouse populations with multiple sclerosis given a Mediterranean diet rich in unsaturated fats. He found that Vitamin D deficiency was also a result of obesity and, once corrected, alleviated paralysis and kidney deterioration associated with the disorder. It also improved the prognosis and survival of the mice.
“Modern life makes us all prone to Vitamin D deficiency,” said Prof. Shoenfeld. “We live in labs, offices, and cars. When Vitamin D is secreted in fat tissue, it is not released into the body, which needs Vitamin D to function properly. Since Vitamin D supplements are very cheap and have no side effects, they are an ideal compound that should be prescribed to anyone at risk of a compromised immune system.”
Prof. Shoenfeld welcomes the general trend toward personalized medicine, and believes his research can be a basis for specific therapies to treat autoimmune syndrome. “If a patient is at risk, he or she should be told to do everything in his or her power to maintain a healthy weight,” he said.
Source: San Diego Jewish World © 2014 San Diego Jewish World (11/11/14)
Prematurely severe cognitive impairment in multiple sclerosis patients could be an effect of autoantibodies against the N-methyl-D-aspartate (NMDA) receptor complex, with natalizumab (Tysabri) withdrawal a potential contributor, a case report from Germany suggested.
In an MS patient who had to be confined to a nursing home at age 39 because of cognitive deficits amounting to dementia, immunoglobulin G-type antibodies to the NMDA receptor's NR1 subunit were found in cerebrospinal fluid samples, according to Klemens Ruprecht, MD, of Charité-Universitätsmedizin Berlin, and colleagues.
These autoantibodies are "the characteristic laboratory finding of anti-NMDA receptor encephalitis," they wrote online in JAMA Neurology.
When severe cognitive deficits appear at young ages, Ruprecht and colleagues concluded, they could "be related to a superimposed antibody-mediated autoimmune encephalitis."
Cognitive deficits are common in MS patients but the mechanisms underlying them are not well understood, the researchers noted. Normally these come on gradually and at later ages. However, as in the current case, occasionally such deficits appear early and progress rapidly. In such cases, clinicians should consider causes outside the MS disease process, Ruprecht and colleagues suggested.
"The diagnosis of those patients will require a high degree of clinical suspicion as cognitive symptoms are rather frequent in MS and may mask or be confounded with features of antibody-mediated encephalitides," they wrote. "Nevertheless, testing for antineuronal antibodies appears warranted in patients with MS with unusual neuropsychiatric symptoms."
Also, in the patient who was the subject of the case report, the anti-NMDA antibody pathology may have had some relation to treatment with natalizumab.
The woman was first diagnosed with MS at age 33. Her disease course was unremarkable until age 37 when she gave birth, and then rapidly developed cognitive deficits marked primarily by memory loss. She was treated aggressively with MS therapies including natalizumab, cyclophosphamide, and mitoxantrone, with no impact on the progression of cognitive decline.
At age 43, during her fourth year of nursing home residency, she underwent a complete re-evaluation that included analysis of current and stored serum and CSF samples. At that point, anti-NMDA antibodies were discovered in the CSF samples, including those taken shortly after the cognitive symptoms appeared.
The natalizumab was withdrawn 2 years after the patient started on it, out of concern for the risk of progressive multifocal leukoencephalopathy since she had also been on immunosuppressive therapy.
Five months later, she developed a "fulminant" MS relapse, the researchers indicated, which was accompanied by a spike in anti-NMDA antibody titers -- a sign that the latter may have had some connection to the natalizumab withdrawal.
Ruprecht and colleagues noted that the drug suppresses CD138-positive plasma cells. "Therefore, it seems plausible that natalizumab withdrawal facilitated entry of NMDA receptor antibody-producing plasma cells to the central nervous system," they wrote.
The patient died of urosepsis last December, almost 8 years after the onset of cognitive symptoms.
She represented only the second known case of anti-NMDA encephalitis in an MS patient, the researchers indicated, and the first in whom the antibodies targeted the receptor complex's NR1 subunit (NR2B was the target in the previous case).
But they suggested the comorbid conditions may occur more frequently than these case reports might suggest, because cognitive impairments are common in MS and clinicians may not think to look for other causes.
The study was funded by the German government. Authors reported relationships with Bayer Healthcare, Merck Serono, Biogen Idec, Novartis, Ovamed, Teva, Diamed, Genzyme, and Sanofi.
Primary source: JAMA Neurology
Source reference: Fleischmann R, et al "Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis" JAMA Neurology 2014; DOI: 10.1001/jamaneurol.2014.1817.
Source: Medpage Today © 2014 MedPage Today, LLC (11/11/14)
A study entitled “Longitudinal Follow-up of a Cohort of Patients with Incidental Abnormal Magnetic Resonance Imaging Findings at Presentation and Their Risk of Developing Multiple Sclerosis” published in the International Journal of MS Care reports that asymptomatic patients accompanied by Magnetic Resonance Images suggestive of MS are more prone to develop MS.
Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. Currently, there is no cure for MS, which affects more than 2.3 million people throughout the world. The disease is characterised by destruction of the myelin layer within nerve cells. This leads to a wide range of neurological symptoms affecting visual, motor, and sensory capabilities. However, individuals at risk of developing MS are frequently asymptomatic. Thus, the diagnostic criteria have been evolving, and magnetic resonance imaging (MRI) is being used increasingly to assess dissemination of central nervous system lesions in time and space. Diagnosing MS, however, has to include at least one clinical event.
In this study, the authors wanted to determine risk factors for developing MS in patients who presented incidental abnormal MRI but did not exhibit typical symptoms of MS.
Researchers evaluated 30 patients from MS clinic at the Henry Ford Hospital with “abnormal brain MRI” but without any clinical manifestations of MS. These patients were followed during a period of up to 5.5 years.
The authors found that patients who had no symptoms and no MRI results suggestive of MS developed MS during the period analysed. On the contrary, asymptomatic patients who exhibited MRI findings indicative of MS, as measured by the Barkhof criteria, were likely to develop MS. These patients were usually accompanied by abnormal Cerebrospinal fluid (CSF) testing results. Thus, in some patients, occurrence of Radiologically Isolated Syndrome (RIS) is an asymptomatic period before the onset of MS.
The authors suggest their findings are helpful for physicians when deciding for further follow-up tests when presented with patients lacking both symptoms and MRI findings suggestive of MS. Further large-scale tests are needed to confirm their observations that RIS increases the risk to develop MS in a later period and determine additional characteristics that may predict the likelihood of developing MS in the future.
Source: © Copyright 2014 BioNews Services LLC (05/11/14)
Teva Pharmaceutical Industries Ltd. and Active Biotech today announced the expansion of the laquinimod clinical development program with the initiation of the ARPEGGIO trial, which will evaluate the potential of laquinimod to treat primary progressive multiple sclerosis (PPMS) There are no approved therapies available for the treatment of PPMS beyond symptom management.
“Teva prides itself in striving to help patients with neurodegenerative diseases through research and innovation,” said Michael Hayden, M.D., Ph.D., President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries, Ltd. “Laquinimod has been shown to modulate several significant pathways common to key neurodegenerative disease. More specifically, it modulates the immune cell lineages in the periphery and in the CNS. We look forward to the results from the study.”
The ARPEGGIO study will evaluate the efficacy, safety and tolerability of laquinimod in patients with PPMS with a primary endpoint of percent brain volume change (PBVC) through MRI analysis. PPMS is characterised by the worsening of neurologic function without distinct relapses (also called attacks or exacerbations). Approximately 15 percent of MS patients fall into the PPMS category.
The study, A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations In MRI and Clinical Outcomes (ARPEGGIO) is a multinational, multicenter, randomised, double-blind, parallel-group, placebo-controlled, Phase II clinical trial.
ARPEGGIO is intended to serve as a proof-of-concept study for potential treatment with laquinimod in PPMS. The trial will evaluate two doses of laquinimod (0.6 and 1.5mg/day) in PPMS compared to placebo. The primary endpoint of the study is brain atrophy as defined by PBVC from baseline to week 48. Secondary endpoints include time to confirmed disability progression, the number of new T2 lesions and change in the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score. ARPEGGIO has an estimated completion date of H2 2017.
Source: Finances © 2014 Finances International Ltd (04/11/14)
Genzyme, a Sanofi company, announced today enrollment of the first patient in a multicenter Phase II clinical trial to evaluate Genzyme’s investigational infusion therapy vatelizumab in patients with relapsing remitting multiple sclerosis (RRMS). The trial, called EMPIRE, is designed to assess the efficacy of vatelizumab vs. placebo in RRMS patients. The safety, tolerability and pharmacokinetics of vatelizumab will also be assessed.
Multiple sclerosis is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Uncontrolled inflammation within the CNS leads to inflammatory damage that is associated with demyelinating lesions and neurodegeneration in patients with MS. Vatelizumab is a humanized monoclonal antibody that targets VLA-2, a collagen-binding integrin expressed on activated lymphocytes. The mechanism of action of vatelizumab is not known, although it is hypothesized to block VLA-2 on activated immune cells, leading to interference with collagen-binding in areas of inflammation, and thus may reduce the inflammatory cascade in MS.
“Continuous inflammation and neurodegeneration from the onset of multiple sclerosis can lead to significant disability,” said Eva Havrdova, MD, PhD, MS Center, Department of Neurology, First Medical Faculty, Charles University, Prague. “The EMPIRE trial should enable us to assess vatelizumab’s ability to impact the acute inflammatory components of MS and evaluate its potential as an effective MS treatment.”
Genzyme is developing vatelizumab in MS in partnership with Glenmark Pharmaceuticals. In addition to its marketed therapies, Genzyme has an MS R&D pipeline focused on investigational treatments to address unmet needs for relapsing and progressive forms of MS through research in selective immunomodulation, neuroprotection and remyelination.
“We are pleased to commence patient enrollment for our vatelizumab trial in relapsing MS,” said David Meeker, President and CEO, Genzyme. “This milestone demonstrates Genzyme’s long-term commitment to MS and aligns with our pipeline strategy to focus on areas of unmet need.”
EMPIRE is a global phase 2a/2b double-blind, randomized, placebo-controlled study assessing the efficacy, safety and dose-response of vatelizumab in patients with active RRMS. The study duration is 12 weeks. The study is expected to enroll 168 patients at 55 sites in 10 countries. For more information about the vatelizumab trial, visit www.clinicaltrials.gov.
Source: Finances © 2014 Finances International Ltd (03/11/14)
Undiagnosed sleep disorders may be at the root of the most common and disabling symptom of multiple sclerosis—fatigue, according a new study published online in the Journal of Clinical Sleep Medicine.
Conducted by researchers at University of California, Davis in Sacramento, California, the study involved more than 2,300 people with the condition. More than 70% of participants screened positive for one or more sleep disorders.
Results of the study, which may be the largest of its kind involving victims of MS, suggest that sleep disorders may be a “hidden epidemic” among the MS population.
“A large percentage of MS subjects in our study are sleep-deprived and screened positive for one or more sleep disorders,” says Steven Brass, director of the Neurology Sleep Clinical Program and co-medical director of the UC Davis Sleep Medicine Laboratory.
“The vast majority of these sleep disorders are potentially undiagnosed and untreated,” he says. “This work suggests that patients with MS may have sleep disorders requiring independent diagnosis and management.”
Sleep disorders such as obstructive sleep apnea and insomnia may affect the course of the disease, the authors say, as well as the overall health and well-being of sufferers.
MS is a chronic, inflammatory disease of the central nervous system thought to be an autoimmune condition, according to the National Multiple Sclerosis Society. It can cause loss of vision and balance, slurred speech, tremors, numbness, extreme fatigue, problems with memory and concentration, paralysis and more. Most victims are women diagnosed between the ages of 20 and 50.
Nearly 38% of the study participants screened positive for obstructive sleep apnea, yet only about 4% reported being diagnosed with the disorder, researchers said. Nearly 32% suffered from moderate to severe insomnia and nearly 37% from restless legs syndrome. More than half—nearly 52%—said it took them more than a half hour to fall asleep at night, and nearly 11% reported taking a medication to fall asleep.
Source: Bed Times © 2014 BedTimes (03/11/14)
MS doctors and patients push for repurposing of Simvastatin for treating secondary progressive MS(03/11/14)
SIR – A number of repurposed medicines have shown strong preliminary evidence that they could be effective in the treatment of multiple sclerosis (MS), but Britain lacks a system by which old drugs can be relicensed for new purposes.
Simvastatin is a medicine originally licensed for treating high cholesterol, but in a recent clinical trial it proved effective in slowing brain atrophy in secondary progressive MS by more than 40 per cent. Further evidence is required to confirm these results but, if successful, simvastatin would address a significant need for which there is currently no alternative available. Simvastatin’s patent expired in 2004 and we believe it would require a licence in order to be made widely available to people with MS on the NHS. The mechanism to achieve this does not exist, even though repurposing is a fast and cost-effective way of providing new treatments.
The Off-patent Drugs Bill, which will have its second reading in the House of Commons on November 7, seeks to address this issue, thus providing access to medicines that could help tens of thousands of people with untreatable MS.
Dr Jeremy Chataway
Consultant Neurologist, National Hospital for Neurology and Neurosurgery, University College Foundation NHS Trust and St Mary's Hospital
Professor Sue Pavitt
Chair, UK MS Clinical Trials Network Steering Group
Professor in Applied Health & Translational Research, University of Leeds
Progressive MS patient
Chief Executive, MS Society
Professor Siddharthan Chandran
MacDonald Professor of Neurology
Director, Anne Rowling Regenerative Neurology Clinic & Centre for Clinical Brain Sciences, University of Edinburgh
Professor Gavin Giovannoni
Professor of Neurology, Barts and the London School of Medicine and Dentistry
Professor Kenneth Smith
Head of Department of Neuroinflammation, University College London
There is currently no mechanism in place in Britain to allow drugs to be relicensed for new purposes. Source: Daily Telegraph © Copyright of Telegraph Media Group Limited 2014 (03/11/14)
Closing Northern Ireland's only dedicated respite centre will have a devastating impact on people with multiple sclerosis, a woman who uses the unit has said.
It is one of a number of cuts to the health service announced on Thursday.
More than 4,000 people in Northern Ireland are affected by MS, one of the highest rates in the world.
The unit, in Dalriada Hospital in Ballycastle, will close until March next year.
It has 12 beds where patients can get respite.
Rita Gallagher, who has just come back from two weeks respite care there, said the closure would have a serious impact on her and her family.
"Respite works both ways. I get the respite, but my husband, my family, get the respite too," she said.
"Whenever I am in Ballycastle, I've got my independence and I feel filled with energy to go on.
"I get so much encouragement to stand up and not lie under MS."
On Thursday, Patricia Gordon, director of the MS Society in NI, said she was "deeply concerned".
"There are more than 4,000 people living with MS in Northern Ireland - one of the highest rates in the world - and yet MS services have been dramatically reduced in recent months causing serious distress for local families," she added.
"Regular, appropriate breaks, are crucial for maintaining the wellbeing of carers and people with MS. Inadequate respite provision can lead to declining health, increasing pressure on carers and unnecessary and costly hospital admissions.
"Rumours have been circulating for years about the future of the MS Regional Respite Unit in Dalriada Hospital, Ballycastle, and this announcement is a devastating blow for people who rely on this service. "
Source: BBC News © British Broadcasting Corporation 2014 (31/10/14)
An encouraging experimental drug that is being developed for Multiple Sclerosis continues to show promise in being able to offer neuroprotective benefits — an effect that could slow MS. Masitinib, which is being developed by AB Science for numerous neurological indications, including Alzheimer’s disease, progressive multiple sclerosis, and amyotrophic lateral sclerosis (ALS), is now showing signs of being able to offer neuroprotection in stroke as well.
Stroke, both ischemic and hemorrhagic, is the second-leading cause of mortality worldwide and currently lacks effective treatments, leading to very poor prognosis to those who have been affected. Stroke, or cerebrovascular accident (CVA) is caused by abnormal blood supply, either lack of blood flow — ischaemic — or hemorrhage. The current treatments for ischaemic stroke include measures to lower blood pressure, reducing cerebral edema, temperature control, glucose regulation, and antiplatelet and fibrinolytic treatments. Recently, a new strategy for treating experimentally induced ischemic stroke in mice and rats were proposed with neuro protection as the underlying principle.
The neuroprotective effect is achieved with Masitinib, an oral tyrosine kinase inhibitor, and the results of the pre-clinical trial were announced by AB Science and published in the online version of the journal Naunyn-Schmiedeberg’s Archives of Pharmacology. The study is entitled “Neuroprotective effect of masitinib in rats with postischemic stroke.”
The study showed Masitinib administration in animal models of stroke was efficient in reducing stroke-related brain infarct size. Thus, the authors suggest that Masitinib represents a potential new therapy for the treatment of ischemic stroke, offering neuroprotection to stroke patients, particularly in the acute stage. However, researchers note that further investigation is needed to confirm the results obtained and understand the mechanism of action of Masitinib.
Dr. Ivan Kocic, study leading author noted, “Mast cells are present on both sides of the blood-brain barrier (BBB) and interact with neurons, glia, blood vessels, and other hematopoietic cell. Mast cells disrupt the permeability of the BBB when they degranulate. Mast cells are also involved in neuro inflammation responsible for neuronal alteration and engage in a cross-talk with microglia and astrocytes. Masitinib, by blocking mast cell degranulation on the blood side of the BBB (i.e. extracerebral), may restore integrity of the BBB and reduce neuro-inflammation. This preclinical study, showing the potential of masitinib to improve therapeutic outcome of ischemic stroke, most probably via preservation of BBB integrity, provides further evidence of masitinib’s prospective role in neurodegenerative diseases.”
Because many proposed therapies for both MS and Stroke center on neuroprotective effects, the positive data from this current study lends more credence to the possible use of masitinib in Multiple Sclerosis as well. Currently, AB Science is actively engaged in a Phase III clinical trial for the MS indication, entitled “A Phase 2b/3 Study to Compare Efficacy and Safety of Masitinib to Placebo in the Treatment of Patients With Primary Progressive or Relapse-free Secondary Progressive Multiple Sclerosis,” which will test the therapy for 96 weeks on participants with progressive forms of multiple sclerosis.
Source: Multiple Sclerosis News Today © Copyright 2014, BioNews Services, LLC (31/10/14)
Biogen Idec Inc., maker of the popular multiple sclerosis (MS) pill dimethyl fumarate (Tecfidera), announced the death of a patient taking the drug who succumbed to complications from a rare brain infection. Executives broke the news during a conference call with analysts last Wednesday.
The brain infection known as progressive multifocal leukoencephalopathy (PML) took the life of a European patient who had been on the popular pill for more than four years. The patient was taking part in a long-term safety study of Tecfidera.
"The patient was a participant in the ongoing ENDORSE extension study," confirmed Catherine Falcetti, associate director of public affairs for Biogen, in an interview with Healthline.
“This patient was treated with Tecfidera for 4.5 years as part of the ENDORSE study,” explained Falcetti. “They developed PML and recently died due to complications associated with aspiration pneumonia.”
MS Drugs Suppress the Immune System
The majority of MS disease modifying drugs have an impact on the immune system. They suppress lymphocytes — T-cells or B-cells — to slow the disease by blocking the inflammation that is characteristic of MS.
But toying with the inner workings of the immune system can have serious consequences, one of which is lymphopenia, or low white blood cell count. While depleting these cells acts to tamp down the immune response in MS patients and bring their disease under control, it also opens the door for viral and bacterial invaders to gain the upper hand.
“The occurrence of PML is not limited to people who have MS, and even if a person has been exposed to the virus and has taken immune-modulating therapies, it does not mean that they will develop PML,” Bruce F. Bebo Jr., Ph.D., executive vice president of research for the National Multiple Sclerosis Society (the Society), told Healthline in an interview. “So far, in people with MS, PML has occurred mostly in people who have taken natalizumab (Tysabri).”
According to the National Institute of Neurological Disorders and Stroke (NINDS), the best treatment for PML is “reversal of the immune-deficient state, since there are no effective drugs that block virus infection without toxicity.” NINDS also states that a plasma exchange will help hasten removal of the drug from the patient’s body.
The U.S. Food and Drug Administration (FDA) has given special permission to treat PML patients with several new experimental drugs that have been effective against the infection in early testing.
“The FDA keeps a watchful eye on adverse events that occur both during a drug’s clinical trials and after it enters the market,” said Bebo. “The National MS Society has confidence in the agency’s role, and we are following the FDA’s investigation and will provide updates if and when more information is available.”
If you have concerns about your own lymphocyte count or JCV status, speak with your doctor. They can order a complete blood count to reveal if you have lymphopenia. They may also order a free JCV antibody test known as Stratify JCV, developed by Biogen after another of their MS drugs, Tysabri, was found to put some patients at risk for PML.
As for the Society’s recommendation, “There is currently insufficient information about possible measures that a person can take to prevent PML,” Bebo said, “outside of those measures developed to reduce the risk of PML for people taking or considering taking Tysabri.”
Source: Healthline Copyright © 2005 - 2014 Healthline Networks, Inc (31/10/14)
Researchers from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine recently developed a software tool that helps researchers understand the complex genetic origins of many autoimmune diseases and, ultimately, to better diagnose and treat them. The study was published yesterday in Nature.
One in every twelve Americans are affected with autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes, rheumatoid arthritis, and asthma. What happens in these kinds of diseases is that the immune system begins to attack the body’s own cells and tissues. This new study connects insights into genetics with the origins of these diseases — a connection that the tool’s creators believe will serve as a key asset for diagnosing and treating autoimmune diseases like MS.
The researchers developed a mathematical tool to more intensively probe existing DNA databases, which in turn has allowed them to discover that certain DNA variations contribute to the development of diseases and, if inherited, can signify a higher predisposition for becoming sick.
Through their method, the researchers analyzed data from previous studies regarding 21 autoimmune diseases, and thoroughly examined their scientific fundamentals. From this analysis, they found specific immune cells that are actually responsible for the diseases.
Data from 39 large-scale studies called GWAS, the genome-wide association studies, was analyzed. Many GWAS analyses have been conducted, and each one enlisted a large number of participants allowing researchers to identify large blocks of DNA within the human genome and within each genetic variant related to a disease that might represent risk factors. Until now, the GWAS examination has rarely pointed to altered proteins, and few protein-encoding gene variants in a large amount of DNA evidence like this one were associated with the diseases under investigation.
The genetic risks identified through GWAS studies suggest that the answer may reside in DNA variations that are not within genes. Therefore, medical benefits have emerged from large-scale studies of human genetic variations conducted in the wake of the Human Genome Project.
Researchers figured that specific genetic variants in several autoimmune diseases can change patterns of the genes’ activity in ways that affect immune system functions. This study focused on “epigenetic” characteristics in which genes’ activity is affected, but the DNA sequences of the affected genes remain untouched. As a result, these variations in DNA do not occur in genes’ zones; the majority occur in functional DNA fragments known as “enhancers.”
DNA can bend back by supporting itself in a chromosome’s structural proteins, and a piece of DNA, usually long and stringy, can interact with another strand. Enhancers fold in like this to bind to DNA switches and activate genes. The enhancers identified in this study and that play a role in the autoimmune diseases were DNA sequences different from DNA-sequence, which were previously thought to be crucial for enhancers to work and are a novelty, as they function as sequences that are actually functional.
Alex Marson, MD, PhD, UCSF Sandler Faculty Fellow and the author of the study, said in a press release: “Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology.”
Mapping enhancers in specialized immune cells and tracking patterns of altered gene activation in GWAS studies allowed the researchers to associate this phenomena with the respective immune diseases. Many of them were found to be related to immune cells known as “T helpers.” The study suggests that genetic variation may be triggering a response from these immune cells to stimuli within their surroundings to increase the risk of autoimmunity.
Marson and his team link the cause of MS to the immune system and not to the genetic variations concerning the nervous system. Results show that MS is an autoimmune disease: “This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” said David A. Hafler, MD, professor of neurology and immunobiology, and chair of the Department of Neurology at Yale and Marson’s collaborator.
These new findings will ultimately “enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen aberrantly fired-up immune responses,” cited from the UCSF press release.
The major funding for this study came from the National Institutes of Health and the National Multiple Sclerosis Society, and through it, Marson intends to understand how these newly identified DNA variants in enhancers affect cells and cause diseases, and how these consequences can be mitigated through DNA manipulation.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (31/10/14)
Ministers are considering drastically cutting the main Employment and Support Allowance sickness benefit, internal documents seen by the BBC suggest.
New claimants, judged to be capable of work with appropriate support, could be given just 50p more per week than people on job seekers allowance.
Current recipients get almost £30 per week more.
The Department for Work and Pensions said the ESA proposals were not government policy.
The papers reveal that the government has also been forced to hire extra staff to clear the backlog on the benefit.
Some 100 healthcare professionals are being hired to carry out fitness-for-work tests. The staff, who will be employed through the Pertemps agency, will help to reduce a backlog of more than 600,000 cases.
They will be in addition to any extra staff brought in when a new contractor is announced shortly to replace ATOS. The BBC understands that the American firm, Maximus, has been selected.
Leaked documents this summer showed that ministers considered ESA - formerly known as incapacity benefit - to be "one of the largest fiscal risks currently facing the government".
They also revealed concerns about claimants moving off jobseekers allowance onto ESA.
Giving consideration to cutting the differential paid to ESA recipients in the Work Related Activity Group (WRAG) - individuals who have to prepare for employment - is a reflection of that concern.
They currently get £28.75 more per week but the documents show plans are being discussed to cut that to just 50p more than jobseekers allowance. People receiving JSA, who are aged 25 or over, currently get £72.40 per week.
Employment and Support Allowance is paid to approximately two million people. Claimants have to undergo a work capability assessment to determine whether they are eligible and at what level.
Labour MP Dame Anne Begg, who chairs the Commons Work and Pensions Select Committee, said she would support overhauling the delivery of ESA but "did not envisage" any reduction in the value of the benefit.
"That's not reform, that is just saving money. I hope that is not something the government is going to come forward with."
Problems with the current provider, the French firm ATOS, which was appointed by the last Labour government, led to the firm reaching an agreement with the government earlier this year to leave its contract early.
Ministers raised concerns about the quality of assessments being carried out by ATOS which has led to a backlog of cases. The backlog is currently running at more than 600,000.
As ministers focus assessments on new claimants, recipients who should have been re-assessed under the terms of the benefit are not being seen, creating much of the backlog. Most of those receiving Incapacity Benefit, who should also have been assessed, are also not being tested.
The Office for Budget Responsibility said in a report earlier this month that "the backlog of applications encourages claimants previously not found eligible for ESA simply to reapply".
A spokesman for the DWP said "We are committed to supporting those people who are able to work to make the positive move into employment.
"The current work capability assessment contract was inherited from the previous government - and we have taken numerous steps to improve it. We will shortly announce a new provider. No one should doubt our commitment to ensuring that people who need an assessment get the best possible service and are seen in the quickest possible time."
Source: BBC News © British Broadcasting Corporation 2014 (30/10/14)
Decision comes as a blow to patients who are paying up to €500 a month for Fampridine.
The Health Service Executive has rejected a second application from the makers of a drug that helps people with multiple sclerosis to walk to have it covered by State-funded drug schemes.
The decision will come as a blow to MS patients who are paying up to €500 a month for Fampridine (known commercially as Fampyra), which greatly increases mobility among some of those with the condition.
The HSE first rejected the reimbursement of the drug in May 2013, saying the manufacturer, Biogen Idec, had failed to demonstrate or provide any formal justification for the prices it proposed.
Its drugs committee recommended further discussions take place with neurologists about new drugs that are emerging to treat MS, before Fampridine was reconsidered. Discussions with Biogen Idec started again in July and the company said it offered “additional and significant reductions” in price.
However, yesterday the HSE told Independent TD Denis Naughten “the manufacturer has been unable to demonstrate the cost-effectiveness of Fampridine in the Irish healthcare setting”.
“The HSE decision on Fampridine is in line with many other European countries which have also, to date, not provided the drug under their public health systems.”
Mr Naughten said: “Rather than both sides continuing to horse trade on this life-altering drug, I’m proposing that the HSE and the company sit down and let Ireland become a specific pilot to design a roll-out scheme and pricing structure for Fampyra.”
Outlining his proposal Mr Naughten said: “With 8,000 people with MS in Ireland, which is a relatively small cohort, and in light of the fact that the northwest of Ireland has one of the highest incidence of multiple sclerosis in the world, we are in an ideal situation to evaluate which patients can benefit from this drug.
Mr Naughten called on the HSE and the Government to enter direct talks with the manufacturer with the aim of making Ireland a pilot country for rolling out the drug.
The National Centre for Pharmacoeconomics, which rules on the cost-effectiveness of new drugs, found Fampyra would cost nearly €7,000 a patient each year. It said the €20 million annual cost to the State over five years would take money from other areas.
Source: The Irish Times © 2014 The Irish Times (30/10/04)
A new human clinical trial testing the drug ATL1102 to treat Multiple Sclerosis was approved by FDA, carrying the promise of new therapeutics to affected patients.
Antisense Therapeutics Limited (ANP) announced recently in a press release the FDA’s positive decision to approve their request to submit an Investigational New Drug (IND) application in the U.S. This decision allows ANP to initiate a long-term Phase IIb clinical trial for the treatment of Multiple Sclerosis (MS) with ATL1102.
ANP is currently looking for a pharmaceutical partner for the ATL1102 program development.
Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system. Currently without a cure, MS affects more than 2.3 million people worldwide, 300,000 to 400,000 of whom live in the United States alone. The disease is characterised by destruction of myelin layer within nerve cells, probably caused by a hyper-reactive immune system, with accumulation of white blood cells (leukocytes) in the central nervous system. This leads to a wide range of neurological symptoms affecting visual, motor, and sensory capabilities.
ATL1102 is an antisense inhibitor (belonging to the second generation of inhibitors) of CD49d, a subunit of VLA-4 (Very Late Antigen-4) and a key player regulating immune cell recruitment to inflamed endothelia and other sites of inflammation. Thus, inhibiting VLA-4 potentially prevent leukocytes recruitment, delaying disease progression. VLA-4 is a clinically validated target in the treatment of MS.
ANP showed previously that ATL1102 effectively reduced MS lesions in a Phase II clinical trial in patients with relapsing-remitting multiple sclerosis (RRMS), with superior results when compared to Tysabri® (natalizumab), a monoclonal antibody drug to the VLA-4 receptor. While Tysabri® was reported to cause a potential lethal viral brain infection (progressive multi focal leukoencephalopathy, PML), ATL1102 was safer and equally effective.
Antisense Therapeutics’ CEO and Managing Director Mark Diamond commented, “The FDA Response is an excellent outcome and important step in moving ATL1102 forward into late-stage clinical development and to capitalize on the substantial development and investment made to date on this key project asset. We look forward to providing further updates as we advance development and commercialisation plans for this exciting new therapeutic to treat MS.”
Source: Multiple Sclerosis News T oday © Copyright 2014 BioNews Services, LLC (29/10/14)
Six Case Western Reserve scientists are part of an international team that has discovered two compounds that show promise in decreasing inflammation associated with diseases such as ulcerative colitis, arthritis and multiple sclerosis. The compounds, dubbed OD36 and OD38, specifically appear to curtail inflammation-triggering signals from RIPK2 (serine/threonine/tyrosine kinase 2). RIPK2 is an enzyme that activates high-energy molecules to prompt the immune system to respond with inflammation. The findings of this research appear in the Journal of Biological Chemistry.
"This is the first published indication that blocking RIPK2 might be efficacious in inflammatory disease," said senior author Derek Abbott, MD, PhD, associate professor of pathology, Case Western Reserve University School of Medicine. "Our data provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics."
In addition to Abbott and his medical school colleagues, the research team included representatives of Oncodesign, a therapeutic molecule biotechnology company in Dijon, France; Janssen Research & Development, a New Jersey-based pharmaceutical company; and Asclepia Outsourcing Solutions, a Belgium-based medicinal chemistry company.
The normal function of RIPK2 is to send warning signals to cells that bacterial infection has occurred, which in turn spurs the body to mobilize white blood cells. The white blood cells identify and encircle pathogens, which cause blood to accumulate in the region. It is this blood build-up that leads to the red and swollen areas characteristic of inflammation. When this process goes awry, the inflammation increases dramatically and tissue destruction ensues. RIPK2 works in conjunction with NOD1 and NOD2 (nucleotide-binding oligomerization domain) proteins in controlling responses by the immune system that lead to this inflammation process.
In this research project, investigators applied state-of-the-art genetic sequencing to learn the unique set of genes driven specifically by NOD2 proteins. They ultimately zeroed in on three specific NOD2-driven inflammation genes (SLC26a, MARCKSL1, and RASGRP1) that guided investigators in finding the most effective compounds.
Oncodesign searched its library of 4,000 compounds that targeted kinases, and after exhaustive study, narrowed the selection down to 13. Then investigators tested the 13 compounds in mouse and human cells and found that two compounds, OD36 and OD38, were most effective in blocking RIPK2.
"Based on the design of OD36 and OD38, we have developed with Oncodesign fifth-generation compounds that are even more effective than the first-generation OD36 and OD38," Abbott said. "Our next step is to seek a larger pharmaceutical company that can move these compounds forward into Phase 1 clinical trials in humans."
Source: News-Medical.Net Copyright 2000-2014 AZoM.com Limited (27/10/14)
Canadian collaboration advances promising research targeting progressive Multiple Sclerosis(22/10/14)
Development of new therapies for progressive multiple sclerosis (MS) is getting a boost this fall as the first project funded through the MS Society of Canada-Centre for Drug Research and Development (CDRD) collaboration is launched. The study, which was selected from over thirty applications from around the world, will be led by Canadian researcher Dr. Craig Moore (Memorial University, Newfoundland). The six-month project will identify and validate new drug targets for progressive MS, with a particular focus on understanding how inflammation in the brain leads to subsequent tissue injury and repair. This research, which stems from Dr. Moore's previous work at McGill University (Quebec), is to be performed at CDRD's fully-integrated drug development and commercialization centre in Vancouver.
"We've identified several different molecules in cells of the immune system that could be targeted to help promote repair in the MS affected-brain," says Dr. Craig Moore. "Together with CDRD, my research team aims to modify the brain microenvironment to resist damage and encourage repair. With state-of-the-art technology and biologically-relevant human brain samples, we are currently developing and testing methods that will enable the discovery of drugs to treat progressive MS."
Funding this work marks an important step in the continuing collaboration between CDRD and the MS Society, which was formed with the objective of accelerating the development of safe and effective treatments for people living with MS. Drug development and business experts at CDRD will work very closely with Dr. Moore to advance his research towards clinical trials and subsequent new therapies for progressive MS.
"In today's world of drug development, the critical value of all stakeholders coming together -- from the investigators conducting the breakthrough research, to foundations, translational centres, industry, government, and of course patients themselves -- cannot be overstated," says Dr. T. Michael Underhill , CDRD's Co-Scientific Director. "The work we are beginning with Dr. Moore is a great example of how CDRD can bring these many parties, their facilities and expertise together to focus resources where they can be of greatest direct benefit to patients."
Although ten drugs are available in Canada to reduce inflammation and control the frequency of relapses in persons living with MS, none are proven to stop or reverse the progressive accumulation of tissue damage and subsequent disability. Because most individuals with MS are affected by this progression during their lives, there is an urgent need to develop drugs for this aspect of the disease.
"We heard from people across the country that research needs to be accelerated to bring tangible, life-improving benefits for people living with MS sooner rather than later," says Dr. Karen Lee, MS Society of Canada's Vice-President, Research. "By working closely with CDRD, and funding Dr. Craig Moore's innovative research, the MS Society affirms its commitment to support research that will bring safe and effective treatments for MS, and uncover clearer answers about why progression occurs and how it can be halted and repaired."
CDRD is Canada's fully-integrated national drug development and commercialization centre, providing expertise and infrastructure to enable researchers from leading health research institutions to advance promising early-stage drug candidates. Its mandate is to de-risk discoveries stemming from publicly-funded health research and transform them into viable investment opportunities for the private sector -- thus successfully bridging the commercialization gap between academia and industry, and translating research discoveries into new therapies for patients. Canada's Networks of Centres of Excellence Program has recognized CDRD as a Centre of Excellence for Commercialization and Research (CECR).
Source: Market Wired © Copyright Marketwire L.P (22/10/14)
A joint study by researchers from Germany and the US has found that nearly 60% of patients with multiple sclerosis (MS) and uveitis were diagnosed with each condition within five years.
Researchers from the Oregon Health and Science University in the US and the University of Heidelberg in Germany, examined the records of uveitis patients from each university. The study, which is the largest retrospective study of MS in uveitis patients, examined data taken from over 8,000 patients between 1985 and 2013.
The teams found that MS was 18 times more likely to occur in Americans with uveitis and 21 times more likely to occur in Europeans with uveitis, than in those general populations without uveitis.
The study also showed that MS was diagnosed in 29% of patients before uveitis was diagnosed, both MS and uveitis were diagnosed simultaneously in 15% of patients, and MS was diagnosed after uveitis in 56% of patients.
Wyatt Messenger, from the Oregon Health and Science University, who led the research, said: "With a population size four-times larger than any study to date on this topic, our study provides a wealth of clinical information.
"Knowing more about the onset of MS may enable patients to seek treatment earlier, therefore slowing the progression of the disease and limiting the damage done to the nervous system."
Source: American Academy of Ophthalmology (22/10/14)
The US Food and Drug Administration (FDA) approved Genzyme’s application to include new information about its multiple sclerosis drug teriflunomide (Aubagio) on its label.
The new labeling content is efficacy and safety data from two Phase III trials of the drug. One trial, a study known as TOPIC is described in the Sept., 2014 issue of The Lancet Neurology. In it Aaron Miller, MD and colleagues report that in 618 relapsing-remitting multiple sclerosis patients assigned to the drug or placebo those who got the drug had a significantly reduced risk of relapse. The patients got a single daily oral dose of either 14 mg or 7 mg (or placebo) for up to 108 weeks.
The study was conducted from Feb 13, 2008 to Aug. 22, 2012 at 112 medical centers in 20 countries. The patients getting teriflunomide did better than placebo at either dosage at preventing relapses without serious side effects.
Miller is medical director of The Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai Hospital in New York, NY. In a statement from Genzyme, Miller said “Aubagio is the only oral multiple sclerosis treatment that has demonstrated a positive effect on disability progression in two Phase III clinical studies and is the only oral therapy with supporting published efficacy data on the treatment of patients who have experience a first clinical attack.”
The drug was originally approved for US use in 2012. Pooled data from TOPIC and two other studies involving 2,000 subjects found that though patients experienced adverse events including decreased white blood cell count, peripheral neuropathy, skin reactions and increased blood pressure, the rate at which the subjects reported these events was about the same as in subjects who were taking placebos.
The drug is an immunomodulator with anti-inflammatory properties. It is believed to reduce the number of activated lymphocytes in the central nervous system. It is contraindicated for patients with severe liver problems and in women who are pregnant or may become pregnant since animal studies indicate teratogenicity.
Source: HCPLive Copyright HCPLive 2006-2014 Intellisphere, LLC (21/10/14)
Scientists looked at about 4,700 people who received vaccines against hepatitis B (Hep B) and the human papillomavirus (HPV), and found no long-term risk of developing multiple sclerosis (MS) or similar nervous-system diseases.
Some anti-vaccination groups had raised concerns that the proteins in the Hep B and HPV vaccines could lead to the destruction of myelin, the insulating material that surrounds the parts of nerve cells called axons. Such damage, called demyelination, is the hallmark of several neurodegenerative autoimmune diseases — most commonly, MS.
Previous studies on this topic have been small. While most have found no connection between vaccination and MS, two studies did suggest a slight increase in risk, so the issue has remained controversial.
This latest study is the largest to date and followed patients for three years after their vaccinations, said the researchers at Kaiser Permanente Southern California, a company that offers health insurance (and does not produce any vaccines or drugs). The results are published today (Oct. 20) in the journal JAMA Neurology.
The researchers wrote that the small risk of developing MS seen in some earlier studies suggests that the vaccine, like an infection, may accelerate the disease's progression in patients who already have MS or other neurodegenerative autoimmune diseases. It may be that after vaccinations, patients move more quickly from the "subclinical" stage of the disease, when no outward symptoms are seen, to a stage with visible symptoms, the researchers said.
The lead author of the report, Dr. Annette Langer-Gould, noted that the new study could not fully rule out a connection between the HPV vaccine and MS because the sample size of vaccinated patients was limited. Therefore, a larger study would be needed to confirm the results, she said.
However, the authors wrote that any association is likely coincidental. For example, young women are the group with the highest risk for MS, and they receive the HPV vaccine at a time when they could be diagnosed with MS. The situation is analogous to how autism reveals itself in babies coincidentally around the age of several vaccinations.
Source: Yahoo! News © Yahoo! Inc. 2014 (21/10/14)
Estimating typical Multiple Sclerosis disability progression speed from clinical observations(20/10/14)
Murray G. Brown, Mark Asbridge, Vern Hicks, Sarah Kirby, Thomas J. Murray, Pantelis Andreou, Dong Lin
Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods.
Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979–2010. Progression speed is measured by rate-of-change in range EDSS 0–6 and by survival time at irreversible endpoints EDSS 1–9. Midpoint censoring-bias-reduction methods are applied to clinical observations.
Typical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed.
Estimates of typical disease progression speed from 1979–2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts’ survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within and across study groups and time periods, than unadjusted estimates, and are, arguably, more relevant for various stakeholders. The application of censoring-bias-reduction methods to other multiple sclerosis clinical databases may reduce variability in estimates of disability progression speed worldwide.
Source: PLOS © 2014 Brown et al (20/10/14)
A study published in the October, 2014 issue of Nature Medicine points to a new target for the treatment of multiple sclerosis (M.S.). Inhibiting this target, in a mouse model of the disease, was shown to inhibit the disease in its most advanced stages.
The landmark paper, “B4GALT6 regulates astrocyte activation during CNS inflammation,” was authored by Lior Mayo, Francisco J. Quinta et al. at Harvard Medical School. Abdolmohamad Rostami, M.D. Ph.D., professor and chair of the department of neurology at Thomas Jefferson University, together with Assistant Professor of Neurology Bogoljub Ciric, Ph.D., authored a commentary article, “Astrocyte-derived lactosylceramide implicated in multiple sclerosis,” about the research for Nature Medicine.
“These findings provide a basis for targeting astrocytes, in particular LacCer signaling, as an alternative to most existing M.S. therapies, which modulate the immune system,” said Dr. Rostami. Patients and researchers have been frustrated by the limited effectiveness of available therapies for M.S., especially for “progressive” M.S., a devastating form of the disease that continues to progress with no interruption.
As Rostami and Ciric write in their commentary, the researchers started by investigating a puzzle in M.S. biology. M.S. is thought of as a disease in which the immune cells attack the neuron’s “insulating” tissue, myelin, which helps speed the signals passing from one cell to the next. A type of brain cell, called an astrocyte, appears to play two roles in the disease – protecting and re-myleninating cells early on, and then later, it appears to participate in the inflammatory reaction that fuels the disease.
Exploring this question, the researchers found that the gene B4GALT6 encodes an enzyme that makes LaCer (latosylceramide) — a lipid-signaling molecule. Increasing LaCer production worsens the disease, while inhibiting LaCer halts progression in a mouse model of late-stage disease, suggesting that this enzyme could be a potent target for developing a novel class of therapies against M.S.
Rostami and Ciric write that LaCer appears to contribute to disease progression by activating astrocytes, which in turn activate inflammatory signals that damage nerve cells; it also contributes to the repression of genes associated with remyelinization.
Drs. Rostami and Ciric were particularly impressed with the studies that bridged the finding to human disease. The Harvard team also showed that in samples taken from humans with M.S., B4GALT6 expression levels were increased, as were markers of astrocyte activation, suggesting that a similar pathway may be at play in humans.
Source: Thomas Jefferson University Copyright © 2014 Thomas Jefferson University (15/10/14)
Evotec AG, a German company specializing in the provision of drug discovery resources to biotech companies and learning institutions, announced that is going to begin three new research projects for the treatment of multiple sclerosis (MS), which will be supported by funds from the German Federal Ministry of Education and Research.
The scientific approaches being used in the three novel research projects will focus on cytokine regulation, neuroprotection, and tolerance induction for further advancing efforts to develop therapies for multiple sclerosis. The work is based on research from the Deutsches Rheuma-Forschungszentrum, an institute of the Leibniz Association, which will feature the work of Prof. A. Hamann, as well as researchers from the University Medical Center Hamburg-Eppendorf, with the collaboration of Prof. M. Friese and Dr. J. Herkel.
The company intends to use their drug discovery platform, as well as their project management capabilities and market presence, to help identify and facilitate candidate drugs through novel therapeutic approaches that are able to effectively tackle MS. Evotec will later commercialize them, and expects to be able to create viable competitors for the current treatments, which are mostly based on disease-modifying approaches that are used in treating patients with the relapsing-remitting form of the disease. The projects are expected to run for one and a half and three years, and are funded by a budget of more than $6.3 million dollars.
“These novel approaches to fight MS, the disease with the highest socioeconomic impact worldwide, perfectly fit to our EVT Innovate strategy to approach disease-modifying innovation and to identify first-in-class molecules eagerly sought for by the biotech and pharmaceutical industry,” said the Chief Scientific Officer of Evotec, Cord Dohrmann. ”We are proud to partner with these leading German research institutions and groups to translate their exceptional disease know-how into drug candidates and furthermore into novel products.”
Evotec had recently announced it was launching a line-up groundbreaking studies focused on the disease that affects the protective covering of nerve cells, leading to disability and loss of quality of life. Some of the companies partners include Bayer, Boehringer Ingelheim, CHDI, Genentech, Janssen Pharmaceuticals, MedImmune/AstraZeneca, Roche and UCB.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (15/10/14)
SMC first to introduce oral Gilenya® as a first line treatment option for people with a severe form of MS(14/10/14)
SMC first to introduce oral Gilenya® as a first line treatment option for people with a severe form of MS
• Scottish people with a severe form of relapsing remitting multiple sclerosis are first in UK to get access to once daily pill fingolimod as a first line treatment option1
• Once daily pill fingolimod reduces the risk of relapses by 67% compared to placebo2
Today, the Scottish Medicines Consortium (SMC) has accepted once daily pill fingolimod (Gilenya®) as a first line option for people with a severe form of relapsing remitting MS, which has been shown to reduce the risk of relapses by 67% compared to placebo.1,2 This is the first time that an oral treatment has been made available as a first line treatment option for people with this severe form of MS - known as rapidly evolving severe relapsing remitting MS (RES RRMS).1
The SMC heard from patient groups that MS is an incurable progressive disease with devastating effects on those with the condition and their families.1 Symptoms can include intense pain, mobility problems, severe depression, fatigue, incontinence and loss of vision.1 MS affects over 100,000 people in the UK, with rates highest in Scotland.3,4
85% of people with MS are diagnosed with the relapsing remitting form - when symptoms flare up aggressively - known as relapses.5 There are different types of RRMS, including highly active and RES RRMS.6 In September 2012, the SMC agreed to reimburse fingolimod for people with highly active RRMS who are failing on first line interferon injections.7 Today’s decision means that fingolimod is now also reimbursed for RES RRMS – when a person has two or more disabling relapses in one year with associated MRI changes.1 The SMC’s decision to broaden access to fingolimod means this is the first time that people with this more severe form of RRMS will have the choice of a once daily pill as a first line treatment option.1
Prior to today’s decision, only one SMC approved treatment was available for people with RES RRMS – a hospital-based infusion called natalizumab required every 28 days.1 Fingolimod is a once daily pill that can be taken at home after the first dose, avoiding the need to travel to hospital every month. It has been shown to reduce relapses by 67% compared to placebo in those with RES RRMS (ARR 0.24 for fingolimod and 0.74 for placebo).2 The analysis was conducted in a subgroup of patients from the original phase III FREEDOMS trial.
Scottish patients with RES RRMS will have access to once daily pill fingolimod as a first line treatment option before those in the rest of the country. This is because the SMC process allows manufacturers to submit new data at any time. NICE is set to review fingolimod alongside a range of other MS treatments in 2015. This means that people with this severe form of RRMS north of the border will have an increased choice of first line treatments before their southern counterparts.
Today’s announcement follows a series of recent decisions by the European Commission and NHS England to extend the use of fingolimod to a wider group of people, just three years after its original licence was granted in March 2011.
To date, more than 100,000 people worldwide have been treated with fingolimod in clinical trials and in the post-marketing setting.8 Fingolimod has been approved in 80 countries.8
References 1. SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya®). October 2014
2. Devonshire V, Havrdová E, Radue EW et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012; 11:420-28
3. The Scottish Parliament. Briefing for the Public Petitions Committee. http://www.scottish.parliament.uk/ResearchBriefingsAndFactsheets/Petitions%20briefings%20S3/PB10-1353.pdf Last accessed 10 October 2014.
4. MS Society. What is MS? http://www.mssociety.org.uk/about_ms/what_is_ms/index.html Last accessed 10 Oct 2014
5. MS Society. http://www.mssociety.org.uk/what-is-ms/types-of-ms/relapsing-remitting-rrms Last accessed 10 October 2014
6. MS Trust. http://www.mstrust.org.uk/atoz/types.jsp Last accessed 10 October 2014
7. SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya®). SMC No. (763/12). 12 March 2012
8. Gilenya World Watch. http://www.gilenya-world-watch.com/English.html Last accessed 10 October 2014
9. European Commission. Community register of medicinal products for human use. Gilenya. http://ec.europa.eu/health/documents/community-register/html/h677.html Last accessed 10 October 2014.
10. NHS England commissioning guideline for Gilenya. June 2014
Source: Novartis (14/10/14)
Concert Pharmaceuticals Inc. announced Phase 1 data of CTP-354, a novel, potentially first-in-class, non-sedating, once-daily oral treatment for spasticity. In this multiple ascending dose trial, no sedation or ataxia was observed with CTP-354 and the drug was generally well tolerated across all dose cohorts.
Concert expects to initiate a Phase 2 clinical trial evaluating CTP-354 in patients with spasticity associated with spinal cord injury by the end of 2014.
"We are very pleased to have completed our clinical evaluation of CTP-354 in this Phase 1 trial. We remain on track to advance the program into Phase 2 testing later this year, initially targeting spasticity in patients with spinal cord injury followed by the start of a Phase 2 trial in multiple sclerosis patients in early 2015," said Roger Tung, President and Chief Executive Officer.
The Phase 1 multiple ascending dose clinical trial was a randomized, double-blind, placebo-controlled study in 30 healthy volunteers. The primary objective of the trial was to evaluate the safety, tolerability and pharmacokinetics of 10-day repeat dosing of 2 mg, 6 mg and 12 mg of CTP-354.
Clinical highlights include: CTP-354 was generally well tolerated. There were no serious adverse events and no treatment discontinuations. The most common adverse events were dose-related mild and moderate dizziness and somnolence (drowsiness). No sedation or ataxia was observed at the doses evaluated. Across all doses, plasma half-life was approximately 20 hours at steady state. CTP-354 exposure was generally dose-proportional across daily doses ranging from 2 mg to 12 mg. Administration of CTP-354 under both fed and fasted conditions provided similar exposure, indicating that it can be dosed without regard to meals.
The company previously reported positive results from both a Phase 1 single ascending dose trial and a Phase 1 brain imaging trial as measured by positron emission tomography, or PET imaging. The long half-life and pharmacokinetic profile observed in the single ascending dose support once-daily dosing of CTP-354. In addition, CTP-354 provided high and sustained brain GABAA receptor occupancy levels in the brain imaging trial in both single and repeat doses.
Based on the results of the Phase 1 trials, Concert intends to advance CTP-354 into Phase 2 clinical evaluation later this year. The Phase 2 program is projected to include two trials: one evaluating spasticity associated with spinal cord injury and one evaluating spasticity associated with multiple sclerosis.
Source: NASDAQ © NASDAQ OMX Group, Inc (14/10/14)
The immunosuppressive drug fingolimod (trade name: Gilenya) was approved for an expanded therapeutic indication in May 2014: It is now also available for adults with highly active relapsing remitting multiple sclerosis (RRMS) who had received other pretreatment than interferon beta (IFN-β). In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether the drug offers an added benefit over the appropriate comparator therapy in this patient group.
According to the findings, such an added benefit is not proven: For some of the patients, the drug manufacturer presented no data. For other patients, the available study data either showed no differences between the treatment groups, or the data were not evaluable.
G-BA specifies appropriate comparator therapy
The Federal Joint Committee (G-BA) distinguishes between two patient groups for the assessment: In patients with highly active RRMS despite full previous treatment (no interferon beta), fingolimod was to be compared with glatiramer acetate or interferon beta. In patients with incomplete previous treatment, the G-BA distinguishes between two cases for the appropriate comparator therapy: In patients who had received glatiramer acetate, this medication was to be optimized and continued. In patients who had received a different drug, treatment was to be changed to interferon beta or glatiramer acetate.
Only data of few study participants relevant for the assessment
One relevant study was available for the early benefit assessment, an approval study on fingolimod (TRANSFORMS), which compared treatment with fingolimod versus treatment with IFN-β1a in adults with RRMS. However, the disease was rated as "highly active" in only nearly half of the 866 participants. Only 263 of these 402 patients had received full previous treatment. Only 42 participants, i. e. a little less than five percent of the total study population, had not been treated with interferon beta (17 patients in the fingolimod arm, 25 in the interferon beta arm). However, only these patients correspond to the subpopulation relevant for this benefit assessment, because it is only this subpopulation that fingolimod had received expanded approval for. The informative value of the results was considerably limited because only data of few participants were evaluable.
Differences between treatment arms not statistically significant
No deaths occurred during the total study duration of 12 weeks. There were differences between the fingolimod and the interferon beta group with regard to relapses and disability progression, but these were not statistically significant.
No evaluable data were available for the patient group for which fingolimod was newly approved regarding other aspects of the outcome "morbidity", e.g. fatigue or activities of daily living, and for the outcome "health-related quality of life". One of the reasons for this is that different proportions of patients were not considered in the analysis.
There were group differences in side effects (serious adverse events and treatment discontinuation due to adverse events), which again were not statistically significant.
Dossier without relevant study on patients with incomplete treatment
In its dossier, the manufacturer presented no relevant study for patients who had not received full previous treatment.
In summary, an added benefit of fingolimod is therefore not proven for patients with highly active relapsing remitting multiple sclerosis (RRMS) who had received a different pretreatment than interferon beta.
Discrepancy between approval and study population
In 2011, fingolimod had been approved for two therapeutic indications: for rapidly progressive severe RRMS and for highly active RRMS that had been pretreated with interferon beta. For these two patient groups, IQWiG had published a dossier assessment according to AMNOG in January 2012.
In this first assessment the problem had already occurred that participants with different types of RRMS had been included in the relevant study, and that the authorities had then limited the approval to specific, relatively small patient groups. Since the first approval and assessment, the manufacturer apparently conducted no further studies for the expansion of approval.
G-BA decides on the extent of added benefit
The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.
Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (13//10/14)
The National Institute for Health and Care Excellence has changed guidelines for Multiple Sclerosis.
Thousands of people may be being wrongly diagnosed with Multiple Sclerosis or not diagnosed at all, health experts have warned as they changed guidelines to improve detection of the condition. The National Institute for Health and Care Excellence said that as many as one in 10 cases was misdiagnosed and called for more thorough scans and tests to be carried out.
Around 100,000 people are thought to have MS in Britain.
The updated guidance for the NHS said patients should have a comprehensive review of all aspects of their care at least once a year.
Other key recommendations for healthcare professionals to follow include referring people with suspected MS to a consultant neurologist and offering people with MS an appropriate single point of contact to speak about their care, concerns and different treatment options.
Nice also suggested multidisciplinary teams made up of experts including neurologists, MS nurses, GPs, psychologists, speech and language therapists, occupational therapists, and physiotherapists should oversee care.
People with MS should also be encouraged to exercise and be offered supervised exercise programmes for those who struggle with mobility and fatigue.
Currently, those with MS can be left for more than a year without having their condition and medication monitored but the updated Nice guidance aims to ensure that people with MS have their condition and treatments reviewed more regularly.
Dr Paul Cooper, consultant neurologist at the Greater Manchester Neuroscience Centre and chairman of the Guideline Development Group (GDG), said currently some people are receiving "excellent care and support" but others around the country are not.
"The care someone receives should not depend on where they live, we want to ensure that throughout the country people with this distressing and disabling disease have prompt access to specialists who understand their needs and can help improve their condition," he added.
The life-long condition of the central nervous system affects both the brain and spinal cord. Its causes are complex and not completely understood and there is currently no cure.
Typical early symptoms include, limb weakness, lack of coordination, loss of sight, and bladder and bowel problems, which usually develop in sufferers' twenties.
Rates of MS vary with latitude: It is more common in Europe than in the Tropics, and affects more northerners than southerners in the UK.
Professor Mark Baker, clinical practice director at Nice, said: "About 100,000 people in the UK have MS, with symptoms usually appearing in younger people. It can be a highly disabling condition that people live with for many years.
"MS can significantly affect a person's quality of life: they may have to give up work and may also struggle with their mobility. We know that people with MS tend to die earlier than others. This is why it is important to give people access to the best treatments and specialists who can help them live as normal and as long a life as possible."
The Nice guidance does not recommend taking fampridine or the cannabinoid drug Sativex, with the CDG advising that there are better treatments available already on the NHS.
Dr Cooper added: "The substantial cost of sativex and fampridine compared to the modest benefit does not justify their use; there are better ways to improve care for people with MS."
Source: Daily Telegraph © Copyright of Telegraph Media Group Limited 2014 (09/10/14)
MS researchers are focusing on the content of the gut’s microbiome as a possible contributor to the body’s autoimmune attack on its nervous system.
Multiple sclerosis (MS) is an electrical disorder, or rather one of impaired myelin, a fatty, insulating substance that better allows electric current to bolt down our neurons and release the neurotransmitters that help run our bodies and brains. Researchers have speculated for some time that the myelin degradation seen in MS is due, at least in part, to autoimmune activity against the nervous system. Recent work presented at the MS Boston 2014 Meeting suggests that this aberrant immune response begins in the gut.
Eighty percent of the human immune system resides in the gastrointestinal tract. Alongside it are the trillions of symbiotic bacteria, fungi and other single-celled organisms that make up our guts’ microbiomes. Normally everyone wins: The microorganisms benefit from a home and a steady food supply; we enjoy the essential assistance they provide in various metabolic and digestive functions. Our microbiomes also help calibrate our immune systems, so our bodies recognize which co-inhabitants should be there and which should not. Yet mounting evidence suggests that when our resident biota are out of balance, they contribute to numerous diseases, including diabetes, rheumatoid arthritis, autism and, it appears, MS by inciting rogue immune activity that can spread throughout the body and brain.
One study presented at the conference, out of Brigham and Women’s Hospital (BWH), reported a single-celled organism called methanobrevibacteriaceae that activates the immune system is enriched in the gastrointestinal tracts of MS patients whereas bacteria that suppress immune activity are depleted. Other work, which resulted from a collaboration among 10 academic researcher centers across the U.S. and Canada, reported significantly altered gut flora in pediatric MS patients while a group of Japanese researchers found that yeast consumption reduced the chances of mice developing an MS-like disease by altering gut flora.
Sushrut Jangi, a staff physician at Beth Israel Deaconess Medical Center in Boston who co-authored the BWH study, thinks that regional dietary influences might even be at play. “The biomes of people living in different areas and who consume Western versus non-Western diets are demonstratively different,” he says. “People who emigrate from non-Western countries, including India, where MS rates are low, consequently develop a high risk of disease in the U.S. One idea to explain this is that the biome may shift from an Indian biome to an American biome,” although there is not yet data to support this theory.
The microbiome theory is gaining so much steam in academia that a coalition of four U.S. research centers called the MS Microbiome Consortium recently formed to investigate the role of gut microorganisms in the disease. The group presented data in Boston showing significantly different gastrointestinal bacterial populations in patients treated with the MS drug glatiramer acetate compared with untreated subjects. How exactly the drug suppresses MS activity is unknown but the findings suggest that perhaps it works in part by altering gut flora and, as a result, suppressing abnormal immune activity. “The gut is well-positioned for an important role in the development of autoimmune disease, including MS.,” says Ilana Katz Sand, an assistant professor of neurology at Mount Sinai Medical Center in New York City and member of the MS Microbiome Consortium. “But important questions remain, such as how MS medications affect the microbiome, how an individual’s microbiome may affect treatment responses, whether particular bacterial species are associated with more severe disease and ultimately whether we can manipulate the microbiome to benefit our patients.”
Katz Sand says that dietary and probiotic approaches to treating MS are worth pursuing, as is a less palatable approach: fecal transplantation. Yet answers in science and medicine are rarely simple, she added, pointing out that in all likelihood MS arises from a complicated confluence of genetic and environmental influences that might ultimately trigger autoimmune activity. Beyond just our gut flora well over 100 genetic variants—many related to immune function—are now known to contribute to the disease as are external factors including vitamin D deficiency (MS is more common at higher latitudes), smoking and increased salt intake.
Further confounding our ability to pinpoint root causes is that our genetic code influences how our bodies and brains respond to these external factors. It could be that both genes and environmental stimuli lead to pathologic microbiomes or that some unfortunate combination of these factors leads to a common autoimmunologic pathway that ravages myelin. “We know the microbiome shapes our immune system and that MS is an immune-mediated disease. We also know that genes influence our microbiomes and immune systems,” says David Hafler, professor of neurology and immunobiology at Yale University School of Medicine who was at the conference but not involved in the microbiome work presented. But there must be nongenetic factors contributing to the disease, too, given that the incidences of MS and other autoimmune disorders are increasing.
“Maybe it’s a lot of little factors like low vitamin D, increased body mass index and increased salt intake,” Hafler says, “but I wouldn’t be surprised if it was one big thing, much like how H. pylori was found to cause ulcers. No one’s identified a clear bug that’s driving MS but I think it’s important we keep looking.”
Source: Scientific American © 2014 Scientific American, a Division of Nature America, Inc (08/10/04)
A drug derived from cannabis, which many people with multiple sclerosis say helps ease their symptoms, has been ruled too expensive to be used by the NHS in England even though it is approved for Wales.
In new guidelines for the diagnosis and treatment of people with the disabling disease, the National Institute for Health and Care Excellence (Nice) says the price set by the manufacturer of Sativex (nabiximols) is too high for the benefit it gives patients. But the decision opens up the sort of “postcode lottery” that Nice was set up to end, with MS patients in Wales able to use the drug on the NHS while those in England either have to buy it themselves or go without. Some will use the illegal drug instead.
A second drug, Fampyra (fampridine), designed to improve people’s ability to walk, has been rejected by both England and Wales. Neither drug is routinely available in Scotland.
“The substantial cost of Sativex and fampridine compared to the modest benefit does not justify their use; there are better ways to improve care for people with MS,” said Dr Paul Cooper, a consultant neurologist who chaired the guideline development group.
In a Guardian podcast, he suggested Wales had been “a little naive” in their assessment of Sativex: “They have taken information from the drug company at face value without seeing the original data and they’ve used dosages and potential benefits that we would not agree with.”
But the MS Society’s chief executive, Michelle Mitchell, said the rejection of the two drugs by Nice was disappointing. “Surely we should be striving for the most innovative treatment and care to be made available to people with MS, not limiting options even further,” she said.
The charity published a survey of nearly 4,000 people with MS that found 82% of those taking Sativex considered it essential or a high priority. The main reasons people gave for not taking Sativex were that it was not available where they lived – prior to Nice’s decisions, the NHS makes local decisions about funding the drug – or that they would have to pay privately.
“I experience very painful spasms around my ribs, the MS hug, and tightness in my arms and legs. I’ve been told that Sativex could give me some relief but it seems so out of reach,” said Shona Garrett, 38, from Lowestoft, who was diagnosed two years ago and is on a waiting list for the drug in her area. “I also experience nerve pain like constant pins and needles in my feet, and I’ve heard Sativex could help with this too. No one has offered me any other options.”
She and her husband had discussed paying for the drug privately, but they had been told it would cost £500 a month, which is more than they can afford.
About 100,000 people in the UK have MS. It tends to hit younger people and can lead to serious long-term disability.
The guideline says people with suspected disease should be referred promptly to a consultant neurologist for diagnosis. Among other recommendations are that they should have a single expert to speak to about their care, concerns and treatment options so they are not shuttled about between different doctors and nurses. They should also be encouraged and helped to exercise.
The MS Trust said although it welcomed its publication, “regrettably, we believe that the guideline falls short. Though it contains a number of welcome recommendations, it also contains some significant gaps and omissions. Overall we believe it demonstrates a lack of ambition to provide what people with MS need, that is, a genuinely comprehensive description of best practice in MS care.”
Source: The Guardian © 2014 Guardian News and Media Limited (08/10/14)
Type 1 diabetes, ulcerative colitis, and multiple sclerosis are among the more well-known autoimmune diseases. But according to the AARDA, there are more than 150 rare autoimmune diseases, which affect around 50 million Americans. Even with this large number, scientists are still in the dark regarding interventions that can help cure these diseases. But this might change with the discovery of a molecule called NAD+ that has the potential to reverse autoimmunity.
What is autoimmunity?
When an intruding pathogen, such as a virus or bacterium, enters our bodies, our innate immune system gets activated, immediately sending out its soldiers (antibodies and immune cells) to identify and eliminate the pathogen, thus protecting us. But sometimes something goes wrong with this innate immunity and it starts regarding the body’s own tissues as foreign and repeatedly sends out soldier cells to attack them.
Autoimmune diseases can affect any part of the body, including the heart, brain, nerves, muscles, joints, lungs, kidneys, etc. There is still no established cause for autoimmunity, but genetic factors are considered to play a major role.
This new research conducted by Brigham and Women's Hospital (BWH) has identified NAD+ (Nicotinamide adenine dinucleotide), a naturally occurring molecule in living cells, plants, and food that has the potential to turn “destructive” cells that attack healthy tissues into “protective” cells. The molecule has also been found to reverse disease progression by restoring tissue damaged by the autoimmunity process.
"Our study is the first to show that NAD+ can tune the immune response and restore tissue integrity by activating stem cells," said Abdallah ElKhal, senior author, in a statement. "These findings are very novel and may serve for the development of novel therapeutics." The study is published online Oct. 7, in Nature Communications.
NAD+ plays an essential role in several metabolic processes. To test the action of NAD+ in pre-clinical trials, the scientists used experimental autoimmune encephalomyelitis, a pre-clinical model for human multiple sclerosis. They found that NAD+ could regulate the differentiation of immune cells called CD4+ T cells that have an established role in many aspects of autoimmune inflammation. Mice having NAD+ were administered with CD4+ T cells. They showed a significant delayed onset of disease, as well as a less severe form, therefore demonstrating the molecule's protective properties.
"This is a universal molecule that can potentially treat not only autoimmune diseases, but other acute or chronic conditions such as allergy, chronic obstructive pulmonary disease, sepsis, and immunodeficiency," said coauthor Stefan G. Tullius.
The scientists also successfully demonstrated the tissue-restoring capability of NAD+. This, they say, can benefit patients with advanced tissue damage caused by autoimmune diseases. The scientists are now exploring the other medical benefits of NAD+.
"Since this is a natural molecule found in all living cells, including our body, we hope that it will be well-tolerated by patients," said ElKhal. "Thus, we hope that its potential as a powerful therapeutic agent for the treatment of autoimmune diseases will facilitate its use in future clinical trials."
Source: Medical Daily © 2014 IBT Media Inc (08/10/14)
Research supports the slowed processing speed in the executive deficits found in individuals with multiple sclerosis (MS), according to a paper from the Kessler Foundation.
The investigators wanted to further explore cognitive deficits, since they affect nearly half the population of MS patients. These disabling symptoms can adversely affect patients' quality of life. Data was collected from 50 MS patients and 28 healthy controls and all patients were evaluated through executive functioning tasks both with and without a processing speed element. The tasks included the Trail Making and Wisconsin Card Sorting tests.
The researchers found the MS patients performed on tasks related to executive function compared to their healthy counterparts. While analyzing the data for speed control, the scientists discovered the differences between the healthy and MS group disappeared. The data also revealed no difference on executive tasks with non-processing speed demands.
Disease progression was also something the researchers investigated throughout this study in the MS group. For MS patients, higher atrophy was associated with greater deficits on speeded executive tasks. However, the relationship vanished when the researchers controlled for processing speed. The researchers noted there was no association between atrophy and performance when analyzing non-processing speed executive tasks.
“Our results point to slowed processing speed as the mechanism underlying deficits in executive function,” Nancy Chiaravalloti, PhD, said in a press release. “Understanding this association is an important step toward the development of effective cognitive rehabilitation strategies for individuals with MS. We should focus our efforts on 2 key domains - processing speed and memory.”
Executive deficits in MS may be explained by slow processing speed, the researchers concluded in their paper. Slowed processing speed may be a primary impairment which underlies other cognitive functions. They believe it is important to unwrap processing speed contributions to executive function, which would be an important step toward the development of appropriate treatment and rehabilitation techniques for MS patients.
"Additional neuropsychological measures should be included in future studies,” Chiaravalloti added. “We also need to focus on the contribution of specific brain pathology, such as frontal atrophy and lesion load, to executive deficits.”
Source: Rehabilitation Psychology & HCPLive Copyright HCPLive 2006-2014 (07/10/14)
Smoking appears to increase the likelihood of developing neutralizing antibodies to natalizumab (Tysabri, Biogen Idec), which cause the drug to have little, if any, therapeutic effect in multiple sclerosis (MS), a new study suggests.
The study was presented by Tomas Olsson, MD, Karolinska Hospital, Stockholm, Sweden, at the recent MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.
"The lung seems to be an important immunoreactive organ where irritation such as smoking may increase risk not only for inflammatory diseases, but also neutralizing antibodies to biologicals like interferon β and monoclonal antibodies such as natalizumab," he concluded.
"While smoking should not prohibit use of natalizumab, the percentage of patients developing antibodies, neutralizing the effect of the treatment, is not negligible," Dr Olsson commented to Medscape Medical News. "Therefore patients should be advised about our findings. This comes on top of an increased risk for MS with smoking, and probably a worse disease course."
In his presentation, Dr Olsson explained that smoking is thought to contribute to the induction of neutralizing antibodies to interferon β-1a, so he and his colleagues aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of MS.
The study was based on 1338 natalizumab-treated patients with MS included in either of two Swedish case-control studies in which information on smoking habits was collected. Treatment-related information was obtained from the Swedish national MS registry and antibody status from the Swedish Nab lab. Enzyme-linked immunosorbent assay was applied before therapy start and after 6, 12 and 24 months. Through use of logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies.
Results showed that compared with nonsmokers, the odds ratio (OR) of developing anti-natalizumab antibodies was 2.4 (95% confidence interval [CI], 1.2 - 4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking.
The increased risk remained when smoking within 2 years prior to screening was considered (OR, 2.7; 95% CI, 1.5 - 5.1).
Still Try Natalizumab in Smokers
Commenting on the study for Medscape Medical News, Heinz Wiendl, MD, University of Münster, Germany, called this an "interesting observation," but he said the findings would not discourage him from using natalizumab in smokers.
"The prevalence of neutralizing antibodies to natalizumab is quite low — maybe affecting around 5% to 9% of patients. We can easily identify the patients who develop these antibodies because they don't respond to the drug."
He continued: "If a patient has neutralizing antibodies the drug effect will be zero. Natalizumab is a strong drug and there should be an obvious reduction of relapses and MRI lesions when a patient starts on it. If this does not happen, I think we can assume there are neutralizing antibodies present and then we would switch to a differemt treatment."
Dr Olsson has received nonrestricted MS research grants and/or compensations for lectures and advisory boards from Biogen Idec, Genzyme, Novartis, TEVA, and Merck. Dr Wiendl reports honoraria and consultation fees from Bayer HealthCare, Biogen Idec, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme BioVentures, and Teva Pharmaceutical Industries.
MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract PS5.4. Presented September 11, 2014.
Source: Medscape Multispeciality © 1994-2014 by WebMD LLC (06/10/14)
Approximately 110 multiple genetic variations were previously identified by genome-wide association studies (GWAS) to be associated with Multiple Sclerosis (MS). Now, that number has increased, with more than 159 genetic variants identified, thanks to new research presented by Philip De Jager, M.D., of Brigham and Women’s Hospital, Harvard Medical School and the International MS Genetics Consortium at the ACTRIMS-ECTRIMS conference in Boston.
The team led by Dr. De Jager performed the first comprehensive meta-analysis of existing MS-GWAS, spanning approximately 14,000 individuals with the disease. The researchers identified unknown genetic variants, and further studies involving 2,000 individuals led to confirmation of 48 new variants — for now.
With the confirmed identification of these new genetic variants, the team proposed to understand how the variants relate to MS susceptibility. Dr. De Jager noted, “the majority of the MS genes seemed to be related to immune function and expressed on immune cells.” The authors hypothesized the new variants could be related with alterations to brain function. To test their hypothesis, they examined the newly genetic variants in older, MS-free postmortem frontal lobes’ tissues. “[This is] exciting because there are at least some disease effects that may be related to alteration of gene expression inside the brain,” commented the author. Since the analysis was performed with the whole tissue, at the moment the authors can’t confirm the source cell type for these genes, as Dr De Jager noted, “Some of these changes may be driven by changes in the brain’s immune cells like changes in the microglia.”
Notably, Dr. De Jager highlighted how certain genome regions harbor multiple different variants that impact the risk for MS. Hence, to develop reliable predictive tests for MS, it is crucial to study each of these variants and fully understand their functional impact on MS.
The current study explains less than half of the heritability of MS, so Dr. De Jagers’ team and the International MS Genetics Consortium are committed to identify more genetic variants for MS susceptibility and to study it thoroughly.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (03/10/14)
Like conducting an errant orchestra to play together, researchers are guiding processes that go awry in multiple sclerosis to repair themselves.
The conductor walks to the stand and takes his place in front of the orchestra. He raises his baton and, with a dramatic flourish, one hundred individuals come to life. From nowhere, the stillness becomes a beautiful harmony as each member takes their part in a complex symphony.
Consider the workings and structure of the human brain – our most complicated organ – in terms of this orchestra. When it works, it is capable of something more remarkable than the greatest musical compositions in human history, but when it is affected by a condition such as multiple sclerosis (MS), "the brain's tightly orchestrated biological functions become discordant – the conductor begins to fail at their job and several instruments go out of tune," said Professor Robin Franklin, Head of Translational Science at the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute and Director of the MS Society Cambridge Centre for Myelin Repair.
His research team and those led by other Stem Cell Institute researchers Drs Thóra Káradóttir, Mark Kotter and Stefano Pluchino are each looking at a different aspect of this errant orchestra. They hope that their collective knowledge will one day help 're-tune' the brains of MS patients to self-repair.
In its simplest terms, MS is a disease in which the immune system turns on itself, destroying the oligodendrocytes that make a protective sheath called myelin, which encases nerve fibres. This halts the transmission of neural messages, and eventually leads to nerve fibre damage, resulting in a progressive loss of movement, speech and vision for the 100,000 people in the UK who have MS. However, the complexities of treating the disease go beyond simply stopping the destruction of myelin, said Franklin: "The myelin damage causes a build-up of debris, which needs removing, and the environment surrounding the cells needs to be conducive to regenerating the sheath. When we think about repairing the damage, we need to be considering several different biological phenomena at the same time."
Although there are drugs available for modifying the early stages of MS – including alemtuzumab (Lemtrada), developed in Cambridge – there are no treatments that regenerate the damaged tissue. Moreover, although the disease evolves over decades, with periods of remission followed by relapses, there is no treatment once patients have reached the progressive stage (estimated to be about 50% of current patients).
Oligodendrocytes – the master manufacturers of myelin – are formed by a type of stem cell in the brain called oligodendrocyte progenitor cells (OPCs), and are responsible for re-wrapping, or remyelinating, the bare axons with myelin in response to injuries or diseases. But this regenerative ability decreases with age and MS. "As the disease progresses, the need for intervention that galvanises the natural healing process becomes ever more important," explained Franklin. "Working with colleagues at the Harvard Stem Cell Institute, we've shown that the effects of age on remyelination are reversible, which gives us some confidence that we can use the brain's own OPCs for myelin regeneration."
However, to understand how to stimulate the brain's own repair mechanisms first requires an understanding of how the brain detects injury and initiates repair.
Thóra Káradóttir believes that one way the brain 'senses' problems are afoot is through the drop in how fast neural messages are passed across the brain. "The difference in speed between an intact neuron and a damaged one can be like comparing the speed of a cheetah to a tortoise," she said. "I'm eavesdropping on the information superhighway by attaching electrodes to neurons and OPCs." Her findings show that damaged fibres release a molecule called glutamate. "It's their 'cry for help' to OPCs. If it doesn't happen, or if the OPCs don't 'hear', then repair is reduced." She is working with Numedicus, a company that specialises in developing secondary uses for existing drugs, to test drugs that she hopes will be able to amplify this signal and increase the repair process.
Meanwhile, Robin Franklin's team has shown that it's possible to kick-start OPCs, driving the formation of oligodendrocytes and sheath formation, using a drug that targets retinoid X receptor-gamma, a molecule found within OPCs. The results are positive and clinical trials will shortly commence in collaboration with Dr Alasdair Coles from the Department of Clinical Neurosciences and the MRC Centre for Regenerative Medicine at the University of Edinburgh.
What's interesting about the rejuvenation of remyelination is that the treatment primarily affected inflammation in demyelinating lesions, and specifically the recruitment of cells called macrophages. These are the body's 'big eaters' – their role is to search out and gobble up rubbish. "We have identified myelin debris as a potent inhibitor of stem cells. Learning how it is being sensed by stem cells enabled us to overcome this inhibition by using drugs such as ibudilast. A clinical trial to test these effects is currently undergoing preparation," explained Mark Kotter. Franklin and Kotter's work is representative of an interesting turn in MS research within the field. Increasingly, investigators are looking at how the environment around the damage can be improved to help natural remyelination. "It's a curious paradox," said Franklin. "MS is caused by the immune system but components of the immune system are also key to its recovery."
Stefano Pluchino's team, for instance, has shown that injecting brain stem cells into mice with MS works in a surprising way. Instead of making new oligodendrocytes (or other brain cells), the cells seem to work by re-setting the damaging immune response, creating better conditions for the brain's own stem cells to replace or restore what has been damaged. He is now developing more-efficient stem cells and new drugs, including nanomedicines, to foster the healing of the damaged brain.
Given the complex landscape of abnormal activities happening in the MS brain, will combination therapies be the way forward? "Certainly," said Franklin. "Over the next ten years we will see an increased understanding of the fundamental biology in MS, we will identify more targets which may yield effective drugs and we'll have more-refined strategies for running clinical trials. What makes Cambridge rare is the spectrum of skills here – from understanding the fundamental biology of myelin repair through to clinical trials."
Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (03/10/14)
Patient groups often shout loudly for access to drugs but are quieter about their links to industry. Sophie Arie and Chris Mahony ask whether this is acceptable given increasing demands for transparency elsewhere in medicine,
The recent decision that the multiple sclerosis drug nabiximols should be available on the NHS in Wales was met by MS charities as a small triumph for patients. Access to the drug, a cannabinoid spray that eases spasticity, had previously been denied because of its cost.
“As a charity we have campaigned over a long period for Sativex [nabiximols] to be widely available because of the significant impact that MS spasticity can have on daily activities,” Amy Bowen, director of service development at the Multiple Sclerosis Trust, told the BBC.1
She expressed hope that the recommendation would lead to the drug being more easily accessible in the rest of the UK.
The MS Trust failed, however, to mention either in media interviews or in lobbying documents, that it receives funding from the German drug giant Bayer, which markets the drug in the UK. The company donated £5000 (€6400; $8200) to the MS Trust in 2013 and 2012.2 3
On its website, the charity provides information about its corporate funding only in its annual review, and even this is not prominently displayed. Corporate funding is listed as a lump sum of £54,121 towards the back of the annual review, without naming individual companies or specifying how the funds were used. There is one reference within further tables of figures to a restricted grant from Sanofi.4
The Association of the British Pharmaceutical Industry requires drug companies to disclose all the details of their relations with patient groups and charities systematically and prominently on their websites. These show that, in addition to the £5000 from Bayer, the MS Trust has received significant sums in recent years from several other producers of MS drugs, including £15 000 from Genzyme, a Sanofi company which makes teriflunomide and over £50,000 from Biogen Idec, which makes interferon beta 1a, fampridine, and dimethyl fumarate and has several more MS treatments in development.5
The MS Trust did not respond when asked whether greater transparency would be better, but it said in a statement that the charity’s independence and integrity was protected by its policy on working with the drug industry, which is on its website.6
“At the MS Trust we believe that if a drug has been assessed as safe and effective and given a licence, we should do our utmost to ensure it is accessible to all who might benefit. We do this for all licensed MS drugs, regardless of the manufacturer,” the statement said.
In June this year, the head of the MS Society, Michelle Mitchell, wrote a letter in the Daily Telegraph, co-signed by several MS experts,7 criticising the National Institute for Health and Care Excellence (NICE) for blocking access to the “life-changing” drugs nabiximols and fampridine even though “they are licensed and proven to be effective at helping people walk more easily and control painful muscle spasms.” Yet the letter did not mention that the MS Society had received money from the companies who make and market those drugs.
MS Society and drug company funding
The MS Society received over £21,000 from Biogen Idec, £46,000 from Genzyme, and £5000 from Bayer in 2013. The charity names its corporate donors on the “corporate supporters” page of its website,8 but to find the sums involved you have to look at the last element of the annual accounts on page 50 of its 54 page annual review.9
“We know this is a sensitive issue and that we have to draw the balance between receiving money that enables us to achieve our charitable aims and ensuring that we maintain our independence,” said Nick Rijke, executive director of policy and research at the MS Society. “We’re very careful and are confident we have the balance right. We keep the amounts low and we publish them precisely to ensure that there is no risk of being compromised.
The society’s policy on working with drug companies states that no more than 5% of its income in any one year can come from these sources and, the charity says, in 2013 0.6% of its income came from them.10
The case of the MS charities is only a recent example of what could be perceived as an almost universal conflict of interest for patient groups. Nearly all such groups receive funding from drug companies and most are, by definition, the greatest champions of the products those companies sell. But the amount of information, and the prominence it is given on charities’ websites, varies enormously. Some charities have clear and comprehensive information about funding on the primary pages of their websites. Many provide only partial information, often recorded in areas of their annual reports which may be hard to find.
So does it matter if charities fail to mention their corporate donors when campaigning in favour of the drugs they make?
Questions over independence
Drug companies are a key source of funding for many patient groups, and the companies say that their financial support for charities is a logical “partnership” between those with a common interest in improving treatment and care for patients. Most charities campaign for access to newly licensed drugs for their patients and would do so with or without corporate funding, on the basis that their patients deserve to benefit from all licensed drugs for their condition. Most consider the issue to be resolved by policies on working with industry that include a limit on the proportion of total income to be received from corporate donors and avoiding donations from only one company.
Yet, there is growing concern that charities, like any other sector, should be more transparent about their funding given that they are widely perceived by patients, the public, and policy makers to be independent.
“Any time any organisation takes money from anybody for any purpose there is potential for a conflict of interest,” says Jeremy Taylor, chief executive of National Voices, the national coalition of health and social care charities in England.
But when “a charity advocating for groups of patients takes money from a pharmaceutical company,” the case is even more compelling, he says. “There is the risk of allowing your charitable objectives to be distorted to serve the interests of commercial organisations or simply being seen as serving the commercial need of the other organisations.”
Patient groups have gained influence in recent years as the internet has allowed them to reach larger numbers of patients. Many are now run by professionals with qualifications and careers in the charity sector rather than patients and, as government has become more keen to work with stakeholders, their potential to influence policy has grown.
Little research has been done into how health charities are funded and how transparent they are about that funding.
“In recent years we have seen the rise of patient and public engagement,” says Angela Coulter, director of the Health Services Research Unit at the University of Oxford. “They [patient groups and health charities] are sitting round policy making tables in many countries, and if they are not open about the fact they receive money from drug companies then how can you evaluate the quality of their advice?”
Position of influence
In the case of a regulatory body such as NICE, the experts drawing up guidelines are aware of the financial ties of patient representatives to the companies whose drugs are being assessed. Patient experts giving advice to advisory committees declare any conflicts of interests at the committee meetings, but their input is considered to be unacceptable only if they have personally received a payment that relates to a drug or treatment under review. If they are an employee of a patient organisation that receives funds from a drug company, their advice may still be taken into account.
“Being aware of any financial relationship with the sponsor provides context for the advisory committee’s consideration of the information and views being put forward by the expert” NICE’s chief executive Andrew Dillon told The BMJ.
“Almost all patient groups have some sort of funding from the companies involved in that disease, so to refuse input to anyone taking this funding would preclude them all,” says Ken Paterson a former head of the Scottish Medicines Consortium, the Scottish equivalent of NICE. Ten charities (including the MS Society) advised the SMC to recommend drugs made by their donors for NHS use recently, according to a report by the Sunday Herald newspaper. The charities did not recognise any conflict of interest, but one accepted that it needed to reduce the proportion of its funding that came from corporate donors.11
“We at the SMC are very aware of their connections [to industry] and factor that in when listening to what they have to say,” Paterson explains. “But the wider public believe them to be totally independent,” he says. “Politicians and wider society need to be aware that they [patient groups] may not be entirely unbiased when they protest at decision over drug funding. There may be some levels of subliminal influence. This is why any money changing hands should be transparent.”
Support of patient groups is not the only way that drug companies have the potential to influence people. Companies often fund conferences for doctors and publications for patients produced by patient groups. Patient representatives are also often paid to deliver lectures at educational meetings or make presentations at conferences. And charities frequently use their large databases of patient members, to canvass opinion or gather data on patient experiences and wishes.
There have only been a few reported cases of charities’ activities being clearly compromised by their relations with a drug company and there is no reason to suspect that this is widespread. But the cases that have come to light have fuelled concern over a need for a culture of full disclosure throughout the sector, which could help patient groups avoid unintentionally giving credibility and sincerity to a drug company’s agenda.
“‘Marketing’ in research’s clothing can pass charities by without them realising,” says Paul Wicks, vice-president, innovation, at PatientsLikeMe a company set up in 2004 to help patients access and share data.
Sara Rigarre, a patient and campaigner for patient participation in healthcare in Sweden, thought this was the case when she noticed that a survey sent from the charity she belonged to, the Swedish Parkinson’s Disease Association, seemed to be worded to encourage patients to ask their doctor for Duodopa (carbidopa-levodopa), made by Australian drug company AbbVie. The survey was funded by AbbVie but sent to members of the charity with no mention of a corporate sponsor. It was presented as research into the variations in care and needs around the country but omitted to ask respondents to state where they lived. The Swedish pharmaceutical industry trade body, LIF, has since referred the case to its information examiner (IGM), a qualified doctor who examines information and marketing practices in the industry, who concluded that the survey constituted “marketing of a prescription drug to the public” and fined the company Kr140 000 (£12 000; €15 000; $19 000) for breaching industry regulations.13
The charity, however, has not recognised the IGM’s finding and insists that the survey was intended to find out more about how patients are referred in different parts of the country. Its secretary general, Inger Lundgren, who sent out the survey from her personal email, told The BMJ she forgot to mention the sponsorship and accepts responsibility for that. The survey did not need to collect patients’ geographical locations, she explained, because the charity already has that information stored on its database of members. The charity has decided not to use the data from the survey. However, it continues to take funding from AbbVie, and other drug companies sponsor activities such as educational programmes for doctors and nurses and awareness campaigns for politicians and the general public, she said. She did not say whether this sponsorship is made clear to those targeted but did state that the charity follows the ethical guidelines and recommendations of the Swedish industry trade body LIF and publishes full details of donations it receives on the LIF website.
“There have been implications for the drug company but nothing has happened to the charity,” Rigarre told The BMJ.
Opinions are divided among health charities between those who are adamant their donors wield no influence and those who believe that charities need to be more transparent about their relationships with industry to preserve their reputations. Some, such as the mental health charity MIND, go so far as refusing any support from industry.
MIND’s fundraising director, Cathleen Miles, says: “Only by remaining totally independent of pharmaceutical companies can we retain that voice of independence and provide objective information to anyone who comes to us for support in making decisions about what treatment is best for them.”
Others believe that clearer guidelines are needed for all health charities to adhere to. But getting such a broad group of charities, which work to different national regulations from country to country, to agree on common rules on transparency could be difficult. There is also concern that federations of patient groups—both national and international—receive funding from industry that is not clearly labelled in individual groups’ accounts because it is channelled through the umbrella group.
Under regulations established by the Charity Commission, charities in the UK are not legally required to name all their donors. A spokesperson for the Charity Commisssion explained that “the legal requirements set a standard that charities must follow but they can, and many do, go over and above the legal expectations. We encourage charities to be transparent. We expect that trustees are diligent in this duty to protect the independence and the reputation of their charity.”
Drug companies in the UK generally adhere to the ABPI’s code of practice,14 which is overseen by the Prescription Medicines Code of Practice Authority (PMCPA). When a company is found to be at fault, it might be required to issue a corrective statement or publish an advertisement. Obviously the authority cannot discipline a patient group.
Taylor says National Voices has recently begun working with the ABPI to produce a joint guide to explain the code and set down some principles for growing the relationship between that industry and partners. The guide could cover the importance of governance, protecting independence, transparency, income diversity, and what to think about when entering an arrangement with a drug company.
“We are hoping it can be an equivalent to the joint ABPI-Department of Health guidance on collaboration between pharma and NHS organisations ,” he says.15 “It is helpful for us to be crystal clear about how much money an organisation receives from whom to do what, but that is not enough. The process of governance and internal scrutiny and discussion are as important. The code itself seems to involve a lot of red tape for the company with various forms—none of which seem to get to the heart of ethics and governance of relationships.”
At an international level, the International Alliance of Patients’ Organisations (IAPO) acknowledges there is a problem.
“We aspire to be as transparent as possible. Different people have a different understanding of what that means,” Jo Groves, the organisation’s chief executive says. “The pharmaceutical industry have got there through a process and patient groups need to do that too.”
But IAPO can only advise its members on best practice; it cannot force them to comply or impose any sanctions if they don’t.
1↵ Wales NHS to offer MS cannabis drug Sativex. BBC News 2014 Aug 15. www.bbc.co.uk/news/uk-wales-28810407
2↵ Bayer. Patient group donations 2013. www.bayer.co.uk/scripts/pages/en/commitment_and_sustainability/our_projects/patient_group_donations/patient_group_donations_2013/index.php.
3↵ Bayer. Patient group donations 2012. www.bayer.co.uk/scripts/pages/en/commitment_and_sustainability/our_projects/patient_group_donations/patient_group_donations_2012/index.php.
4↵ MS Trust. Trustees’ report and financial statements for the year ended 31 July 2013. www.mstrust.org.uk/downloads/ms-trust-annual-review-13.pdf.
5↵ Biogen Idec. Patient organisation support. www.biogenidec.co.uk/patient_organisation_support.aspx?ID=12875.
6↵ MS Trust. Policy on working with pharmaceutical, biotech, medical equipment and research organisations. www.mstrust.org.uk/about/mission.jsp.
7↵ Mitchell M, Hobart J, Weller B, Notcutt W, Kapoor R, Craner M, et al. Nice and MS medicine. Telegraph 2014 Jun 9. www.telegraph.co.uk/comment/letters/10884997/D-Day-on-two-wheels.html.
8↵ MS Society. Our corporate supporters. www.mssociety.org.uk/get-involved/corporate-partnerships/our-corporate-supporters.
9↵ MS Society. Annual report and accounts 2013. www.mssociety.org.uk/sites/default/files/Documents/Governance%20docs/MSSociety-annual-report-and-accounts-2013_0.pdf.
10↵ MS Society. Vision and mission. www.mssociety.org.uk/about-us/about-the-ms-society/mission-and-values.
11↵ Patient groups taking cash from drug firms. Herald2014 Jun 15. www.heraldscotland.com/news/health/patient-groups-taking-cash-from-drug-firms.24489434.
12 ↵ Patients-included Pharma Disingenuous, and busted. http://e-patients.net/archives/2014/01/patients-included-pharma-disingenuous-and-busted.html.
13↵ Pharmaceutical Industry Information Examiner. Decisions on acceptance case No R11 /13, 19 December 2013. www.lif.se/default.aspx?id=98993&ptid=19178.
14↵ Association of the British Pharmaceutical Industry. Code of practice. 2014www.abpi.org.uk/our-work/library/guidelines/Pages/The-Code-of-Practice-for-the-Pharmaceutical-Industry-2014.aspx.
15↵ Department of Health, NHS Confederation. ABPI. Joint working: a quick start reference guide for NHS and pharmaceutical industry partners. 2012. www.abpi.org.uk/our-work/library/guidelines/Pages/joint-working-handbook.aspx.
Source: BMJ 2014;349:g5892 © The British Medical Journal 2014 (03/10/14)
Environmental exposures and the risk of multiple sclerosis Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk.
The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis.
Methods: A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood.
Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated.
Results: Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR?=?1.79, 95% CI: 1.12-2.87, p?=?0.016).
The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR?=?0.56, 95% CI: 0.40-0.78, p?=?0.001). More patients than controls reported smoking and fewer patients reported snuff use.
Conclusions: In this Norwegian MS case control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk.
Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard.
Author: Marte GustavsenChristian PageStine MoenAnja BjÃ¸lgerudPÃ¥l Berg-HansenGro NygaardLeiv SandvikBenedicte LieElisabeth CeliusHanne F Harbo
Credits/Source: BMC Neurology 2014, 14:196
Source: 7thSpace Interactive © 2014 7thSpace Interactive (03/10/14)
Treatment for multiple sclerosis (MS) patients could be revolutionised in ground-breaking trials planned by a Cambridge scientist.
Dr Su Metcalfe, a University of Cambridge senior research associate based at Addenbrooke’s, has won a £150,000 award which will enable her team to proceed to pre-clinical trials in Nanotechnology.
The award is one of only five given out this year worldwide from major pharmaceutical company, Merck Serono, and the first to a UK scientist.
The technology developed for treatment of MS - an incurable autoimmune disease that attacks the central nervous system - by Dr Metcalfe uses tiny ‘smart’ nanoparticles that act as magic bullets to deliver powerful factors known to increase repair of damaged myelin. The key factor is “LIF”, a stem cell protein.
The money from the Merck-Serono’s “Grants for Multiple Sclerosis International” (GMSI) scheme will fund preclinical trials of Metcalfe’s nano-therapeutic device that taps into the body’s natural mechanisms for repair and avoids use of drugs.
“Nanotechnology is now recognised as a key platform for healthcare,” said Dr Metcalfe. “Our ‘smart’ technology allows us to target delivery of molecules able to repair myelin and also reduce inflammation.
“By using a nanoparticle platform where the safety in humans is already confirmed, a hugely important feature for rapid progress towards the clinic, we can now expect to move to clinical trials within three to five years.”
Multiple sclerosis commonly affects young adults and in the UK alone, more than 100,000 people have MS with 2,500 being diagnosed each year.
The disease causes damage to the nerve sheaths, or myelin, which normally insulate the electrical activity of nerve fibres in the brain and spinal cord.
Specific nerves become inflamed and lose function and this disrupts messages from the brain to parts of the body, resulting in early symptoms of MS, such as impaired vision.
The award will link a small team of experts including bioengineer Dr Tarek Fahmy of Yale University who prepares the smart nanoparticles, Professors David Baker and Gavin Giovannoni who lead preclinical and clinical trials in MS at Queen Mary’s University of London, and Dr Anna Williams who works on progressive MS at the University of Edinburgh.
This GMSI project exploits nanotechnology to harness the power of Leukaemia Inhibitory Factor (LIF), a potent stem cell cytokine able to both oppose inflammatory immunity and promote myelin repair - both highly relevant to treatment of MS.
Source: CambridgeNewsUK Copyright © 2014 Local World (02/10/14)
San Francisco Bay Area-based Glialogix, Inc., a biopharmaceutical company that specializes in developing novel treatments for multiple sclerosis (MS), announced yesterday that they have closed a Sponsored Research Agreement with Fast Forward, a non-profit organization that aims to accelerate MS treatment development. Glialogix will receive funding for one of their pipeline products for neuroprotection, GLX1112, which has shown efficacy in slowing disability progression and potentially repairing neuronal damage — one of the main priorities of the National Multiple Sclerosis Society (NMSS).
Fast Forward, founded by the NMSS, will be supporting Glialogix through cutting-edge pharmacokinetic testing, preclinical models and mechanistic research on GLX1112. According to Thad Reeder, Ph.D., the company’s CSO and lead researcher for the drug, it has already shown promising results in progressive forms of MS.
Glialogix CEO, Mark Moore, Ph.D., explained that there is a great need for effective treatments for progressive MS, as this type tends to cause the most disability and does not respond to treatments indicated for relapsing MS. At present, while there are several drugs being tested for treating progressive forms of MS, most patients are treated with RRMS therapies, as these are the only drugs approved by the FDA for treating progressive MS in the United States. In other countries, progressive MS patients often have no access to therapies, and are forced to cope with symptoms and disabilities on their own.
Dr. Moore concluded by stating that he looks forward to collaborating with Fast Forward on the development of a viable progressive MS therapy, and is confident this new agreement is the boost GLX1112 is waiting for.
Source: Multiple Sclerosis News today © Copyright 2014 BioNews Services (02/10/14)
A new study has found that people with multiple sclerosis may reduce perceived fatigue and increase mobility through a series of combined strength training and fitness exercises.
The research from the Miguel Hernández University of Elche, supervised by Professor Raúl Reina, aimed to analyze the effects of strength training on the fatigue that MS patients suffer. A total of 19 participants (5 men and 14 women) were split into two groups. Most took part in a 12-week training program, whilst others were included in a control group. The research was conducted in collaboration with the Neurology Department of Elche General Hospital.
A first phase of general fitness was followed by a personalized intervention program based on each patient’s maximum force. The scientists assessed the effects of training and found that the experiment group gained "a fair amount" of functionality while the control group remained stable.
One patient, who was diagnosed the illness in 2007, says she has noticed improvements in her daily routine: “I was used to a life with limitations and now I can pick up my son and go with him to the park on foot."
The training and data collection process took place on campus, both at the sports facilities and the university’s Sport Research Centre. Meanwhile, perceived fatigue was registered daily, weekly and monthly through specific questionnaires. Each patient’s muscle strength was assessed by isokinetic dynamometry and functional tests.
The study also includes an analysis of motivational aspects and an interview on the perception of the effects of sport. This part is especially interesting as it shows an improvement of the participants’ quality of life, although the University will continue working with the MS patients to see the long term effects.
Source: Science 2.0 © 2014 ION Publications LLC (01/10/14)