Types of MS
Doctor offers new model for MS(22/04/15)
Multiple sclerosis may be more of a continuum than three distinct types of disease, and a new model attempts to capture that nuance reports MedPage Today.
The "topographical" model could provide a new way of looking at disease course, Stephen Krieger, MD, of Mount Sinai in New York City, claims.
"There's thought that MS is more of a continuum," Dr Krieger said.
"We should not think in terms of those categories, but we should think of it as a mixture of relapses and progression and how specifically they mix together."
Currently, MS is classified as being in one of three groups: relapsing-remitting, secondary progressive, and primary progressive. But Dr Krieger, a protege of Fred Lublin, MD, who created the three-category model, said the system doesn't accurately capture the range of disease.
"There's real diagnostic uncertainty," Dr Krieger told MedPage Today.
"It takes us years to figure out which category someone is in. A lot of progressive patients stay like they are for years. You're not always sure which category someone fits into, nor do those categories tell us how someone's disease is going to progress."
For his new model, which Dr Krieger calls a "true admixture of inflammation and progression" that describes the clinical course of MS in a more biologically informed way, he incorporated five factors: topographical distribution of lesions and the relapses they cause, relapse frequency, relapse severity, relapse recovery, and progression rate.
It essentially suggests the clinical manifestations of MS are a consequence of the interplay between inflammatory lesions - the relapsing part of the disease - and generalised loss of functional capacity, as seen in the progressive part of the disease.
To illustrate the concept, Dr Krieger came up with a peak-and-pool model. There's a shallow end that drops off into a deep end, where the shallow end represents the spinal cord and optic nerve, the mid-section represents the posterior fossa, and the cerebral hemispheres constitute the deep end.
At the same time, brain lesions appear as topographic peaks that rise from the floor of the pool. The water's surface is the clinical threshold, and when the central nervous system lesions' peaks cross it, a relapse or flare occurs.
Disease progression is represented by a falling water level, which essentially represents a loss of neurons and declining brain volume, something that can be measured on MRI, Dr Krieger said. The model also implies progression could take the form of relapses as these peaks start to rise above the water, Krieger said.
The very visual disease representation was the result of a pro bono collaboration with Harrison and Star, a healthcare communications company.
When asked what his mentor Lublin thought about the challenge to his work, Dr Krieger said he's been "incredibly supportive."
"He thinks it's really interesting, and he wants to see me make it into an applied model for prediction," Dr Krieger said.
"We'll try to operationalise it over the coming couple of years and figure out how to do precise metrics. We'll figure out how to take a clinical trial database and apply that and figure out things we otherwise couldn't."
Source: MedPage Today © 2015 MedPage Today, LLC (22/04/15)
A Canadian study has found no link between the delayed onset of secondary progressive multiple sclerosis and treatment with beta-interferons.
In the study, Beta-interferon Exposure And Onset Of Secondary Progressive Multiple Sclerosis, published in the European Journal Of Neurology, the researchers set out to examine the association between beta-interferons and the onset of secondary progressive MS in patients with relapsing-remitting MS.
Beta-interferons are the most widely prescribed drugs for patients with MS, but whether or not treatment with beta-interferons can delay the onset of secondary progressive MS onset has always been unclear.
The scientists took 794 patients with relapsing-remitting MS and compared them with a healthy control group. The outcome was gauged from the start of treatment with beta-interferons to confirmation of the onset of secondary-progressive MS.
In the published results, the researchers reported: “The median follow-up for the beta-interferon-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3 years, and the proportions of patients reaching secondary progressive MS were 9.2 per cent, 11.8 per cent and 32.9 per cent, respectively. After adjustment for confounders, beta-interferon exposure was not associated with the risk of reaching secondary progressive MS when either the contemporary or the historical untreated cohorts were considered.”
The study concluded that, amongst patients with relapsing-remitting MS, use of beta-interferons was not associated with a delayed onset of secondary progressive MS.
Source: Eur J Neurol. 2015 Apr 6. doi: 10.1111/ene.12698. & PMID: 25846809 (13/04/15)
MedDay, a biotechnology company focused on the treatment of nervous system disorders, has provided further information about the design of its pivotal clinical trial (MS-SPI) to investigate the efficacy and safety of MD1003 in the treatment of primary and secondary progressive multiple sclerosis.
MS-SPI is a randomised, double-blind, multicenter, placebo-controlled (2:1) trial of MD1003, 300 mg/day, in patients with progressive MS who have demonstrated progression in the two years prior to enrolment.
A total of 154 patients with a baseline EDSS (Expanded Disability Status Scale) score of between 4.5 and 7 were enrolled from 16 MS reference centres across France. Treatment duration was one year.
The primary endpoint for the study was defined as the proportion of patients who improved at nine months (M9), with confirmation at 12 months (M12). Improvement was defined as either a decrease in EDSS or an improvement in TW25 (a timed 25-foot walk) of at least 20 per cent. The comparison for each outcome was the best EDSS and TW25 scores obtained at the screening and randomisation visits.
The main secondary endpoints evaluate the effect of MD1003 in stabilising or slowing down the rate of progression. These endpoints include the change in EDSS between M0 and M12, the proportion of patients with progression at M9 confirmed at M12 and the change in TW25.
Frédéric Sedel, MD, Chief Executive Officer of MedDay, said: “This trial was particularly ambitious. This is the first time a study in progressive MS has evaluated the proportion of patients improved at M9 and confirmed at M12.”
MD1003 is an investigational medicine thought to have both pro-myelinotic effects and to enhance the supply of energy for nerve impulse transmission. MD1003 is an active pharmaceutical ingredient administered at a dose of 300 mg /day.
Source: Business Wire © 2015 Business Wire (07/04/15)
MS drug 'may already be out there'(01/04/15)
Depression and heart-disease drugs are to be tested in a trial to find treatments for multiple sclerosis from existing medicines, reports the BBC.
There are currently no treatments in the secondary progressive stage of the condition and doctors hope the necessary drugs are already out there, but have never been tested on MS.
More than 400 people will take part in the trial at University College London and the University of Edinburgh.
Walking, balance, speech, and vision can all become impaired in the later stages of the disease.
There are treatments in the early phases of MS to prevent the frequency or severity of relapses but there is nothing once the symptoms progresses.
The MS-Smart trial will test the safety and effectiveness of three drugs used in other conditions:
Amiloride - licensed to treat heart disease
Fluoxetine - used in depression
Riluzole - for Motor Neurone Disease
They were identified after a review of previously published research into drugs that appear to protect the nerves from damage.
Researchers believe these treatments could slow down the progress of MS and the trial will be the first time they have been tested on such a large number of patients.
Dr Jeremy Chataway, a consultant neurologist and lead researcher on the trial based at UCL, said there was "huge unmet need".
He told the BBC: "It may be the case that we have already invented the drugs we need to treat MS.
"In the same way that aspirin was developed as a painkiller and is now used to treat stroke patients, we may well have invented the drugs that we need, we just don't know that they work in different situations than what they were invented for.
"One of the advantages is they are very cheap, and we know a great deal about them as they have been tested on millions of people around the world in their original indication.
"So it's much more of a running start when we use drugs that we aim to repurpose."
Prof Siddharthan Chandran, a clinical neurologist at the University of Edinburgh, said: "This is a landmark study that seeks to not only test three potential treatments, but also showcase a new approach to clinical trials for progressive neurological conditions."
MS-Smart is a phase two trial, making sure the drugs are safe and demonstrate sufficient effectiveness before they are tested in a larger number of people.
If successful, it could lead to new ways of using the existing drugs to modify the way the disease develops.
Source: BBC News © British Broadcasting Corporation 2015 (01/04/15)
A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.
Source: The Lancet Neurology Copyright © 2015 Elsevier Limited (12/01/15)
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)
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)