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Pathological mechanisms in progressive multiple sclerosis(12/01/15)

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.

Full Text 

Source: The Lancet Neurology Copyright © 2015 Elsevier Limited (12/01/15)

Clinical focus in MS: Novel approaches to progressive disease(20/11/14)

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.

Other Approaches

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."

About CDRD
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)

No easy answers for managing secondary progressive MS(04/06/14)

For multiple sclerosis patients who have transitioned to secondary progressive disease despite use of disease-modifying treatments (DMTs), their management must still rely on physicians' instincts and the patients' wishes, clinicians here agreed.

Evidence-based medicine has almost nothing to say about whether DMTs continue to offer a benefit to patients who have moved from relapsing-remitting to secondary progressive MS (SPMS) because the existing trials were badly flawed, said Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center here.

Taking the "stop DMTs" side in a point-counterpoint debate at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Stüve argued that the lack of demonstrable benefit and the adverse effects of DMTs militates against continuing them.

But his opposite number on the debate platform -- Michael Carrithers, MD, PhD, of the University of Wisconsin in Madison -- as well as audience members countered that there are some biological reasons to believe that DMTs could be beneficial, even if the hard trial evidence is lacking.

And, Stüve admitted (to the audience's murmured approval), stopping DMTs "is a difficult decision because patients feel like you're abandoning them."

Several clinicians in the packed meeting room agreed that, purely from a patient engagement perspective, it's necessary to give them some kind of treatment. For example, one said he routinely adds methotrexate.

"You have to do something," another said. If the clinician has nothing to offer, added a third, patients "think you're giving up." But nobody advocated mitoxantrone -- the only FDA-approved treatment for SPMS -- the evidence for which has been criticized.

In the end, Stüve lost an electronically recorded vote by a landslide -- only about 10 of the nearly 100 attendees indicated they would stop DMTs in a hypothetical patient with progressing disability, no relapses in 20 years, and no significant adverse effects from his long-standing DMT.

The only current evidence backing DMTs such as interferon-beta for SPMS comes from three trials conducted in the 1990s and early 2000s with interferon-beta.

For all three of them -- one conducted in Europe and two in the U.S.  -- the topline results indicated a benefit. But Stüve called attention to these trials' inclusion criteria and the resulting sample characteristics. Patients experiencing relapses within the past year were accepted, mean disease durations were under 10 years, and time since SPMS diagnosis was just 2 years.

All of which, he suggested, indicates that many of the patients in these trials probably did not have true SPMS. One of the trials actually reported a reduction in relapse rates as one of the favorable outcomes -- even though SPMS patients aren't supposed to be having relapses.

As a result, the overall benefits seen in the trial probably were concentrated in those who still had substantial inflammatory activity not consistent with SPMS, Stüve suggested.

But Carrithers and some audience members responded that inflammation does not always die down completely when a patient transitions to SPMS.

Carrithers pointed to a small study published in 2005 in which SPMS patients who had interferon-beta withdrawn showed accelerated disability progression and, importantly, new MRI lesions.

On the other hand, he noted that many of the patients in the earlier "successful" trials of interferon-beta in SPMS had not received the drug previously. Hence, the results can't be generalized to those currently on such medications, for whom the question is whether to withdraw them.

One audience member insisted that inflammation remains a feature in SPMS but is "locked behind the blood-brain barrier" where it is less apparent in standard tests. She argued that it is vital to keep treating patients with DMTs in order to keep these smoldering inflammatory processes in check.

During the electronic vote, most of the audience indicated that they would like to switch a hypothetical patient who had been on interferon-beta to another type of DMT. About two-thirds of those voters wanted specifically to try natalizumab (Tysabri), a very potent drug for relapsing-remitting MS but with unclear benefits in progressive forms.

Debate moderator Dennis Bourdette, MD, of Oregon Health and Science University in Portland, tried to canvas the audience for an explanation of that choice. He never got one, but some in the room complained that health system and insurer policies would prevent it anyway. Natalizumab is relatively expensive and since it is not approved for SPMS, most payers won't cover it.

A phase III trial of natalizumab in SPMS is now underway -- with enrollment criteria more to Stüve's liking -- and both he and Carrithers indicated that its results would go at least part way toward settling the now-unanswered question of DMTs for the condition.

Carrithers said that a trial specifically aimed at withdrawal of DMTs in SPMS patients is needed as well. Bourdette pointed out that just such a trial was reported last month at the American Academy of Neurology's annual meeting -- it found that 90% of those stopping DMTs remained stable after a median of 3 years off treatment, but a few showed renewed MRI lesion activity.

Until the evidence is clearer, though, panelists and audience members seemed to agree that physicians will have to base their clinical decision-making on their own experience and individual patients' characteristics and wishes.

Stüve and Carrithers both said MRI scans are vital. Patients should continue to be treated as long as they still show lesion activity, they agreed.

The debate was organized with support from the Department of Veterans Affairs, with which Bourdette, Carrithers, and Stüve are affiliated.

Carrithers reported research funding from Biogen Idec. Bourdette and Stüve declared they had no relevant financial interests.

Source: MedPage Today © 2014 MedPage Today, LLC (04/06/14)

Researchers lead committee to define the clinical course of multiple sclerosis(29/05/14)

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment for clinical trials, and treatment decision-making. Researchers at Icahn School of Medicine at Mount Sinai, part of the International Committee on Clinical Trials of MS, collaborated to re-examine the standardized MS clinical course descriptions originally published in 1996 and recommend refined phenotype descriptions that include improved clinical descriptive terminology, MRI and other imaging techniques, analysis of fluid biomarkers and neurophysiology. The proposed 2013 revisions will appear in the May 28, 2014, online issue of Neurology, the medical journal of the American Academy of Neurology.

"Our goal for modifying the 1996 definitions is to better characterize patients with MS and provide a framework for both clinical research and ongoing clinical care," says Fred D. Lublin, MD, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at The Icahn School of Medicine at Mount Sinai, and the article's lead author. "These revisions should make communication with patients and among physicians clearer and should also enhance the design, recruitment and conduct of clinical trials, which will further help us understand the disease."

Multiple sclerosis is a potentially debilitating disease in which the body's immune system eats away at the protective sheath (myelin) that covers the nerves. Damage to myelin causes interference in the communication between the brain, spinal cord and other areas of the body and may result in deterioration of the nerves themselves. MS can be difficult to diagnose because symptoms often come and go, symptoms vary widely and there is no cure. However, treatments may help reduce MS attacks, manage symptoms and lessen disease progression.

The 1996 clinical course descriptions provided standardized definitions for four MS clinical courses, which included: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). While these descriptions were believed to represent the spectrum of clinical subtypes of MS, it was recognized that the descriptions might change over time as a result of advanced imaging techniques and biological markers.

In reconsidering the prior MS disease course descriptors, the advisory group recommends that the core MS phenotype descriptions of relapsing and progressive disease be retained, with some modifications. The consensus is that disease activity detected by clinical relapses or imaging (gadolinium-enhancing lesions or new or unequivocally enlarging T2 lesions) as well as progression of disability can be meaningful additional descriptors of either relapsing or progressing disease. Evidence of disease activity and clinical progression, which by current understanding reflects ongoing inflammatory or neurodegenerative disease, may impact prognosis, therapeutic decisions and clinical trial designs and outcomes.

To assess disease activity, the group recommends at least annual clinical assessment and brain imaging for relapsing MS. For progressive MS, annual clinical assessment is recommended, but there was no consensus on the optimal frequency of imaging. They suggest that progression be determined annually by history or objective measure of change. Thus, the existing course descriptions should be sub-categorized based on activity or progression. For example a patient with relapsing-remitting (RR) MS who had a new gadolinium-enhancing lesion on a current MRI would be considered to be RR-active. Conversely, "non-active" could be used the same way to indicate a patient with a relapsing course but no relapses or new MRI lesions during the assessment period. Inclusion of activity as a modifier of basic clinical course phenotype allows elimination of the progressive relapsing (PR) category because a PPMS patient who has an acute attack (thus fulfilling the prior criteria for PRMS) would be considered PP-active.

Another recommendation is that clinically isolated syndrome (CIS), which was not included in the initial MS clinical descriptors, but is now recognized as the first clinical presentation of a disease that shows characteristics of inflammatory demyelination that could be MS, be included in the spectrum of MS phenotypes. Prospective follow-up of most such patients should determine their subsequent disease phenotype. Radiologically isolated syndrome (RIS), where incidental imaging findings suggest inflammatory demyelination in the absence of signs or symptoms should not be considered a separate MS phenotype.

"Our understanding of multiple sclerosis has come a long way since the original phenotype classifications were standardized 18 years ago," says Dr. Lublin. "Future long-term longitudinal and cohort studies, imaging studies, prospective follow up and research is needed to better understand and define MS phenotypes, allowing us to continue to refine the framework for clinical research and care for the patients who turn to us for help."

Source: Medical Xpress © Medical Xpress 2011-2014 (29/05/14)