Magazine Article | June 1, 2016

Developing New Therapeutics For Progressive MS

Source: Life Science Leader

By Wayne Koberstein, Executive Editor, Life Science Leader magazine
Follow Me On Twitter @WayneKoberstein


The following KOLs participated in this virtual roundtable on new therapeutic approaches in development for MS.

Each of the members of our virtual-roundtable panel speak from multiple perspectives — treating patients, teaching students, conducting research, and even running clinical trials. Tackling the first question in the discussion, they deliver useful details about emerging treatments for progressive MS, including why major disease-modifying therapies may not enter the space for many years.

This is the concluding installment of our three-part series on new therapeutic mechanisms for neurodegenerative diseases. Here, as in the first two parts, we have brought together a “virtual roundtable” comparing the views of key scientific opinion leaders with some of the companies developing new therapeutics for progressive MS. (See Part One, “Aiming at Alzheimer’s,” March 2016, and Part Two, “Parsing Out Parkinson’s,” April 2016.)

First, it is important to understand MS comes in more than one form. Relapsing/remitting and progressive MS are the two primary disease types, with the latter dividing into the primary progressive and secondary progressive forms. Relapsing/remitting MS initially affects about 85 percent of patients, with the remainder suffering primary progressive MS; secondary progressive MS normally follows in refractory patients 20 to 30 years after initial diagnosis of relapsing disease. So the typical MS patient experiences periodic episodes of lost neural function for decades, then the episodes end and, instead, the condition gradually worsens until death. All the MS forms have this in common — the disease destroys myelin, the protective sheath around nerve channels, and what follows is incremental impairment of movement, cognition, and perception.

All but a few current drug therapies for MS treat the relapsing/remitting types, and almost all belong to the broad class of anti-inflammatories. Although the leading medicines are expensive, they do a good job of staving off disease symptoms and relapses for patients unless they develop progressive MS. Thus, the greatest unmet need and opportunity for innovation in this space is with progressive disease types. (See the sidebar, “Disputed Causes, United Cause.”)

In our virtual roundtable, we stitch together the separate inputs of participants into one comprehensive discussion by a panel of disease experts — KOLs and scientists who are leading some of the most advanced research in their field. This month, we tap the thoughts of three KOLs in the MS area. (See “KOL Panelists.”)

Separate cameos of selected companies suggest some new avenues for MOA (mechanism of action) and drug development in the MS space. As in the other parts of the series, our virtual panel discusses not only the scientific, regulatory, and other practical hurdles that lie before new approaches, but also the issues that will affect any candidates that ultimately survive the development gauntlet and enter medical practice. Those include the possible use of therapeutic agents with different MOAs in combinations, the methods and authority for configuring combinations, and the challenges of clinical trial design, postmarket regulation, payer pushback, and patient education.

What are the most promising therapeutic targets/mechanisms for progressive multiple sclerosis?

COETZEE: We’ve seen a lot of progress addressing inflammatory stages of MS, although there are still opportunities to develop more specific therapies that can bypass adverse events such as opportunistic infection. There’s high potential for developing therapeutics that target neuroprotection and the multiple mechanisms that appear to drive disease progression, including CNS-based innate immunity, mitochondrial failure, and signals within lesions that stall or stop oligodendrocyte precursor cells from maturing into fully functional oligodendrocytes capable of mediating remyelination.

There are likely multiple targets for stimulating endogenous myelin repair, both antagonists to “stop” signals and agonists for “go” signals. There’s also potential for developing stem-cell therapies; however this approach has some commercial challenges. Moreover, as more and more is understood about the gut microbiome, there’s potential for developing probiotics as immunomodulators.

The recent clinical findings with ocrelizumab, targeting B cells, are remarkable. The MS community has known for decades that B cells play a role in the disease, yet most therapeutic approaches either have targeted inflammatory cells of the immune system or are broadly active agents that limit the influx of many types of immune cells into the CNS. We expect more therapeutic progress to be made by directly targeting B cells and by understanding their role in the promotion and maintenance of disease progression.

FOX: We need to develop new approaches to treating progressive MS that are not anti-inflammatories. We must find a biomarker for progressive MS equivalent to the new lesions on MRI that we use in Phase 2 trials for relapsing MS. My colleagues and I are helping to lead an NIH-funded study comparing five different imaging metrics head-to-head in a 255-patient Phase 2 trial. One of the goals is to test the drug, and if it works, that would be wonderful. But the more important contribution of the trial will be comparing the imaging metrics and selecting the best biomarker for progressive MS Phase 2 trials.

Research scientists are doing whatever they can to understand the basic biology, develop animal models and high throughput screening assays, evaluate therapeutic approaches, create Phase 2 trial models to help test new therapies efficiently and effectively, and identify better clinical outcome metrics of disability for use in Phase 3 trials. Still, I believe the problem is not that we can’t show a therapy is effective — it is that we don’t have a therapy. We don’t have a molecule.

GREEN: The most promising area for new therapies, to my mind, relates to myelin regeneration and repair. There is an endogenous, preexisting pool of stem cells in the brain that are precursors for the oligodendrocytes damaged by the disease. It has been a mystery for several decades, since those precursors were first detected in the brains of MS patients and even within their lesions, exactly why these cells cease to function as they should. The other areas mentioned are all potentially promising, and it’s possible that all play an important role in the degeneration. I feel some of the most exciting data on therapeutic efficacy in people suggests the myelin regenerative capacity could be harnessed for treating MS.

I believe inflammation is almost certainly the initiator of the disease process, and degeneration is a subsequent development that arises because of the early inflammation. We are doing a remarkably good job and an increasingly better job of addressing the initial inflammation, but there may be persistent inflammation that gets trapped within the brain where it is not directly addressed by most of our therapies. By the time someone gets diagnosed, there are already substantial amounts of brain injury, and unless we reverse the damage, degeneration may continue. Despite our extremely potent anti-inflammatory therapies, at best we are only delaying the degenerative, progressive phase of the disease. So I don’t believe the progressive form of the disease is really separate; it just occurs at a different time. Besides the oligos, restoration of mitochondrial function may be equally beneficial and also shows promise for protection from neurodegeneration at-large, not limited to MS.

Is there a need for development of ways to diagnose and treat MS patients as early as possible in the disease course, before serious symptoms appear?

COETZEE: In MS, we’ve seen real progress in immunotherapies which, when taken early enough, could change the trajectory of the disease. We need, though, to hit MS earlier, before the damage is done, and so we need much better diagnostic biomarkers. There’s also a lot of progress being made, thanks to the large-scale GWAS [Genome-Wide Association Study] and other “omics,” toward understanding who is at risk and how MS is triggered. This may lead to early detection and prevention.

FOX: The positive outcomes of the ocreluzimab primary progressive trial do highlight that if we can catch progressive MS early enough in patients with active inflammation, an anti-inflammatory may still be helpful, so that’s good. But we lack the biomarkers needed for early diagnosis of the progressive form of MS.

GREEN: Unfortunately, delayed diagnosis is almost written into our diagnostic criteria, because when we diagnose someone, there are two basic criteria — dissemination in time and dissemination in space. There has to be evidence that the disease has spread, even by the time of its initial diagnosis. As a consequence, when we first diagnose people, there’s already damage, and often extensive damage.

We need better biomarkers to detect disease early — but biomarkers alone won’t get us there. We understand the pathophysiology of MS far better than we understand the pathophysiology of any other neurodegenerative disease. We have a much better sense of the factors that initiate the disease process and then allow the ongoing inflammatory injury at the early disease phase. However, we need to understand the biological processes underlying degeneration better to develop both drugs and biomarkers.

We already have the only biomarker that has been predictive of clinical success and useful in Phase 2 clinical programs in clinical neuroscience: new lesions detected by MRI. That is one of the main reasons all the antiinflammatory drugs exist in MS, and the space attracts continued interest from industry and investors. The development of additional biomarkers has also marched ahead, though it still needs a significant amount of validating work. Some of the most promising are measurements of atrophy in the nervous system — whole-brain atrophy on MRI and atrophy as measured on Optical Coherent Tomography — and functional assessments such as electrophysiology. One form of electrophysiology, evoked potentials [measuring cortical responses to a repetitive electrical stimulus], are making a resurgence because they likely measure myelin injury and processes that drive some of the degeneration.

How likely is it that some future drug therapies, each one hitting a different target, will prove complementary if used in combinations?

COETZEE: It’s fair to say that in MS there are powerful immunotherapeutics available to quell the adaptive immune responses thought to drive much of the neuropathology. It’s likely that if a successful endogenous or exogenous reparative therapy is developed, it would need to be given in tandem or staged with an immunomodulator to prevent destruction of the newly repaired tissues. Effort is under way to advance therapeutic development of compounds with repair or remyelinating activity in the absence of effect on the adaptive immune system.

FOX: Combinations are inevitable because, for the progressive MS patients who still have active inflammation, we will need to use an anti-inflammatory in addition to something that stops the progression. In the past, we asked whether a patient had relapsing MS or secondary progressive MS. We have now reconceptualized the disease, and we ask: Does the patient have active inflammation — yes or no? Does the patient have gradual progression — yes or no? If the first answer is yes, then we use an anti-inflammatory. In the future, if the second answer is yes, we will use a therapy developed for progressive MS. In the trial that I’m leading, the Phase 2 trial of ibudilast in secondary and primary progressive MS, we allow patients currently on some of the anti-inflammatory therapies to remain on them. In the past, patients had to stop those therapies to go into a secondary progressive MS trial.

GREEN: When we do have better treatments for progressive forms of MS, patients might need multiple treatments because of different disease processes that all need to be tackled. This may not wait until patients become progressive because there is an overlap between refractory and progressive states. We also don’t know for sure whether specific biomarkers will be tightly tied to specific mechanisms. If a particular therapeutic agent helped with mitochondrial survival, you might measure the response to therapy in a different way than you would for a remyelinating therapy.

There likely will be significant overlap between the meaningful biomarkers. Will predictive biomarkers that work with one mechanism of action work with others? In the case of the antiinflammatories, the answer has been, yes, the anti-inflammatories that work on a variety of MOAs all seem to align with the same set of biomarkers from MRI. But even though MRI has been hugely important in the development of MS drugs to date, we should not presuppose MRI will be the meaningful biomarker for antidegenerative or neuroreparative therapies. New techniques will be developed in conjunction with new therapies. Oftentimes, biomarkers and therapies develop in tandem, because we must test out effective therapies to assess whether a biomarker has a meaningful result and then use the biomarker to assess effect. It is an iterative process.

Could combinations of new drugs pose medical, regulatory, or economic issues for treatment of MS?

COETZEE: Based on what we know today, it is difficult to predict if the cost of an expensive single treatment or combination of treatments would pose a treatment crisis. It is critical that patients with MS have affordable access to the medication that is most likely to produce the best outcome, support adherence, and maintain quality of life. The other challenge with MS is establishing a value framework for these treatments. Unfortunately, this is an area that is still in its infancy for MS.

FOX: On the access question, I’ve not found an insurance plan that denies coverage of MS therapies in general. It does come down to a question of which therapies are covered and what patients have to try first and either fail or not tolerate in order to move on to the next therapy. MS docs have been a little bit spoiled in past years, in that we’ve been able to use any MS drug we wanted, and the insurance would approve it. It’s not surprising to see the situation change considering the list prices of these drugs are around $50,000 a year, though with the manufacturers’ rebates, they may cost the health plan around $40,000 a year. Cost will be a significant issue in the development of progressive MS drugs, especially if used in combination with anti-inflammatory drugs.

GREEN: MS patients constitute 0.1 percent of the total population, and yet currently MS care consumes somewhere between 3 and 5 percent of the healthcare budget in the United States. In part that is a reflection of success; it means we’re spending money as a society and as a healthcare system because we’re being successful. But on the other hand, those treatment costs are probably outsized, especially when considering the limited efficacy of some of the agents. That raises many important questions that will take engagement from many different stakeholders, from MS patients, to providers, to healthcare systems, to the rest of society. Treatment reduces costs for care, and it reduces lost productivity in a way that may more than offset those costs. I am someone who wants to see us develop therapies that make a major difference, but the biggest challenge will be properly pricing them so they reflect all the time and resources pharmaceutical companies, the government, and academic institutions and research teams have invested, yet at the same time, recognize the limitations on healthcare resources.

FOX: One issue might make a big difference in cost. A typical MS patient will be diagnosed at about the age of 32. Then they go on an MS drug, and we have no idea when to stop the drug, though they may live another 50 years. So they may be on a $40,000 drug for years, and then if they evolve into progressive MS, another expensive therapy may be added. But what we don’t know about the initial, anti-inflammatory MS therapy is when it can be stopped. Dr. John Corboy at the University of Colorado is leading a randomized trial aimed at when to stop MS therapies. It won’t give us all the answers, of course, but it’ll start answering whether and when patients no longer need their anti-inflammatory therapy.

GREEN: We don’t know enough about whether, with long-term treatment, the immunology of the disease process turns off. Inflammation may not be important late in the disease because the inflammatory process has caused so much damage to the nervous system that now the prevailing and operative process becomes degeneration. It might be we need some degree of ongoing and persistent dialdown on the inflammatory process. But maybe if we turn off the inflammatory phase of the disease for 30, 20, 10 years, or maybe even less, it will turn off permanently. Some recent data from use of the drug alemtuzumab suggests turning off the disease for as little as five years might have a significant effect. These are challenging questions, and they require long-term follow-up on patients, which is a huge practical and logistical undertaking and hugely expensive. It could only be done with support by federal government, large advocacy groups like the National MS Society, and potentially by single-payer health systems in countries that are smaller than ours.

To what extent might the underlying causes for neurodegenerative diseases (NDs) be similar or the same — and thus perhaps respond to the same therapeutic mechanisms of action (MOAs)?

COETZEE: It’s very likely that some laterstage pathways, such as degenerative mechanisms, are similar across a spectrum of NDs. But from what we know right now, early stages of most NDs are distinct and driven by different causes. Therefore each ND will likely require individualized approaches to stop the primary assault early enough to preserve function. That said, there are clearly similarities between MS and Alzheimer's disease. For example, both display mitochondrial dysfunction, a link to oxidative stress, and both show signs of inflammation. In MS, the importance of controlling inflammation is well-established and is the mechanism of several approved therapeutics. However, the role of inflammation in Alzheimer's has yet to be firmly established, even though signs of inflammation are evident. Early life exposure to environmental factors such as smoking and Epstein-Barr can drive both conditions, the difference being the genetics of the response to those stimuli. Also, we don't fully understand the role of activated microglia in initiating and/or promoting inflammation, but this is clearly a component of several NDs.

FOX: We’re better off when we understand what’s going on in different fields. In Alzheimer’s, there has been a major focus for years on developing inhibitors of the amyloid precursor protein and more recently the BACE-1 protein that clears the amyloid precursor protein. Is that the right thing? I don’t know, but there are other potential mechanisms in Alzheimer’s such as dystrophic neurites in the tubular endoplasmic reticulum, which have nothing to do with amyloid precursor protein cleavage or BACE-1. So, until we figure out what causes those other diseases, it will be hard to know specifically how relevant MS mechanisms might be to other NDs.

GREEN: There is no question better understanding of the MS mechanisms might have spillover effect on understanding of other neurodegenerative disease areas, for two big reasons: shared mechanisms and a head of steam, or momentum for continued progress in clinical neuroscience. When people in the drug development or business side of the pharmaceutical and biotech industry look at the neurodegenerative space now, they see mostly failure with all the tested therapeutic candidates. But even small successes really help drive the field forward because they show it is not a lost cause. We just have to find the right drugs, the right times to administer the drugs, and the right ways to measure the drugs’ effectiveness. It is a tall order, but it’s not out of range. Step by step, we will make inroads and progress that shift the paradigm.

What does the pharma/biopharma industry need to do to ensure the new treatments reach patients, and soon?

COETZEE: The industry’s focus needs to be on progressive aspects of MS and stopping neurodegeneration. We’re in need of reliable and robust biomarkers for early diagnosis and response to therapy, and better regulator-approved clinical outcome measures that will reduce the time and numbers of patients it will take to show benefit in both proof-of-concept and registration trials. Because of the considerable failure rate for clinical trials in MS and other NDs, pharma needs incentives to stay in the field. NDs pose considerable clinical development challenges related to duration of study, cost, and enrollment. Although the markets addressed by NDs are considerable, there is added risk for the clinical indications, so some concessions or incentives might promote more development in the space.

The pricing of new treatments for all NDs will be an ongoing and significant issue. We understand the need to maintain an environment that encourages research and investment by pharma. At the same time, people need access to new therapies, and access includes affordability and insurance coverage. Identifying and confirming credible connections between various NDs might stimulate clinical R&D. For MS, we need to gain a better understanding of the pathophysiology of progression before we can identify meaningful new therapeutic targets.

FOX: Progressive MS is neglected in that we have no effective therapies, not in the sense there were no trials done. We’ve done many, many trials; it’s just that they were negative. They didn’t work, I believe in part, because we kept throwing one anti-inflammatory drug or another at a disease state that’s not driven by inflammation. Whether it is an errant inflammatory response to the degeneration or degeneration in response to inflammation, no one knows for sure.

We now have a very nice paradigm in relapsing MS: Do a six-month, Phase 2 trial with about 150 patients. If you show that your drug reduces new lesions in MRI, you proceed to your Phase 3 trial to look for reduction in clinical relapses, which will be the basis of FDA approval. Almost invariably the drug shows benefit and gets approved, unless there’s a safety signal. But in progressive MS, we have a couple of challenges. One, we are not really sure what the pathophysiology is. What is really going on that is causing these patients to have a gradual, little by little decline in their function? We don’t know. Two, we have no Phase 2 outcome metric; progressive patients get few or no new lesions in MRI. Although sponsors have tried a few drugs in progressive MS, it’s been in trials of 1,000+ patients followed over two years.

What industry companies have been doing over the last 10, 15 years is taking their success in relapsing, remitting MS and just slapping it on progressive MS, hoping that it’ll work, and unfortunately it hasn’t. But I believe industry has now gotten the message to stop and break out of the old pattern.

GREEN: Industry will be well-served to associate itself and support research that comes out of smaller biotech companies. Those companies have the potential to be nimble, responsive, and innovative in a way that’s very hard for huge corporate organizations. Some of those companies will grow out of the research done by academics within the university laboratories. Can academic institutions figure out a way to cultivate and support that kind of research? The jury is partially out on that. There are challenges for both types of very large institutions because many people consider themselves stakeholders in that process, yet some may not have adequate knowledge of what needs to get done, and some may be too focused on bureaucratic processes rather than accomplishment. We learned from the IT industry that small-company qualities such as nimbleness, responsiveness, innovation, and idea-fermentation are all crucial elements to success in science-based fields.


Strictly speaking, MS is not classified as a neurodegenerative disease but as an inflammatory one. Inflammation has been the center of drug R&D in the MS space because it is so obviously present at the sites where the disease has destroyed myelin. But no absolute consensus on that point has ever existed and, as the scientific opinion leaders in our virtual roundtable note and discuss, a central question has sustained doubt about the inflammation hypothesis: Why do the anti-inflammatories that work so well in relapsing patients fail so utterly in progressive ones? Some argue that inflammation may present at the disease sites only because of some other pathology. Competing explanations include neurodegeneration similar to the kind observed in Alzheimer’s and Parkinson’s, perhaps due to mitochondrial disease, rogue T-cells, genetic disorder, or some other hard-to-observe factor.

Most of the actual research and development of new approaches in the progressive MS space now happens in university and hospital settings, often funded by the public, not industry. The larger companies that now dominate the relapsing market have mainly tried, without much success, to apply their existing or next-generation anti-inflammatory drugs to the progressive form. A smattering of small companies, where the line between academia and industry often blurs, are working on novel approaches for progressive MS, and we feature some of them here, in Part 3 of Hot New Therapeutic MOAs Versus Neurodegenerative Diseases.


In Phase 3 with MD-1003 (biotin), which targets neuron metabolism and may help myelin repair, for treatment of primary and secondary progressive MS

Frederic Sedel, M.D., Ph.D., CEO: Progressive MS is a consequence of ongoing inflammation, chronic demyelination, and axonal neurodegeneration. Although immunosuppressive and immunomodulatory drugs may delay progression in patients who have ongoing inflammatory activity (“active” progressive MS), these drugs are relatively ineffective in patients who have no inflammatory activity but who continue to progress (“not active” progressive MS). The axonal degeneration in progressive MS is thought to arise from an increased energy demand in chronically demyelinated axons, which, together with some mitochondria dysfunction, create a virtual hypoxia phenomenon culminating in progressive axonal loss.

Mega-doses of pharmaceutical grade biotin have a unique mechanism of action which is specifically suitable to target neurodegeneration (and not inflammation). Biotin is a co-enzyme for several “carboxylases,” or catalysts critical for energy synthesis in the mitochondria and is also a coenzyme for the acetyl CoA carboxylase (ACC) which is expressed by myelin-forming cells (the oligodendrocytes). Thus, biotin potentially acts on two targets related to progressive MS: (1) it activates energy production that protects against axonal degeneration, and (2) it potentially activates the synthesis of fatty acids required for some myelin repair.

On the other hand, since biotin is not expected to have any beneficial impact on inflammation, it is not expected to be suitable to decrease the relapse rate or to decrease the inflammatory part of progressive MS, especially in patients with active progressive MS. As a consequence, if approved, it is expected that high-dose biotin would be the treatment of choice in patients with not active progressive disease. In the active progressive disease form, it is expected to be used in combination with other immune system targeting drugs to be certain that patients remain without superimposed inflammation. The fact that neurodegeneration is expected to occur in all patients with progressive MS suggests that biotin should be suitable for all patients with or without additional immunosuppressive treatments.


In a Phase 2b trial with a novel drug (MIS416) for patients with secondary progressive MS

Simon Wilkinson, Managing Director, CEO: MIS416 is an immune modulating microparticle of bacterial origin developed and manufactured by our company. Our current Australian and New Zealand-based Phase 2b trial has enrolled 93 subjects with relapse-free active disease and is on schedule to report in Q3 2017. The reported improvements in a range of MS-related signs and symptoms arising from previous open-label studies, together with an ongoing compassionate use program, have helped inform the design of our current 2b trial.

In contrast to the acute peripherally driven autoimmune pathology, which is the predominant feature of relapsing remitting phase MS, we view secondary progressive MS (SPMS) as a neurodegenerative disease where inflammation is still significantly involved in disease pathology, but the nature of that inflammation has fundamentally changed. In large part, this shift in the type, location, and duration of inflammation in progressive MS accounts for why the present autoimmune blocking RRMS drug strategies have failed to achieve a sustained and meaningful effect in progressive disease.

Instead of targeting adaptive immune cells such as auto-reactive T cells, our drug candidate modulates the myeloid-derived innate immune cells, which play an important role limiting inflammation and promoting tissue repair inside the CNS. This last point is pivotal. We are directly modulating specific innate cells that are either resident in the CNS, can be licensed to access the CNS, or can exercise an effect inside the CNS. As a result, the chronic CNS resident inflammation, which is a hallmark of SPMS, can be down-regulated, while at the same time myelin repair can be supported by improved clearance of myelin debris. Modulating these same cells can also up-regulate the secretion of important tropic factors that can directly promote neuronal survival and axon regeneration.

By adopting this strategy of taking advantage of inherent myeloid cell plasticity, it becomes possible to trigger multiple therapeutic modalities, which in turn might help in the treatment of other CNS disorders. We think MIS416 has the potential to be the CNS anti-inflammatory tool in the toolbox approach to treating many CNS disorders or injuries. While CNS resident inflammation won't be the cause of disorders such as refractory epilepsy or Alzheimer's disease, its presence is unhelpful, to say the least. If we can safely and effectively manage the inflammatory component of these conditions, then it may help clear the way for other drugs, which might be specifically targeted to the underlying disease mechanism, to work more effectively.


Nearing first data from a Phase 2b study of Tcelna, a T cell therapy, for secondary progressive MS

Neil Warma, President, CEO, Director: Our approach with Tcelna is about influencing the immune system as a way to mediate disease, which starts with restoring the function of the body’s immune system. We prime or boost or reboot the body’s immune system to allow the body to fight the disease itself. We want to eventually apply our T cell approach to a number of autoimmune diseases, but the one the company has focused on from its inception is multiple sclerosis. We have run a half-dozen clinical trials treating early stage, relapsing MS and progressive MS patients with an autologous cell therapy, where the side effects are minimal. In the case of MS therapies, that is a huge advantage.

We see MS as an autoimmune disease; a small number of T cells turn rogue and attack the body’s own cells, and in the case of MS, they attack and destroy not only the insulating myelin sheath around neurons in the brain, but also the oligodendroglial cells that produce myelin, over the course of years. We clone each patient’s own rogue T cells, attenuating them with radiation, and present a large number of the cloned cells to the body’s immune system through subcutaneous injection, where T regs are exposed to them and go off to destroy the rogue cells throughout the CNS. This prevents further destruction of myelin sheath and of the oligo cells. In theory, some sort of repair and improvement should then take place, and we actually saw that in one of our clinical studies. It showed a reversal in disability, a first for any MS therapy. Typically, the aim is merely to slow down the rate of progression. Rarely do you stabilize, and never have we seen the condition actually reverse, indicating some sort of neuroprotection or improvement.

We are now reaching the end of a Phase 2b clinical study in secondary progressive MS. The trial has 190 patients in 35 centers across the U.S. and Canada, with brain atrophy and disease progression the key endpoints in the two-year, placebocontrolled, randomized study. We’re expecting results from the trial early fourth quarter of 2016. We could potentially commercialize Tcelna with Merck/Serono, but we have developed the manufacturing and distribution solutions for this cell-based therapy in-house.