Wednesday, October 29, 2008
Improving Therapeutic Options for Multiple Sclerosis: An Interview With Edward Fox, MD, PhD
Elizabeth Samander, PhD
Medscape Neurology & Neurosurgery. 2008; ©2008 Medscape
New data from key trials in multiple sclerosis (MS) regarding novel therapeutic approaches were presented at the World Congress on Treatment and Research in Multiple Sclerosis held from September 17-20, 2008, in Montreal, Canada. Medscape Scientific Director Elizabeth Samander, PhD, interviewed Edward Fox, MD, PhD, about the results of these trials and what implications these results may have on clinical practice and the future management of patients with MS.
Medscape: Dr. Fox, in your opinion, what were the most compelling research findings presented at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRIMS) meeting this year?
Dr. Fox: The overall message from the meeting this year was that a number of medications are currently being investigated that hold great promise for the treatment of multiple sclerosis (MS). Research was presented from numerous trials involving novel therapies, including monoclonal antibody and oral products. There was a substantial amount of evidence presented on both of those categories, including further data from completed phase 2 trials and descriptions of ongoing phase 3 trials. The number of medications that we have under current investigation is really quite large, so it is difficult to see the timeline for these medicines actually being brought to market. We had hoped that these studies would fully enroll quickly, so that we would have finalized data coming within the next few years. However, it is likely that there will be some delays because of the large number of competing trials with slower-than-expected enrollment.
Monoclonal antibody agents discussed at the meeting included alemtuzumab, rituximab, and daclizumab.[1-6] Those antibodies have certainly been well-tested in phase 2 trials, and plans are ongoing for phase 3 trials in relapsing-remitting MS. There was also a phase 3 trial regarding rituximab[1,5,7] for the treatment of primary progressive MS. The primary endpoint of time to confirmed disease progression did not show a statistically significant difference between rituximab and placebo. However, subcohort analysis suggested a benefit for those patients with active magnetic resonance imaging (MRI) at entry into the study. I think that the overall feeling about B-cell depletion in the treatment of MS is very positive. We are looking forward to other studies, including ones on ocrelizumab, another monoclonal antibody, which can selectively deplete B cells and thereby reduce MS disease activity.
The data presented on the alemtuzumab trial was further information from the phase 2 trial, which showed a highly significant decrease in the number of relapses seen in patients on alemtuzumab compared with patients receiving interferon beta-1a subcutaneously 3 times weekly. The data presented were on a 3 year follow-up trial designed to evaluate the percentage of patients who were clinically disease-free. These were patients who did not have relapses and did not have a progression of disability during the course of the trial. The superiority of alemtuzumab compared with beta-interferon was sustained throughout the 3 years on study. Within the third year it was found that 71% of the patients who were on alemtuzumab were clinically disease-free compared with 38% of those who were receiving interferon beta-1a. These findings have led to the development of 2 phase 3 trials currently enrolling patients.
Medscape: What other novel therapeutic approaches are undergoing clinical trials?
Dr. Fox: The oral medications discussed at this meeting included cladribine,[9-11] fingolimod,[12-14] BG-00012,[15,16] teriflunomide,[1,13,17] and laquinimod. All of these oral agents, as well as several others, are showing promise for the treatment of MS. It may be that any or all of these products will have success in the treatment of MS, but at this time we're still in the discovery phase for the safety as well as for the efficacy of these medications.
The phase 2 trials that have been performed have primarily been based on looking for a reduction in new MRI activity in patients with multiple sclerosis. They all have shown various degrees of benefit in reducing gadolinium-enhancing lesions on MRIs during the course of the phase 2 trials. However, these trials were rather short and generally were not powered to show significant clinical outcomes. An exception was the phase 2 trial on fingolimod, which did show a substantial reduction in relapse rate as well.
The phase 3 trials are going to be looking not only at reduction in MRI activity, but will also be looking at the important clinical measures that will be required for these medications to be licensed. Those include a reduction in relapse rate and prevention of sustained accumulation of disability compared with placebo. These clinical outcome measures may or may not be found despite the MRI evidence that has been seen in the past, because there has been a disconnect between MRI activity and clinical activity seen in several previous agents tested for MS.
Medscape: There is evidence that disease-modifying treatments, although partially effective, are associated with injection-related side effects and suboptimal patient adherence. These findings may suggest that novel therapeutic strategies, including oral therapies, monoclonal antibodies, symptomatic treatments, and combination regimens, are warranted. What is the role of these novel agents in the therapeutic armamentarium with respect to first-line use, add-on treatment for failed first-line therapy, or as an effective induction agent?
Dr. Fox: Certainly our hope is that there's going to be an increased number of agents available for the treatment of MS, but it's going to be necessary to determine at what stage of disease we would use these medications. The strategy of phase 3 trials is typically in first-line treatment of relapsing-remitting MS, in a placebo-controlled trial evaluating medication over a period of 2 years. This certainly gives us an idea as to what its overall effectiveness can be, and the newer treatments will be evaluated for the ability to reduce relapses and accumulation of disability. Phase 3 trials will also have to show an acceptable safety profile and risk management plan. The first-line agents that we currently have on the market, glatiramer acetate and the beta interferons, will likely continue to have a role in first-line therapy when we look at long-term efficacy and safety measures of the newer medicines. It will likely take a number of years to determine the true safety of the monoclonal and oral agents, and their overall use as first-line therapies will depend on these data.
The concern that we have about using any of the new agents as an add-on treatment for failed first-line therapy is again, a safety issue. If it's being used in a combination with other immunomodulatory or immunosuppressive therapy, we cannot currently define the safety of such an approach. This has been a major concern lately with the findings of opportunistic infections such as progressive multifocal leukoencephalopathy in patients who are immunosuppressed. Switching from ineffective first-line therapy to a new therapy is going to be the most likely use in clinical practice soon after these agents reach the market.
Using any of these agents as an effective induction agent is going to require more data from trials where this has been specifically tried. Older medications such as mitoxantrone have been tested as induction therapies with some very favorable results, but the novel agents that are being investigated right now have not been similarly tested.[20-24] Therefore, I believe that the novel agents are likely to be used as first-line or second-line agents rather than initially as induction agents.
Medscape: What is the evidence for agents optimized for neuroprotection and neurorepair?
Dr. Fox: Ideally, any medication that we use as a preventive medicine for MS would have neuroprotective and neurorepair abilities. Research has shown a frequent association of better clinical outcomes if there's prevention of atrophy. The concept of neuroprotection is that we are preventing axonal loss and neuronal loss during the early stages of MS prior to the onset of disability. All of the trials that are looking at atrophy measures are addressing this issue to some degree, but we would like to have advanced imaging metrics to look more directly at the preservation of axonal and neuronal function.
The World Congress and Treatment for Research of Multiple Sclerosis Meeting had a substantial amount of data that were presented regarding these advanced imaging metrics, including magnetic resonance spectroscopy (MRS) and magnetization transfer imaging (MTR). Measurement of neuronal loss by optical coherence tomography (OCT) is also a very promising method of evaluating the degree of atrophy seen in MS. It is likely that the novel therapies currently being investigated will also be tested in a similar manner. It is reassuring to know that we are seeing some positive data on neuroprotection. Improving repair mechanisms may require a new type of medication that would stimulate the production of new myelin growth rather than working as an immunosuppressant medication.
Medscape: What are the limitations and benefits of these novel therapeutic agents, with respect to safety and efficacy, compared with long-approved therapies such as interferon beta and glatiramer acetate?
Dr. Fox: The-first line therapies that we are currently using for the treatment of MS have been on the market for a number of years. The users of these medicines have a certain comfort level with these medications now and the understanding that the long-term data have indicated a relatively good safety profile.
Immunomodulating therapies do not appear to cause the degree of risk that the immunosuppressant therapies may cause. We understand the risk-benefit ratios of the medicines that have been on the market for a number of years, but the novel therapies that are currently under investigation will undoubtedly have a higher degree of uncertainty as to their safety for many years to come. It is quite possible that the novel therapies are going to have immunosuppressant activity that could lead to increased risk for opportunistic infections, limiting their use as first-line therapies.
The efficacy measures, on the other hand, may show direct or indirect evidence of superiority to the first-line therapies. If indeed the therapeutic abilities of these novel therapies are great enough, then we may accept a higher risk potential with these medications and use them as first-line therapy. However, I don't think that the true measure of a medication's safety will be known at the time it enters the market.
Medscape: Does the increase of potential therapeutic agents complicate how to choose first-line therapy?
Dr. Fox: I think with the advent of more choices, we're going to have a greater divide among practicing neurologists as to how they approach the disease. Right now there's fairly good uniformity among neurologists in terms of how to treat early MS. There are differences in opinion about the optimal medication strategies for people with aggressive or chronic disease. But early active disease is currently treated by a limited number of agents that have relatively similar outcome measures in terms of their ability to control the disease. If we have new medicines available to us over the next several years that have a much different risk-benefit ratio with greater promise of disease control but increased risk, I feel that there's likely to be a group of neurologists who will use these medications first line. But there will be a number of other neurologists who are much more conservative in their acceptance of the new medications and will limit the new medicines only to those patients who have failed existing therapies.
Medscape: The fields of genetics and proteomics are beginning to play a large part in the discovery of novel therapeutic targets. How do these newly identified targets impact the development of individualized therapeutic strategies?
Dr. Fox: As we understand the pathology of MS better, we may find that certain medications are tailored for some patients more than others. For example, the biomarkers that may eventually be used for MS would determine whether we would want to use therapies that were depleters of B cells, T cells, monocytes, or a wide-spectrum immunosuppressant.[26,27] Critical to this line of thinking is the understanding of the mechanism of action of our current medications, which remains somewhat murky to this day, because MS is a highly variable and unpredictable disease with different pathologies among different patients. If we understood the pharmacogenomics of MS better, we might be able to tailor appropriate therapies much more accurately.
Medscape: What are some of the outstanding challenges in the treatment of MS that need to be addressed in the future?
Dr. Fox: Balancing the risks and benefits of medications in the treatment of MS has become increasingly important in the last few years. The major challenge in understanding the nature of this disease is elucidating the prognostic factors for an individual patient, so that we may prevent the development of permanent disability that at this point cannot be alleviated. If we can determine which patients have early, aggressive MS before the development of axonal loss and atrophy, we stand a much greater chance of being able to appropriately determine who might require stronger immunosuppressant. Our challenge going forward is to address both the inflammatory and the degenerative nature of MS with medications that effectively control the disease. Data presented at the World Congress on Treatment and Research in Multiple Sclerosis suggests we are now closer to that goal.
Medscape: Thank you Dr. Fox for sharing this information and your insights with us today.
This activity is supported by an independent educational grant from Teva.
1. Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci. 2008 Sep 17. [Epub ahead of print].
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4. Brinar V for the CAMMS223 Study Group. Alemtuzumab Phase 2 Extension Study Design (CAMMS223): assessing long-term outcomes and potential benefits of additional alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P17.
5. Naismith R, Trinkaus K, Fairbairn M, Lauber J, Piccio L, Cross A. Rituximab as add-on therapy for breakthrough disease: clinical effects over 24 weeks. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P476.
6. Neyer L, Singer R, Wang H, Caras I. Daclizumab exhibits efficacy in multiple sclerosis subjects positive for interferon-beta neutralizing antibodies. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P479.
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9. Guarnaccia J, Rinder H, Smith B. Preferential effects of cladribine on lymphocyte subpopulations. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P55.
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11. Rieckmann P, Giovannoni G, Cook S, et al, for the CLARITY Study Group. Cladribine tablets in relapsing-remitting multiple sclerosis: study design of the 2-year, phase III b CLA RITY (CLA dRibine tablets Treating multiple sclerosis orallY) extension study. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P453.
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14. Montalban X, Comi G, Anel J, et al. Oral fingolimod (FTY 720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P400.
15. MacManus D, Miller D, Kappos L, R. Gold, et al. The effect of BG00012 on conversion of gadolinium-enhancing lesions to T1-hypointense lesions. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P459.
16. Gold R, Kappos L, Miller D, et al. Safety profile of BG00012, an oral formulation of dimethyl fumarate for patients with relapsing MS. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P50.
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20. Vollmer T, Panitch H, Bar-Or A, et al. Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Mult Scler. 2008;14:663-670. Abstract
21. Le Page E, Leray E, Taurin G, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008;79:52-56. Abstract
22. Filippi M, Le Page E, Leray E, Edan G, Comi G. Magnetic resonance imaging results of a 3-year randomized trial comparing two therapeutic strategies in aggressive relapsing-remitting multiple sclerosis: mitoxantrone as induction for 6 months followed by interferon-b-1b versus interferon-b-1b. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P254.
23. Perumal J, Hreha S, Caon C, et al. Intense immunosuppression as the initial disease-modifying therapy in clinically active relapsing multiple sclerosis. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P490.
24. Ramathal J, Boggild M. Glatiramer acetate following mitoxantrone induction in relapsing-remitting multiple sclerosis: extended experience. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P498.
25. Balcer L. OCT: window on multiple sclerosis. Parallel Session 5 of Advances in Imaging Techniques of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Scientific Program S43.
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27. Melnikov A, Scholtens D, Reder A, Balabanov R, Stefoski D, Levenson V. Composite methylation profiles of blood DNA as biomarkers for multiple sclerosis. Disease-modifying therapy-part 2. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P869.
Interviewer: Elizabeth Samander, PhD, Scientific Director, Medscape LLC
Interviewee: Edward J. Fox, MD, PhD, Clinical Assistant Professor, University of Texas Medical Branch, Round Rock, Texas
Disclosure for Interviewer: Elizabeth Samander, PhD, is a member of the professional editorial group at Medscape and has reported no relevant financial relationships.
Disclosure for Interviewee: Edward J. Fox, MD, PhD, has disclosed that he has received grants for clinical research from Biogen-Idec, BioMS, EMD-Serono, Genzyme, Opexa Therapeutics, Sanofi-Aventis, and Teva Neuroscience. Dr. Fox has also disclosed that he has received grants for educational activities from Bayer, Biogen-Idec, EMD-Serono, Pfizer, and Teva Neuroscience. Dr. Fox has also disclosed that he has served as an advisor or consultant to Bayer, Biogen-Idec, EMD-Serono, Genzyme, Opexa Therapeutics, and Teva Neuroscience.