Improving Therapeutic Options for Multiple Sclerosis

Improving Therapeutic Options for Multiple Sclerosis: An Interview With Edward Fox, MD, PhD

Elizabeth Samander, PhD

Medscape Neurology & Neurosurgery. 2008; ©2008 Medscape
Posted 10/16/2008

Editor's Note

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,[8] 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.[4] 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.[18] 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.[19] 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.[25] 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.
References

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].
2. Gasperini C, Cefaro LA, Borriello G, et al. Emerging oral drugs for multiple sclerosis. Expert Opin Emerg Drugs. 2008;13:465-477. Abstract
3. Burton JM, O'Connor P. Novel oral agents for multiple sclerosis. Curr Neurol Neurosci Rep. 2007;7:223-230. Abstract
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.
7. Hawker K. Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial. Parallel Session 10 of Late Breaking News of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Scientific Program S78.
8. Dörner T, Burmester GR. New approaches of B-cell-directed therapy beyond rituximab. Curr Opin Rheumatol. 2008;20:263-268. Abstract
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.
10. Laugel B, Challier J, Siegfried C, Chvatchko Y, Weissert R, Galibert L. Cladribine exerts a modulatory effect on T-cell activation. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P80.
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.
12. Kappos L, Radue E, O'Connor P, et al., for the FREEDOMS Study Group. Oral fingolimod (FTY 720) in patients with relapsing multiple sclerosis: 3-year results from a phase II study extension. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P72.
13. Kappos L, Polman C, Radue E, et al. Oral fingolimod (FTY 720) in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a 2-year phase III trial (FREEDOMS). Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P73.
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.
17. Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on terfilunomide. Int MS J. 2008;15:62-68. Abstract
18. Comi G, Abramsky O, Arbizu T, et al., for the LAQ/5062 Clinical Advisory Board and Study Group. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 9-month double-blind active extension of the multi-center, randomized, double-blind, parallel-group placebo-controlled study. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P31.
19. Gold R. Combination therapies in multiple sclerosis. Neurology. 2008;255 Suppl 1:51-60.
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.
26. Garcia-Montojo M, Alvarez-Lafuente R, Dominguez-Mozo M, De las Hera V, Bartolome F, Arroyo R. MxA and MMP-9/TI MP-1 ratio as biomarkers of treatment efficacy and disease activity in multiple sclerosis patients. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster 452.
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.

Magnetic Resonance Imaging Can Predict Who Will Develop Multiple Sclerosis: Presented at WCTRMS

By Louise Gagnon

MONTREAL -- September 24, 2008 -- Specific magnetic resonance imaging (MRI) scans can predict which patients will develop multiple sclerosis (MS), according to retrospective research presented here at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRMS).

The Betaferon/Betaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study is a randomised, double-blind, placebo-controlled, parallel-group clinical trial that was carried out among 468 patients whose first clinical event suggestive of MS happened within 60 days of trial entry. The study found that treatment with interferon (INF) beta-1b 250 mcg prevented the onset of clinically definite multiple sclerosis (CDMS) by 1 year.

Patients in the BENEFIT study were assigned to either early treatment, which was IFN beta-1b from the start of the trial, or delayed treatment, which was initial placebo followed by IFN beta-1b therapy after conversion to CDMS or upon completing 2-year follow-up.

Principal investigator Bastiaan Moraal, MD, VU Medical Center, Amsterdam, Netherlands, speaking at an oral session here on September 19, said that this analysis examined radiological rather than clinical endpoints.

"We were looking at which type of lesions measured at baseline would predict conversion to clinically definite multiple sclerosis or McDonald multiple sclerosis," said Dr. Moraal.

In this analysis, blinded raters assessed baseline MRI parameters using T2-weighted and postcontrast T1-weighted sequences. Statistical analysis was employed to assess the predictive value of each baseline MRI parameter and treatment interaction.

Investigators found overall conversion to CDMS was 42%, with factors such as the presence of =>9 T2 lesions and =>3 periventricular lesions demonstrating predictive value. They found that conversion rose with the cumulative number of positive criteria. No specific advantage was demonstrated for a threshold of =>3 Barkhof criteria.

"Patients whose treatment was delayed and had 4 positive Barkhof criteria had a higher chance of conversion to CDMS and McDonald MS compared to those with early treatment and fewer positive Barkhof criteria at baseline," explained Dr. Moraal.

Investigators found that prognostic value was affected by treatment (P = .002) for 4 positive Barkhof criteria. The prognostic value was not influenced by therapy for CDMS.

"We saw that, with one exception, the predictive value of MRI values was not affected by treatment," said Dr. Moraal.

Future analysis will examine the predictive value of MRI variables at 3, 6, and 9 months to assess the impact of those variables on conversion to either CDMS or McDonald MS.


[Presentation title: Baseline Magnetic Resonance Imaging Predictors for Conversion to Clinically Definite Multiple Sclerosis and McDonald Multiple Sclerosis, Based on Integrated 3-Year Data From the BENEFIT Study. Abstract 51]

Data From MediciNova's Two-Year Phase II Clinical Trial of MN-166 in Multiple Sclerosis Presented At the World Congress for Treatment and Research in

SAN DIEGO, Sep 18, 2008 (GlobeNewswire via COMTEX News Network) -- MediciNova, Inc., a biopharmaceutical company that is publicly traded on the Nasdaq Global Market (Nasdaq:MNOV) and the Hercules Market of the Osaka Securities Exchange (Code Number: 4875), today announced that data from the completed two-year Phase II clinical trial of orally administered MN-166 for the treatment of multiple sclerosis (MS) was presented today in two poster presentations at the World Congress for Treatment and Research in MS being held in Montreal, Canada.

The first presentation entitled "Clinical Effect of the Neuroprotectant MN-166 in Relapsing Forms of MS: Year 2 Data" (Poster 48), given by Dr. Richard Gammans, Chief Development Officer of MediciNova, reported that MN-166 treatment resulted in positive findings on three independent measures indicative of a potential disease-progression modifying effect. The poster can be accessed at: http://www.medicinova.com/MN-166-Relapsing-MS.html. The findings include:

* Sustained disability progression was significantly less likely (by approximately 50 percent) in those patients receiving MN-166 at either 30 or 60 mg per day for 24 months than in those patients receiving the drug for 12 months (p=0.026). Sustained disability progression was measured as a greater than or equal to 1.0 point increase from baseline in the Expanded Disability Status Scale (EDSS) score for four consecutive months. This positive clinical finding was corroborated by positive findings on two separate radiologic measures.

* The Phase II clinical trial demonstrated that the significant reduction in brain volume loss (p=0.035), as measured by cranial magnetic resonance imaging (MRI) scans, observed after 12 months in patients treated with 60 mg per day of MN-166 compared to placebo was again demonstrated in year two of the study. Brain volume loss was significantly less (p=0.030) in patients who received 60 mg per day of MN-166 for 24 months compared to the other treatment groups.

The second presentation entitled "Ibudilast Reduces Conversion of New Inflammatory Lesions to Persistent Black Holes in Active Relapsing Multiple Sclerosis" (Poster 271), given by Dr. Hanneke Hulst of VU University Medical Center, Amsterdam, The Netherlands, reported that the Phase II data demonstrated that MN-166 treatment resulted in positive findings on independent MRI measures indicative of a neuroprotective effect. The findings include:

* MN-166 treatment at 60 mg per day significantly reduced the relative risk for conversion of new inflammatory lesions identified at month two to Persistent Black Holes (PBH), an MRI indicator of neuronal loss, eight months later at month ten by 37 percent (p=0.011); such lesions that remain unchanged for eight months are considered PBHs as compared to transient inflammatory lesions that are more closely associated with relapses. MN-166 treatment at 30 mg per day resulted in a trend toward reducing evolution to PBH (p=0.074). Loss of brain volume and development of PBHs on MRI have been shown to correlate with clinical progression and disability in MS patients.

"We are pleased that the WCTRIMS Scientific Program Committee accepted two presentations on different aspects of the results from our recently completed Phase II clinical trial of MN-166," said Yuichi Iwaki, M.D., Ph.D., President and Chief Executive Officer of MediciNova, Inc. "The significant favorable effects on measures of disability progression and reduced neuronal damage observed in the study, as described in these presentations, are quite exciting and representative of the type of new treatment being sought by the MS scientific community according to our advisors. We are excited to be part of advancing MS treatment in a new direction and look forward to confirming these findings in future clinical trials with the assistance of a corporate partner."

The two-year randomized, double-blind, placebo-controlled Phase II clinical trial included 297 patients with relapsing MS. In the second year of the study, all patients were on drug. Patients who received 30 or 60 mg of MN-166 per day during the first 12 months of the study remained on the assigned dose for the second 12 months of the study; patients who received placebo during the first 12 months of the study were randomized to receive either 30 or 60 mg of MN-166 per day (double-blind maintained) during the second 12 months of the study. Clinical and radiological outcomes were evaluated.

MN-166 was well tolerated at all doses over the 24 months of this Phase II clinical trial. Of the 297 patients enrolled in the study, 82.5 percent, or 245 patients, completed the full 24 months of the study. The most common adverse events possibly related to MN-166 included mild, transient gastrointestinal disturbances and depression.

First-year efficacy results of this clinical trial were announced in March 2007 and described more completely at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in November 2007. Clinical results from the completed two-year clinical trial were announced in April 2008.

About MN-166

MN-166 is a novel, orally administered compound being evaluated for the treatment of MS. MN-166 increases the release of neuronal growth factors and inhibits leukotriene activity, phosphodiesterases and nitric oxide synthase. MN-166 may also suppress the production of pro-inflammatory cytokines (IL-1beta, TNF-alpha) and may enhance the production of the anti-inflammatory cytokines (IL-4, IL-10).

MediciNova acquired an exclusive, worldwide (excluding Japan, China, Taiwan and South Korea), sublicensable license to MN-166 for the treatment of MS, excluding ophthalmic solution formulations, from Kyorin Pharmaceutical Co. Ltd. For the past 18 years, MN-166 has been marketed in Japan and South Korea as Ketas(r) for the treatment of asthma and cerebrovascular disorders. Data from the existing clinical trial and post-marketing surveillance databases, which includes treatment of an estimated 3.2 million patients with these disorders, indicate that Ketas(r) is well tolerated.

About MediciNova

MediciNova, Inc. is a publicly-traded biopharmaceutical company focused on acquiring and developing novel, small-molecule therapeutics for the treatment of diseases with unmet need with a specific focus on the U.S. market. Through strategic alliances primarily with Japanese pharmaceutical companies, MediciNova holds rights to a diversified portfolio of clinical and preclinical product candidates, each of which MediciNova believes has a well-characterized and differentiated therapeutic profile, attractive commercial potential and patent assets having claims of commercially adequate scope. MediciNova's pipeline includes six clinical-stage compounds for the treatment of acute exacerbations of asthma, multiple sclerosis, asthma, interstitial cystitis, solid tumor cancers, Generalized Anxiety Disorder, preterm labor and urinary incontinence and two preclinical-stage compounds for the treatment of thrombotic disorders. MediciNova's current strategy is to focus its resources on the development and commercialization of two prioritized assets in its development pipeline: MN-221 for the treatment of acute exacerbations of asthma and MN-166 for the treatment of multiple sclerosis. MediciNova will seek to monetize its other product candidates at key value inflection points. For more information on MediciNova, Inc., please visit www.medicinova.com.

The MediciNova, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=3135

Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding MediciNova's clinical trials supporting safety and efficacy of product candidates and the potential novelty of such product candidates as treatments for disease, plans and objectives for present and future clinical trials and product development, strategies, future performance, expectations, assumptions, financial condition, liquidity and capital resources. These forward-looking statements may be preceded by, followed by or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "would," or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements, include, but are not limited to, the risks and uncertainties inherent in clinical trials and product development and commercialization, such as the uncertainty in results of clinical trials for product candidates, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials and the timing, cost and design of future clinical trials and research activities, the timing of expected filings with the FDA, MediciNova's failure to execute strategic plans or strategies successfully, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to raise sufficient capital when needed, intellectual property or contract rights, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2007 and its subsequent periodic reports on Forms 10-Q and 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements.

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New data presented at WCTRIMS* supports the importance of early and sustained treatment with Betaseron®

Earlier treatment initiation and longer exposure to Betaseron was associated with improved long-term outcomes in multiple sclerosis

MONTREAL, CANADA, September 19, 2008 Data presented at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRIMS) demonstrated that early initiation of Betaseron� (interferon beta-1b) treatment had a greater impact on long-term outcomes, when compared to delayed treatment.

The study, sponsored by Bayer HealthCare Pharmaceuticals, used data from the 16-Year Long-Term Follow-up Study of Betaseron to investigate the relationship between timing of drug initiation and length of exposure to treatment, and long-term outcomes. It demonstrated that initiating Betaseron treatment early in the disease reduced the risk of negative long-term outcomes, including conversion to secondary progressive multiple sclerosis (SPMS), reaching a confirmed EDSS of 6.0 or the use of a wheelchair. The study also found that the longer patients stayed on treatment, the better their long-term outcomes were.1

"The new analysis confirmed that in MS, timing of treatment is important. The findings showed that even if two patients are treated for an equivalent length of time, the one who started therapy earlier in the disease course had a better long-term outcome," said Douglas Goodin, MD, Director of the Multiple Sclerosis Center at UCSF Medical Center. "Patients and physicians should take these results into consideration when making treatment decisions."

A second study, called CogniMS, also presented at WCTRIMS, demonstrated that cognitive deficits can be measured early in the course of MS. The investigators suggested that such cognitive deficits may be clinically important for MS management decisions.

"Studies are now showing that apart from disease progression and relapse rates, cognition is another area that is impacted early in the course of the disease. In fact, there is a correlation between the level of disability at the start of treatment and cognitive function 16 years later. More research is needed to determine how treatment might benefit long-term cognitive outcome," said Dr. Goodin.

"The data presented here underscore the need to help patients start therapy earlier and stay on treatment for the long-term," said, Ludger Heeck, Ph.D. Vice President and General Manager, Specialty Medicine Bayer HealthCare Pharmaceuticals Inc. "Bayer is committed to helping provide both the medication and the support services that people need to help treat their MS. We pioneered the concept of customized MS support services, and our best-in-class BETAPLUSTM program goes far beyond treatment to offer a wide range of beneficial services for people with MS. From having dedicated MS nurses who can provide practical help and advice, to offering product enhancements like our new thinnest needle and optional autoinjector that can help make injection administration more comfortable, we continue to lead the way in helping people with MS start on and stay on treatment."

About the Trials
The 16-Year Long-term Follow-up Study is a multicenter observational study that collected data from patients with relapsing-remitting MS (RRMS) who participated in the pivotal North American trials for Betaseron. Several statistical methods were used to assess patient data and examine the relationship between timing of drug exposure and long-term outcomes. Drug exposure was measured as the medication possession ratio (MPR) defined as the actual time the patient received therapy divided by the total time possible before a negative outcome was reached (or at data censor). A statistical method called recursive partitioning was then used to divide treatment groups into "high" or "low" exposure and to determine the relationship between length of drug exposure and long-term outcomes. The use of MPR reduces the bias introduced in long-term trials by the tendency of patients who are doing well on therapy stay on therapy and for patients who are doing poorly to stop a particular therapy. Other statistical approaches including Propensity Scoring were used to control for other known sources of bias.1

CogniMS is a two-year observational study involving 1509 patients with early MS (diagnosed within two years) who were treated with Betaseron and assessed every six months using tests to measure cognition, fatigue and health-related quality of life. The trial includes patients from 32 countries2 and is currently ongoing.

About Betaseron
Betaseron is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

The most commonly reported adverse reactions are lymphopenia, injection-site reaction, asthenia, flu-like symptom complex, headache and pain. Gradual dose titration and use of analgesics during treatment initiation may help reduce flu-like symptoms. Betaseron should be used with caution in patients with depression. Injection-site necrosis has been reported in four percent of patients in controlled trials. Patients should be advised of the importance of rotating injection sites. Female patients should be warned about the potential risk to pregnancy. Cases of anaphylaxis have been reported rarely. See "Warnings," "Precautions," and "Adverse Reactions" sections of full Prescribing Information. More information, including the full Prescribing Information, is available at www.betaseron.com.

About Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Diabetes Care, and Pharmaceuticals divisions. Bayer HealthCare Pharmaceuticals comprises the following business units: Women's Healthcare, Diagnostic Imaging, General Medicine, which includes Cardiology and Primary Care and Specialty Medicine, which includes Hematology, Oncology and Multiple Sclerosis. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

Media Contact:
Marcy Funk
Bayer HealthCare Pharmaceuticals
973-305-5385

Forward-Looking Statements
This news release contains forward-looking statements based on current assumptions and forecasts made by Bayer Group management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in our annual and interim reports to the Frankfurt Stock Exchange and in our reports filed with the U.S. Securities and Exchange Commission (including our Form 20-F). The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

*WCTRIMS is the first joint meeting of ECTRIMS (the European Committee on Treatment and Research in Multiple Sclerosis) and its counterparts in North and Latin America: ACTRIMS and LACTRIMS

*DS Goodin, G Ebers, AT Reder, et al. Early Treatment with Interferon Beta-1b is Associated with Improved Long-Term Outcome in Multiple Sclerosis. World Congress on Treatment and Research in Multiple Sclerosis 2008.

*S Fredrikson, DW Langdon, K Kim, et al. Cognition, Fatigue, Depression and Health-Related Quality of Life in Early Multiple Sclerosis: Baseline Data from CogniMS, a Multinational Longitudinal Study. World Congress on Treatment and Research in Multiple Sclerosis 2008.

Glatiramer Acetate Decreases Severity of Relapsing-Remitting Multiple Sclerosis: Presented at WCTRMS

By Louise Gagnon

MONTREAL -- September 20, 2008 -- Glatiramer acetate has been shown to be efficacious in several outcomes among patients with relapsing-remitting multiple sclerosis (RRMS) when a scale other than the Expanded Disability Status Scale (EDSS) was used, according to research presented here at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRMS).

A study of 251 patients was presented by investigator Joseph Herbert, MD, New York University, New York, New York, who described the EDSS as not truly reflective of clinical patient outcomes.

In the pivotal study, glatiramer acetate resulted in a 29% decrease in relapse rates compared with placebo. While patients treated glatiramer acetate did show improvement in their EDSS score, Dr. Herbert described the scale as an insufficiently sensitive measure of disease progression.

He presented the study findings in a poster session here on September 19

In this study, Dr. Herbert employed a Multiple Sclerosis Severity Score (MSSS) algorithm that relates MS disability as measured by EDSS to disease duration from the time of first symptom.

"This measure is a more useful outcome measure, because it corrects for certain flaws in the EDSS," said Dr. Herbert in an interview. "It accounts for duration of disease. The EDSS needs to be considered in the context of duration of disease."

This study enrolled patients who had EDSS scores of between 0 and 5. The researchers randomised 125 patients to subcutaneous injections of glatiramer acetate at 20 mg/day and 126 to placebo. Patients were followed for approximately 35 months.

Subjects in this study were divided into 6 groups according to their disease severity, explained Dr. Herbert. At study entry, the median MSSS scores for patients treated with glatiramer acetate and those treated with placebo were similar (4.59 vs 4.29; P = .1). At the end of the study, the median MSSS change from study entry was significantly greater in patients treated with glatiramer acetate compared with those treated with placebo (-0.73 vs -0.19; P = .0019).

With the revised grading of patients according to the MSSS, fewer patients who received glatiramer acetate were categorised as having severe disease. Specifically, more patients treated with glatiramer acetate were reclassified as having less severe illness (49% vs 31%) and fewer patients were reclassified as having more severe illness (16% vs 26%; P < .0014).

"There was a significant drop in severity for the treated patients," said Dr. Herbert. "There was a reassignment toward the higher grades with placebo patients."

The data support the use of the MSSS scale to measure changes in disability in patients with RRMS.

"We are suggesting that, since EDSS and duration of disease must be collected to begin with, that [MSSS] should be used as an outcome measure," said Dr. Herbert. "There is a true change in the intrinsic severity of the disease over 3 years, which is quite dramatic."

Funding for this study was provided by Teva Pharmaceutical Industries Ltd.

[Presentation title: Glatiramer Acetate Reduces Multiple Sclerosis Severity: Analysis of Patients From the US Pivotal Study Using the Multiple Sclerosis Severity Score. Abstract P454]