JUNE 2011 • WWW.CLINICALNEUROLOGYNEWS.COM MULTIPLE SCLEROSIS 11 MS Oral Options Warrant Cautious Optimism

BY SHERRY BOSCHERT commented after the session that with the expected ap- Both doses showed significant improvements, com- provals of several oral agents over the next few years, pared with placebo, in brain disease activity on various EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY “I’m getting concerned that MRI tests, although some MRI there’s going to be a little bit of a Both teriflunomide measures of disease activity were HONOLULU – Oral therapies for relapsing-remitting free-for-all coming.” But he doses reduced the significantly better only in the multiple sclerosis that are in development have neu- added, “It’s good to have options. annualized high-dose group, compared with rologists feeling both excited and a bit apprehensive. We’re all thrilled.” relapse rate by placebo. “There are a whole slew of orals coming,” Dr. Mariko The only head-to-head com- approximately Results of the 2-year, random- Kita said in an interview at the meeting. “It’s really ex- parison of an oral therapy against 31%, compared ized, double-blind study of citing, but I think it will be challenging for the clinician” another active treatment for mul- with placebo. laquinimod that was presented because there will be inadequate guidance on which tiple sclerosis so far is a study of earlier at the meeting showed an drug or drugs to prioritize in treatment and how best fingolimod vs. interferon, he not- DR. MILLER annual relapse rate of 0.304 on to combine various therapies. ed. Direct comparisons of the laquinimod, a 23% reduction “I think it’s going to be very in- various oral agents will be need- compared with a rate of 0.395 on placebo. The laquin- timidating, actually,” said Dr. The challenge of ed to help clinicians develop treat- imod group also showed 33% less brain atrophy and sig- Kita, director of the multiple scle- the oral drugs ment strategies, said Dr. Green- nificant improvements in brain disease activity on var- rosis center at Virginia Mason will come from a berg, a neurologist at the ious MRI measures. Medical Center, Seattle. lack of guidance University of Texas Southwestern Both teriflunomide and laquinimod seemed relative- She comoderated a session on on which drug or Medical Center, Dallas. ly well tolerated, but among 11 women who became multiple sclerosis trials that in- drugs to prioritize Gilenya may have some supe- pregnant in the TEMSO study, 3 of 4 spontaneous abor- cluded a report on a pooled analy- in treatment. rior efficacy, compared with tions occurred in the teriflunomide groups. Six of the sis of safety data on the only ap- once-weekly interferon dosing, other pregnant women underwent induced abortions, proved oral therapy for multiple DR. KITA Dr. Kita said, but its potential ad- and one woman successfully delivered a healthy baby. sclerosis, fingolimod (Gilenya). verse cardiovascular effects and “I thought that the teriflunomide study was inter- (See story on p. 10.) The session also included positive “downstream consequences in terms of effects on dif- esting. It was impressive to see that a fairly low dose like phase III clinical trial results for the experimental oral ferent organ systems makes another oral daily alterna- that, which seems to be very well tolerated, could have therapy teriflunomide. Earlier in the meeting, separate tive with less toxicity that much more appealing.” effects on both the MRI and on the clinical end points,” investigators reported positive phase III clinical trial re- Dr. Aaron Miller of Mount Sinai School of Medicine, Dr. Kita said. “My concern for it is making sure that we sults for the experimental oral therapy laquinimod. New York, and Dr. Jerry S. Wolinsky of the University understand what the impact is on the female popula- Another oral agent under study, BG-12 (dimethyl fu- of Texas, Houston, presented results of the Terifluno- tion, on the childbearing years.” marate), received Fast Track designation from the Food mide Multiple Sclerosis Oral (TEMSO) trial during the Dr. Kita said she has no relevant conflicts of interest. and Drug Administration and is in phase III clinical tri- session. The multinational, double-blind study ran- Dr. Greenberg disclosed financial relationships with als. Cladribine (Leustatin), which is currently market- domized 1,088 patients with relapsing-remitting mul- DioGenix, Biogen Idec (which is developing BG-12), ed as chemotherapy for certain leukemias and lym- tiple sclerosis to a single daily dose of 7 mg or 14 mg EMD Serono (which is developing cladribine), Teva phomas, initially was rejected by the FDA when it was of teriflunomide or placebo for 2 years. Neurosciences (which is developing laquinimod), and submitted for approval as an oral therapy for multiple Both doses reduced the annualized relapse rate by ap- the Greater Good Foundation. sclerosis. Following resubmission by the manufacturer, proximately 31%, compared with placebo. The annu- Sanofi-Aventis, which is developing teriflunomide, the FDA in early 2011 sent a letter to the company ac- alized relapse rate was 0.37 in each of the treatment funded TEMSO. Dr. Miller, Dr. Wolinsky, and many of knowledging sufficient data on the drug’s efficacy in groups and 0.54 in the placebo group. The risk of dis- their associates in the study disclosed relationships multiple sclerosis but requiring more data on safety and ability progression also was significantly reduced by with Sanofi-Aventis and with numerous other compa- risk-benefit considerations before it could be approved. 30% in the 14-mg group but was not significantly dif- nies that make therapies for multiple sclerosis. Three Dr. Kita’s comoderator, Dr. Benjamin N. Greenberg, ferent in the 7-mg group, compared with placebo. coinvestigators were employees of Sanofi-Aventis. ■ No Improvement in MS With Ginkgo biloba, Simvastatin

BY SHERRY BOSCHERT The two groups also did not differ sig- tion on a study of 307 treatment-naive bo (3 vs. 2.5). These and other measures nificantly in secondary outcomes (in- patients who were starting treatment were not statistically significant differ- FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY cluding perceived cognitive deficits, fam- with interferon-beta-1a (IFN-beta-1a, ences between groups, but suggested a ily reports of cognitive deficits, fatigue, or Avonex) for relapsing-remitting multi- trend toward more disease activity in the HONOLULU – Ginkgo biloba and sim- depression) or in rates of adverse events. ple sclerosis. They were randomized to simvastatin group compared with place- vastatin were not helpful in patients with In the ginkgo group, one patient had an add-on therapy with either placebo or 80 bo, Dr. Sørensen said. relapsing-remitting multiple sclerosis in MI and one developed a severe depressive mg/day of simvastatin (40 mg/day in Based on the findings of this multi- separate randomized controlled trials. episode requiring hospitalization, but the first month) for 1-3 years. Patients center study, simvastatin cannot be rec- Treatment with ginkgo at 120 mg these were not attributed to ginkgo. were followed clinically every 3 months ommended as an add-on to IFN-beta-1a twice a day for 12 weeks produced no While the study found no short-term and brain MRIs were conducted at base- therapy for relapsing multiple sclerosis, significant, short-term improvements in cognitive benefits from ginkgo, it did not line and after 1 year of treatment. At but patients taking statins for treatment cognitive function in a study of 121 pa- assess any potential long-term benefits, least 1 year of follow-up was completed of hypercholesterolemia or to prevent tients. The addition of simvastatin (Zo- Dr. Lovera said. There are no approved by 136 patients in the simvastatin group cardiovascular disease should not be dis- cor) to interferon therapy for multiple and 132 in the placebo group. couraged from taking them during IFN- sclerosis in a separate study did not sig- In the study, the annualized docu- beta-1a therapy, Dr. Sørensen said. nificantly reduce the annualized relapse There was a trend mented relapse rate was 31% higher in Dr. Lovera and two of his associates rate after 1-3 years, investigators report- toward more the simvastatin group (0.19) compared disclosed financial relationships with ed at the meeting. disease activity with the placebo group (0.14), but the EMD Serono, Teva Pharmaceuticals, In the first study, both the ginkgo and in the simvastatin difference was not statistically signifi- Biogen Idec, and/or Pfizer. The ginkgo placebo groups had improved average group, compared cant, said Dr. Sørensen of the Danish and placebo were provided by Dr. Will- scores on a battery of neuropsychologi- with placebo. Multiple Sclerosis Center in the Rigshos- mar Schwabe GmbH, Karlsruhe, Ger- cal tests. There were no significant dif- pitalet, Copenhagen. many. The U.S. Department of Veterans ferences between groups in scores on the DR. SØRENSEN The annualized total rate of docu- Affairs funded his study. Paced Auditory Serial Addition Test, the mented and undocumented relapses was Dr. Sørensen and multiple associates California Verbal Learning Test II, the treatments for impairment of cognition 15% higher in the simvastatin group disclosed financial relationships with Bio- Controlled Oral Word Association Test, in people with multiple sclerosis, which (0.44), compared with the placebo group gen Idec, Merck Serono, Teva Neuro- or the Stroop Color–Word Test, said Dr. affects 40%-50% of patients. (0.38). Patients who received simvastatin science, Genmab, Novartis, Bayer Scher- Jesus Lovera of Louisiana State Univer- Dr. Per Soelberg Sørensen and his as- had more new or enlarging T2 lesions on ing, and/or Sanofi-Aventis. The study sity, New Orleans. sociates reported in a separate presenta- MRI than did those who received place- was funded by Biogen Idec. ■