Allison Gandey

October 27, 2010

October 27, 2010 (Gothenburg, Sweden) — A series of phase 2 clinical trials in multiple sclerosis (MS) have all returned positive results, and investigators are making plans for new studies.

The findings for 3 new experimental drugs were presented here at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. Firategrast, ocrelizumab, and ofatumumab are all in the pipeline for relapsing-remitting MS and so far are gaining ground.

David Miller, MD, from the University College London Institute of Neurology in the United Kingdom, presented results on firategrast. The drug is a new anti-alpha 4 therapy similar to natalizumab (Tysabri, Biogen Idec) but is administered orally.

Firategrast is being developed by GlaxoSmithKline, the company that sponsored the current phase 2 clinical trial. The multicenter, double-blind, placebo-controlled, dose-ranging study included 343 patients with relapsing-remitting MS.

Number of new gadolinium-enhancing lesions during treatment.

The study had a 4-week run-in phase followed by 24 weeks of treatment and 12 weeks of follow-up. Participants were randomized to receive placebo, 150 mg or 600 mg twice a day of firategrast, or a high-dose option at 900 mg for women and 1200 mg twice a day for men. Dr. Miller explained there are sex differences in drug exposure in the high-dose groups, which prompted separate doses for men and women. His group is continuing to study the reasons for these variations.

The research team obtained brain magnetic resonance imaging (MRI) scans at 4-weekly intervals. They found the primary outcome was statistically significant for the 900- and 1200-mg firategrast group compared with placebo. The adjusted mean rate of gadolinium-positive lesions was 2.69 vs 5.31 (P = .0026 for a 49% decrease).

Dr. Miller reports a significant decrease in new T2 lesions in this high-dose group (P = .009). He also notes a nonsignificant trend toward fewer relapses with increasing dose.

The investigators noticed substantial variability in blood level as a function of dose. They are currently looking into the mechanism for these discrepancies.

Firategrast was generally well tolerated at all dose levels. Adverse events included vomiting, infections, particularly urinary tract and respiratory, and rash. At this time, no evidence of progressive multifocal leukoencephalopathy (PML) has been noted.

During a highlights session at the end of the meeting, Jeffrey Cohen, MD, from the Cleveland Clinic Foundation in Ohio, said, "Overall, these results provide support to take this agent forward."

Speaking to Medscape Medical News, session chair Anders Svenningsson, MD, from Umeå University Hospital in Sweden said he agrees this agent should continued to be studied. "I am skeptical," he noted, "and I expect it won't be as good as natalizumab, but it is certainly promising that it's an oral agent, and so far there is no evidence of PML, so it should be investigated."

Dr. Svenningsson says a higher dose might be in order to improve efficacy.

Ocrelizumab Targeting B Cells

New data for ocrelizumab were also presented during the session. It is a recombinant humanized anti-CD20 monoclonal antibody being developed by Genentech and Biogen. Ocrelizumab is similar to Idec Pharmaceutical's rituximab, which targets B cells.

Dr. Ludwig Kappos

Presenter Ludwig Kappos, MD, from the University Hospital in Basel, Switzerland, pointed out that B cells may contribute to MS through antibody-dependent and independent mechanisms.

The new phase 2 trial evaluated efficacy by brain MRI lesions and dose safety. Investigators looked at 220 patients with relapsing-remitting disease.

Patients were randomized to receive intravenous ocrelizumab at 600 mg or 2000 mg or placebo or weekly interferon beta-1a intramuscular injections as an open-label arm of the trial. The primary endpoint for the study was the total number of gadolinium-enhancing lesions.

The secondary endpoints included annualized relapse rate, new or persisting gadolinium-enhancing T1 lesions, change in T2 lesion volume from baseline, adverse events, and tolerability.

Both doses of ocrelizumab showed highly significant differences in total number of gadolinium-enhancing T1 lesions compared with placebo (P < .0001). The relative reductions were 89% for the lower dose and 96% for the higher dose.

"The primary endpoint was met," Dr. Kappos showed delegates here. "The trial also met the clinical endpoint of annualized relapse rate." This was significantly reduced at week 24 (0.125, P = .0005, and 0.169, P = .0014) vs placebo (0.637). This represents a reduction of 80% and 73%.

The total number of new and persisting gadolinium-enhancing T1 lesions was lower in both ocrelizumab groups (P < .0001). Change in T2 lesion volume at week 24 was not significantly different.

"These results are very impressive and certainly warrant further phase 3 studies," Dr. Cohen said.

Serious adverse events occurred in 1.8% of the lower-dose group and 5.5% of the higher-dose group. Infections were similar in all treatment groups. Infusion-related events during first treatment were more common with ocrelizumab. One patient in the high-dose group died of acute-onset thrombotic microangiopathy at week 12 of treatment. Dr. Kappos acknowledged during his talk this was a serious and unfortunate outcome. The death in the ocrelizumab study is capturing news headlines.

Despite these concerns, Dr. Svenningsson said he believes this approach remains promising. "This is a very attractive compound that is similar to rituximab, which is already in use," he noted. "Rituximab has a very acceptable safety program in rheumatology. This study confirms the mechanism in MS, and now we'll need to continue evaluating its safety."

Ofatumumab Another Anti-CD20

Per Soelberg Sorensen, MD, from Copenhagen University Hospital in Denmark, presented new phase 2 results for ofatumumab. The chimeric anti-CD20 monoclonal antibody is being developed by Genmab. Like rituximab and ocrelizumab, the new drug targets B cells.

In this small, multicenter, double-blind, randomized, placebo-controlled trial, investigators tested the efficacy of increasing doses of intravenous ofatumumab in patients with relapsing-remitting disease. A total of 26 patients were randomized to ofatumumab and 12 to placebo.

These results, taken together with previous findings of rituximab and ocrelizumab, support the important role of B cells in MS pathogenesis.

Investigators performed MRI at baseline and every month until week 24. Following treatment, the team found the mean cumulative number of new gadolinium-enhancing lesions from weeks 8 to 24 was 0.04 in the combined ofatumumab group compared with 9.69 in the combined placebo group. The estimated relative reduction is 99.8% (90% confidence interval, 94.7 – 100; P < .001).

Similar reductions occurred for the cumulative number of total gadolinium-enhancing lesions and new and enlarging T2 lesions. All doses of ofatumumab resulted in peripheral B-cell depletion.

At week 24, the mean CD19+ B-cell count was reduced by 78%, 95%, and 98% in the 100-, 300-, and 700-mg groups. No safety signals have emerged, Dr. Sorensen noted. "In this small number of subjects, the magnitude of MRI efficacy is very promising and warrants further study," he said.

"These results, taken together with previous findings of rituximab and ocrelizumab," Dr. Cohen agreed, "support the important role of B cells in MS pathogenesis."

The firategrast study was sponsored by GlaxoSmithKline. Dr. Miller received compensation from the company and from Biogen Idec, Novartis, and Bayer Schering Pharma. The ocrelizumab study was funded by Genentech and Biogen. Dr. Kappos received compensation from the companies. He has also worked with Roche, Actellion, Advancell, Allozyne, Barofold, Bayer Health Care, Bayer Schering, Bayhill, Biomarin, Boehringer Ingelheim, CSL Behring, GeNeuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, Sanofi-Aventis, Santhera, Shire, Teva, UCB, and Wyeth. The ofatumumab study was sponsored by Genmab. Dr. Sorensen received compensation from the company.

26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS): Parallel Session 8 and 10. Presented October 15 and 16, 2010.

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