Phase 2 MS clinical trial data continues to show durable reductions in relapse rate

Sep 14 2009

Genzyme Corporation (Nasdaq: GENZ) reported today that four-year follow-up data from its completed Phase 2 multiple sclerosis (MS) trial continued to show durable reductions in relapse rate and sustained accumulation of disability three years after the majority of patients received their last course of the investigational compound alemtuzumab. The CAMMS223 Phase 2 trial compared alemtuzumab to an approved MS therapy Rebif^® (interferon beta-1a) in early, relapsing-remitting multiple sclerosis (RRMS) patients who had received no prior therapy. The accumulated four-year efficacy and safety data from the Phase 2 trial will be presented today in Germany at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, one of the largest annual international MS conferences. Three-year CAMMS223 trial data were reported in the New England Journal of Medicine (NEJM) last October.

“These longer-term Phase 2 data showed durable reductions in the occurrence of relapses and the accumulation of disability, extending for several years after patients’ last treatment,” said Alasdair Coles, MD, Senior Lecturer, Department of Clinical Neurosciences, University of Cambridge, a lead investigator of the Phase 2 clinical trial. “These findings confirm the extended duration of response observed in our pilot studies with alemtuzumab in patients with relapsing MS.”

In the trial, alemtuzumab was given to patients in two or three annual cycles of not more than five days per cycle, while Rebif was given to patients three-times per week, every week for three years.

The four-year analysis of early RRMS patients from the CAMMS223 trial found that patients taking once-yearly cycles of alemtuzumab reduced their risk of relapse by 72 percent and the risk of sustained accumulation of disability by 73 percent compared to patients treated with the active comparator Rebif. These data closely mirror the three-year findings reported in the NEJM manuscript. Further, the annualized relapse rate and disability risk measured from year three to four remained at the same low level observed in prior years of the study.

The additional review data were obtained from patients participating in CAMMS223 beyond the initial three-year study period. The dataset analyzed consists of the originally-planned three years of patient follow-up, additional continuous post-three-year follow-up, and follow-up of patients who initially discontinued but returned to the study to participate in the risk management program. Approximately 15 percent of patients participating in the post-three-year follow-up used non-study MS disease modifying therapies. A sensitivity analysis that censored these patients found that the risk of relapse and sustained accumulation of disability similarly favored alemtuzumab.

Pivotal Phase 3 MS Trials Enrolled

The company also announced that its CARE-MS II Phase 3 trial, one of two pivotal trials of alemtuzumab in the treatment of MS, has completed enrollment. The company’s CARE-MS I Phase 3 trial completed enrollment earlier this year. CARE-MS I, a randomized trial comparing alemtuzumab to Rebif, is studying early, active RRMS patients who have received no prior therapy. CARE-MS II, which also compares alemtuzumab to Rebif, is studying RRMS patients who relapsed while on other MS therapies. Patients who enrolled at the start of both trials in 2007 will soon complete the protocol-specified two years of follow-up and begin to move into an extension trial. The extension trial allows patients previously treated with Rebif to receive alemtuzumab. Patients previously treated with alemtuzumab will be allowed to take another treatment cycle as needed.

“The enrollment of both pivotal trials is a significant accomplishment,” said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. “This achievement reflects strong interest from patients and significant support from our clinical investigators and patient organizations around the world.” Data from the trials are expected to be available in 2011 for regulatory filings, and approval is anticipated in 2012.

No Additive Infection Risk

Investigators also reported at ECTRIMS that repeated cycles of alemtuzumab did not lead to an additive increase in the risk of infection. “Alemtuzumab modulates the immune system, but this important analysis showed that there were a limited number of serious or severe infections and that infection rates did not increase with additional cycles of alemtuzumab,” said Sibyl Wray, MD, Director, Hope Neurology MS Center, Knoxville, Tennessee, an investigator in the alemtuzumab-MS program and lead author of the analysis of infectious adverse events abstract. In reviewing the CAMMS223 three-year data, researchers determined that infectious adverse events declined in incidence over time. In the Phase 2 trial, no life-threatening or fatal infections occurred in either the alemtuzumab or Rebif trial arms, and patients who did experience an infection responded to conventional therapies over a normal course of time.

Anti-Drug Antibody Impact Not Seen

Researchers reporting at ECTRIMS also found that anti-alemtuzumab antibodies did not affect alemtuzumab’s outcomes through three years of patient follow-up and up to three annual treatment cycles. “Anti-drug antibodies have been shown to negatively impact the efficacy and safety of some MS treatments, but this has not been seen with alemtuzumab through three years of follow-up,” said Krzysztof Selmaj, MD PhD, an investigator in the alemtuzumab-MS program, co-author of the NEJM publication, and lead author of the new report on anti-alemtuzumab antibodies. He explained that “the annual dosing regimen allowed the anti-drug antibody concentration to decline to a low level before the next treatment was administered.” Blood serum measurements taken one, three, and 12 months after treatment as part of the CAMMS223 study found that anti-alemtuzumab antibodies peaked after one month and thereafter declined until re-exposure.

Reduction In Disability Despite Relapse History, Patient Characteristics

As previously reported in the Phase 2 trial, the mean disability of patients improved from baseline when they were treated with alemtuzumab, reflecting the recovery of neurological functions previously impaired by MS. By contrast, the mean disability of patients on Rebif worsened. Researchers reported at ECTRIMS that patients who experienced a relapse just prior to alemtuzumab treatment had similar rates of improvement in disability compared to patients who did not suffer such a relapse. “This is a significant finding as it showed that relapse history had no correlation with the improvement in disability observed, and suggests that alemtuzumab reverses preexisting disability through other mechanisms,” said Dr. Coles, author of the abstract. Investigators also report at ECTRIMS that alemtuzumab patients who experienced sustained reduction in disability and a reversing of pre-existing disability did so regardless of patient sex, age, race, country, or disease duration or activity at initiation of treatment.