Positive Drug Data for MS

NEW ORLEANS—In a packed ballroom at the Annual Meeting of the American Academy of Neurology in New Orleans on Tuesday, April 24, researchers presented a host of positive data from several clinical trials of potential therapies for multiple sclerosis.

The first batch of results came from a Phase III trial of BG-12 (dimethyl fumarate), a small molecule made by Biogen Idec that confers anti-inflammatory and cytoprotective effects, likely through the nuclear factor E2-related factor 2 (Nrf2) transcriptional pathway, which modulates oxidative stress and delivers neuroprotective benefits. The study, called CONFIRM, is the second Phase III trial for the drug. (Results for the first, called DEFINE, were reported at ECTRIMS last October.) The 1430-patient trial compared two doses of the drug with placebo and with glatiramer acetate. As in the first trial, the drug met its primary endpoints, reported Robert Fox, a neurologist at the Cleveland Clinic in Ohio: The two groups of patients on BG-12 experienced a reduction in annualized relapse rate of 44% to 51% compared to placebo, whereas the relapse rate for patients on glatiramer acetate declined by 29%. In an MRI component of the study, in which approximately half of the subjects participated, the BG-12 groups also showed a statistically significant drop in several measures of lesion number and volume.

In contrast to the DEFINE trial, CONFIRM didn’t show a statistically significant impact on disability, but CONFIRM was not powered to demonstrate that effect, Fox says, and the placebo group had a low event rate, which diluted the result. Approximately 30% of patients discontinued the drug, with 12% doing so because of adverse events (compared to 10% for placebo). On the strength of DEFINE and CONFIRM, the company submitted the drug for approval in Europe and the U.S. earlier this year.

Next, researchers presented data from two Phase III trials of alemtuzumab, a monoclonal antibody that targets CD52 and is administered once per year. The drug depletes B and T lymphocytes, and scientists have proposed that when these cells repopulate, they rebalance the immune system. The trials, sponsored by Genzyme and Bayer Healthcare, compared alemtuzumab to interferon β-1a in patients with active disease who had relapsed on a prior therapy (CARE-MS II) and in treatment-naïve patients (CARE-MS I).

Positive data for the drug in both of the CARE-MS studies were presented last year, but Jeffrey Cohen, a neurologist at the Cleveland Clinic in Ohio, presented some new data from CARE-MS II on Tuesday: In the 840-patient study, those in the group taking alemtuzumab showed a statistically significant improvement in mean Expanded Disability Status Scale (EDSS) score, whereas those on interferon β-1a showed a mean worsening in EDSS score. In addition, 29% of patients on alemtuzumab showed a 6-month sustained reduction of disability, compared to 13% on interferon β-1a. Cohen noted that the drug not only reduced the risk of worsening but also increased the likelihood for improvement. He also pointed out that more patients on interferon β-1a had discontinued treatment than had those on alemtuzumab, suggesting that the latter drug was well-tolerated, although patients taking it experienced a high rate of mild-to-moderate thyroid disorders. (Genzyme reported the trial’s primary outcomes—a 49% reduction in relapse rate and 42% reduction in sustained accumulation of disability—last November.)

In a second presentation on alemtuzumab, Alasdair Coles, a neurologist at Cambridge University in the U.K., recapped the CARE-MS I data, most of which had been reported at ECTRIMS last October. Although this trial did not show a treatment effect on the EDSS score, he noted that it did show improvements on measures of neurological impairment and new lesions.

A tantalizing first splash of data from the CombiRx trial, the longest-running longitudinal study of combination therapy for MS, was also presented yesterday. The study, funded by the U.S. National Institute of Neurological Disorders and Stroke, with drugs donated by Biogen Idec and Teva, began enrolling patients in 2005 and followed some individuals for 90 months. The study aimed to determine whether drugs that are effective alone might boost each other’s power when combined; 1008 patients received either interferon β-1a, glatiramer acetate, or both. In yesterday’s talk, Jerry Wolinksy of the University of Texas Health Science Center at Houston presented imaging data showing that the drug combination was better than each drug alone at reducing new lesion activity and accumulation of total lesion volume. More on CombiRx to come later in the week.

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