Genzyme Corp.’s investigational multiple sclerosis drug alemtuzumab not only slowed disease progression in the Phase III CARE-MS II trial, it reversed disability in nearly a third of patients whose disease had relapsed on prior therapy, the Sanofi subsidiary reported April 24 at the American Academy of Neurology annual meeting in New Orleans.

The company released top-line data in November showing the trial had met both of its co-primary endpoints of relapse rate and sustained accumulation (worsening) of disability with high statistical significance. Patients taking alemtuzumab had a 49% reduction in relapse rate compared to the comparator group, which took interferon beta-1a (Roche’s Rebif), over the two-year study, as well as a 42% reduction in the risk of sustained accumulation (worsening) of disability, as measured by the Expanded Disability Status Scale (EDSS), a scale of 0-10 in which high numbers mean more disability.

New results presented April 24, show the mean EDSS score for patients who took alemtuzumab decreased during the two-year period, while the mean score for patients given Rebif increased (-0.17 versus 0.24). In the end, 29% of patients treated with alemtuzumab had a six-month sustained reduction in disability compared to 13% with Rebif (their EDSS score dropped one point or more and stayed low for at least six months).

Genzyme saw a hint of reversal of disability in Phase II and set up the Phase III development program with a high hurdle to confirm the finding, Michael Panzara, Genzyme’s therapeutic area head for multiple sclerosis, immune disease and neurology, said in an interview. The company chose Rebif, which “is known to have a disability slowing effect,” as a comparator going for six months of sustained accumulation of disability as a primary endpoint.

On Track For Regulatory Filings During Second Quarter

The company plans regulatory filings for alemtuzumab, under the proposed trade name Lemtrada, this quarter. Genzyme acquired rights to alemtuzumab from Bayer HealthCare LLC in 2009, and, while Genzyme has the lead on its development, Bayer contributes funding, retains the right to co-promote globally and would receive contingent payments based on sales revenue ([See Deal]).

“The data we have suggest alemtuzumab could be used anywhere across the MS spectrum,” Genzyme Therapeutic Head Michael Panzara said.

It is not certain what indication Genzyme will seek, Panzara said. “The data we have suggest it could be used anywhere across the spectrum. … Our goal is to ensure that appropriate patients receive this to treat their MS in the setting of disease activity.”

With the alemtuzumab filing, three MS therapies will be pending at FDA, two of them owned by Sanofi. The company filed its oral, once-daily teriflunomide last year, with an action date anticipated sometime in June Also see "Sanofi's Oral Aubagio Jostles For Position In Multiple Sclerosis Market" - Pink Sheet, 21 October, 2011.. Biogen Inc. filed its oral candidate BG-12 in both the EU and U.S. in February, which could mean a December approval

About CARE-MS II

The trial enrolled 840 patients who had relapsed on either beta interferon or glatiramer acetate (Teva Pharmaceutical Industries Ltd.’s Copaxone). They received either an injection of Rebif 44 mcg three times per week or two courses of alemtuzumab 12 mg by I.V. a total of eight times. The first course was administered on five consecutive days at the start and the second administered on three consecutive days 12 months later.

In the extension study of the two Phase III trials, CARE II and the earlier CARE I, which compared alemtuzumab and Rebif in treatment-naïve patients, patients are allowed to receive an additional three day course of treatment if necessary due to disease activity, said Panzara. But it’s an as-needed approach because “a significant proportion of patients remained relapse and disability free several years, up to four years following their last treatment course,” he said.

The CARE II data are affirming after results for disability prevention were numerically better but not significantly different from Rebif in CARE I Also see "Top-Line Results For Sanofi/Genzyme's MS Drug Lemtrada Leave Investors Wanting More" - Pink Sheet, 11 July, 2011.. When full results were released later that year, it was revealed that the trial design had assumed a worse response for Rebif than actually occurred; the power of the study to detect a treatment effect was undermined by the low rate of disability events in that arm ([A#111031d1]).

In CARE II, 15.9% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event compare to 5% with Rebif, and 0.9% of alemtuzumab-treated patients developed immune thrombocytopenia during the two-year study period.

The autoimmune effects have been described from the early days of alemtuzumab in MS, said Panzara. In previous studies it has gone as high as 30%, but the severity of over 90% is mild to moderate and those cases are treated appropriately. “What is interesting and very telling about how this is viewed by patients and physicians is we don’t have people dropping out of the study because of [a thyroid condition]. They continue on the study; they actually get their treatment again, even if they develop it before their second infusion. It’s not a barrier to them receiving it because they are experiencing efficacy.”

Regarding ITP, which is much more uncommon and caused a death in Phase II before it was identified as a risk with alemtuzumab, those cases now are detected early through a monitoring program that also looks for thyroid and renal disorders, he said. In Phase III the risk management program detected all the cases of ITP, and there was full recovery.

Sanofi/Genzyme MS Drug Lemtrada Scores High Against Rebif

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