Alemtuzumab significantly reduces relapses in multiple sclerosis vs interferon beta-1a in a Phase III study

Sanofi (EURONEXT: SAN and NYSE: SNY) and its subsidiary Genzyme announced today new results from the CARE-MS I trial, the first of two randomized, Phase III clinical trials comparing the investigational drug alemtuzumab (Lemtrada™) to Rebif® (high dose subcutaneous interferon beta-1a) in patients with relapsing-remitting multiple sclerosis (MS). New data show that 78 percent of patients treated with alemtuzumab remained relapse-free for two years, providing statistically significant improvement over interferon beta-1a (78 percent vs 59 percent at two years, p<0.0001) and meeting this secondary endpoint. The CARE-MS I results were presented today at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Genzyme is developing alemtuzumab for relapsing MS in collaboration with Bayer HealthCare.

As previously reported, treatment with alemtuzumab resulted in a 55 percent reduction in relapse rate compared to interferon beta-1a over two years of study (p<0.0001), satisfying this co-primary endpoint and meeting the predefined protocol criteria for declaring the study a success. At the two year time point, very few alemtuzumab patients (8 percent) experienced a sustained increase, or worsening, in disability as measured by the Expanded Disability Status Scale (EDSS) (vs 11 percent of patients in the interferon beta-1a group). However, the difference between groups for this coprimary endpoint were not statistically significant (p=0.22) and there was no difference in the mean EDSS score between groups.

The CARE-MS I trial compared treatment with alemtuzumab (12 mg/day by IV administration for 5- days, with a second 3-day IV administration one year later), to treatment with subcutaneous interferon beta-1a (44 mcg administered by injection three times per week) in 581 patients with relapsing/remitting MS who had received no previous treatment to suppress MS, except for steroids.

“CARE-MS I confirms that, in a head-to-head comparison with Rebif, disease activity is significantly reduced in patients with early relapsing-remitting multiple sclerosis treated with alemtuzumab, over the first two years of observation,” said Professor Alastair Compston, Chair of the Steering Committee overseeing the conduct of the study and head of the Department of Clinical Neurosciences at the University of Cambridge, United Kingdom. “These data support the robust efficacy profile and potential that alemtuzumab offers for patients with relapsing-remitting multiple sclerosis requiring a more effective option than currently available therapies.”

“Lemtrada’s robust effects over and above those of Rebif on relapses and a variety of clinical and imaging endpoints reinforces its potential as an effective treatment option for MS patients,” said David Meeker, M.D., Chief Operating Officer, Genzyme. “We look forward to the results of CARE-MS II, our second Phase III study, later this year to extend these results by confirming Lemtrada’s effects in patients with continued disease activity while receiving another MS treatment.”

Additional findings from the CARE-MS I study presented today include other secondary endpoints that suggest positive outcomes with alemtuzumab. Improvement in Multiple Sclerosis Functional Composite (MSFC) scores was observed in alemtuzumab-treated patients, as compared to interferon beta-1a (0.12 vs 0.05 mean change from baseline at year two, p=0.012). MSFC is a composite measurement of physical and cognitive function.

The effect of alemtuzumab on reduction in T2-hyperintense lesion volume compared to interferon beta-1a was -9.3 vs -6.5 median percent change at year two (p=0.31). Other MRI outcomes suggested that alemtuzumab provided improvement over interferon beta-1a across a number of image-related endpoints, generally consistent with the effects observed in the clinical endpoints. Statistically significant improvement was observed for alemtuzumab over interferon beta-1a in the percentage of patients with new and enlarging T2-hyperintense lesions (49 vs 58, p=0.035); with new gadolinium-enhancing lesions (15 vs 27, p=0.0006); and with new T1-hypointense lesions (24 vs 31, p=0.05). In addition, alemtuzumab-treated patients experienced less change in brain parenchymal fraction (BPF), a measure of brain atrophy, compared to interferon beta-1a (-0.87 vs -1.49 median percent change from baseline, p<0.0001), a highly statistically significant result.

CARE-MS I Safety Findings

Common adverse events associated with alemtuzumab in the CARE-MS I study included infusion-associated reactions which were generally mild to moderate. Additionally, the incidence of infections was increased, the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were predominantly mild to moderate in severity and none were life-threatening or fatal.

The incidence of serious adverse events was similar between the two treatment arms (18.4 percent for alemtuzumab vs 14.4 percent for interferon beta-1a). Relating to autoimmune disorders, 18.1 percent of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event and 0.8 percent developed immune thrombocytopenia (ITP) during the two-year study period. There were no cases of anti-GBM disease. Cases of autoimmunity were detected and managed using conventional therapies. Patient monitoring for immune cytopenias and thyroid or renal disorders is incorporated in all Genzyme-sponsored trials of alemtuzumab for the investigational treatment of multiple sclerosis.

Additional Information

Another Phase III clinical trial, CARE-MS II, is currently underway, evaluating alemtuzumab against interferon beta-1a in relapsing-remitting MS patients who have relapsed while on therapy. Top-line results from that trial are expected to be available in the fourth quarter of 2011.

The company expects to file for U.S. and E.U. approval of alemtuzumab in relapsing MS in the first quarter of 2012, and alemtuzumab has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA). Since it is not yet approved for the treatment of MS, alemtuzumab must not be used in MS patients outside of a formal, regulated clinical trial setting in which appropriate patient monitoring measures are in place.

*Lemtrada™ is the proprietary name submitted to health authorities for the company’s investigational multiple sclerosis agent alemtuzumab.

About the CARE-MS I Trial

CARE-MS I (The Comparison of alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) trial was designed to evaluate whether the investigational MS therapy alemtuzumab could achieve meaningful efficacy and safety improvements over the approved, active comparator interferon beta-1a, a standard treatment for relapsing MS.

CARE-MS I was a Phase III, global, randomized clinical trial comparing treatment with alemtuzumab (12 mg/day for a 5-day IV administration, with a second 3-day IV administration one year later), to treatment with subcutaneous interferon beta-1a (44 mcg administered by injection three times per week) in 581 patients with relapsing-remitting MS who had received no previous treatment to suppress MS, except for steroids. Patients were randomized at a ratio of 2 to 1 to receive alemtuzumab or interferon beta-1a. Co-primary efficacy endpoint assessments were performed at regularly scheduled visits by independent, evaluating neurologists who were blinded to the patients’ treatment assignments.

The CARE-MS I trial had co-primary endpoints: reduction in relapse rate and six months sustained accumulation of disability (SAD) †. Based on the criteria set forth in the study protocol, CARE-MS I is defined as a success if both co-primary endpoints are met (p<0.05) or if one co-primary endpoint is met against a more stringent measure of statistical significance (p<0.025). Secondary outcome measures include: Percentage of relapse-free patients at year two; Expanded Disability Status Scale (EDSS) change from baseline; Percent change in magnetic/resonance imaging (MRI)-T2- hyperintense lesion volume at year two; and Multiple Sclerosis Functional Composite (MSFC) change from baseline.

†Sustained Accumulation of Disability (SAD) – Clinical representation of the worsening of a patient’s level of disability; CARE-MS 1 monitored this endpoint over the course of six months.

About Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody being studied as a potential therapy for relapsing MS. Alemtuzumab targets the cell-surface glycoprotein CD52, which is highly expressed on T- and B-lymphocytes. Preliminary research suggests that alemtuzumab initially depletes the T- and B-cells that may be responsible for the cellular damage in MS. This depletion of T- and B-cells is followed by a distinctive pattern of lymphocyte repopulation. Alemtuzumab appears to have little or no effect on other cells of the immune system. In addition to the completed CARE-MS I study, another Phase III trial, CARE-MS II, will evaluate alemtuzumab against interferon beta-1a in relapsing-remitting MS patients who have relapsed while on therapy.

Genzyme has the worldwide rights to alemtuzumab and has primary responsibility for the development and commercialization of alemtuzumab in MS. Bayer HealthCare has been codeveloping alemtuzumab in MS with Genzyme. Bayer HealthCare retains an option to co-promote alemtuzumab in MS and upon regulatory approval and commercialization would receive contingent payments based on sales revenue.