(AAN) Alemtuzumab/Rebif comparison--Phase 3 study (RRMS)

 
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PostPosted: Wed May 02, 2012 1:18 pm    Post subject: (AAN) Alemtuzumab/Rebif comparison--Phase 3 study (RRMS) Reply with quote

Presented at the AAN conference in New Orleans, April 21-28, 2012:

Quote:
[S01.006] Efficacy and Safety Results from Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I (CARE-MS I): A Phase 3 Study in Relapsing-Remitting Treatment-Naïve Patients


Alasdair Coles, Cambridge, United Kingdom, Vesna Brinar, Zagreb, Croatia, Douglas Arnold, Montreal, QC, Canada, Jeffrey Cohen, Solon, OH, Christian Confavreux, Lyon, France, Edward Fox, Round Rock, TX, Hans Hartung, Dusseldorf, Germany, Eva Havrdova, Praha 2, Czech Republic, Krzysztof Selmaj, Warsaw, Poland, Howard Weiner, Boston, MA, Gavin Giovannoni, London, United Kingdom, Miroslav Stojanovic, Kragujevac, Serbia, Stephen Lake, Newton, MA, David Margolin, Michael Panzara, Cambridge, MA , Alastair Compston, Cambridge, United Kingdom

OBJECTIVE:

Compare alemtuzumab and interferon beta-1a (IFNB-1a) on top-line clinical efficacy and safety outcomes in the phase 3 pivotal study: CARE-MS I.

BACKGROUND:

Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool.

DESIGN/METHODS:

CARE-MS I was a 2-year, randomized, rater-blinded, active-comparator, trial comparing alemtuzumab to IFNB-1a in active, treatment-naïve relapsing-remitting MS (RRMS) patients. Alemtuzumab treatment was 12mg/day iv for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly for 24 months. Primary efficacy endpoints were relapse rate and time to 6-month sustained accumulation of disability (SAD).

RESULTS:

581 patients from 98 centers in 16 countries were randomized 2:1 to alemtuzumab or IFNB-1a. Mean age was 33; mean EDSS was 2; mean time since first episode was 2 years.

Alemtuzumab reduced relapse rate by 55% compared to IFNB-1a (p<0.0001). Relatively few patients experienced SAD: 8% of alemtuzumab patients and 11% of IFNB-1a patients (hazard ratio=0.70, p=0.22). 89.9% of alemtuzumab patients experienced an infusion-associated reaction, the most common adverse event. Infections were increased (67.3% of alemtuzumab patients versus 45.5% of IFNB-1a patients) but of predominantly mild to moderate severity (no life-threatening or fatal infections); 18.1% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event versus 6.4% of IFNB-1a patients and 0.8% of alemtuzumab patients developed immune thrombocytopenia versus 1.6% of IFNB-1a patients.

CONCLUSIONS:

Alemtuzumab significantly reduces the relapse rate in RRMS patients compared to an active comparator. Effect on disability accumulation was not significantly different, possibly due to the very low incidence of disability accumulation in the sample overall. The safety profile for alemtuzumab was consistent with previous studies.

These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved.

Supported by:

Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals.

Category - MS and Related Diseases: Clinical Science

Tuesday, April 24, 2012 2:15 PM

Session S01: Multiple Sclerosis: Clinical Trials: Clinical Outcomes (1:00 pm-2:45 PM)

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PostPosted: Tue Nov 06, 2012 9:39 pm    Post subject: CAREII trial Reply with quote

The CAREII trial is discussed in Medical News Today, November 2, 2012.
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PostPosted: Tue Dec 04, 2012 7:26 pm    Post subject: Pivotal trials of alemtuzumab in MS Reply with quote

From Journal Watch Neurology Alert, December 4, 2012:

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Pivotal Trials of Alemtuzumab in MS

Two randomized trials provide evidence on alemtuzumab's efficacy and safety in treating multiple sclerosis — one in treatment-naive patients, the other in patients who relapsed on standard treatment.


Alemtuzumab is a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes. It is FDA approved for treatment of B-cell leukemia but not for treatment of multiple sclerosis (MS). Researchers conducted two multicenter, phase III, manufacturer-funded, 2-year trials of alemtuzumab to treat early relapsing–remitting MS.

In the trial by Cohen and colleagues, the investigators randomized 581 treatment-naive patients in a 2:1 ratio to intravenous alemtuzumab (12 mg daily for 5 days at baseline, then daily for 3 days at 12 months) or subcutaneous interferon beta-1a (IFNβ-1a; 44 μg 3 times per week). Coprimary endpoints were relapse rate and time to 6-month sustained accumulation of disability. Relapses occurred in 22% of the alemtuzumab group versus 40% of the IFNβ-1a group (P<0.0001), a 54.9% improvement. Sustained disability accumulation occurred in 8% of the alemtuzumab group versus 11% of the IFNβ-1a group (hazard ratio, 0.70). Most alemtuzumab recipients (90%) had infusion-associated reactions, 3% of which were serious. Thyroid-associated adverse events occurred in 18% of alemtuzumab recipients and immune thrombocytopenia in 1%. Two alemtuzumab recipients developed thyroid papillary carcinoma. One patient died after discontinuing corticosteroids for presumed autoimmune pancytopenia.

The trial conducted by Coles and colleagues included 840 patients with at least one relapse with interferon beta or glatiramer therapy, who were randomized 1:2:2 to receive 44 μg of subcutaneous IFNβ-1a, 12 mg of intravenous alemtuzumab, or 24 mg of alemtuzumab, following the same regimen as in the first trial, with the same coprimary endpoints. The 24-mg alemtuzumab group stopped recruitment mid-study to increase recruitment in the 12-mg group; outcomes are reported only for the 12-mg group. Relapses occurred in 35% of the alemtuzumab group versus 51% of the IFNβ-1a group (P<0.0001), a 49.4% improvement. Sustained disability accumulation occurred in 13% of the alemtuzumab group versus 20% of the IFNβ-1a group (HR, 0.58). The rate of infusion-associated reactions was 90% among the alemtuzumab recipients, and 77% had infections (mostly mild-to-moderate) compared with 66% in the IFNβ-1a group. Thyroid disorders occurred in 16% of alemtuzumab recipients and immune thrombocytopenia in 1%.

Comment:

The findings of these two phase III trials confirm the previously reported beneficial effects of alemtuzumab against an active comparator. Alemtuzumab is the only drug shown to have superiority over IFNβ-1a in disability outcomes in a monotherapy phase III trial. However, the effectiveness comes at the price of increased autoimmunity during immune reconstitution. The significant risk for autoimmunity and the high rate of infusion-related reactions decrease the attractiveness of alemtuzumab for treatment-naive patients. It would likely be prescribed for patients with active disease who have failed interferon or glatiramer acetate therapy, especially those who are JC virus antibody–positive (and therefore at increased risk for progressive multifocal leukoencephalopathy from natalizumab; JW Neurol May 29 2012).

— Samia J. Khoury, MD

Dr. Khoury is the Jack, Sadie, and David Breakstone Professor of Neurology, Harvard Medical School, and Co-Director of the Partners MS Center, Brigham and Women's Hospital, Boston.

Citation(s):

Cohen JA et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012 Nov 24; 380:1819.

Coles AJ et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012 Nov 24; 380:1829.

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