Alemtuzumab CARE-MS Trials Published

Susan Jeffrey

November 01, 2012

Full results of phase 3 trials of alemtuzumab (Lemtrada, Genzyme/Sanofi) confirm that treatment was associated with reductions in relapse rates in patients with relapsing-remitting multiple sclerosis (MS), and in 1 trial, there was also reduced sustained accumulation of disability vs standard treatment with interferon beta-1a.

In the phase 3 Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis 2 (CARE-MS II) trial, alemtuzumab significantly reduced relapse rates and sustained accumulation of disability when used as a first-line therapy compared with standard therapy with interferon beta-1a in patients with relapsing-remitting MS.

Results from CARE-MS I, a phase 3 comparison of alemtuzumab and interferon beta-1a in treatment-naïve patients, showed a significant reduction in relapse rates at 2 years, but there was no significant effect on sustained accumulation of disability with alemtuzumab.

CARE-MS I and CARE-MS II trials were published online November 1 in the Lancet. Both have been presented previously, and were reported by Medscape Medical News, at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) in 2011 and at this year's American Academy of Neurology's 64th Annual Meeting, respectively. They were funded by Genzyme (Sanofi) and Bayer Schering Pharma.

Cost an Issue?

Alemtuzumab is a monoclonal antibody that targets CD52, present on T and B cells. It is already approved for the treatment of chronic lymphocytic leukemia (CLL) under a different brand name (Campath, Genzyme). On the strength of the CARE-MS findings, using a lower dosage and frequency in MS, the drug has been submitted to the US Food and Drug Administration (FDA) for review for an MS indication.

In September, though, Genzyme announced that the FDA had issued a "Refuse to File" letter on its supplemental Biologics License Application, asking for a revision in the presentation of the data so that regulators might "better navigate" the application.

In the meantime, the company said it has limited access to the Campath alemtuzumab product in the United States and the European Union to prevent off-label use of it in MS prior to approval.

"As we prepare to commercialize alemtuzumab for MS, we are in the process of working with health authorities around the world to implement changes in the way Campath will be made available in the future," Genzyme spokesman Bo Piela, vice president of communications, told Medscape Medical News.

"Our intention is to establish patient access programs through which we will provide Campath free of charge wherever permitted, in countries where the product has been available commercially. In many countries, we have begun the process of implementing these patient access programs."

In an editorial accompanying the new publication, the Lancet points out that alemtuzumab, licensed for the treatment of leukemia, has been used off-label in MS for many years. The CARE-MS trials "have been keenly awaited by clinicians and patients wishing to establish evidence for this practice," the editorial notes.

The editorial calls the CARE-MS results "encouraging: compared with an established and widely used first-line treatment — interferon beta 1a — alemtuzumab was found to significantly reduce relapse rate not only in previously untreated patients with relapsing-remitting multiple sclerosis, but also in those who had relapsed despite first-line treatment. Notably, in the latter group, the risk of sustained accumulation of disability was also decreased."

The editorial notes the withdrawal of the drug by Genzyme prior to the submission for approval in the United States and Europe.

"However, there is concern that with a licence for multiple sclerosis, the cost of alemtuzumab could rise and might become too expensive for many patients (and health systems). Additionally, discontinuation of the supply might result in patients with multiple sclerosis, who have already started treatments, not being able to get their vital second course," the editorial notes. In these trials, alemtuzumab was given for 5 days at baseline and then for 3 days after 1 year.

"Multiple sclerosis runs a chronic and progressive course, eventually disabling many patients. More effective, affordable, evidence-based treatments with long-term benefits are desperately needed," the editorial concludes. "Finding promising treatments such as alemtuzumab is important. But so is keeping alemtuzumab accessible and affordable if its early success in these trials proves to be of enduring value."

The efficacy of alemtuzumab, as with all drugs, comes with a price of adverse events: in these studies, they include infusion-associated reactions, infections, and autoimmune diseases — mainly thyroid disorders but also immune thrombocytopenia, "both of which require careful monitoring and management."

CARE-MS I

CARE-MS I was a 2-year, rater-masked, controlled trial that included patients previously untreated for relapsing MS. Patients were randomly assigned in a 2:1 ratio to receive either intravenous alemtuzumab, given in a dose of 12 mg for 5 days, followed at 12 months by 3 additional days of treatment. Interferon beta-1a (Rebif, Serono Inc) was given subcutaneously in a dose of 44 μg 3 times per week.

Coprimary endpoints were relapse rate and time to 6-month sustained accumulation of disability in all patients who received at least 1 dose of the assigned study drug; data on 96% of interferon patients and 97% of alemtuzumab patients were included in this analysis.

Fewer patients in the alemtuzumab group relapsed during follow-up, a significant 54.9% improvement with alemtuzumab, the researchers, with first author Jeffrey A. Cohen, MD, from the Mellen Center, Cleveland Clinic, report. On the basis of Kaplan-Meier estimates, significantly more patients in the alemtuzumab group were relapse-free at 2 years.

Table 1: CARE-MS I: Relapse Rate and Patients Free of Relapse by Treatment

Endpoint Interferon Beta-1a Alemtuzumab Rate Ratio (95% Confidence Interval) P Value
Relapse rate (%) 40 22 0.45 (0.32 - 0.63) < .0001
Relapse-free at 2 years (%) 59 78 < .0001

 

Fewer patients on alemtuzumab had sustained accumulation of disability, but this difference did not reach statistical significance.

Table 2: CARE-MS I: Sustained Accumulation of Disability by Treatment

Endpoint Interferon Beta-1a Alemtuzumab Hazard Ratio (95% Confidence Interval) P Value
Sustained accumulation of disability (%) 11 8 0.70 (0.40 - 1.23) .22

 

In terms of side effects, 90% of patients in the alemtuzumab group had infusion-associated reactions, only a small proportion of which (3%) were seen as serious, the researchers report.

Infections, mostly mild or moderate in severity, were seen in 67% of alemtuzumab-treated patients vs 45% of those treated with interferon beta-1a. Herpes infections, predominantly cutaneous herpes infections, were seen in 16% of alemtuzumab patients vs 2% of those receiving interferon.

Thyroid-associate adverse events by 24 months were seen in 18% of alemtuzumab pateitns and 6% of interferon beta-1a patients. Immune thrombocytopenia was seen in 3 alemtuzumab patients (1%) vs none in the interferon arm, and 2 patients on alemtuzumab developed thyroid papillary carcinoma.

"Our safety profile was consistent with the more than 20 years' experience with alemtuzumab in open-label and smaller randomized controlled trials in multiple sclerosis," Dr. Cohen and colleagues conclude. "Secondary autoimmunity, the main safety issue, was effectively detected with a comprehensive monitoring system," they add. "The substantial efficacy of alemtuzumab in relapsing-remitting multiple sclerosis needs to be balanced against potentially serious but treatable adverse effects."

CARE-MS II

CARE-MS II also compared alemtuzumab and interferon beta-1a, but in patients who had at least 1 relapse despite first-line therapy with either interferon beta-1a or glatiramer acetate, both standard therapies for MS.

Patients in this trial were randomly assigned in a 1:2:2 ratio to receive interferon or intravenous alemtuzumab in a dose of 12 mg per day or 24 mg per day. "The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessment," the investigators, with lead author Alasdair J. Coles, FRCP, from the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom, write.

Coprimary endpoints for this trial were relapse rate and time to 6-month sustained accumulation of disability comparing alemtuzumab 12 mg to interferon beta-1a in all patients receiving at least 1 dose of study drug. In all 202 of 231 interferon patients (87%), and 426 of 436 alemtuzumab patients in the 12-mg arm were included in the primary analysis.

Again, more patients receiving interferon beta-1a relapsed than those treated with alemtuzumab, for a significant 49.4% improvement in relapse rate with alemtuzumab. Similarly, significantly more patients were relapse-free with alemtuzumab at 2 years than those on interferon.

Table 3. CARE-MS II: Relapse Rate and Patients Free of Relapse by Treatment

Endpoint Interferon Beta-1a Alemtuzumab Rate Ratio (95% Confidence Interval) P Value
Relapse rate (%) 51 35 0.51 (0.39 - 0.65) < .0001
Relapse-free at 2 years (%) 47 65 < .0001

 

However, unlike CARE-MS I results, CARE-MS II showed a significant reduction in the sustained accumulation of disability with alemtuzumab over interferon beta-1a, a 42% improvement with alemtuzumab.

Table 4. CARE-MS II: Sustained Accumulation of Disability by Treatment

Endpoint Interferon Beta-1a Alemtuzumab Hazard Ratio (95% Confidence Interval) P Value
Sustained accumulation of disability (%) 20 13 0.58 (0.38 - 0.87) .0098

 

Among the 435 patients allocated to alemtuzumab 12 mg, 90% had infusion-associated reactions and 77% had infections vs 66% of patients in the interferon beta-1a group; most were mild to moderate, and none were fatal. Thyroid disorders were seen in 16% of those receiving alemtuzumab, and 3 (1%) had immune thrombocytopenia.

"Alemtuzumab is the first treatment for multiple sclerosis to show improved efficacy on clinical endpoints against an active comparator in one phase 2 and two phase 3 trials," Dr. Coles and colleagues conclude.

"Significant effects on clinical and MRI indicators of inflammatory disease activity were accompanied in this study by slowing of cerebral atrophy and accumulation of physical disability and, for many patients, by improvements in disability," they write. "We conclude that, with appropriate monitoring to reduce the risk of potentially serious but nonetheless treatable adverse effects, alemtuzumab offers the prospect for effective immunotherapy in patients with relapsing-remitting multiple sclerosis whose disease has advanced despite use of a first-line treatment."

The CARE-MS studies were funded by Genzyme (Sanofi) and Bayer Schering Pharma. Dr. Cohen reports receiving consulting fees from Biogen Idec, Elan, Five Prime Therapeutics, Lilly, Novartis, Teva, and Vaccinex; lecture fees from Novartis and Waterfront Media; and research support paid to his institution from Biogen Idec, Genzyme, Novartis, and Teva. Dr. Coles reports receiving consulting fees from Genzyme, lecture fees from Merck Serono, and research support paid to his institution from Genzyme.

Lancet. Published online November 1, 2012. Abstract, Abstract, Editorial

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