PHILADELPHIA — Three-year imaging follow-up of patients with multiple sclerosis (MS) treated with alemtuzumab (Lemtrada, Genzyme/Sanofi) in pivotal phase 3 trials shows that the majority are free of disease-related activity on magnetic resonance imaging (MRI) and show slowing in the rate of brain volume loss.
The Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis trials, reported previously, showed superior efficacy of alemtuzumab compared with interferon beta-1a in patients with MS who were treatment-naive (CARE-MS I) and who had relapsed on prior therapy (CARE-MS II).
"The majority of alemtuzumab-treated CARE-MS I and II patients were free of MRI activity in their third year of follow-up," Douglas Arnold, MD, NeuroRx Research and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, told researchers here at the American Academy of Neurology (AAN) 66th Annual Meeting. "Alemtuzumab slowed the yearly rate of volume loss over 3 years to a range that approaches that of normal aging. These findings provide strong support for both treatment-naive patients and patients who have relapsed on prior therapy," as well as the clinical findings in the trials, he said.
Alemtuzumab 12 mg is given as an infusion over the course of 5 days and then again, 1 year later, over the course of 3 days. Retreatment in year 3 was administered on recurrence of disease activity, which occurred only in 18% of CARE-MS I patients and 20% of CARE-MS 2 patients, Dr. Arnold said.
"It's important to note that the majority of patients in this 3-year follow-up received no treatment for 2 years; in fact, since they received their second course of alemtuzumab at the beginning of year 2," he added. "Despite being treatment-free for 2 years, they had these remarkably effective outcomes on MRI."
Less than 3% of patients were treated with any other disease-modifying therapy during year 3.
The US Food and Drug Administration (FDA) declined approval for alemtuzumab for its supplemental Biologics License Application in December 2013, which disappointed many, patients and neurologists alike, as it had largely been expected to be approved on the strength of the CARE-MS trials.
The FDA took the position that Genzyme had not submitted evidence from adequate and well-controlled studies demonstrating that the benefits of treatment outweighed its serious adverse effects, the company noted in a release at that time.
"Genzyme understands that the conclusion is related to the design of the completed phase 3 active comparator studies of Lemtrada in relapsing-remitting MS patients. FDA has also taken the position that 1 or more additional active comparator clinical trials of different design and execution are needed prior to the approval of Lemtrada. Genzyme strongly disagrees with the FDA's conclusions and plans to appeal the agency's decision," the release stated.
More recently, on April 7, the company announced that after "constructive discussions" with the FDA, their application will be resubmitted in the second quarter of this year.
"The resubmission will provide information to specifically address issues previously noted by the FDA in its December 27, 2013 Complete Response Letter," the company said in a statement. "In light of the planned resubmission, the company does not expect to pursue an appeal at this time."
Edward Fox, MD, PhD, from the Multiple Sclerosis Clinic of Central Texas, Round Rock, coauthor on this paper, and a member of the steering committee for the CARE-MS trials, told Medscape Medical News that the response addresses the FDA suggestion that these trials were poorly designed.
"Problems that the FDA had with the trial design were ones that we felt were adequately answered by the care that was taken to have blinded observing neurologists performing disability examinations; having a blinded set of MRI readers, as represented by Dr. Doug Arnold at this meeting; and to have a panel of neurologists determine whether a relapse had occurred during the trial without knowledge of the treatment arm for that patient."
The data are also being reorganized in a way to underline how the limitations of this open trial design were compensated by a "rigorous program of blinding the raters and MRI readers," he said.
In this current report, 349 patients from the CARE-MS I and 393 CARE-MS II patients entered the extension phase. Of these, as noted, 18% and 20% received retreatment. Retreatment was given to patients who had a clinical relapse or breakthrough activity on MRI, defined as 2 or more new lesions.
At month 36, the proportion of alemtuzumab-treated patients with new or active lesions was not statistically significantly different from month 24 for gadolinium-enhancing lesions, new or enlarging T2 hyperintense lesions, and new T1 hypointense lesions.
"In year 3, patients maintained approximately 90% suppression of gadolinium-enhancing activity and maintained about 75% suppression of new or enlarging T2 lesion formation," Dr. Arnold said.
Table 1. Lesion Counts With Alemtuzumab Treatment at Year 2 vs Year 3
|Endpoint||CARE-MS I||CARE-MS II|
|Year 2||Year 3||Year 2||Year 3|
|Gadolinium -enhancing lesions, %||7.0||9.8||8.7||13.5|
|New and enlarging T2 lesions, %||22.2||27.7||23.7||31.0|
|New T1 lesions, %||6.7||10.8||7.2||12.5|
The majority of patients in both trials were free of MRI activity at years 2 and 3 (CARE-MS I, 77% and 72%, respectively; CARE-MS II, 76% and 68%, respectively).
In terms of lesion volume, alemtuzumab significantly decreased T2 and T1 lesion volume compared with baseline at year 2 (P < .0001) and year 3 (P < .01) in the treatment-naive patients in CARE-MS I. However, there was a small but significant increase in T2 and T1 lesion volume in year 3 vs year 2.
In CARE-MS II, mean lesion volume remained below baseline at year 3 in these patients who relapsed on previous therapy, but there was a small but significant increase in T1 lesion volume at year 3 vs year 2 (P < .0001).
Treatment with alemtuzumab also slowed the reduction in brain parenchymal fraction over the course of 3 years in both trials, approaching levels seen with normal aging, Dr. Arnold noted.
Table 2. Median Yearly Rate of Brain Atrophy Over the Course of 3 Years With Alemtuzumab
|Time Period||CARE-MS I||CARE-MS II|
|Year 0 to 1||−0.59||−0.48|
|Year 1 to 2||−0.25||−0.22|
|Year 2 to 3||−0.19||−0.10|
"We're having increased interest in the definition of a disease-free state, where there's no active disease, no sign of either clinical or radiographic activity," Dr. Fox said. "For a patient to be considered free from active disease, they should have no signs of a clinical relapse and no breakthrough disease on their MRI. If a patient has been able to achieve that, then continued monitoring would still be appropriate for them to make sure they maintained that state, but to have seen at a length of time of 2 years since the last dosing that there was a maintenance of control of disease was very reassuring."
In terms of safety, patients who are retreated remain in the active extension trial. "Right now, I can state that the safety profile of the redosings of this medicine was in line with what was seen in previous dosings," Dr. Fox said.
Alemtuzumab is already approved elsewhere. On June 28, 2013, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use adopted a positive opinion supporting marketing authorization for alemtuzumab, and on September 17, the EMA approved alemtuzumab for the treatment of adult patients with relapsing-remitting MS with active disease defined by clinical or imaging features. The EMA did not limit the use of alemtuzumab to second-line treatment.
In December, Health Canada also approved alemtuzumab for management of adult patients with active disease defined by clinical and imaging features, but in Canada, it is limited to those with an inadequate response to interferon-beta or other disease-modifying therapies.
The study was supported by Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceutical. Dr. Arnold received personal compensation for activities with Acorda, Bayer Healthcare, Biogen Idec, Merck Serono, Genentech, Genzyme, GlaxoSmithKline, MedImmune, Novartis, Receptos, Roche, sanofi-aventis, Teva, and NeuroRx Research; holds stock and/or stock options in NeuroRx Research; and has received research support from Bayer HealthCare. Dr. Fox has received personal compensation for activities with Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Opexa, Roche, Sanofi, and Teva and research support from Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Opexa, Roche, Sanofi-Aventis, and Teva. Disclosures for all coauthors appear in the abstract.
American Academy of Neurology (AAN) 66th Annual Meeting: Emerging Science Abstract 008. Presented April 30, 2014.
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Cite this: Alemtuzumab Extension Shows Durable MRI Effects in MS - Medscape - May 02, 2014.