The US Food and Drug Administration (FDA) has approved alemtuzumab (Lemtrada, Genzyme, a Sanofi Company) for the treatment of relapsing forms of multiple sclerosis (MS).
"Because of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS," notes a company statement released late Friday.
The alemtuzumab label includes a boxed warning risk for serious, sometimes fatal autoimmune conditions and serious, life-threatening infusion reactions, according to the release, and the drug may cause an increased risk for malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders.
"Lemtrada is only available through a restricted distribution program, the Lemtrada REMS (Risk Evaluation and Mitigation Strategy). This program has been developed to ensure that access to Lemtrada in the US is only through certified prescribers, healthcare facilities and specialty pharmacies and to also ensure that patients are enrolled in the REMS program," the company statement said.
"The program is intended to help educate healthcare providers and patients on the serious risks associated with Lemtrada and the appropriate periodic monitoring required to support the detection of these risks for 48 months after the last infusion," it says. The REMS is based on a developmental risk management program that was successfully implemented in the phase 2 and phase 3 trials and allowed for early detection and management of some of the serious risks associated with the drug, it notes.
Alemtuzumab, 12 mg, is given in two annual treatment courses, the first as an intravenous infusion delivered over 5 consecutive days, and the second over 3 consecutive days 12 months later.
In September 2012, Genzyme announced that the FDA had issued a "Refuse to File" letter on its application, asking for a revision in the presentation of the data so that regulators might "better navigate" the application. In November 2013, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee gave the drug a mixed review, and in December 2013, the FDA declined approval for the drug.
The agency took the position that "Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects," the company said in a release at the 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 also said one 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.
The declined approval was met with disappointment and frustration among investigators involved in its development, as reported by Medscape Medical News.
"The FDA approval of Lemtrada is a significant milestone for people living with relapsing MS in the United States," Timothy Coetzee, chief advocacy, services and research officer at the National MS Society says in the latest release from Genzyme. "We are pleased that the voices of the MS community have been recognized and that people with relapsing MS will now have access to a new, needed treatment option."
First approved in September 2013 in the European Union, alemtuzumab is now approved in more than 40 countries. Additional marketing applications are under review by regulatory agencies around the world, the release adds.
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 under a different brand name (Campath, Genzyme). However, the company limited access to the Campath alemtuzumab product in the United States and the European Union to prevent off-label use of it in MS before approval.
Approval for this new indication is based on two pivotal phase 3 trials that confirmed treatment was associated with reductions in relapse rates in patients with relapsing-remitting multiple sclerosis (MS). In one trial, there was also reduced sustained accumulation of disability vs standard treatment with interferon β-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 in patients who had had at least one relapse while receiving disease-modifying therapy compared with standard therapy with interferon β-1a in patients with relapsing-remitting MS.
Results from CARE-MS I, a phase 3 comparison of alemtuzumab and interferon β-1a in treatment-naive patients, showed a significant reduction in relapse rates at 2 years, but there was no significant effect on sustained accumulation of disability with alemtuzumab. Findings from the CARE-MS I and CARE-MS II trials were published in The Lancet.
The most common adverse effects of alemtuzumab are rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.
Alemtuzumab is also contraindicated in patients with HIV infection.
"The unmet need in MS remains high," said investigator Edward Fox, MD, PhD, director of the Multiple Sclerosis Clinic of Central Texas in the new statement. "It is a great day for people living with relapsing forms of MS in the United States, who will now have access to this new meaningful treatment."
Full US prescribing information for alemtuzumab, including boxed warning and contraindications, can be found here.
The FDA approval is the second MS treatment for Genzyme after teriflunomide (Aubagio), an oral agent for the treatment of relapsing MS, in September 2012.
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Cite this: FDA Approval for Alemtuzumab (Lemtrada) in MS - Medscape - Nov 15, 2014.