French Pharmaceuticals Multinational Sanofi and its subsidiary Genzyme, which makes Lemtrada, say they strongly disagree with the U.S. Food and Drug Administration’s (FDA) recent rejection of approval of its new Lemtrada (alemtuzumab) drug for treatment of relapsing forms of multiple sclerosis.
After receiving a Complete Response Letter from the FDA for its supplemental Biologics License Application seeking approval of Lemtrada Sanofi says it disagrees with the FDA’s conclusions and plans to appeal the agency’s decision that its Lemtrada application is not ready for approval.
“We are extremely disappointed with the outcome of the review and the implications for patients in the U.S. suffering with multiple sclerosis who remain in need of alternative therapies to manage a devastating disease,” says Genzyme President and CEO, David Meeker, M.D. in a release. “We strongly believe that the clinical development program, which was designed to demonstrate how Lemtrada compares against an active comparator as opposed to placebo, provides robust evidence of efficacy and a favorable benefit-risk profile. This evidence was also the basis for the approvals of Lemtrada by other regulatory agencies around the world.”
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The company notes that the FDA takes the position that Genzyme has not submitted evidence from adequate and well-controlled studies to demonstrate that benefits of Lemtrada outweigh its serious adverse effects. Genzyme says it understands that the conclusion is related to the design of the completed Phase 3 active comparator studies of Lemtrada in relapsing-remitting MS patients. The FDA has also taken the position that one or more additional active comparator clinical trials of different design and execution are needed prior to the approval of Lemtrada.
Lemtrada is already approved in the European Union, Canada, and Australia, and additional marketing applications for the drug are under review by regulatory agencies around the world, Sanofi does not anticipate that the CVR milestone of U.S. approval of Lemtrada by March 31, 2014 will be met.
Sanofi explains that the Lemtrada clinical development program included two pivotal randomized Phase III studies comparing treatment with Lemtrada to EMD Serono Inc.’s Rebif (high-dose subcutaneous interferon beta-1a) in patients with RRMS who had active disease and were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II), as well as an ongoing extension study. They report that in CARE-MS I, Lemtrada was significantly more effective than Rebif at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance. In CARE-MS II, Lemtrada was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was significantly slowed in patients given Lemtrada vs. interferon beta-1a.
The most common side effects of Lemtrada are infusion associated reactions, infections (upper respiratory tract and urinary tract), lymphopenia and leukopenia (low white cell count). Serious autoimmune conditions can occur in patients receiving Lemtrada. Sanofi maintains that comprehensive risk management program will support early detection and management of these autoimmune events.
Some 2.1 million people in the world suffer from MS, including 410,000 in the United States. An autoimmune disease that affects both the central nervous system and the spinal cord, MS is the most common disabling neurological disease in young adults after road accidents, and two to three times more common in women than in men. MS is usually characterized by periods of relapse (when scars in the nerve systems’ protective myelin sheathing occur) followed by periods of complete or incomplete remission. The disease is a highly variable condition, and symptoms depend on which areas of the central nervous system have been affected, can vary from time to time, and can change in severity and duration, even in the same person.
Alemtuzumab is a monoclonal antibody that selectively targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, rebalancing the immune system in a way that potentially reduces MS disease activity. Genzyme holds the worldwide rights to alemtuzumab and has primary responsibility for its development and commercialization in multiple sclerosis. Bayer HealthCare holds the right to co-promote alemtuzumab in MS in the United States. Upon commercialization, Bayer will receive contingent payments based on global sales revenue.
According to an AdverseEvents report, Alemtuzumab was originally approved under the brand name Campath, in 2001 for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL). It is an intravenously infused humanized monoclonal antibody which targets CD52, a glycoprotein found on the surface of normal and malignant lymphocytes. In September 2012, Genzyme removed Campath from the commercial market in preparation for a commercial relaunch of the product as Lemtrada.
AdverseEvents says that last November, FDA reviewers raised significant concerns regarding the safety profile of Lemtrada and the adequacy of the efficacy data, with FDA safety reviewer Dr. Evelyn Mentari noting several “serious and potentially fatal” safety concerns associated with the use of Lemtrada, including:
• The incidence of an array of autoimmune diseases including immune thrombocytopenia (ITP), autoimmune hemolytic anemia, immune pancytopenia, anti-glomerular basement membrane (Anti-GBM) disease, membranous glomerulonephritis, thyroid disorders, endocrine ophthalmopathy, acquired hemophilia A, type 1 diabetes mellitus, acute epitheliopathy of the retina, and autoimmune skin disease.
• Undifferentiated connective tissue disorders, along with the incidence of malignancies, notably including thyroid cancer and melanoma.
Using FAERS data (from 11/01/1997 to 12/31/2012), aggregated and standardized by the AdverseEvent RxFilter process, AdserseEvents say they identified 3,450 serious adverse events which listed alemtuzumab (Campath) as a suspect drug. Of these reports, 1,976 listed alemtuzumab as the primary suspect. The most commonly reported side effects were pyrexia, cytomegalovirus infection, and chills. AdverseEvents identified 862 hospitalizations and 536 patient deaths where alemtuzumab was indicated as the primary suspect.
The report goes on to say:
“We identified 115 cases which listed alemtuzumab as the primary suspect drug which involved blood autoimmune disorders, endocrine autoimmune disorders, skin autoimmune disorders, general autoimmune disorders, anti-glomerular basement membrane (anti-gbm) disease, diabetes, melanoma, or malignant thyroid cancer. Note: In order to calculate the total number of cases involving blood autoimmune disorders, endocrine autoimmune disorders, skin autoimmune disorders, general autoimmune disorders, anti-glomerular basement membrane (anti-gbm) disease, diabetes, melanoma, or malignant thyroid cancer, we aggregated reports listing the following adverse events: MedDRA Preferred Term: Anti-glomerular basement membrane antibody positive, MedDRA Preferred Term: Anti-glomerular basement membrane antibody, MedDRA High-Level Term: Autoimmune disorders NEC, MedDRA High-Level Term: Blood autoimmune disorders, MedDRA High-Level Term: Diabetes mellitus (incl subtypes), MedDRA High-Level Term: Endocrine autoimmune disorders, MedDRA High-Level Term: Skin autoimmune disorders NEC, MedDRA High-Level Term: Skin melanomas (excl ocular), and MedDRA High-Level Term: Thyroid neoplasms malignant.”
Hence the FDA’s decision that one or more clinical trials of different design and execution are required before Lemtrada can be approved.
Sanofi’s headquarters are located in Paris, France, and it maintains offices and facilities in more than 100 countries, including U.S. subsidiary Sanofi-Aventis U S Inc. in Dallas. The company’s Genzyme subsidiary focuses on rare diseases and multiple sclerosis.