From FDA Approvals > Medscape Medical News
September 12, 2012 — The US Food and Drug Administration (FDA) has approved a second oral agent for the treatment of relapsing forms of multiple sclerosis (MS), teriflunomide (Aubagio, Genzyme/Sanofi).
“In a clinical trial, the relapse rate for patients using Aubagio was about 30% lower than the rate for those taking a placebo,” said Russell Katz, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “Multiple sclerosis can impair movement, sensation, and thinking, so it is important to have a variety of treatment options available to patients.”
The most common side effects experienced by patients in clinical trials include diarrhea, abnormal liver tests, nausea, and hair loss, the statement notes. A boxed warning will alert prescribers to the risk for liver problems, including death, and a risk for birth defects with use of teriflunomide. “Physicians should do blood tests to check liver function before a patient starts taking Aubagio, and periodically during treatment,” the FDA statement notes.
The boxed warning points out that, based on animal studies, the drug may be teratogenic, important because many patients with MS are women of childbearing age. “For this reason, Aubagio is labeled as Pregnancy Category X, which means women of childbearing age must have a negative pregnancy test before starting the drug and use effective birth control during treatment.”
The drug will be dispensed with a patient Medication Guide, the statement adds, “that provides important instructions on its use and drug safety information.”
Aaron Miller, MD, Medical Director of the Corrinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, was a member of the steering committee involved in the development of this drug. “It’s exciting to have another oral option available for people with MS,” he told Medscape Medical News.
“This is the second oral agent, and one that carries perhaps some ease of getting patients on the drug compared to the existing oral agent, and also it appears to be a very safe agent based on 2 very large clinical trials plus a very long history of use of leflunomide, a drug for which [teriflunomide] is an active metabolite,” Dr. Miller said.
Leflunomide is used to treat rheumatoid arthritis and has a history of an estimated 2.1 million patient-years of exposure, according to a statement from Genzyme.
“We are greatly encouraged to see a new oral therapeutic option become available to people living with MS,” said Timothy Coetzee, MD, chief research officer at the National MS Society, in the Genzyme release. “With collaborative research underway around the world today, this is an extremely hopeful time for anyone who is diagnosed with MS.”
TEMSO, TENERE, TOWER
Teriflunomide is a once-daily oral immunomodulator developed as a disease-modifying therapy for MS. It reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in de novo pyrimidine synthesis for DNA replication. As a result, the drug reduces T- and B-cell proliferation and function in response to autoantigens but preserves the replication and function of cells living on their pyrimidine pool, including hematopoietic cells or memory T cells, through the so-called salvage pathway.
Approval is based on results of a program of phase 3 trials. Results of the TEriflunomide Multiple Sclerosis (TEMSO) trial, published in the New England Journal of Medicine in 2011, showed a significant reduction in annualized relapse rate and sustained accumulation of disability with both the 7- and 14-mg daily doses vs placebo.
A second phase 3 trial, TENERE, showed the agent was similar to interferon beta-1a (Rebif, Merck Serono), a standard approved treatment for MS.
A third trial, Teriflunomide Oral in people With relapsing-remitting multiplE scleRosis (TOWER), showed a significant reduction in annualized relapse rates and sustained accumulation of disability with the 14-mg dose vs placebo. A second dose studied in this trial, 7 mg, showed a reduction in relapse rate but not in sustained accumulation of disability.
In these trials, the incidence of serious adverse events was similar between teriflunomide- and placebo-treated patients, the Genzyme statement notes. The most common adverse events associated with treatment were increased alanine aminotransferase levels, alopecia, diarrhea, influenza, nausea and paresthesia.
Two other phase 3 trials are still ongoing, the TOPIC trial in early MS or clinically isolated syndrome, and TERACLES, investigating teriflunomide as an adjunct to therapy with interferon.
Genzyme also has a second candidate treatment for MS under consideration by FDA with the phase 3 program of alemtuzumab (Lemtrada). Alemtuzumab is given for 5 days intravenously, then for 3 days 1 year later, and has been shown to be superior to interferon in the CARE-MS 1 and CARE-MS 2 trials.
The company hopes teriflunomide could provide an option for first-line therapy, while alemtuzumab would provide an alternative for patients who continue to have disease activity on first-line treatment. Genzyme reported earlier this month though that they received a Refuse to File letter from the FDA on alemtuzumab, asking for revisions to the presentation of the data so regulators could “better navigate” the application.
“We have had constructive dialogue with the FDA, and we are very confident in our ability to address the agency’s request and resubmit rapidly,” noted David Meeker, president and CEO of Genzyme, in a company release at the time.
“We are very excited to introduce Aubagio as a new treatment option that can make a difference in the lives of people with multiple sclerosis,” Meeker said in the new Genzyme statement. “The approval of our first MS therapy represents an important milestone for Genzyme and underscores our commitment to long-term leadership and partnership in the MS community.”
Fingolimod (Gilenya, Novartis) was the first oral treatment approved in September 2010 for relapsing MS. Since then, changes have heen made to the label to reflect FDA concerns about cardiovascular effects of the drug after the first dose.
A release from Novartis on the teriflunomide approval underlines the safety record of fingolimod.
“Novartis pioneered the advent of oral MS treatments with the introduction of Gilenya (fingolimod), the only once-a-day oral disease modifying therapy (DMT) for relapsing MS with proven efficacy beyond an injectable therapy (interferon beta-1a),” the statement notes. “Gilenya is approved for first line therapy, and studies have consistently shown that it works across multiple disease activity measures.”
In postmarketing experience, the statement adds, fingolimod “has a demonstrated safety profile established in both clinical trials and real-world use in approximately 41,000 patients worldwide.”
Two other candidates for oral treatment are in late-stage investigation: BG-12 (dimethyl fumarate, Biogen Idec) has been shown in 2 phase 3 trials, DEFINE and CONFIRM, to reduce relapse rates, and has been submitted for review to the FDA and the European Medicines Agency.
Another agent, laquinimod (Teva Pharmaceuticals Inc./Active Biotech), had something of a setback when large phase 3 trials ALLEGRO and BRAVO showed somewhat divergent results; now, a third large trial, CONCERTO, will hopefully clarify effects of the drug.
Dr. Miller reports he has been a member of the steering committee that has been involved in the development of teriflunomide.
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