快樂小藥師 Im pharmacist nichts glücklich

The US Food and Drug Administration (FDA) has approved a second oral agent for the treatment 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 cause fetal harm, 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.

TEMSO, TENERE, TOWER

Teriflunomide is a once-daily oral immunomodulator developed as a disease-modifying therapy for MS. The active metabolite of leflunomide, teriflunomide 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.

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, the Rare Disease Unit of Sanofi, in a company release at the time.

Fingolimod (Gilenya, Novartis) was the first oral treatment approved in September 2010 for relapsing MS. Since then, changes have been made to the label to reflect FDA concerns about cardiovascular effects of the drug after the first dose.

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.