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Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.
"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.
Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.
• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.
The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.
That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.
• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.
Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.
Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).