Dr. Miller: In my opinion, there’s not necessarily a best treatment option to recommend to most individual patients, with rare exceptions. The best treatment option is the option of an acceptable, approved disease-modifying therapy that the patient feels comfortable taking.
Now, clearly, most patients would have a preference, from a quality of life point of view, for an oral therapy over an injectable therapy. Nonetheless, some patients prefer the comfort and security of knowing that the injectable agents have been around for a substantial number of years and have an extremely favorable safety profile, and we know that we’re not going to get any surprises with the interferons or glatiramer acetate.
However, if the patient does not want to take an injectable medicine, then there are a number of options. And in every case, I personally discuss all of the available options with patients. We now have eight drugs that are FDA-approved for treatment of relapsing MS.
With regard to those choices, natalizumab is probably our most effective agent. It reduces relapse rates by about 68%, which is substantially more than with any of the other agents (Polman CH et al. N Engl J Med. 2006;354:899-910). Now, one has to have the caveat that natalizumab has not been tested head to head in a clinical trial with any other agent. Nonetheless, I think most MS specialists do believe that it is the most effective agent. Now, natalizumab, of course, carries the concern of the development of PML [progressive multifocal leukoencephalopathy] in patients who have been on the drug for a while and who are infected with JC virus, the causative agent for PML. We now have the ability to obtain JC virus–antibody testing, which absolutely should be done before prescribing this drug. In patients who are antibody-negative, the risk of PML is exceedingly low. The reported figures cite a hypothetical risk of less than 1 in 10,000 (Bloomgren G et al. N Engl J Med. 2012;366:1870-1880). We now test patients at least every 6 months for JC virus. So if a patient is antibody-negative, then natalizumab is an excellent option.
Moving to the oral options, we currently have two FDA-approved options, fingolimod and teriflunomide. And we’re awaiting the expected approval of BG-12.
Fingolimod is a quite effective oral agent and very well tolerated in its once-a-day usage (Kappos L et al. N Engl J Med. 2010;362:387‐401; Khatri B et al. Lancet Neurol. 2011;10:520; Cohen JA et al. N Engl J Med. 2010;362:402‐415). It needs to be avoided in patients with certain cardiac risk factors, and there still is some lingering concern about the potential for unusual infections, or even neoplasms, with prolonged usage (U.S. Food and Drug Administration. Gilenya [fingolimod]: Drug Safety Communication. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm284355.htm. Accessed January 28, 2013; U.S. Food and Drug Administration. Gilenya [fingolimod] Risk Evaluation and Mitigation Strategy. www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm227965.pdf. Accessed January 28, 2013). That’s not because we have seen those signals, but just because of the way the drug works in terms of lowering circulating lymphocyte counts very dramatically.
Teriflunomide is a once-a-day oral agent available in two doses, but generally the 14 mg higher dose will be prescribed, because it’s more effective. This drug appears to be approximately equal in efficacy to the interferons (Genzyme, a Sanofi company. Press Release, December 20, 2011. http://online.wsj.com/article/PR-CO-20111220-900070.html. Accessed January 8, 2013), and by inference to glatiramer acetate. It’s generally well tolerated, and the safety profile is very similar to leflunomide, which is a drug that’s been on the market for over a decade to treat rheumatoid arthritis. So we have a good sense of what to expect with teriflunomide. There are important tolerability and safety considerations when considering this drug (Aubagio [teriflunomide] Prescribing Information. http://products.sanofi.us/aubagio/aubagio.pdf. Accessed January 9, 2013). This would certainly not be a good drug to use in a woman of childbearing age who still has some contemplation of pregnancy. Teriflunomide carries a category X pregnancy rating because of the risk of teratogenesis, and so women who use this drug must absolutely be counseled to make sure that they are practicing an effective contraceptive method. Patients considering the use of teriflunomide should also be informed that liver enzymes need to be monitored monthly for the first 6 months. Patients should also know about the possibility of GI side effects—nausea or diarrhea—and the possibility of mild hair thinning. Teriflunomide candidates should also be informed about the need to do an accelerated elimination protocol when they stop teriflunomide, because the drug remains in the body for a very long time, perhaps even as long as 2 years. So generally, patients who come off the drug will take cholestyramine three times a day for 11 days to get rid of all of the teriflunomide.
Finally, if one is having this conversation after the approval of BG-12, one should note that the efficacy of that drug appears to be comparable to that of fingolimod, with approximately a 50% reduction in relapse rate (Fox R et al. New Engl J Med. 2012;367:1087-1097; Gold R et al. New Engl J Med. 2012;367:1098-1107).
Narrator: It should be noted that there is the caveat that these two drugs have not been compared in a head-to-head trial.
Dr. Miller: BG-12 has been tested against glatiramer acetate, but not against the other oral medications, so you have to take that difference in annualized relapse rate reduction with a grain of salt. Again, patients should be informed of the possibility of gastrointestinal side effects—nausea and vomiting in particular—and the possibility of flushing.