Aubagio approved in the UK for MS:
Previously approved by the FDA in September 2012, the oral MS drug teriflunomide (Aubagio) has now been accepted for use in the United Kingdom (UK) National Health Service by the National Institute for Health and Care Excellence (NICE) for the treatment of patients with relapsing-remitting MS. Teriflunomide (14-mg dose) had been approved by the European Medicines Agency (EMA) in August 2013. Two doses of Aubagio were tested in two phase 3 placebo-controlled studies. Results from the first study showed a 31% reduced risk of relapses for both the 7-mg and 14-mg doses compared to placebo, and reductions of disability progression of 23.7% and 29.8%, respectively. Results from the second phase 3 study, published January 23 online in Lancet Neurology, showed reduced risk of relapse of 22% for the 7-mg dose and 36% for the 14-mg dose vs placebo, and reduction of disability progression of 4.5% and 31%, respectively. Risks associated with Aubagio include lowered peripheral leukocytes, raised liver enzymes, reversible hair thinning and diarrhea, and possible birth defects.
NICE says "no" to Tecfidera:
Dimethyl fumarate (Tecfidera, aka BG12) was approved this month by the EMA as a first-line treatment for RRMS. However, NICE has declined coverage of Tecfidera at this time. Sir Andrew Dillon, NICE Chief Executive, said: "When reviewing the evidence for dimethyl fumarate, the Appraisal Committee concluded that there were still questions to be answered about the clinical and cost effectiveness of the drug for adults with relapsing-remitting multiple sclerosis." NICE has requested additional information and further clarification from Biogen idec regarding trial outcomes and pairwise comparisons of cost-effectiveness estimates of Tecfidera and other disease-modifying therapies prescribed for MS. Dillon said: "We want to ensure that we have as much information as possible to make an informed final recommendation."
Tecfidera is an oral tablet taken twice a day. In two phase 3 placebo-controlled studies, Tecfidera reduced the number of relapses by 53% and 34% compared to placebo, and reduced the risk of disability progression by 38% in one trial and 21% in the other (which is not statistically significant). The most common side-effects associated with Tecfidera are flushing and gastrointestinal events, including diarrhea, nausea, abdominal pain, and upper abdominal pain. Risks associated with Tecfidera include decreased lymophocyte counts, raised liver enzymes (in the first 6 months of treatment), and possible birth defects.
Studies suggest caution in using Gilenya:
In clinical trials, changes in female menstrual cycles was not a reported adverse event associated with Gilenya (fingolimod). However, a case report of three young women who developed amenorrhea within 6 months of starting Gilenya was recently published. The women in Kuwait experienced irregularities in their menstrual cycles in the first 3 months, which progressed to an absence of cycles by the 5th or 6th month. The women’s cycles returned to normal 2-3 months after they stopped taking Gilenya (Alroughani, 2014).
A separate report reinforces the need for effective contraception in women taking Gilenya. Exposure to Gilenya during the early stages of pregnancy may be linked to an increased risk of birth defects (Jones, 2014). A review of the safety-related pregnancy data surround oral disease-modifying drugs for MS, including fingolimod, dimethyl fumarata, laquinimod, and firategrast, was also published (Lu, 2014).
A 12-month phase 2 extension study of fingolimod in Japanese patients with RRMS demonstrated efficacy and safety in patients who received fingolimod continuously for 12 months or who switched from placebo to fingolimod in months 7-12. Of 147 patients who completed the 6-month core study, 143 entered the extension phase of the trial. However, three individuals positive for AQP4-antibodies developed relapses very rapidly after starting fingolimod (Kira, 2014). Approximately 65% patients diagnosed with neuromyelitis optica (NMO) test positive for AQP4-antibodies (Sato, 2014). Findings from the extension study suggest that fingolimod lacks benefit in AQP4 antibody-positive patients and caution is needed if introducing fingolimod in patients with idiopathic central nervous system demyelinating disease, including NMO or opticospinal MS (Kira, 2014).
Reduced relapses after switching from beta interferon to fingolimod:
Sometimes it is difficult to decide which drug to choose when switching from one disease-modifying treatment to another. But knowing more about what might happen when you switch can help you to decide.
In a retrospective study published this month, researchers assessed the differences in relapse rates among two groups of patients with MS who switched from an interferon beta therapy (such as Avonex, Betaseron, Rebif, or Extavia) to either fingolimod (Gilenya) or glatiramer acetate (GA; Copaxone) using an insurance claims database. In the 90 days before switching, 33.3% of patients in either group had experienced at least one relapse.
In the 360 days after switching medications, the proportion of patients with at least one relapse was lower in the fingolimod group (12.9%) than in the GA group (25.0%), and annualized relapse rates (ARRs) were lower with fingolimod (0.19) than with GA (0.51). Patients treated with fingolimod had a 59% lower probability of experiencing a relapse, 62% fewer relapses per year and a longer time to relapse (360 vs. 274 days) than patients treated with GA. However, authors note that it may take up to 9 months for Copaxone to become fully effective, but only 3 months for Gilenya, so the higher relapse rates seen in the GA group could reflect a loss of disease control as a result of this difference.
Relapse risk after switching from Tysabri to Gilenya:
In another study, researchers collected data from patients with MS (n=333) who were switching from natalizumab (Tysabri) to fingolimod (Gilenya) after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; 71% were JCV positive). Data was collected regarding treatment with Tysabri, the duration and management of the washout period (WP) after stopping Tysabri, and any relapses or adverse events occurring during the WP and during the 6 months after patients started Gilenya.
During the washout period, 27% of patients relapsed. The risk for relapse was 3.2 times higher for patients who stopped natalizumab because of poor tolerance or lack of efficacy. Washout periods shorter than 3 months were associated with 77% lower risk of relapse during the WP, but also with less disease activity before natalizumab treatment. Twenty percent (20%) of patients relapsed during the first 6 months of treatment with fingolimod, while 3% stopped fingolimod due to issues with efficacy, tolerance, or compliance. Researchers found that the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P"‰="‰.05). They also recommend that washout periods should be shorter than 3 months (Cohen, 2014).
Alroughani R. Fingolimod-associated amenorrhea: a report of three cases. Mult Scler. 2014 Feb 10. [Epub ahead of print]
Bergvall N, Makin C, et al. Relapse Rates in Patients with Multiple Sclerosis Switching from Interferon to Fingolimod or Glatiramer Acetate: A US Claims Database Study. PLoS One. 2014 Feb 6;9(2):e88472. doi: 10.1371/journal.pone.0088472. eCollection 2014.
Cohen M, Maillart E, et al. Switching From Natalizumab to Fingolimod in Multiple Sclerosis: A French Prospective Study. JAMA Neurol. 2014 Feb 24. doi: 10.1001/jamaneurol.2013.6240. [Epub ahead of print]
Confavreux C, O’Connor P, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar;13(3):247-56. doi: 10.1016/S1474-4422(13)70308-9. Epub 2014 Jan 23.
Jones B. Multiple sclerosis: Study reinforces need for contraception in women taking fingolimod. Nat Rev Neurol. 2014 Feb 11. doi: 10.1038/nrneurol.2014.22. [Epub ahead of print]
Kira J, Itoyama Y, et al. Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. BMC Neurol. 2014 Jan 29;14:21. doi: 10.1186/1471-2377-14-21.
Lu E, Wang BW, et al. A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis. CNS Drugs. 2014 Feb;28(2):89-94. doi: 10.1007/s40263-013-0131-5.
Sato DK, Callegaro D, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014 Feb 11;82(6):474-81. doi: 10.1212/WNL.0000000000000101. Epub 2014 Jan 10.