The competition in the treatment of multiple sclerosis has been heating up. Merck (MRK), Novartis (NVS), Sanofi (SNY), Biogen (BIIB), and Teva (TEVA) have all invested heavily in developing an oral drug to treat multiple sclerosis.
Merck dropped out when it gave up on Cladribine. Novartis is jumping into the market, but has limited experience, while multiple sclerosis stalwarts like Biogen and Teva are getting ready to release new drugs with the hope of easier administration and improved efficacy. Since multiple sclerosis is a variable disease, the more treatment options that are available, the better for the patient.
Gilenya was Novartis' first entry into the multiple sclerosis market and it has had mixed results so far. After being fast tracked by the FDA for approval, patients taking Gilenya had some serious side effects that required the FDA to monitor the drug more closely. These side effects have hampered Gilenya's growth. Gilenya does have the distinct advantage of being the only one drug currently approved by the FDA. Sales have been growing year over year, and in 2011 Gilenya brought in over $500 million in revenues for Novartis.
Sales of Gilenya started off strong due to extremely strong data in a Phase III study published by the New England Journal of Medicine. The study showed that Gilenya was superior to interferon beta-1a (Avonox) in reducing relapse rates in patients with multiple sclerosis. This study also had two patients on the 1.25mg dose of Gilenya die due viral infections. Patients on this dose also had higher rates of discontinuation due to side effects, than patients taking Gilenya 0.5mg or Avonox.
It is important to not that the 1.25mg dose was not approved by the FDA and currently only the 0.5mg dose is available. Another trial called the FREEDOMS trial once again showed that Gilenya was statistically superior at reducing relapse rates, this time Gilenya was compared to placebo. Once again, the higher dose of Gilenya showed higher rates of severe side effects, while the 0.5mg dose was similar to placebo.
Mostly known as a generic manufacturer, Teva has a few name brand medications. By far the most successful is Copaxone, which is a mainstay for the treatment of multiple sclerosis. In the next couple of years, Copaxone will lose its patent protection, and Teva is hoping that laquinimod can help reclaim some of those lost sales. Laquinimod is taken orally once daily, and is a immunomodulator.
Of the four drugs presented, laquinimod is the least likely to be successful. Originally getting a fast track designation by the FDA, subsequent studies yielded poor results, which led to Teva not to apply for a new drug application with the FDA. However, a recent study showed positive results and Teva plans to go ahead and file with the EMA so an FDA application could be coming.
Teva's biggest obstacle in getting FDA approval will be will be previous trials that failed to meet their goals. One thing laquinimod does have in its favor is that it is tolerated extremely well and doesn't seem to have some of the major side effects that plague multiple sclerosis drugs.
ALLEGRO: The most recent study involving laquinimod was generally positive and published in the New England Journal of Medicine. The ALLEGRO study focused on patients with relapsing multiple sclerosis and followed them for two years. It compared laquinimod to placebo, and found that it significantly decreased relapse rates. This study was generally considered successful, the study also showed that laquinimod was tolerated extremely well.
BRAVO: Another study that compared laquinimod to placebo, the BRAVO trial yielded positive and negative results. The bad news was that laquinimod did not meet its primary end point, which was to reduce annualized relapse rates. The good news was that although the patients were randomly assigned, the group taking laquinimod as a whole had more progressed multiple sclerosis. When taking this into account, laquinimod was shown to significantly reduce relapse rates. Once again, laquinimod was tolerated extremely well.
Biogen is the world leader in multiple sclerosis, with its injectable treatments Avonex and Tysabri. With BG-12, Biogen might have a true blockbuster on its hands, which will help it maintain itself as the global leader. BG-12 appears that it might be safer than Gilenya and more effective than laquinimod. The only major weakness of BG-12 appears that it has to be taken multiple times a day. Biogen has already submitted an NDA to the FDA, so it could become available later this year. In a few years time, BG-12 will most likely be the most successful of all the oral MS drugs.
DEFINE: The DEFINE trial compared BG-12 to placebo. The results were impressive, with a 50% reduction in relapses. Secondary endpoints were also met with BG-12 reducing lesions and disability progression compared to placebo. BG-12 also showed no increase risk of infection compared to placebo, which is very important.
CONFIRM: The results from the second of BG-12's Phase III trials mirrored the results of the DEFINE trial. The study compared BG-12 twice daily and three times daily to placebo with patients that have relapsing multiple sclerosis. It decreased relapse rates by 34% to 45%, while also outperforming Copaxone in a comparison arm. Even more impressive BG-12 had a similar side effect profile to the patients taking placebo.
Sanofi looks like it will have the third oral multiple sclerosis drug on the market after Gilenya and BG-12. Unfortunately, it looks like it might be the odd man out. Terifluonomide doesn't have the advantage of being the first available like Gilenya, and its data is not as impressive as BG-12. Terifluonomide is an active metabolite of leflunomide, which Sanofi markets for the treatment of Rheumatoid arthritis.
TEMSO: The TEMSO trial compared terifluonomide once daily to placebo in the treatment of patients with at least one relapse in the previous year. The primary endpoint measured relapse rates. Terifluonomide was shown to decrease relapse rates by 31% compared to placebo. The 14mg dose of terifluonomide was also shown to significantly decrease the number of patients with confirmed disability progression. Terifluonomide also reported a few side effects, including nausea, diarrhea, hair thinning, and elevated alanine aminotrasferase levels.