Patients, clinicians and researchers in the world of multiple sclerosis treatment are awaiting the next meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) October 13-16 in Gothenburg, Sweden. There has been some late breaking news on the upcoming oral treatments published in anticipation of the meeting, and leaked to generate pre-meeting hype. Multiple sclerosis (MS) is an autoimmune disease during which the patient’s immune system attacks the myelin sheaths covering the neuronal axons in the central nervous system. This immune response causes inflammation around the neurons and the destruction of the myelin sheath results in neurodegeneration. Clinical signs are variable and can include weakness, numbness, tingling sensations, balance problems, stumbling, depression and blurred vision. The severity of symptoms, the frequency of symptoms and the rate of progression varies widely, but fifty percent of patients will need help walking within 15 years after the onset of disease. Most commonly, the disease is characterized by clinical bouts of disease that are followed by partial or complete recovery. Symptoms may then be inactive for months, or even years. This form of MS (which affects about 85% of MS sufferers) is called relapsing-remitting MS. Until last year, all the therapies for MS were injectable biologics. Although none of the therapies stop the disease, it is well accepted that early treatment is desirable to slow the non-reversible neurodegeneration due to myelin sheath damage. The most common first line treatment is injections of interferon beta-1, an immune modulator. Interferon beta-1 treatment generally decreases the rate of relapse by 30% compared to no treatment. There are four interferon beta-1s on the market in the US. Biogen Idec’s Avonex has the largest market share because it only has to be injected once a week. Merck KGaA (Rebif), Bayer (Betaseron) and Novartis (Extavia) also have versions of interferon beta on the market. A second first-line treatment is marketed by Teva (Copaxone).
In late 2010, the first oral therapy for multiple sclerosis was approved by the FDA. The drug called Gilenya (fingolimod) is a sphingosine-1 phosphate receptor modulator that showed reduction in rate of relapses comparable to interferon, but was a once a day pill instead of requiring injections (1). The state of art at that time was reviewed by this Boston Health News Examiner (First Multiple Sclerosis pill approved in US will change treatment paradigm), and outlined the tense race between 4 competitors for the oral market. The closest competitor was Cladribine (Merck KGaA), a preferential inhibitor of DNA synthesis and repair in T and B cells. It was designed to be taken over 5 days only once or twice a year, but it’s immunosuppressive effects lasted for months. In November 2009, the FDA rejected the application due to incompleteness. The EMEA rejected the application in Europe in 2010, and Merck withdrew it’s European application. Early this year, the FDA issued a complete response letter requesting a substantial amount of additional data, and the word is that Merck KGaA may have abandoned this drug. It is likely that alarm bells went off at both the EMEA and the FDA due to the extremely prolonged effect of the 5 day course of treatment and fears of sequellae from long term, non-reversible immunosuppression. So, Novartis has had a pleasant surprise as it’s closest competitor is no longer breathing down their neck, and Gilenya is still the only oral therapeutic for MS on the market.
Also apparently out of the running is Teva’s laquinimod, which did not reach it’s primary endpoint of reduction in relapse rate compared to placebo in a study reported in August 2011. Teva is sticking to it’s guns, as it reanalyzed the data and observed that there were differences in baseline MRI scans between the laquinimod-treated and placebo-treated groups. If they normalized for this, the laquinimod group did show statistical improvement, but no drug to treat MS has ever been approved based on normalized data, and it is not likely that the FDA will accept this as supporting an approvable drug. Perhaps Teva should stick to formulating generics and leave the more complicated task of clinical trial design and implementation to others with that specific expertise.
There are still 2 more drugs in the race, and both reported positive results this week. In the Oct 6 New England Journal of Medicine (2) the phase 3 results of a trial of teriflunomide (Sanofi-Aventis) in 1088 patients was reported. Teriflunomide blocks new pyrimidine synthesis thereby inhibiting proliferation of T and B lymphocytes. This once a day oral drug was compared to placebo in a 2 year trial comparing two doses, both administered once a day. Both doses decreased relapse rate significantly compared to placebo, and the authors reported that time to relapse was longer and the number of patients without any relapse during the trial was greater. The change in brain lesion volume as measured by MRI was also smaller in patients treated with both doses of teriflunomide. The annualized relapse rate in placebo treated patients was 0.54, and was 0.37 in patients treated with both doses of drug. Let’s compare this to the data supporting the approval of Gilenya. The annualized relapse rate of the placebo treated patients in the Gilenya study was 0.4 compared to 0.18 and 0.16 for the two doses of Gilenya. You can see how hard it is to compare different studies involving 2 drugs treating the same disease. Unless the rate of relapse was identical in the placebo group, it is unknown if the differences in patient populations were responsible for the differences in relapse rate between placebo and drug treatment. We will await head to head comparisons, which will surely happen once both drugs are approved. The safety profile of teriflunomide appears relatively benign. The prodrug of teriflunomide, leflunomide, has been used to treat patients with rheumatoid arthritis since 1998, and the safety profile in more than 19 million patient years of exposure has been collected and has not revealed any adverse events to raise concerns. Two cases of progressive multifocal leukoencephalopathy (a brain infection as a result of immunosuppression that was responsible for Tysabri being temporarily pulled from the market in 2005) has been reported in two patients taking leflunomide.
The final contender is Biogen Idec’s BG-12, or dimethyl fumarate, a small molecule that activates the Nrf2 transcriptional pathway and appears to defend against oxidative stress-induced neuronal death, protects the blood brain barrier, and increases myelin integrity in the CNS. This is a unique mechanism, for rather than an immune suppressant, BG-12 enhances a protective effect while also acting as an anti-inflammatory. In preparation for the ECTRIMS meeting, data supporting excellent efficacy was disclosed yesterday on the ECTRIMS website. A sticking point for BG-12 in past trials was that the initial dosing in the phase 2 studies was three times a day, a regimen that is difficult to enforce. Importantly, the latest phase 3 study indicated both twice a day dosing and three times a day dosing were equally efficacious at reducing the relapse rate compared to placebo. And, safety data was quite reassuring as serious adverse events occurred at a similar rate in patients taking placebo and treated twice or three times a day with BG-12. The details of these data have yet to be reported in a refereed journal, but most certainly will be reported after the presentation at ECTRIMS. Also ongoing is a trial examining treatment with BG-12 compared to placebo and copaxone, a first line treatment for MS. This trial is expected to be completed and reported by the end of 2011, and should complete the package to file for approval to the FDA.
In summary, Gilenya appears to be forging ahead as a first line competitor to interferon beta, and teriflunomide and BG-12 are close behind, hopefully giving MS patients multiple choices. The side effects of Gilenya include lymphopenia and bradycardia (slow heart beat after the initial doses) and these do not appear to be problems with the newer drugs, although all appear to be relatively safe.
1. Ludwig Kappos, L., Radue, E-W., O'Connor, P., Polman, C. et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. N Engl J Med. 362:387-401. 2010
2. O'Connor, P., Wolinsky, J.S., Confavreux, C., et al. Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis. N Engl J Med. 365:1293-1303. 2011.
Comments