First Multiple Sclerosis pill approved in US will change treatment paradigm

Multiple sclerosis (MS) is an autoimmune disease in which the patients 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.  The first signs usually appear between the ages of 20 and 50 years, and most commonly, the disease is characterized by clinical bouts of disease that are followed by partial or complete recovery.  Symptoms may then be inactivefor months, or even years.  This form of MS (which affects about 85% of MS sufferers) is calledrelapsing-remitting MS.About three times as many women as men are affected, and the highest geographic prevalence is in areas of cooler climates, namely Northern Europe, North America, Australia and New Zealand.  The lowest prevalence is in equatorial regions such as Sub Saharan Africa.  Although much is known about MS, including the immediate cause, the initiating events and explanations regarding the interesting geographic prevalence, sex predilection, and reasons for the highly variable clinical course are still not understood (1).

Until last week, 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.  After the diagnosis, 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-1’s on the market in the US.  Avonex (Biogen Idec, Cambridge, MA)) has the largest market share because it only has to be injected once a week.  Biogen claims that there are 135,000 patients presently taking Avonex.  Rebif (Merck KGaA) is injected three times a week subcutaneously.  Betaseron (Bayer) and Extavia (Novartis) are injected 3 or 4 times a week.  Teva also has an interesting non-interferon drug approved for first line use in relapsing-remitting MS.  Copaxone is a mixture of four naturally occurring amino acids(L-alanine, L-glutamine, L-lysine, and L-tyrosine) which seems to work as an immune modulator in some MS patients.  This drug has a significant market share, probably because it does not have the common flu like side effects which patients get following injections of interferon.  The fact that all these drugs are actively used by neurologists is explained by the fact that none of them work in all patients, and none of them alter significantly the progressive course of the disease. But, these drugs do significantly reduce the number and severity of relapses in a percentage of patients.

In 2004 the FDA issued approval of Tysabri from Biogen Idec (Cambridge, MA).  This is a monoclonal antibody against the alpha 4 chain of VLA-4, and acts as an integrin receptor antagonist.  It is administered as a monthly iv infusion.  It is a significant immune  suppressant, as evidenced by the occurrence of 24 cases of progressive multifocal leukoencephalopathy (PML), a viral disease of the CNS which attacks individuals with compromised immune systems.  These cases of PML precipitated removal of Tysabri from the market by the FDA in 2005.  The FDA allowed sales again in 2006 following reassessment and a determination that the benefit outweighed the risk, as Tysabri is only approved as a second line therapy in patientswith high disease activity despite treatment with a interferon betaorpatients with rapidly evolving, severe, relapsing-remitting multiple sclerosis.   Biogen now claims that 48,800 people have been treated with Tysabri. 

In the past few years, the race to develop small molecule therapies for this burgeoning market has really heated up, with the leader of the pack being Novartis’s Gilenya against Merck KGaA’s cladribine.  Last week, Novartis was declared the winner as Gilenya was approved by the FDA.  Gilenya was originally developed to prevent organ rejection after kidney transplantation, but was toxic at the doses required for this indication.  The dose for MS is 1/5 the organ rejection dose and this dose appears to be relatively safe.   This drug is a sphingosine 1-phosphate receptor modulator and the precise mechanisms of action in MS is not understood, but it seems to act by reducing the release of white blood cells from lymph nodes and therefore reducing the white blood cell influx into the CNS.  Side effects can be quite notable and consistent, though not life threatening.  Bradycardia is the most common side effect and patients are instructed to take their first dose in the doctor’s office and wait for 6 hours before leaving to enable assessment of the severity of this side effect.  Reduction in lymphocyte count to 20-30% of baseline values also commonly occurs.  Less common is macular edema in about 0.4% of patients. Gilenya has been tested in over 2,600 patients, and demonstrated a reduction in relapse rate, and a reduction in the active lesions as measured by MRI compared to placebo in a two year trial.  There was also a 1 year clinical trial comparing Gilenya to interferon beta (Avonex), and patients treated with Gilenya had reduced rate of relapses, and a reduction in newly enlarged MRI lesions indicating less active disease at 1 year compared to patients on Avonex (2).  Gilenya is a once a day pill approved as a first line treatment, so it could clearly dig into the interferon market and be a blockbuster. 

The loser was Merck KGaA’s cladribine, an approved treatment for hairy cell leukemia (leukemic reticuloendotheliosis).  For the oncology indication it is administered iv or sq, but Merck has made it into an oral pill for treatment of MS.  Cladribine accumulates intracellularly and results in the inhibition of DNA synthesis and repair, and subsequent apoptosis.  Cladribine preferentially accumulates in lymphocytes and produces rapid and sustained reductions in CD4+ and CD8+ cells and rapid, though more transient, effects on CD19+ B cells, with relative sparing of other immune cells.  It has been tested as an oral pill in MS patients, administered for only a course of 5 days, 2 or 4 times a year.    The results demonstrated significant reduction in the relapse rate at both doses compared to placebo after 2 years, as well as a reduction in lesions visualized on MRI.  Cladribine is already approved for MS in Australia and Russia, but in November 2009 the FDA rejected Merck’s application due to incompleteness.  Merck resubmitted the application, and it is presently under priority review.  But on Monday, the European Medicine Agency rejected cladribine citing concerns about cladribine’s effect on the immune system and the four cases of cancer that developed in patients on the trial.  Merck’s stock dropped 10.2% on Friday after the news broke and many analysts think this rejection by the European agency will make approval by the FDA less likely.  It may be that the extremely infrequent dosing, and the subsequent long-term immune suppression make the safety of this drug a concern to regulatory agencies.

There are several other small molecule treatments for MS in clinical trials including Biogen’s phase 3 oral BG-12.  This drug is dimethyl fumarate, a small molecule which 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.  Initial data in phase II has demonstrated reduced lesion activity by MRI, although relapse rates were not significantly improved likely due to inadequate numbers of patients in this phase II study.  This pill is administered three times a day, which may negatively impact patient compliance.  Biogen expects phase III results in 2011.   Teva and Sanofi Aventis also have oral drugs for MS in development.  Laquinimod (Teva) received Fast Track designation from the FDA in February 2009. Two pivotal global phase III clinical trials are fully enrolled and results are anticipated next year.Teva claims laquinimod is both neuroprotective and anti-inflammatory.  Teriflunomide (Sanofi-Aventis) blocks new pyrimidine synthesisthereby inhibiting proliferation of T and B lymphocytes.  This once a day oral drug is presently being tested in phase III trials in relapsing remitting MS patients.  The results of one phase III trial are expected to be presented at the Meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on October 15 in Gothenburg, Sweden.  Press reports from Sanofi indicate the results were positive.

The large market for MS and the unmet medical need to identify better treatments has driven an enormous effort to improve choices for patients with MS.  This work appears to be on the verge of providing new and exciting options for patients and neurologists, and it is hoped that one or more of these new therapies will advance the quality of life of MS patients and perhaps alter the course of the disease well beyond what is available today.

1. Noseworthy, J.H., Lucchinetti, C., Rodriguez, M., et al.  Medical Progress:  Multiple Sclerosis.  New Engl J Med.  343:  938-952.  2000.
2. Cohen, J.A., Barkhof, F., Comi, G., et al.  Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.  New Engl. J Med.  362:  402-415.  2010