Oral Therapies for Multiple Sclerosis – Fingolimod (FTY 720) and Cladribine: How Close are Novartis and Merck KGaA to FDA Approval?

These are interesting days for the first oral therapies targeting multiple sclerosis (cladribine and  fingolimod or FTY720) indeed, with both positive and negative events making news over the last several weeks.  On November 30th 2009,  Reuters reported that the FDA had issued Merck KGaA a ‘refuse to file’ letter, which in effect is the FDA’s way of  saying that the New Drug Application (NDA) is incomplete and we believe dramatically decreases any chance of a mid 2010 release date for this drug.  On the flip side, and a more positive one, The New England Journal of Medicine  recently published three articles detailing what in our view are very well executed clinical trials- two with fingolimod and one with cladribine.  Given the high level of interest and some of the complexities we thought we would delve a little deeper. 

Multiple sclerosis is a chronic, debilitating autoimmune disease that affects the brain and spinal cord. MS causes the body to direct antibodies and white blood cells against proteins in the myelin sheath that surrounds the nerves in the brain and spinal cord. This may cause inflammation and areas of scarring on nerves resulting in loss or decrease in function. An estimated 400,000 Americans have MS with about 2.5 million cases worldwide. 

Current therapy for MS is focussed on prevention of relapses and/or slowing of disease progression using immunomodulatory drugs.  FDA approved therapies include Avonex (interferon beta-1a IM ), Betaseron  and Extavia, (interferon beta-1b SC ),  Copaxone (glatiramer acetate SC),  Rebif (interferon beta-1a SC), Novantrone (mitoxantrone IV) and Tysabri (natalizumab IV).   Some analysts place worldwide expenditures on these drugs at greater than 8 billion dollars annually.  Unlike fingolimod and cladribine which are pills taken by mouth, all of the above therapies are delivered by the intramuscular (IM) route, the subcutaneous (SC) route or the intravenous (IV) route. 

Fingolimod is a sphingosine-1-phosphate-receptor modulator that is thought to work by preventing movement of lymphocytes from lymph nodes and in doing so decreases the damage that these lyphocytes can exact on the central nervous system.  Cladribine’s mechanism of action is different – 2-chlorodeoxyadenosine triphosphate – an active metabolite of cladribine accumulates in cells, disrupts their metabolism and leads to cell death.   Cladribine preferentially impacts lymphocytes and in doing so decreases the number of so called ‘autoagressive’ cells available to attack the nervous system. 

The two recently published clinical trials in the New England Journal of Medicine showed efficacy for cladribine (CLARITY trial) and fingolimod (FREEDOMS trial) when compared to placebo over a 2-year period.  Statistical significance was achieved for the primary endpoint – which was the annualized relapse/recurrence rate in both trials.  In fact, the relative risk reduction was reported as an impressive 50%+ reduction in both trials.  In  a third trial comparing fingolimod to interferon beta 1a, fingolimod was superior. 

Those familiar with the Tysabri story are well aware of the importance of safety when considering immune response modifiers in the treatment of multiple sclerosis and  the safety profile of cladribine and fingolimod will surely be closely scrutinized going forward.  A detailed discussion of the safety of these oral therapies is not possible here however adverse events of note described in these three trials included herpetic infections,  solid tissue cancers, macular edema, basal cell carcinoma, melanoma, breast cancer, transient bradycardia, first- and second-degree heart block,   and lymphocytopenia.  Should approval of either of these agents occur, physicians and patients will need to do the requisite risk/benefit analysis before initiating treatment and FDA mandated post marketing surveillance will likely be critical in addressing any long term safety concerns.

This brings us to the next question – will physicians and patients get the chance?  Well, as mentioned in the first paragraph Merck KGaA was issued a ‘refuse to file’ letter for cladribine suggesting anything but imminent approval while Novartis  filed its NDA for fingolimod in late January 2010.    Interested readers are directed to www.nejm.org to access the three clinical trials referred to above in their entirety as well as an excellent accompanying editorial.  Thanks for reading.

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