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.

Antegren is a humanized monoclonal antibody designed to inhibit the migration of immune cells into tissues where they may play a role in causing or propogating an inflammatory response. The company states that it is the first alpha-4 antagonist in the new selective adhesion molecule (SAM) inhibitor class. Approximately 2,800 patients have received natalizumab in clinical trials for both Crohn’s disease and MS; headache, fatigue, and nasopharyngitis were the most commonly reported side effects. BioHorizon has currently assigned Antegren a first in class 75/100 innovation status variable score.

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. BioHorizon utilizes an incident case number of 10, 400 new cases of MS in the U.S. per annum and assigns an 11/100 value to the burden of illness variable.

BioHorizon is currently monitoring 23 emerging technologies for the treatment of Multiple Sclerosis. Of these 23 drugs, Avonex®, Betaseron®, Rebif®, and Copaxone® are already approved for this indication while Antegren is the only Phase III technology currently in the BioHorizon database. Although currently designated as Moderate Impact technology, we feel that the high degree of innovation exhibited by this treatment and the large unmet medical need surrounding MS will result in significant technology impact. Health Services clients should commence preliminary assessment activities within the next quarter and watch for news regarding approval.

Technology Details
Target Disease / Indication: Multiple Sclerosis
Technology Classification: Drug
Body System: Nervous System
Program Area: Medicine/Neurology
Regulatory Status: Phase III
BioHorizon Impact Score: 53/100 – Moderate Impact