Benefit-Risk of Immunomodulators in Multiple Sclerosis. Alemtuzumab and Next?

By the 30th of December 2013, the Boston-based company Genzyme, part of the Sanofi Pharmaceutical group, announced that it had received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) for its supplemental Biologics License Application seeking approval of alemtuzumab (Lemtrada ® ) for the treatment of relapsing forms of multiple sclerosis (MS).A Complete Response Letter informs companies that an application is not ready for approval.The FDA wanted to see more evidence from controlled clinical trials that demonstrate the benefits of alemtuzumab outweigh the safety risk of the drugs [1].Alemtuzumab, recently approved in the European Union, Canada and Australia, is a monoclonal antibody that selectively targets the CD52 receptors expressed on the surface of B and T cells: this induces a depletion of lymphocytes over the long term.Alemtuzumab was originally developed to treat B-cell chronic lymphocytic leukemia.The mode of administration is by intravenous infusion with treatment cycles of a few days: in the pivotal Phase III studies CARE-MS I and II, the first cycle was of 5 days during which patients received 5 infusions of 12 mg of alemtuzumab, after one year, the second treatment cycle lasted 3 days with 3 IV infusions of 12 mg alemtuzumab.The efficacy of the drug appears high as in the first Phase III study (CARE MS I) [2] including 563 patients with relapsing remitting MS (RRMS), alemtuzumab was compared to interferon β1a, a reference MS treatment; the annualized relapse rate ratio (ARR), a standard metrics for clinical trials in RRMS, was of 0.18 in the alemtuzumab arm representing a decrease of 53% compared to interferon β1a.In the other Phase III trial (CARE-MS II) [3] in 798 RRMS patients, the ARR was 0.26 in the alemtuzumab 12 mg group, i.e. a decrease of 50% compared to the group treated with interferon β1a.These efficacy results appear all the more significant as differences of ARR of similar magnitude were seen with recently registered MS drugs such as fingolimod or dimethyl fumarate, but in comparison to placebo and not to an active MS treatment.The safety profile of alemtuzumab includes very frequent infusion reactions (headache, rash, nausea, pyrexia, etc), a tendency to more frequent infections (upper respiratory, urinary and herpetic infections in particular), and the occurrence of B cell mediated autoimmune disorders such as thyroid disorders (hyper-or hypothyroidism), immune mediated thrombocytopenia AbstractEnd of December 2013, alemtuzumab, a monoclonal antibody for multiple sclerosis (MS) with an immunomodulator action targeting CD52 receptors and inducing decrease counts of lymphocytes B and T was rejected by the Food and Drug Administration, as the registration dossier had not shown convincing evidence that the benefit of the drug would overreach its safety risks.The question is in fact more global as immunomodulators constitute the majority of the newly registered drugs and drugs in clinical development for MS.The knowledge accumulated by the time these drugs are registered does not suffice to ascertain their safety profile.This is preoccupying as these treatments are intended to be administered to young patients who need to be treated for decades.Cumulative risks over years with such treatments are at the moment unknown but are certainly non negligible.Despite significant benefits of immunomodulation in the treatment of MS, the solution for treatment of disorders with auto-immune origin is likely to come from targeting more specific factors to avoid long-term depression of the immune system.Research and development in this direction need to be actively encouraged.

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