Targeted Therapy for Myasthenia Gravis

Myasthenia gravis is a severe neuromuscular disease primarily caused by complement activating autoantibodies directed towards the skeletal muscle acetylcholine receptor. Present treatments are ineffectiveand uniformly have adverse effects, which negatively impact quality of life. Despite being a rare disease, myasthenia gravis is a costly one with a hospitalization expense of half a billion dollars in 2013. The investigative team through extensive basic and preclinical assessment have demonstrated the complement system as a valid therapeutic target, which has been further confirmed by the recent FDA approval of a first generation complement inhibitor as treatment for generalized myasthenia gravis. We have shown in proof- of-concept investigations the ability to target a complement inhibitor to the neuromuscular junction and moderate disease severity in rodent models of myasthenia gravis. The work led to issuance of U.S. Patent No. 8,961,981 for targeting a therapeutic to the neuromuscular junction and our establishment of ARC BioTechnology, LLC to develop the technology for human use. If we are successful in fulfilling the expectations of our candidate drug profile, we will produce a drug with limited toxicity associated with systemic complement inhibition, prolonged duration of action, and enhanced efficacy compared with presently available drugs and those in development. In Phase 1 of the STTR we propose three mile-stone driven specific aims in order to develop a lead compound for phase 2 development. Aim 1 will achieve small batch synthesis of a series of constructs with a complement inhibitor domain and a domain targeting the compound to proteins concentrated at the neuromuscular junction. Aim 2 will identify lead compound (s) through validated in vitro assays of complement inhibitory activity and affinity for target proteins. Aim 3 assesses lead compound(s) for moderation of severity in validated animal models of myasthenia gravis produced by administration of antibody directed against the acetylcholine receptor or immunization with purified acetylcholine receptor. Successful completion of the milestones will trigger progression to Phase 2 to assess efficacy and pharmacodynamics of the lead compound.Myasthenia gravis is a rare neuromuscular, autoimmune disease that can produce significant muscle weakness at times leading to death. Treatments exist, but none are curative, and they are limited by significant adverse effects. We propose to develop a drug which will specifically inhibit the complement system, the major driver of muscle injury, focused to the site of pathology, the nerve-muscle communication point. If successful, our drug would be a major advance from first generation complement inhibitors by limiting systemic toxicity, prolonging duration of activity, and improving efficacy.