Preclinical Evaluation of RA101495, a Potent Cyclic Peptide Inhibitor of C5 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Abstract Regulation of the terminal phase of the complement component pathway is a clinically validated approach for the therapeutic treatment of complement disorders. Inhibition of complement activation at the C5 level with the monoclonal antibody eculizumab has successfully been used for the treatment of rare disorders such as PNH and aHUS. However, even in these settings there remains a continued unmet need primarily due to need for intravenous administration, lack of activity in patients with C5 mutations and lack of universal access. Ra Pharmaceuticals has developed a macrocyclic synthetic peptide, RA101495, which binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative or lectin pathways. In vitro studies also demonstrated that RA101495 is capable of preventing MAC assembly after thrombin mediated complement activation and is a potent disruptor of the interaction in between C5b and C6. Inhibition of complement activity was evaluated in cynomolgus monkeys following single- and multi-dose subcutaneous (SC) administration. RA101495 exhibited high SC bioavailability and low, single doses fully inhibited complement-mediated hemolytic activity (>95%). Repeat dosing was well tolerated in monkeys and rats at high multiples of the projected human therapeutic dose and resulted in sustained and predictable inhibition of complement activity. RA101495 fully inhibited the hemolysis of erythrocytes from PNH patients after activation of the alternative pathway. The synthetic peptide offers a novel therapeutic approach for inhibiting C5 for the treatment of disorders caused by or associated with complement dysregulation. As a product designed for convenient self-administration, RA101495 should provide an attractive option over monoclonal antibody therapy for patients with PNH and aHUS, including those with C5 polymorphisms and other complement disorders, especially those associated with hypercoagulable states. Disclosures Ricardo: Ra Pharmaceuticals: Employment. Arata:Ra Pharmaceuticals: Employment. DeMarco:Ra Pharmaceuticals: Employment. Dhamnaskar:Ra Pharmaceuticals: Employment. Hammer:Ra Pharmaceuticals: Employment. Fridkis-Hareli:Ra Pharmaceuticals: Consultancy. Rajagopal:Ra Pharmaceuticals: Employment. Seyb:Ra Pharmaceuticals: Employment. Tang:Ra Pharmaceuticals: Employment. Tobe:Ra Pharmaceuticals: Employment. Treco:Ra Pharmaceuticals: Employment.