RA101495, A Subcutaneously Administered Peptide Inhibitor of Complement Component 5 (C5) for the Treatment of Generalized Myasthenia Gravis (gMG): Phase 1 Results and Phase 2 Design (S31.006)

Objective: - Evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of RA101495 healthy volunteers (Phase 1) - Design a Phase 2 study of RA101495 in gMG patients Background: Acetylcholine receptor (AChR) antibodies activate the classical complement cascade in gMG, and induce both membrane attack complex (MAC) formation and tissue damage at the neuromuscular junction. Inhibition of C5 is a therapeutic target with a strong biological rationale for AChR-antibody positive gMG. RA101495 a potent, subcutaneously-administered macrocyclic peptide, binds C5 and inhibits its cleavage into C5a and C5b, preventing the production of MAC. RA101495 is in Phase 2 clinical development for the treatment of paroxysmal nocturnal hemoglobinuria and gMG. Design/Methods: In Phase 1, subjects were randomized to receive single (n=14) and multiple (n=4) doses of RA101495 or placebo (n=10), for up to 7 days. Complement inhibition was evaluated using a validated antibody-sensitized sheep red blood cell assay. Based on these data, a multi-center, randomized, double-blind, placebo-controlled Phase 2 study in AChR-antibody positive gMG patients has been initiated. Results: In Phase 1, drug levels in healthy volunteers were consistent with predictions from in-silico modeling, with a terminal half-life of approximately 7 days. Accordingly, exposure increased steadily over 7 days with multiple dosing. Near-complete inhibition of complement activity (≥95%) was achieved within 3 hours after first dose and maintained u003e24h in higher dose groups. No safety concerns were identified. Three RA101495-treated subjects experienced transient and self-limiting mild injection site erythema. The design of the ongoing Phase 2 study in gMG will also be presented. Conclusions: Phase 1 data support the evaluation of RA101495 in a Phase 2 study in gMG. Subcutaneous self-administration of RA101495, if shown effective, may not only enable a broader population of gMG patients to potentially benefit from targeted C5 inhibitor therapy but also ease the treatment-related burden of intravenous options. Study Supported by: Ra Pharmaceuticals Disclosure: Dr. Howard has nothing to disclose. Dr. Kaminski has nothing to disclose. Dr. Nowak has nothing to disclose. Dr. Wolfe has nothing to disclose. Dr. Benatar has nothing to disclose. Dr. Ricardo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. Ricardo holds stock and/or stock options in Ra Pharmaceuticals. Dr. Hoarty has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. Hoarty holds stock and/or stock options in Ra Pharmaceuticals. Dr. DeMarco has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. DeMarco holds stock and/or stock options in Ra Pharmaceuticals. Dr. Farzaneh-Far has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. Farzaneh-Far holds stock and/or stock options in Ra Pharmaceuticals. Dr. Duda has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ra Pharmaceuticals. Dr. Duda holds stock and/or stock options in Ra Pharmaceuticals.