Zilucoplan (RA101495 SC)

Ra Pharma is developing zilucoplan (RA101495 SC) for paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG), and other complement-mediated disorders. The product is designed for convenient, once-daily subcutaneous self-administration.

Zilucoplan is a synthetic, macrocyclic peptide discovered using Ra Pharma’s powerful proprietary drug discovery technology. The peptide binds complement component 5 (C5) with sub-nanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways. By binding to a region of C5 corresponding to C5b, zilucoplan is designed to disrupt the interaction between C5b and C6 and prevent assembly of the membrane attack complex. This activity may define an additional, novel mechanism for the inhibition of C5 function.

Binding Sites

In February 2018, Ra Pharma announced data from the Company’s global Phase 2 program in PNH, in which zilucoplan achieved consistent, sustained, and near-complete inhibition of C5. In treatment-naïve patients, zilucoplan met the primary endpoint, demonstrating a rapid, robust, and sustained reduction in lactate dehydrogenase (LDH) from baseline to the mean of weeks 6-12 and near-complete suppression of complement activity. In transfusion-independent eculizumab switch patients, patients were maintained an overall stable mean LDH level, with one patient withdrawing early due to breakthrough hemolysis and reverting to eculizumab without complications.

Based on feedback provided by the U.S. Food and Drug Administration during End-of-Phase 2 discussions, as well as advice previously provided by the Medicines and Healthcare products Regulatory Agency in the United Kingdom and Health Canada, and pending meeting with the European Medicines Agency in the fourth quarter of 2018, Ra Pharma plans to initiate a global, pivotal, single-arm Phase 3 trial to evaluate the safety and efficacy of zilucoplan in approximately 40 treatment-naïve PNH patients. In addition, Ra Pharma expects to initiate a supportive trial in approximately 40 transfusion-independent patients switching from eculizumab to zilucoplan.

Zilucoplan is currently being evaluated in a Phase 2 study in patients with gMG. The multi-center, randomized, double-blind, placebo-controlled trial enrolled a total of 44 patients. At the outset of the 12-week treatment period, patients were randomized in a 1:1:1 ratio and received daily SC doses of 0.1 mg/kg of zilucoplan, 0.3 mg/kg of zilucoplan, or matching placebo. The Company plans to report top-line data around year-end 2018.

In September 2018, Ra Pharma reported positive results from the Phase 1b, multi-center, open-label, pharmacokinetic (PK) study of zilucoplan in patients with renal disease. The trial enrolled 16 patients, eight with severe renal impairment matched with eight healthy control subjects. The PK profile of zilucoplan was consistent across both groups, with exposures similar in renally-impaired patients and healthy volunteers. These results support the expansion of zilucoplan into complement-mediated renal disorders without the need for dose adjustment.