Phase 2 Study Reveals Positives for Zilucoplan in the Treatment of Myasthenia Gravis


The therapy met both primary and secondary end points across a broad spectrum of patients with generalized myasthenia gravis, including significant reductions in both QMG and MG-ADL scores.

Dr James Howard

James F. Howard, MD, the Distinguished Professor of Neuromuscular Disease and chief of the Neuromuscular Disorders Section in the Department of Neurology at the University of North Carolina School of Medicine

James F. Howard, MD

Zilucoplan has shown positive top-line results in a phase 2 clinical trial evaluating the therapy for the treatment of generalized myasthenia gravis, according to manufacturer Ra Pharmaceuticals.1

Compared to placebo at 12 weeks, the 0.3 mg/kg dose of the therapy achieved a mean reduction from baseline of 6 points in Quantitative Myasthenia Gravis (QMG) score (P = .05) and 3.4 points in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score (P = .04).

Additionally, no patients required rescue therapy when treated with the 0.3 mg/kg dose of zilucoplan. Comparatively, rescue therapy of intravenous immunoglobulin or plasma exchange was necessary for 20% (3 of 15) of those in the placebo arm, and 7% (1 of 15) in the 0.1 mg/kg arm.

The investigational agent (formerly known as RA101495 SC) is a synthetic, macrocyclic peptide that binds complementarily to 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.

“The rapid, profound, and sustained reductions in QMG and MG-ADL observed in this Phase 2 study confirm that complement inhibition was effective across a wide spectrum of MG patients in this study, whether refractory or non-refractory,” said James F. Howard, MD, the Distinguished Professor of Neuromuscular Disease and chief of the Neuromuscular Disorders Section in the Department of Neurology at the University of North Carolina School of Medicine.

“Zilucoplan has the potential to become the first convenient, self-administered, complement inhibitor expanding access for patients living with this chronic, debilitating, neuromuscular disease,” he added.

The trial randomized 44 patients in a 1:1:1 fashion to daily, subcutaneous doses of either 0.1 mg/kg zilucoplan or 0.3 mg/kg zilucoplan, or placebo. All 44 patients completed the 12-week assessment, and 43 patients (98%) have elected to enter a long-term extension study of the active drug.

The QMG and MG-ADL outcomes for the 0.1 mg/kg dose were similar to the higher dose, but less pronounced. They also achieved pre-specified statistical significance on both end points. Additional findings included achieving a pre-specified analysis of the pooled active arms versus placebo, which revealed a placebo-corrected change in MG-ADL at week 12 of -2.2 (2-sided P = .047).

As for adverse events (AEs), treatment with zilucoplan was considered favorable in safety and tolerability, with the majority of AEs being considered mild and unrelated to the study drug. No serious AEs were observed that were related to zilucoplan.

According to Ra Pharma, by binding to a region of C5 corresponding to C5b, zilucoplan is additionally designed to disrupt the interaction between C5b and C6 and prevent assembly of the membrane attack complex. This activity could possibly define an additional, novel mechanism for the inhibition of C5 function. The company has stated that it plans to engage with regulatory agencies, including the FDA, in the first half of 2019 regarding the design of a phase 3 clinical trial evaluating the 0.3 mg/kg dose of zilucoplan versus placebo in patients with generalized myasthenia gravis, based on these data.

“Since the founding of this company, our goal has always been to expand patient access to important therapies,” said Doug Treco, PhD, the founder and chief executive officer of Ra Pharma. “Designed for subcutaneous self-administration, zilucoplan offers convenience and accessibility, giving it the potential to bring C5 inhibition to the forefront of the treatment paradigm for [generalized myasthenia gravis]. We look forward to meeting with regulators to review our Phase 2 data and the design of our planned Phase 3 program with the ultimate goal of transforming the lives of thousands of patients with this disease.”

Nancy Law, the CEO of the Myasthenia Gravis Foundation of America, called the findings “a potential breakthrough for all patients who are struggling every day,” noting that a recent survey conducted by the Foundation noted the satisfaction that patients with myasthenia gravis have with their current treatments is low, making this an unmet need among this patient population.

“We learned that a majority of patients with MG are not satisfied with their current treatments and are interested in effective, at home, self-injectable treatment options,” Law added.


1. Ra Pharmaceuticals Announces Positive Top-line Data from Phase 2 Trial of Zilucoplan in Patients with Generalized Myasthenia Gravis [press release]. Cambridge, Massachusetts: Ra Pharmaceuticals; Published December 10, 2018. Accessed December 10, 2018.

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