Zilucoplan Gets Orphan Designation in Myasthenia Gravis Ahead of Phase 3 Trial


Ra Pharmaceuticals’ macrocyclic peptide inhibitor of complement component 5 is expected to enter phase 3 of its development in the latter half of 2019 after success in a phase 2 trial of its potential in myasthenia gravis.

Dr Treco

Doug Treco, PhD, president and CEO, Ra Pharma

Doug Treco, PhD

According to an announcement from Ra Pharmaceuticals, the FDA has granted an orphan drug designation to the company’s investigational generalized myasthenia gravis treatment zilucoplan.1

The treatment is a self-administered macrocyclic peptide inhibitor of complement component 5 (C5), and thus far in clinical trials has shown success. In May, phase 2 data were presented at the 2019 American Academy of Neurology (AAN) Annual Meeting showing that those treated with a 0.3-mg/kg dose experienced a mean reduction of 6 points in Quantitative Myasthenia Gravis (QMG) score (placebo corrected change, —2.8; P = .05) and a reduction of 3.4 points in Myasthenia Gravis Activities of Daily Living (MG-ADL) score (placebo-corrected change: —2.3; P = .04).­2,3

“gMG is a chronic and debilitating neuromuscular disease that affects more than 60,000 patients in the U.S. who have limited treatment options,” said Doug Treco, PhD, president and CEO, Ra Pharma. “We’ve designed zilucoplan, a macrocyclic peptide inhibitor of C5, as an easy-to-use, self-administered subcutaneous treatment option to address the underlying cause of gMG through targeted complement control.”

“With site activations underway, we are on track to initiate our single, pivotal, 12-week, phase 3 trial of zilucoplan for the treatment of gMG in the second half of this year,” Treco said.

In the phase 2 data—which supported this incoming phase 3 trial—44 patients were randomized 1:1:1 to placebo (n = 15), zilucoplan 0.1 mg/kg (n = 15), or zilucoplan 0.3 mg/kg (n = 14), delivered subcutaneously and daily over the 12-week treatment period.

Additionally, in the open-label extension period (98% retention; n = 43), the higher dose group compared to the placebo group (the 0.3 mg/kg dose remained as such [n = 15] while the placebo patients switched [n = 14]). The change from baseline in QMG through Week 24 was significant for both the original treatment arm (P <.0001) and the original placebo arm (P = .01). This was similarly true for both groups, respectively, for Week 24 change in MG-ADL scores (treatment arm, P <.0001; placebo arm, P = .0004).

Successful results were also observed in the change from baseline for both groups in MG composite score (treatment arm, P <.0001; placebo arm, P = .004) and MGQoL15r score (treatment arm, P <.0006; placebo arm, P = .04) through 24 weeks.

James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, chief, Neuromuscular Disorders Section, University of North Carolina School of Medicine, at AAN 2019, explained that the therapy is designed to ultimately prevent the formation and assemblage of the membrane attack complex in myasthenia gravis, and last December noted that zilucoplan has the potential to become the first convenient, self-administered, complement inhibitor expanding access for patients living with the chronic, debilitating, neuromuscular disease that is myasthenia gravis.2

In the phase 2 trial, its safety and tolerability profile was deemed favorable. As for the need for rescue therapy—administration of intravenous immunoglobulin or plasma exchange&mdash;respective rates of 6% (n = 1) and 0% (n = 0) were observed in the zilucoplan high- and low-dose arms. In comparison, the placebo arm required rescue treatment at a rate of 20% (n = 3).


1. Ra Pharmaceuticals Receives Orphan Drug Designation from the U.S. FDA for Zilucoplan for the Treatment of Myasthenia Gravis [press release]. Cambridge, MA: Ra Pharmaceuticals; Published September 4, 2019. businesswire.com/news/home/20190904005284/en. Accessed September 9, 2019

2. Howard JF, Nowak RJ, Wolfe GI, et al. Zilucoplan, a Subcutaneously Self-Administered Peptide Inhibitor of Complement Component 5 (C5), for the Treatment of Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial and Open-Label Long-Term Extension. Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.

3. 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. businesswire.com/news/home/20181210005188/en/Ra-Pharmaceuticals-Announces-Positive-Top-line-Data-Phase. Accessed September 9, 2019.

Related Videos
Michael Levy, MD, PhD
Michael Kaplitt, MD, PhD
Michael Kaplitt, MD, PhD
video 4 - "Amyloid Cascade Hypothesis of Alzheimer’s Disease"
Video 3 - "Amyloid Precursor Protein and Amyloid Beta Species in Alzheimer’s Disease"
Svetlana Blitshteyn, MD, FAAN, director and founder of Dysautonomia Clinic
© 2024 MJH Life Sciences

All rights reserved.