FDA Clears Zilucoplan IND for Immune-Mediated Necrotizing Myopathy


Zilucoplan, also being developed for generalized myasthenia gravis, is expected to enter into a phase 2 clinical trial in IMNM in the second half of 2019, according to Ra Pharma.

Dr Doug Treco

Doug Treco, PhD, President and Chief Executive Officer of Ra Pharma

Doug Treco, PhD

The FDA has cleared an investigational new drug application (IND) for zilucoplan for the treatment of immune-mediated necrotizing myopathy (IMNM), for which there are no approved therapies. The treatment, designed for subcutaneous self-administration, is expected to be assessed in a phase 2 clinical trial in the latter half of 2019, according to its manufacturer, Ra Pharmaceuticals.1

The phase 2 trial is expected to enroll 24 patients to be assessed over an 8-week treatment period. The primary end point will be the change in CK from baseline to week 8, and upon completion of the trial, participants will have the opportunity to enter into an open-label, long-term extension study with zilucoplan.

“The IMNM program represents a meaningful expansion of our neuromuscular pipeline for zilucoplan, as we aim to leverage the unique properties of a small peptide in tissue-based complement-mediated disorders and build on the success of our phase 2 trial for zilucoplan in generalized myasthenia gravis (gMG),” Doug Treco, PhD, President and Chief Executive Officer of Ra Pharma, in a statement. “We look forward to the initiation of this phase 2 clinical trial in the second half of this year, an important step forward in our efforts to bring innovative and accessible therapies to patients and build a leading complement-focused neurology and neuromuscular portfolio.”

The study will be randomized, double-blinded, placebo-controlled, and take place at a number of sites, with patients expected to be randomized 1:1—stratified based on antibody status (anti-HMGCR+ versus anti-SRP+)—to either daily subcutaneous doses of 0.3 mg/kg zilucoplan or placebo.

IMNM is categorized into a pair of subtypes, defined by the presence of distinct autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or signal recognition particle (SRP). These autoantibodies drive the complement-mediated necrosis of muscle fibers, resulting in severe, progressive, and debilitating proximal muscle weakness for the more than 15,000 patients in the US, European Union, and Japan estimated to have the condition.

“Patients with IMNM face a severe, chronic, debilitating autoimmune disease with limited treatment options and no approved therapies,” said Andrew Mammen, MD, PhD, Muscle Disease Unit Leader, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, in a statement. “Given the availability of diagnostic autoantibodies and the central role of terminal complement activation in the pathophysiology of the disease, zilucoplan has the potential to become a targeted therapy for patients with IMNM.”

Mammen, who is also the principal investigator for the phase 2 study, added that “the results observed in the recent phase 2 clinical trial of zilucoplan in gMg, a neuromuscular disease similarly characterized by autoantibody-mediated complement activation and tissue injury, provide a strong rationale for the clinical evaluation of zilucoplan in this disease.”

Data from that phase 2 trial in gMG was presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania, revealing clinically meaningful and statistically significant improvements in the primary and key secondary efficacy end points, which included a change in baseline in mean Quantitative Myasthenia Gravis (QMG) score, as well as the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis Quality of Life 15-item rating (MGQoL15r) scale, and the MG composite at baseline to Week 12.2

James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, chief, Neuromuscular Disorders Section, University of North Carolina School of Medicine, presented the data at AAN for the higher dose compared to the placebo group from the open-label extension period, of which 98% (n = 43) of patients entered. All told, there had bee 44 patients included in the analysis, 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.

In the study period, the 0.3-mg/kg group was shown to experience a mean reduction of 6 points in QMG score (placebo corrected change, —2.8; P = .05) in addition to a reduction of 3.4 points in MG-ADL score (placebo-corrected change: –2.3; P = .04).3

In the extension period, patients on the 0.3 mg/kg dose remained as such (n = 15) while the placebo patients switched to the 0.3 mg/kg dose (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 also true for both groups, respectively, at Week 24 change in MG-ADL scores (treatment arm, P <.0001; placebo arm, P = .0004).

According to Ra Pharma, zilucoplan and its extended release (XR) formulation are being developed for other tissue-based, complement-mediated disorders with high unmet medical need, in addition to gMG and IMNM. Zilucoplan is an investigational, synthetic, macrocyclic peptide discovered using Ra Pharma's proprietary drug discovery technology, designed to bind complement component 5 (C5) with sub-nanomolar affinity and allosterically inhibit its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.


1. Ra Pharmaceuticals Announces Expansion of Neuromuscular Portfolio with Clearance of IND Application for Zilucoplan for the Treatment of Immune-Mediated Necrotizing Myopathy [press release]. Cambridge, MA: Ra Pharmaceuticals; Published June 4, 2019. finance.yahoo.com/news/ra-pharmaceuticals-announces-expansion-neuromuscular-110000947.html. Accessed June 5, 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, MA: Ra Pharmaceuticals; Published December 10, 2018. businesswire.com/news/home/20181210005188/en/Ra-Pharmaceuticals-Announces-Positive-Top-line-Data-Phase. Accessed May 9, 2019.

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