Dr James HowardJames F. Howard, MD
New positive data from a phase 2 randomized controlled trial and its open-label extension of zilucoplan, formerly known as RA101495 SC, have provided enough evidence to support further evaluation in a phase 3 trial in myasthenia gravis.1

Presented by James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, chief, Neuromuscular Disorders Section, University of North Carolina School of Medicine, at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania, the data revealed clinically meaningful and statistically significant improvements in the primary and key secondary efficacy end points.

“Of note, patients did not have to be refractory to therapy for participation, and all patients were immunized against meningococcus, based on the standard of care, during the screening period, at least 2 weeks prior to the first administration,” Howard said. “Primary end points included a change in baseline in mean Quantitative Myasthenia Gravis (QMG) score, and secondary end points looked at 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.”

“Zilucoplan is a small molecule complement inhibitor targeting C5 A to C6,” Howard explained. The therapy is designed to ultimately prevent the formation and assembly of the membrane attack complex in myasthenia gravis. He has previously expressed that the treatment 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

All told, there were 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, daily over the 12-week treatment 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).­

When the topline data were announced in December 2018, it was revealed that the QMG and MG-ADL outcomes for the 0.1 mg/kg dose were similar to the higher dose, but less pronounced, and 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).2

Howard also presented data for the higher dose compared to the placebo group from the open-label extension period, of which 98% (n = 43) of patients entered. In the extension, 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).

Similar results were seen 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.

As for the need for rescue therapy, defined as the need for administration of intravenous immunoglobulin or plasma exchange, the investigators observed respective rates of 6% (n = 1) and 0% (n = 0) in the zilucoplan high- and low-dose arms. In comparison, the placebo arm required rescue treatment at a rate of 20% (n = 3).

Overall, the Ra Pharmaceuticals product displayed a favorable safety and tolerability profile, which was consistent with what had been observed in prior clinical trials. The company has stated previously that it planned 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.

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REFERENCES
1. 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.
2. 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 May 9, 2019.