Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody–Positive Generalized Myasthenia Gravis

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© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

Figure 1. The (A) complement cascade and (B) depiction of the molecular components of a normal vs AChR⁺ gMG neuromuscular junction and the impact on muscle contraction. Graphics are schematic representations and are not true to scale. In panel A, a truncated version of the full complement cascade is presented with a focus on specific mechanisms relevant to zilucoplan in AChR+ gMG. ACh binds to AChR on normal postsynaptic membrane folds, allowing for normal neuromuscular signaling and muscle contraction. In panel B, autoantibodies against AChR initiate the classical complement cascade, resulting in the deposition of MAC on the postsynaptic membrane, damage to the membrane fold structure, and reduction of AChR expression, resulting in attenuated neuromuscular signaling and muscle contraction. ACh, acetylcholine; AChR, acetylcholine receptor; AChR⁺, acetylcholine receptor positive; C[x], complement component [x]; gMG, generalized myasthenia gravis; MAC, membrane attack complex; NMJ, neuromuscular junction

Figure 2. (A) Activation of the terminal complement cascade in gMG and (B) inhibition by zilucoplan. Graphics are schematic representations and are not true to scale. In panel A, cross-linking of AChRs by anti-AChR antibodies initiates the classical complement cascade, leading to cleavage of C5 and assembly of the MAC. In panel B, zilucoplan binds C5 at the location corresponding to C5b, thereby inhibiting both the cleavage of C5 and the binding of C6 to pre-formed C5b, thus preventing assembly of the MAC. ACh, acetylcholine; AChR, acetylcholine receptor; C[x], complement component [x]; gMG, generalized myasthenia gravis; MAC, membrane attack complex; NMJ, neuromuscular junction

Figure 3. Mean inhibition of complement activity by zilucoplan in a 12-week phase 2 study in patients with generalized myasthenia gravis, as measured by ex vivo sheep red blood cell hemolysis assay. Figure reproduced with permission from Howard JF Jr, Nowak RJ, Wolfe GI, et al. JAMA Neurol. 2020;77;582–592 [65]. LLOQ, lower limit of quantification

Figure 4. Change from baseline through 12 weeks in the double-blind treatment phase [65] and from weeks 12–24 in the open-label extension treatment phase [78] in the (A) QMG, (B) MG-ADL, (C) MG-QoL15r, and (D) MGC scales. Error bars denote SEMs of least squares mean in all randomized participants who received at least one dose of study drug. Double-blind treatment data were presented in Howard JF Jr, Nowak RJ, Wolfe GI, et al. JAMA Neurol. 2020;77;582–592 [65]; open-label treatment data were previously presented at the American Academy of Neurology 2019 Annual Meeting; May 4–10, 2019; Philadelphia, PA [78]. ^aPrespecified significance testing at a one-sided alpha of 0.1 with last-observation-carried-forward analysis of covariance for least squares mean CFB for zilucoplan 0.3 mg/kg vs placebo; placebo recipients were re-baselined to zero upon completion of the 12-week double-blind treatment period. CFB, change from baseline; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite; MG-QoL15r, 15-item Myasthenia Gravis Quality of Life Revised Scale; QMG, Quantitative Myasthenia Gravis; SEM, standard error of the mean

Table 1. Clinical efficacy outcomes at week 12

			Zilucoplan 0.3 mg/kg vs placebo			Zilucoplan 0.1 mg/kg vs placebo
Variable	Placebo	Zilucoplan 0.3 mg/kg	Difference	P value^a	Zilucoplan 0.1 mg/kg	Difference	P value^a
N	15	14	NA	NA	15	NA	NA
QMG	–3.2 (1.2)	–6.0 (1.2)	–2.8 (1.7)	0.05	–5.5 (1.2)	–2.3 (1.7)	0.09
MG-ADL	–1.1 (0.9)	–3.4 (0.9)	–2.3 (1.3)	0.04	–3.3 (0.9)	–2.2 (1.3)	0.05
MG-QoL15r	–2.1 (1.7)	–5.9 (1.7)	–3.7 (2.4)	0.06	–7.4 (1.7)	–5.3 (2.4)	0.02
MGC	–3.3 (1.6)	–7.4 (1.6)	–4.1 (2.2)	0.04	–5.3 (1.5)	–2.0 (2.2)	0.19
QMG decrease ≥3, n (%)	8 (53.3)	10 (71.4)	NA	NS	10 (66.7)	NA	NS
Rescue received, n (%)	3 (20.0)	0 (0.0)	NA	NS	1 (6.7)	NA	NS

Notes: Scale scores and differences are reported as least squares mean (SEM). The table includes data previously presented in Howard JF Jr, Nowak RJ, Wolfe GI, et al.JAMA Neurol. 2020;77;582–592 [65]. ^aOne-sided P values based on a pre-specified significance value of 0.10.

MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite; MG-QoL15r, 15-item Myasthenia Gravis Quality of LifeRevised Scale; NA, not applicable; NS, not significant; QMG, Quantitative Myasthenia Gravis.

Box 1. Drug summary

Drug name	Zilucoplan (RA101495)
Phase	Phase 3 ongoing study
Indication	Treatment of acetylcholine receptor antibody–positive generalized myasthenia gravis
Pharmacology description/mechanism of action	15-amino acid macrocyclic peptide/C5 complement inhibitor
Route of administration	Subcutaneous injection
Chemical structure
Pivotal trial(s)	ClinicalTrials.gov identifier NCT04115293: Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis (RAISE)

Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol. 2020;77:582–592.

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Howard JF Jr, 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 [data blitz presentation 008]. Neurology. 2019;93:e530.

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