Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study

Abstract

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments.

Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population.

Design: Ongoing, multicenter, phase III open-label extension (OLE) study.

Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score.

Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints.

Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses.

Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Keywords: C5 inhibitor; clinical trial; myasthenia gravis; open-label extension; zilucoplan.

Figure 1.

Patient disposition. *Primary reason for discontinuation. AE, adverse event.

Figure 2.

Change from DB baseline in (a) MG-ADL, (b) QMG, (c) MGC, (d) MG-QoL 15r, and (e) Neuro-QoL fatigue* scores up to Week 60. Changes from baseline in MG-ADL, QMG, MGC, and MG-QoL 15r were estimated using an MMRM ANCOVA with baseline score, baseline MG-ADL score, baseline QMG score, baseline score (for MGC and MG-QoL 15r), geographical region, parent study factor, and baseline score × visit (interaction term) as fixed effects and study participant as a random effect. The model included Week 1 to Week 12 (DB treatment period) and Week 13 to Week 60 (OLE period). An unstructured correlation structure was used. Separate models were fitted for each group: PBO/ZLP 0.3 mg/kg and ZLP 0.3/ZLP 0.3 mg/kg. p Values are nominal. *Includes patients from phase III study only. ANCOVA, analysis of covariance; CFB, change from baseline; CI, confidence interval; DB, double-blind; LSM, least squares mean; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite; MG-QoL 15r, Myasthenia Gravis Quality of Life 15-item revised scale; MMRM, mixed-model repeated measure; OLE, open-label extension; PBO, placebo; QMG, Quantitative Myasthenia Gravis; SE, standard error; ZLP, zilucoplan.

Figure 3.

(a) MG-ADL (⩾3-point reduction from baseline), (b) QMG (⩾5-point reduction from baseline), and (c) MSE (MG-ADL score of 0 or 1) responder rates without rescue therapy*. *Patients could receive intravenous immunoglobulin or plasma exchange treatment as rescue therapy concomitantly with zilucoplan if, per the investigator’s judgment, escalation of gMG therapy became necessary due to deterioration of their clinical status or risk of MG crisis. gMG, generalized myasthenia gravis; MG, myasthenia gravis; MG-ADL, Myasthenia Gravis Activities of Daily Living; MSE, minimal symptom expression; QMG, Quantitative Myasthenia Gravis.