Complement Inhibition of Zilucoplan Unaffected When Used Concomitantly With IVIg, Plasma Exchange

James F. Howard, MD

A new analysis from the previously completed phase 3 RAISE study (NCT0331513) and its open-label extension (OLE) showed that zilucoplan (Zilbrysq; UCB Pharma), an FDA-approved therapy for generalized myasthenia gravis (gMG), maintained steady-state concentrations in patients with and without rescue therapy. Overall, these data suggest that zilucoplan may be used concomitantly with other medications like intravenous immunoglobulin (IVIg) or plasma exchange without the need for supplemental dosing.

Zilucoplan, a complement C5 inhibitor, was approved as a treatment for MG in 2023 based on data from RAISE, a large-scale, double-blind, placebo-controlled study. The new analysis, presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, the analysis included patients who received at least 1 week of zilucoplan 0.3 mg/kg in either the core phase 3 study or its OLE. Overall, among those exposed to treatment (n = 200), 21 (10.5%) received IVIg and 10 (5.0%) received plasma exchange.

Led by senior author James F. Howard, MD, Distinguished Professor of Neuromuscular Disease and professor of neurology at The University of North Carolina at Chapel Hill School of Medicine, zilucoplan plasma concentration was measure pre- and post-administration on the day of rescue therapy by liquid chromatography-tandem mass spectrometry. Complement activity was measured by sheep red blood cell lysis assay, with post-measurement taken less than 1 day after rescue.

READ MORE: Concomitant Corticosteroid Use Decreased in Myasthenia Gravis Through Ravulizumab

All told, results showed that mean complement inhibition remained complete (>95%) pre- and post-rescue: 97.1% (0.80) and 97.4% (0.63) for IVIg (10 events with data), respectively. Pre- and post-rescue complement inhibition was 96.3% and 95.9% for plasma exchange (1 event with data), respectively. Using a cutoff date of September 8, 2022, safety data showed that treatment-emergent adverse events (TEAEs) occurred in 188 (94.0%) patients during the analysis.

In the original RAISE study, zilucoplan met its primary end point, showing a placebo-corrected mean improvement of 2.09 points on Myasthenia Gravis Activities of Daily Living (MG-ADL) score. The therapy also demonstrated a clinically meaningful reduction in Quantitative Myasthenia Gravis (QMG) score, a secondary end point, after 12 weeks (least squares [LS] mean change, [–6.19; 95% CI, –7.29 to –5.08] vs placebo: LS mean change, –3.25 [95% CI, –4.32 to –2.17] LS mean difference, –2.94 [95% CI, –4.39 to –1.49] P <.0001).

There were several pieces of zilucoplan-related data presented at AANEM 2024, including a new interim analysis of the phase 3b MG0017 study (NCT05514873). In that study, results showed that switching from IV complement C5 inhibitors to subcutaneous zilucoplan did not raise any safety concerns in adults with acetylcholine receptor auto-antibody positive gMG. In fact, the switch to zilucoplan resulted in higher treatment satisfaction, symptom improvement, and preference for zilucoplan after 12 weeks.⁴

As of August 11, 2023, 8 participants in MG0017 received zilucoplan and 5 completed the 12-week main treatment period. At week 12 in the switch group, the mean change from baseline in MG-ADL and QMG scores were –1.80 (SD, 3.49) and –3.00 (SD, 1.63), respectively. In addition, the mean change from baseline in Treatment Satisfaction Questionnaire for Medication global satisfaction subscore was 26.43 (SD, 19.5) at week 12. Notably, all 5 participants preferred zulicoplan over their previous IV C5 inhibitor.

Click here for more coverage of AANEM 2024.

REFERENCES
1. Weiss MD, Hewamadduma C, Leite MI, et al. Concomitant intravenous immunoglobulin or plasma exchange has no effect on complement inhibition by zilucoplan. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA. ABSTRACT 305.
2. UCB announces US FDA approval of Zilbrysq (zilucoplan) for the treatment of adults with generalized myasthenia gravis. News release. October 17, 2023. Accessed October 17, 2023. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-US-FDA-approval-of-ZILBRYSQR-zilucoplan-for-the-treatment-of-adults-with-generalized-myasthenia-gravis
3. Howard JF, Bresch S, Genge A, et al. Safety and efficacy of zilucoplan in patients with generalized myasthia gravis (RAISE): a randomized, double-blind, placebo-controlled, phase 3 study. 2023;22(5):395-406. doi:10.1016/S1474-4422(23)00080-7
4. Freimer M, Govindarajan R, Khatri B, et al. Safety, Efficacy, and Patient Preference for Subcutaneous Zilucoplan in Myasthenia Gravis After Switching from Intravenous Complement Component 5 Inhibitors: An Interim Analysis of a Phase 3b Study. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.