Zilucoplan Shows Reduction in MG Worsening in Phase 3 RAISE Study for Generalized Myasthenia Gravis


A post hoc analysis of the phase 3 RAISE study evaluating zilucoplan, a complement C5 inhibitor, showed significantly fewer patients experienced worsening and fewer requiring rescue therapy while on medication compared with placebo.

Angela Genge, MD, FRCPC, eMBA, clinical director, executive director, clinical research unit, Montreal Neurological Institute, and chief medical officer, QurAlis

Angela Genge, MD, FRCPC, eMBA

In a new post hoc analysis of the phase 3 RAISE study (NCT04115293) assessing zilucoplan (Zilbrysq; UCB Pharma), an FDA-approved complement C5 inhibitor, findings showed a significantly lower proportion of patients who experienced myasthenia gravis (MG) worsening when treated with the therapy than placebo. Additionally, of those who had treatment-related adverse events (TEAE) of MG worsening, a lower proportion needed rescue therapy during the study at any time.1

In this analysis, 86 patients were randomized to zilucoplan and 88 to the placebo group. There were more patients in the placebo group who showed MG worsening, demonstrated by an MG Activities of Daily Living (MG-ADL) or Quantitative MG (QMG) score of at least 3 or at least a 5-point increase, compared with those in the zilucoplan group (25.0% vs 10.5%, respectively; nominal P<.05, not multiplicity-controlled). In the 8 patients who experienced TEAE of MG worsening in the placebo group, all received rescue therapy. Of the 9 zilucoplan-treated patients who experienced this TEAE, 2 (22.2%) received rescue therapy.

These findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held November 1-4, in Phoenix, Arizona, by lead author Angela Genge, MD, FRCPC, eMBA, clinical director, executive director, clinical research unit, Montreal Neurological Institute, and chief medical officer, QurAlis, and colleagues. In this analysis, investigators assessed MG worsening, MG worsening as a TEAE, and the use of rescue therapy in the RAISE trial. RAISE was a phase 3, double-blind, placebo-controlled study of the complement component 5 inhibitor, zilucoplan, in patients with acetylcholine receptor autoantibody-positive (AChR+) gMG. Conducted from 2019 to 2021, 174 eligible adult patients with AChR+ gMG were included and randomly assigned to either 0.3 mg/kg or zilucoplan (n = 86) or placebo (n = 88) for a 12-week period, followed by an optional open-label extension study (RAISE-XT; NCT04225871).

Clinical Takeaways

  • Zilucoplan, a complement C5 inhibitor, demonstrated a substantial reduction in myasthenia gravis (MG) worsening in patients compared with a placebo group in the RAISE study.
  • Fewer patients treated with zilucoplan required rescue therapy for MG worsening, indicating the potential for improved disease management.
  • These findings may show promise for better outcomes and quality of life for patients with acetylcholine receptor autoantibody-positive generalized MG treated with zilucoplan.

READ MORE: Subcutaneous Efgartigimod PH20 Demonstrates Efficacy for Generalized Myasthenia Gravis in Open Label ADAPT-SC+ Trial

In the new post hoc analysis, MG worsening was defined as at least 3-point or at least 5-point increase from baseline in MG-ADL or QMG scores, respectively, at any time during the study. TEAEs reported as MG worsening were assessed and if the investigator deemed escalation of gMG therapy to be necessary, rescue therapy (IVIg or plasma exchange) was administered concomitantly.

In October 2023, the FDA approved zilucoplan to treat patients with AChR-Ab+ generalized MG based on results from RAISE. In the trial, zilucoplan demonstrated rapid and clinically meaningful improvements in MG-specific efficacy outcomes. After 12 weeks of treatment, zilucoplan met its primary end point, showing a placebo-corrected mean improvement of 2.09 points on MG-ADL score.2

In secondary efficacy outcomes, investigators observed a clinically meaningful reduction in Quantitative Myasthenia Gravis (QMG) score after 12 weeks with zilucoplan (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).3

In terms of safety, zilucoplan demonstrated a favorable profile, with TEAEs occurring in 77% of patients. The most frequently reported TEAEs among treated patients were injection-site bruising (16%), headache (15%), diarrhea (10%), and worsening of MG (10%). Between the 2 groups, the incidence of frequently reported TEAEs were similar, except for injection-site bruising, diarrhea, injection-site pain, and lipase increase, which were more frequent in the zilucoplan group.

In the zilucoplan group, 4 patients discontinued because of a TEAE (one each of aphthous ulcer, mouth ulceration, hepatic enzyme increase, and COVID-19 leading to death) and 2 patients discontinued from the placebo group because of a TEAE (hyperemesis gravidarum and cerebral hemorrhage leading to death). Neither death was considered related to the study drug. Of note, a higher incidence of infections occurred in the zilucoplan group than in the placebo group (27% vs 18%), which was driven by nonserious upper respiratory tract infections (14% vs 7%). No meningococcal or other Neisseria spp infections or anaphylactic reactions occurred in either group.

Click here for more coverage on AANEM 2023.

1. Genge A, Hewamadduma C, Hussain Y, et al. Effect of Zilucoplan on Disease Fluctuation in Patients With Generalized Myasthenia Gravis in the Phase 3 RAISE Study. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; November 1-4, 2023; Phoenix, AZ. Abstract 259.
2. UCB announces US FDA approval of Zilbrysq (zilucoplan) for the treatment of adults with generalized myasthenia gravis. News release. November 1, 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
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