Early Zilucoplan Treatment Maintains Long-Term Benefit in Generalized Myasthenia Gravis


In a new post hoc analysis of RAISE-XT, early responders to zilucoplan maintained their response throughout the long-term open-label extension, irrespective of baseline characteristics.

Miriam Freimer, MD, clinical professor of neurology at The Ohio State University Wexner Medical Center

Miriam Freimer, MD

In a new interim analysis of the phase 3 RAISE-XT open-label extension (OLE) study (NCT04225871) assessing zilucoplan (Zilbrysq; UCB Pharma), a complement component 5 inhibitor, patients with generalized myasthenia gravis (gMG) who responded to the therapy at week 1 maintained their response for almost 90% of their time on long-term treatment regardless of their baseline characteristics. These findings support the early use of zilucoplan and the long-term benefit of the treatment in a broad patient population for those living with gMG.1

Among the participants randomized to receive zilucoplan treatment in RAISE-XT (n = 93), 43.0% (n = 40) were considered responders on Myasthenia Gravis Activities of Daily Living (MG-ADL) and 33.3% of patients (n = 3) were responders Quantitative Myasthenia Gravis (QMG) at week 1. In this set of patients, more than 80% and more than 85%, respectively, remained as responders at each assessment through week 60. These findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held November 1-4, in Phoenix, Arizona, by lead author Miriam Freimer, MD, clinical professor of neurology at The Ohio State University Wexner Medical Center, and colleagues.

Clinical Takeaways

  • Zilucoplan treatment initiated early in patients with myasthenia gravis showed sustained benefits for nearly 90% of their long-term treatment, regardless of baseline characteristics, indicating its potential for diverse patient populations.
  • A significant proportion of patients responding to zilucoplan at week 1 maintained their positive response through week 60, with no substantial differences in baseline characteristics.
  • The results underscore the promise of zilucoplan in providing long-term benefits to patients with myasthenia gravis and suggest a valuable treatment option for this condition.

RAISE-XT featured 199 adult patients with acetylcholine receptor antibody positive (AChR-Ab+) MG who participated in previously the conducted phase 2 (NCT03315130) and phase 3 (NCT04115293) studies. Patients self-administered daily subcutaneous injections of 0.3 mg/kg zilucoplan and were assessed on the primary outcome of treatment-emergent adverse events (TEAEs). At data cutoff (February 18, 2022), participants who continued on to RAISE-XT had a median duration of exposure of 253 days (range, 29-1434).

READ MORE: Treatment Inequality Issues Identified for Patients With Generalized Myasthenia Gravis

For the new analysis, investigators defined MG-ADL and QMG responders by at least a 3-point and at least a 5-point reduction, respectively, from the double-blind baseline without the patients needing rescue therapy. Results showed that responders at week 1 maintained their response for 88.1% and 88.8% of their total time on zilucoplan treatment, respectively, with a median treatment duration of 450 days. In addition, the investigators noted no relevant differences in the baseline characteristics of responders at week 1 compared with the overall gMG sample population.

In the phase 3 RAISE study, zilucoplan demonstrated rapid and clinically meaningful improvements in MG-specific efficacy outcomes in patients with AChR+ gMG. After 12 weeks of treatment, the agent met its primary end point, showing a placebo-corrected mean improvement of 2.09 points on the MG-ADL score.2 In the trial, 174 patients were randomly assigned to either 0.3 mg/kg of zilucoplan (n = 86) or placebo (n = 88) for a 12-week period, followed by an optional RAISE-XT study.

For secondary efficacy outcomes in RAISE, investigators observed a clinically meaningful reduction in 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 As for safety, zilucoplan demonstrated a favorable profile, with treatment-emergent adverse events (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%).

Presented at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 19-22, in Dallas, Texas, interim data from RAISE-XT showed favorable long-term safety profile, with positive efficacy in those who continued treatment from the double-blind period and those who switched from placebo. Throughout the study, 4 treatment-emergent deaths occurred, all in patients with multiple cardiovascular risk factors, and none of them were considered treatment related. Cardiac arrest was the cause in 2 patients, 1 patient experienced head injury, and 1 had severe pneumonia 2 days prior to death. Infections were reported in nearly half (49.2%) of the cohort, although most (86%) were non-serious.

In the previous analysis, patients who switched from placebo to zilucoplan throughout the OLE period demonstrated rapid improvements in MG-ADL. Similarly, those who continued on with zilucoplan demonstrated significant improvements on MG-ADL during the OLE (P = .0002). From double-blind study baseline, zilucoplan-treated individuals achieved LS mean changes in MG-ADL score of –6.30 (95% CI, –7.44 to –5.15). These results were similar for the placebo-switch group, with score reductions of –6.32 (95% CI, –8.00 to –4.65). Scores on key secondary outcomes such as QMG score, Myasthenia Gravis Composite score, and Myasthenia Gravis Quality of Life 15-item-revised, were similar across both treatment groups as well.

Click here for more coverage on AANEM 2023.

1. Freimer M, Leite MI, Vu T, et al. Early Responders with Zilucoplan: An Interim Analysis of RAISE-XT in Patients with Generalized Myasthenia Gravis. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; November 1-4, 2023; Phoenix, AZ. Abstract 41.
2. 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
3. Genge A, Hussain Y, Kaminski HJ, et al. Safety and tolerability of zilucoplan in RAISE-XT: a multicenter, open-label extension study in patients with myasthenia gravis. Presented at: MDA 2023; February 19-22; Dallas, TX. Abstract 145.
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