Zilucoplan Shows Reduction in Fatigue in the Phase 3 Trials for Generalized Myasthenia Gravis


Zilucoplan demonstrated significant and sustained improvements in myasthenic fatigue when compared with the placebo in the phase 3 RAISE study and its extension trial, RAISE-XT.

Michael D. Weiss, MD, FAAN, director of the neuromuscular diseases division, professor of neurology and adjunct professor of rehabilitation medicine at the University of Washington

Michael D. Weiss, MD, FAAN

In a new post hoc analysis of the phase 3 RAISE study (NCT94115293) and its open-label extension, RAISE-XT (NCT04225871), treatment with zilucoplan (Zilbrysq; UCB Pharma) significantly and clinically meaningfully improved myasthenic fatigue compared with placebo and had further improvements that were sustained for up to 60 weeks. These findings suggest zilucoplan has potential in reducing fatigue symptoms in patients living with generalized myasthenia gravis (gMG).1

At the end of RAISE at week 12, least squares mean (LS) change from baseline in the Quality of Life in Neurological Disorders (Neuro QoL) Short Form fatigue T-score was −6.26 for zilucoplan-treated patients with gMG (n = 86) compared with –2.65 for the placebo group (n = 88) (LS difference, –3.61 [95% CI, −6.18 to −1.05]; nominal P = .0060, not multiplicity-controlled). At the conclusion of the 12-week double-blind portion, 95.4% of patients with gMG (n = 166) from RAISE entered RAISE-XT and received zilucoplan treatment.

Clinical Takeaways

  • Zilucoplan demonstrated significant and clinically meaningful improvements in reducing myasthenic fatigue, showing promise for patients with generalized myasthenia gravis (gMG).
  • A high percentage of RAISE trial participants entered the RAISE-XT extension study to continue zilucoplan treatment, with positive long-term results.
  • The analysis revealed sustained improvements in Neuro QoL fatigue scores for both placebo-switch and zilucoplan groups up to week 60, providing potential relief for patients with gMG.

These findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held November 1-4, in Phoenix, Arizona, by lead author Michael D. Weiss, MD, FAAN, director of the neuromuscular diseases division, professor of neurology and adjunct professor of rehabilitation medicine at the University of Washington, and colleagues. In this analysis, Weiss and colleagues assessed the long-term effects of fatigue in patients from RAISE who also entered the RAISE-XT trial, and reported the change in Neuro QoL short form fatigue T-score from RAISE baseline to week 60.

READ MORE: Social Determinants of Health Lead to Greater Suboptimal Treatment Response in Myasthenia Gravis

In RAISE, a double-blind, placebo-controlled phase 3 study, 174 adult patients with acetylcholine receptor antibody positive (AChR-Ab+) generalized MG (MG Foundation of America Disease Class II–IV) were randomized 1:1 to daily subcutaneous zilucoplan 0.3 mg/kg (n = 86) or placebo (n = 88) for 12 weeks between 2019 and 2021. Patients in the study were assessed on the primary outcome of treatment-emergent adverse events (TEAEs). At data cutoff (February 18, 2022), participants had a median duration of exposure of 253 days (range, 29-1434) during RAISE-XT and the OLE portion of the phase 2 study for participants who continued on treatment.

In the new analysis, Neuro QoL fatigue T-scores improved in 1 week for patients who switched from placebo to zilucoplan (placebo-switch group) in the RAISE-XT trial. Further to week 16, Neuro QoL fatigue T-scores improved for placebo-switch and zilucoplan groups and were sustained through week 60 (mean [SD] change from RAISE baseline, –10.71 [11.71, n = 42] and –9.15 [11.65, n = 42], respectively).

Presented at the 2023 Muscular Dystrophy Association Clinical and Scientific Conference, interim data from RAISE-XT continued to highlight zilucoplan’s safety and efficacy profile. At the 24-month period, 84.9% (n = 169) of patients experienced a TEAE, and 23.1% (n = 46) documented serious adverse events. Between the groups, the most common TEAEs were headache and worsening of MG, both occurring in 16.6% of patients.2

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 nonserious.

From the double-blind study baseline, zilucoplan-treated individuals achieved LS changes in Myasthenia Gravis Activities of Daily Living (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 Quantitative Myasthenia Gravis score, Myasthenia Gravis Composite score, and Myasthenia Gravis Quality of Life 15-item-revised, were similar across both treatment groups as well.

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1. Weiss MD, Freimer M, Maniaol A, et al. Effect of Zilucoplan on Fatigue in Generalized Myasthenia Gravis in the Phase 3 RAISE and RAISEXT Studies. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; November 1-4, 2023; Phoenix, AZ. Abstract 285.
2. 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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