Zilucoplan Demonstrates Consistent Efficacy in Phase 3 RAISE Study of Generalized Myasthenia Gravis


Nearly half of patients treated with zilucoplan were considered responders on Myasthenia Gravis Activities of Daily Living (MG-ADL) at the first week, suggesting a rapid onset of efficacy.

Renato Mantegazza, MD, director of the Neuroimmunology and Neuromuscular Diseases Department at the Fondazione Istituto Neurologico "Carlo Besta" of Milan

Renato Mantegazza, MD

In a recent analysis of the phase 3 RAISE study (NCT04115293), Investigators observed a consistent increase in responder rates with treatment of zilucoplan (UCB Pharma) on Myasthenia Gravis Activities of Daily Living (MG-ADL) up to 12 weeks, regardless of baseline disease characteristics.1 The treatment has a Prescription Drug User Fee Action review date with the FDA for the treatment of this patient population set for September 9, 2023.

Among 174 patients with acetylcholine receptor antibody-positive (AChR) generalized myasthenia gravis (gMG) randomized to zilucoplan (n = 86) or placebo (n = 88), responder rates for MG-ADL (73% vs 46%, P <.001) and Quantitative Myasthenia Gravis (QMG) score (58% vs 33%, P = .0012) were significantly higher for the zilucoplan group compared with placebo at week 12. Notably at 1 week, 45% and 32% of zilucoplan-treated patients met the MG-ADL and QMG responder criteria, respectively, vs 30% and 8% of those on placebo. All told, there were no meaningful differences observed in baseline disease characteristics of MG-ADL responders and nonresponders at week 12.

The data were presented at the 9th Congress of the European Academy of Neurology, held July 1-4, in Budapest, Hungary, by lead author Renato Mantegazza, MD, director of the Neuroimmunology and Neuromuscular Diseases Department at the Fondazione Istituto Neurologico "Carlo Besta" of Milan. In the analysis, responders were categorized by achievement of at least 3-point improvement in MG-ADL score, or a at least 5-point improvement in QMG score.

In November 2022, the FDA accepted UCB’s new drug application for zilucoplan using data from the RAISE. In that trial, treatment with 0.3 mg/kg daily of zilucoplan met its primary end point in change in MG-ADL score at week 12, with placebo-correct mean improvements of 2.09 points. Zilucoplan not only met its primary end point, but it showed statistically significant improvements in secondary end points such as QMG score, MGC, and Myasthenia Gravis Quality of Life 15-item Scale score relative to placebo. These improvements were seen as early as 1 week after treatment initiation.2

Presented at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 19-22, in Dallas, Texas, interim data from RAISE-XT, a phase 3, open-label extension (OLE) study of zilucoplan 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.3

RAISE-XT, an ongoing study, featured 199 patients with MG who participated in previously conduced phase 2 (NCT03315130) and phase 3 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 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.

At the 24-month period, 84.9% (n = 169) experienced a TEAE, and 23.1% (n = 46) documented serious AEs. Between both groups, the most common TEAEs were headache and worsening of MG, both occurring in 16.6% of patients. 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.

MG-ADL was rapidly improved throughout the OLE period among those who switched from placebo to zilucoplan. Similarly, the zilucoplan group demonstrated significant improvements on MG-ADL during the OLE (P = .0002). From double-blind study baseline, zilucoplan-treated individuals achieved least square 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, MGC, and Myasthenia Gravis Quality of Life 15-item-revised, were similar across both treatment groups as well.

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1. Mantegazza R, Bresch S, Freimer M. Response to zilucoplan in the Phase 3 RAISE study in patients with generalised myasthenia gravis. Presented at: EAN 2023. July 1-4, 2019; Budapest, Hungary. EPR-132.
2. UCB presents efficacy and safety results for zilucoplan and rozanolixizumab in generalized myasthenia gravis. News release. UCB Pharma. May 10, 2022. Accessed July 11, 2023. https://www.ucb-usa.com/stories-media/UCB-U-S-News/detail/article/ucb-presents-efficacy-and-safety-results-for-zilucoplan-and-rozanolixizumad-in-generalized-myasthenia-gravis
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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