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FDA Accepts NDA for Myasthenia Gravis Treatment Zilucoplan

Zilucoplan, a complement C5 inhibitor, demonstrated a safe and tolerable profile, while meeting its primary and secondary end points in the phase 3 RAISE trial—the basis for its new drug application.

According to an announcement, the FDA has accepted the new drug application (NDA) of UCB Pharma’s investigational, subcutaneously delivered agent zilucoplan for the treatment of adults with acetylcholine receptor antibody positive (AChR-Ab+) generalized myasthenia gravis (gMG). The news comes shortly after the European Medicines Agency validated the Marketing Authorization Application (MAA) of zilucoplan for the same indication.1

Zilucoplan has its NDA supported by data from the pivotal phase 3 RAISE study (NCT04115293), in which treatment with the agent at doses of 0.3 mg/kg daily resulted in meaningful and statistically significant improvements in key gMG-specific outcomes relative to placebo after 12 weeks of treatment. All told, zilucoplan, a self-administered complement component 5 inhibitor, met its primary end point in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at week 12, with placebo-corrected mean improvements of 2.09 points.

"People living with gMG experience high treatment burden, on top of the debilitating impact of the condition, and there is a clear need for additional targeted treatments to support the gMG community. Our goal is to provide a solution that can help meet these needs and transform lives,” Charl van Zyl, executive vice president, Neurology Solutions, and head, EU/International Markers, UCB, said in a statement.1 "The acceptance of the NDA by the FDA as well as the acceptance of the MAA by the EMA, brings us one step further on our journey towards approval for this medicine. We look forward to working with the FDA and EMA to help bring this important new treatment option to patients."

The EMA’s validation of the MAA for zilucoplan formally recognizes that it is complete and the formal review process by the EMA’s Committee for Medicinal Products for Human Use can begin. Zilucoplan was previously granted orphan drug designation by the FDA in 2019 and by the European Commission in 2022. The company did not include projected final review dates for which a decision on the agent may be made.

In RAISE, 174 patients with AChR-Ab+ gMG were randomly assigned to zilucoplan 0.3 mg/kg (n = 86) daily or placebo (n = 88) over the course of 12 weeks. Zilucoplan not only met its primary end point, but it showed statistically significant improvements in secondary end points such as Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite score, 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

Recently, at the 2022 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting, held September 21-24, investigators presented a more detailed analysis of RAISE data. Responders were considered patients who received a reduction of at least 3 points on MG-ADL or at least 5 points on QMG without rescue therapy. Between the 73.8% of those on zilucoplan 0.3 mg/kg were considered responders on MG-ADL compared with 47.1% of those on placebo (odds ratio [OR], 3.182; 95% CI, 1.660-6.098). Similarly, 59.0% of those on active drug and 33.3% of placebo-treated patients showed at least a 5-point reduction in QMG (<.001).3

The safety profile for zilucoplan has also been confirmed across clinical studies. In the analysis of RAISE presented at AANEM 2022, adverse events (AEs) were similar for those on active drug (76.7%) compared with placebo (70.5%). The most common treatment-emergent AEs were injection site bruising, headache, diarrhea, and MG worsening. Rates of discontinuation because of a treatment-emergent AE were low and all patients who completed the 12-week treatment period have entered the ongoing RAISE-XT open-label extension trial (NCT04225871).

When the topline results of RAISE were announced earlier this year, lead trial investigator James F. Howard Jr, MD, said in a statement that "These exciting results give us additional reason to believe that zilucoplan can offer an important step forward in addressing the unmet needs of people living with gMG." Howard, the Distinguished Professor of Neuromuscular Disease and chief of the Neuromuscular Disorders Section at University of North Carolina School of Medicine, added, "As we strive to improve the management of this complex and unpredictable disease, any new medicines will be welcomed by physicians to help us realize our goal of offering effective and flexible treatment approaches in gMG which are tailored to the needs of individual patients."2

REFERENCES
1. UCB announces US FDA acceptance of new drug application and EMA MAA validation for zilucoplan for the treatment of generalized myasthenia gravis in adult patients. News release. UCB Pharma. November 14, 2022. Accessed November 14, 2022. https://www.prnewswire.com/news-releases/ucb-announces-us-fda-acceptance-of-new-drug-application-and-ema-maa-validation-for-zilucoplan-for-the-treatment-of-generalized-myasthenia-gravis-in-adult-patients-301676223.html
2. UCB presents efficacy and safety results for zilucoplan and rozanolixizumab in generalized myasthenia gravis. News release. UCB Pharma. May 10, 2022. Accessed November 14, 2022. 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. Vu T, Genge A, Hussain Y, et al. Efficacy and safety of zilucoplan in myasthenia gravis: responder analysis from the randomized phase 3 RAISE trial. Presented at: 2022 AANEM Annual Meeting; September 21-24; Nashville, TN. Abstract 200.