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

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).

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.²In 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).³As 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.