Switching to Subcutaneous Zilucoplan Raises No Safety Concerns in Myasthenia Gravis

In a new interim analysis of the phase 3b MG0017 study (NCT05514873), switching from intravenous (IV) complement component 5 (C5) inhibitors to subcutaneous (SC) zilucoplan (Zilbrysq; UCB Pharma) did not raise any safety concerns in adults with acetylcholine receptor autoantibody-positive (AChR Ab+) generalized myasthenia gravis (gMG).¹ All told, the switch to zilucoplan indicated higher treatment satisfaction, symptom improvement, and preference for zilucoplan after 12 weeks.

As of August 11, 2023, 8 participants received zilucoplan and 5 completed the 12-week main treatment period. Presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, by lead author Miriam Freimer, MD, neurologist and clinical professor of neurology at The Ohio State University Wexner Medical Center and College of Medicine, and colleagues, 4 (50%) participants reported treatment-emergent adverse events (TEAEs). One reported TEAE, injection-site pruritus, was considered treatment related by investigators. Notably, no serious TEAEs or study discontinuations were reported.

"The interim analysis demonstrated a favorable safety profile similar to the previously reported data. MG symptoms remained stable or improved in the majority of the patients after switching from an IV complement 5 inhibitor to an SC. Final analysis will be presented in the future," Freimer told NeurologyLive^®.

At week 12 in the switch group, the mean change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores were −1.80 (SD, 3.49) and −3.00 (SD, 1.63) respectively. In addition, the mean change from baseline was 26.43 (SD, 19.50) for Treatment Satisfaction Questionnaire for Medication (TSQM-9) global satisfaction subscore at week 12. Notably, all 5 participants preferred zilucoplan over their previous IV C5 inhibitor.

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MG0017 is an ongoing phase 3b, multicenter, open-label, single-arm study assessing daily SC zilucoplan 0.3 mg/kg with a 12-week main treatment period and an optional extension period. Investigators aimed to enrolled 20 patients into the trial and those already enrolled had clinically stable disease on an IV C5 inhibitor and were ready to switch to zilucoplan. The primary end point was incidence of TEAEs. Secondary end points were change from baseline in MG-ADL and QMG scores at week 12. Investigators also assessed patient-reported outcomes, such as treatment satisfaction, using the TSQM-9 global satisfaction subscore (scored from 0–100), and preference.

"Patients reported a higher treatment satisfaction and 80% of the patients preferred this treatment approach. This SC complement inhibitor provides patients with another option to receive this medication," Freimer added. "It allows for more flexibility for patients since it is self administered, doesn’t require IV placement or adjusting schedules to receive an infusion."

At the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held November 1-4, in Phoenix, Arizona, Freimer and colleagues presented an interim analysis of the phase 3 RAISE-XT open-label extension (OLE) study (NCT04225871) showing that patients with gMG who responded to zilucoplan at week 1 maintained their response for almost 90% of their time over long-term treatment regardless of their baseline characteristics.² Among the participants randomized to receive zilucoplan treatment in RAISE-XT (n = 93), 43.0% (n = 40) were considered responders on MG-ADL and 33.3% of patients (n = 3) were responders on 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.

RAISE-XT featured 199 adult patients with 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 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).

In this 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.

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REFERENCES
1. Freimer M, Govindarajan R, Khatri B, et al. Safety, Efficacy, and Patient Preference for Subcutaneous Zilucoplan in Myasthenia Gravis After Switching from Intravenous Complement Component 5 Inhibitors: An Interim Analysis of a Phase 3b Study. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.
2. 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.