Nancy A. Melville
PHOENIX — Early responders to zilucoplan, the newly approved medication for myasthenia gravis (MG), have sustained benefit for up to 60 weeks, new analyses show.
“The information [in the studies] is valuable in making clinical decisions in managing MG, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” Xinli Du, MD, PhD, an assistant professor in the Department of Neurology at VCU, in Richmond, Virginia, who was not involved in the research, told Medscape Medical News.
“Compared to conventional immunosuppressants, which take 3 to 9 months to know if the patient will respond, this is definitely a game-changer,” she said.
The research (abstracts #41 and #285) was presented on November 3 at the 2023 American Association of Neuromuscular Electrodiagnostic Medicine (AANEM) Annual Meeting.
FDA Approval
Approved by the US Food and Drug Administration (FDA) in October and reported by Medscape Medical News at that time, the targeted peptide inhibitor of complement component 5, represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized MG.
The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in MG-specific outcomes in adult patients with mild to severe AChR+ generalized MG.
Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.
In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.
Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a three-point reduction from baseline on the MG Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least five-point reductions in Quantitative MG (QMG), at week 1.
Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.
Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.
Of note, the week 1 early responders had no significant differences compared with the study’s overall population. Participants had a mean age of 49.6 years vs 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the MG Foundation of America criteria.
“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for MG,” said Freimer, director of the Division of Neuromuscular Disorders and the co-director the Myasthenia Gravis Clinic at The Ohio State University, in Columbus.
Impact on Fatigue
In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.
Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being -6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, -3.61; nominal P = .0060).
Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.
Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, -10.71 [n = 42] and -9.15 [n = 42], respectively).
“Fatigue is a challenge for patients with [generalized MG]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue vs placebo during RAISE,” the investigators report.
“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they add.
Favorable Safety Profile
Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well-tolerated in the long-term.
The most common adverse reactions (10% or more) in patients with generalized MG were injection site reactions, upper respiratory tract infection, and diarrhea.
Though additional therapies have also recently entered the market for generalized MG, they are either intravenous or subcutaneous infusions requiring a healthcare professional to administer them.
“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Freimer noted.
However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.
However, she added, “the rapid action benefits shown as early as Week 1 are impressive, and potentially open the door to use as adjunctive therapy in MG crisis.”
“I think zilucoplan definitely adds more excitement to the already active field of MG management,” she said.
The study was funded by UCB Pharma. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the NIH, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Du reports no disclosures.
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