AAN 2023: Zilucoplan eases symptoms in all subgroups in trial

Treatment's effects were consistent, regardless of sex, age, disease duration

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with the experimental therapy zilucoplan eased symptoms of generalized myasthenia gravis (gMG) across different subgroups of patients participating in the Phase 3 RAISE clinical trial.

Trial data showed treatment effects were consistent, regardless of sex, age, disease duration, prior use of certain treatments, or thymoma status.

Findings were shared in a poster, titled “Subgroup outcomes from RAISE: A randomized, Phase 3 trial of zilucoplan in generalized myasthenia gravis,” presented at the American Academy of Neurology (AAN) 2023 Annual Meeting, running April 22–27 in Boston and virtually. Research was funded by UCB, the company developing zilucoplan.

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Zilucoplan led to ‘consistent improvements’ across all subgroups after 12 weeks

Zilucoplan is designed to bind to an immune protein called C5, preventing the activation of the complement system — a part of the immune system that is involved in the autoimmune attack that drives MG. This same immune protein is also targeted by the approved gMG therapies Soliris (eculizumab) and Ultomiris (ravulizumab).

Whereas these approved therapies are administered via infusion into the bloodstream, zilucoplan is given by an under-the-skin injection, which, unlike infusions, can be administered at home.

The Phase 3 RAISE trial (NCT04115293) enrolled 174 adults with gMG who were positive for antibodies against the acetylcholine receptor (AChR), the most common type of MG-causing antibody. Participants were randomly assigned to self-administer zilucoplan (0.3 mg/kg) or a placebo, daily for 12 weeks, or about three months.

Top-line results from RAISE were announced last year and showed the therapy outperformed a placebo in easing MG symptoms and improving life quality in the overall group of participants.

As previously reported, treatment with zilucoplan led to clinically meaningful improvements in the scores of the MG Activities of Daily Living (MG-ADL), a measure of symptom severity. At week 12, scores had dropped by 2.09 points in zilucoplan-treated patients from baseline (the study’s start) compared with the placebo group.

In the AAN poster, researchers conducted analyses of prespecified subgroups of patients. These included subgroups in which patients were grouped by sex (male or female), age (younger than 65 vs. 65 and older), and disease duration (less than five years vs. five years or longer). Analyses also compared patients with and without a thymoma (a tumor in the thymus gland), and those who had previously been treated with non-steroid immunosuppressants and those who had not.

Compared with placebo, treatment with zilucoplan resulted in consistent improvements from baseline for MG-specific endpoints at Week 12 across all subgroups.

Across all these subgroups, greater improvements in MG-ADL scores from baseline to week 12 were consistently observed in patients given zilucoplan. Generally, patients on zilucoplan saw their MG-ADL scores drop by four or five points, whereas those on placebo saw them drop by around three points or less.

Other standardized assessments of disease severity and MG-specific life quality, including the Quantitative MG (QMG), the MG Composite, and the MG Quality of Life 15-item revised scales, generally showed similar trends to MG-ADL scores.

Subgroup analyses comparing patients with higher versus lower MG-ADL or QMG scores at the start of the study also consistently showed more extensive improvements with zilucoplan than with a placebo.

“Compared with placebo, treatment with zilucoplan resulted in consistent improvements from baseline for MG-specific endpoints at Week 12 across all subgroups,” the researchers wrote.

Patients who completed RAISE had the option to enroll in an open-label extension study called RAISE-XT (NCT04225871). All participants in this study are being treated with daily under-the-skin injections of zilucoplan.

Researchers presented data from an interim analysis of this extension study in a separate AAN poster, titled “RAISE-XT: An interim analysis of safety and efficacy in an open-label extension study of zilucoplan in patients with myasthenia gravis.”

The analysis included data from 199 patients, including people with AChR-positive gMG who had participated in RAISE or in MG0009 (NCT03315130), an earlier Phase 2 trial of zilucoplan.

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No new safety concerns reported with long-term zilucoplan treatment

Findings from the extension study have not revealed any new safety concerns associated with long-term zilucoplan treatment. Common side effects observed during treatment included headache, diarrhea, and MG worsening.

Among patients who had been given zilucoplan for 12 weeks in earlier trials, mean MG-ADL and QMG scores remained low — reflecting improvement — after an additional 12 weeks of treatment in the extension study. For patients who had been on a placebo in previous trials, these scores showed a sharp improvement within one week after they started treatment with zilucoplan in RAISE-XT.

After 12 weeks of treatment with zilucoplan in the extension study, patients who had been on placebo or zilucoplan in earlier trials experienced similar reductions in MG-ADL and QMG scores from baseline of the original trial: a reduction of more than six points in MG-ADL and of more than eight points in QMG scores.

In both groups, about three out of every four patients had clinically meaningful improvements in both scores and were considered to be responders in these measures by week 12 of RAISE-XT.

“RAISE-XT demonstrated that zilucoplan was efficacious and well tolerated in the long term, building on data from the 12-week, double-blind Phase 2 and Phase 3 studies,” the researchers wrote.

Note: The Myasthenia Gravis News team is providing coverage of the American Academy of Neurology (AAN) 2023 Annual Meeting April 22-27. Go here to see the latest stories from the conference.