Zilucoplan found effective for gMG in Japanese patients in analyses

New subgroup analysis of Phase 3 RAISE trial also shows therapy's safety

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Daily treatment with zilucoplan was tied to meaningful reductions in symptom severity among the subgroup of Japanese generalized myasthenia gravis (gMG) patients who participated in the Phase 3 RAISE clinical trial, according to new subgroup analyses.

The data add to accumulating trial evidence that the UCB therapy is broadly safe and effective across various subgroups of gMG patients.

The UCB-sponsored study, “Efficacy and safety of zilucoplan in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the phase III randomized RAISE study,” was published in the journal Clinical and Experimental Neuroimmunology.

Japanese authorities approved zilucoplan under the brand name Zilbrysq in late September for certain adults with difficult-to-treat gMG.

Similar applications are under review now by regulators in the U.S. and the European Union — where a regulatory committee granted a positive recommendation for EU approval and a decision is expected later this year.

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Focusing on RAISE results among only Japanese patients

Researchers had noted in the study that “in 2017, there were nearly 30,000 people living with MG in Japan, with a prevalence of 231 per million people, which had almost doubled from 118 per million people in 2006.”

Given those numbers, scientists were eager to seek potential treatments — such as zilucoplan.

“In a subgroup of Japanese patients, zilucoplan showed clinically meaningful improvement in MG-specific outcomes with a favorable safety profile, consistent with the overall RAISE population,” the team now wrote.

Zilucoplan is a small molecule that works by blocking the C5 protein of the immune system’s complement pathway. That protein is thought to be involved in driving the self-reactive immune attacks that cause muscle weakness in gMG. By blocking complement activation, zilucoplan is expected to slow gMG progression and ease disease severity.

Two approved gMG therapies — Soliris (eculizumab) and Ultomiris (ravalizumab) — also target C5, but are given via intravenous or into-the-vein infusions. This therapy, meanwhile, is designed to be self-administered as under-the-skin, or subcutaneous, injections.

The global Phase 3 RAISE trial (NCT04115293), launched in 2019, enrolled 174 adults with gMG who had antibodies against acetylcholine receptors, the most common type of MG-causing antibody. Participants were recruited across 75 trial sites, 11 of which were in Japan.

These patients were randomly assigned to self-inject either zilucoplan (0.3 mg/kg) or a placebo at home, once daily, for 12 weeks or about three months.

Top-line results showed that the therapy led to significant and clinically meaningful reductions in symptom severity relative to the placebo. This was reflected as 2.09-point greater reduction on the MG Activities of Daily Living (MG-ADL) scale.

Other patient- and clinician-rated outcomes related to symptom severity and life quality similarly favored zilucoplan.

Subgroup analyses indicated that the therapy’s superiority over the placebo generally was maintained regardless of sex, age, disease duration, previous steroid use, or the presence of a thymoma, which is a tumor on the thymus gland.

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Benefits seen in these patients as early as 1 week after treatment start

Now, researchers conducted an additional subgroup analysis that included only the 16 Japanese patients who participated in RAISE. Seven were assigned to zilucoplan and nine to the placebo.

Characteristics of these patients were comparable to the general trial patient population. However, no Japanese patient had severe muscle weakness versus about 5% of those in the total population.

In addition, a higher proportion of Japanese patients had undergone a thymectomy — surgery to remove the thymus gland (about 75% vs. 47%) — and were considered treatment refractory, or resistant (about 80% vs. 50%).

Efficacy data showed that zilucoplan-treated Japanese patients experienced a clinically meaningful reduction in MG-ADL scores after 12 weeks that was 4.26 points greater than that observed in the placebo group.

Similar to observations in the overall trial population, the effects of zilucoplan were observed as early as one week after the start of treatment, increased by week 2, and then sustained through week 12.

Moreover, the therapy was linked to clinically meaningful and greater changes in all secondary efficacy outcomes. These included patient- and clinician-reported measures of symptom severity and life quality, relative to the placebo.

Overall, efficacy results for Japanese patients were consistent with the results for the overall population, including the primary and secondary efficacy endpoints [goals].

Due to the small number of patients, statistical significance could not be established in these efficacy analyses.

“Overall, efficacy results for Japanese patients were consistent with the results for the overall population, including the primary and secondary efficacy endpoints [goals],” the researchers wrote.

Among the Japanese patients, the rates of side effects were similar between the zilucoplan and placebo groups. The most common was MG worsening, occurring in three patients in the placebo group and none in the zilucoplan group.

While in the total trial population side effects were more frequent in the zilucoplan group, overall, “no relevant safety differences were observed in the Japanese population, compared with the overall population,” the researchers wrote.

All RAISE participants who completed the main trial, including those in the Japanese subgroup, chose to enter an ongoing open-label extension study called RAISE-XT (NCT04225871), where all are receiving zilucoplan for up to three years. That study is expected to be completed in 2026.