RAISE Subgroup Analysis: Zilucoplan Without Prior Rescue Therapy in gMG

Complement inhibition has become an established strategy in acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG), but its positioning within the broader treatment sequence remains under active discussion.

A prespecified subgroup analysis from the Phase 3 RAISE trial examines whether zilucoplan, a subcutaneous complement component 5 inhibitor, delivers comparable benefit in patients who had not previously received immunoglobulin or plasma exchange (PLEX), therapies typically reserved for more severe or unstable disease.

RAISE was a randomized, double-blind, placebo-controlled study enrolling 174 adults with anti–acetylcholine receptor antibody–positive gMG with baseline Myasthenia Gravis Activities of Daily Living (MG-ADL) scores of at least 6 and Quantitative Myasthenia Gravis (QMG) scores of at least 12. Of the overall population, 54 patients had not received prior immunoglobulin, whether intravenous or subcutaneous, or PLEX before entering the trial. Participants were assigned to daily self-administered subcutaneous zilucoplan 0.3 mg/kg or placebo for 12 weeks while continuing stable background corticosteroids or nonsteroidal immunosuppressive therapies. The primary endpoint was change from baseline to Week 12 in MG-ADL score.

Baseline Characteristics of the Subgroups
Baseline characteristics differed meaningfully in those with prior rescue therapy exposure. Patients without prior immunoglobulin or PLEX tended to have milder disease, reflected in a higher proportion of MGFA Class II status, and a shorter duration from diagnosis, approximately 4.9 to 5.9 years compared with 10.6 to 11.1 years in the prior-treatment subgroup. Fewer had experienced prior myasthenic crisis or undergone thymectomy.

Efficacy Outcomes: MG-ADL and QMG
In patients without prior immunoglobulin or PLEX, mean change from baseline in MG-ADL score at Week 12 was −4.22 with zilucoplan versus −2.61 with placebo. Among those with prior immunoglobulin or PLEX, the corresponding values were −4.93 and −2.94. For context, the overall RAISE population demonstrated mean MG-ADL changes of −4.70 with zilucoplan and −2.85 with placebo.

A similar pattern was observed for QMG scores. In patients without prior immunoglobulin or PLEX, mean change from baseline at Week 12 was −6.48 with zilucoplan compared with −3.04 for placebo. In those with prior exposure, QMG changes were −6.23 and −3.51, respectively. These magnitudes were consistent with results in the full study population, showing QMC changes of −6.31 with zilucoplan and −3.38 for placebo.

Responder analyses also reinforce the consistency of treatment effect. MG-ADL responder rates, defined as a reduction of at least three points from baseline, reached 74.1% in zilucoplan-treated patients without prior immunoglobulin or PLEX and 73.7% in those with prior exposure. QMG responder rates, defined as a reduction of at least five points, were 63% and 57.1% in the two subgroups, respectively. Placebo response rates were lower across both measures.

Safety Profile Across Treatment Histories
Safety findings were broadly comparable and well-tolerated in subgroups. In the subgroup without prior exposure, one treatment-related serious adverse event (worsening aphthous mouth ulceration) occurred in a patient receiving zilucoplan. In the subgroup with prior immunoglobulin or PLEX, five treatment-related serious adverse events were reported, including angioedema, increased lipase, and oral candidiasis in patients receiving zilucoplan, and two events in a placebo-treated patient. Two deaths occurred in the subgroup without prior immunoglobulin or PLEX, with one in each treatment arm; neither was considered treatment-related by investigators.

Interpretation and Clinical Positioning
The analysis is descriptive and limited by subgroup size, particularly in the cohort without prior immunoglobulin or PLEX. Randomization was not stratified by prior rescue therapy exposure, and baseline differences in disease duration and surgical history may influence interpretation. The treatment period was 12 weeks, leaving long-term durability and safety unaddressed.

Immunoglobulin and PLEX are commonly used in moderate to severe gMG, including in myasthenic crisis or when rapid symptom control is required. These approaches carry logistical constraints, including supply limitations for immunoglobulin and the need for specialized equipment and vascular access for PLEX . Zilucoplan’s daily subcutaneous administration offers a distinct delivery model within this context. In Japan, its approved indication allows use after inadequate response to corticosteroids or other immunosuppressants.

Within RAISE, patients who had not previously required immunoglobulin or PLEX experienced improvements in MG-specific outcomes comparable in magnitude to those seen in patients with prior exposure to immunoglobulin or PLEX. The data indicate that complement inhibition with zilucoplan retains efficacy in individuals with shorter disease duration and milder baseline classification.

Reference:
Utsugisawa K, Masuda M, Boroojerdi B, Grimson F, Howard JF Jr; on behalf of the RAISE Study Team. Efficacy of zilucoplan in patients with generalised myasthenia gravis who have not previously received immunoglobulin or plasma exchange: a subgroup analysis from the Phase 3 RAISE study. J Neurol Sci. 2025;474:123550. doi:10.1016/j.jns.2025.123550.