MDA 2024: Benefits of Zilbrysq sustained over 1 year in gMG study
Therapy use leads to rapid reductions in disease severity for new patients
Clinical responses to the approved generalized myasthenia gravis (gMG) therapy Zilbrysq (zilucoplan) have now been sustained for more than a year among adults given long-term treatment, according to interim analyses of the Phase 3 RAISE-XT open-label extension (OLE) study.
For patients who switched from a placebo in earlier clinical trials to active treatment in RAISE-XT (NCT04225871), the analysis demonstrated rapid and sustained reductions in disease severity.
“In this interim analysis of RAISE-XT, [Zilbrysq] demonstrated a favorable long-term safety profile; efficacy was sustained over 60 weeks [about 15 months] of treatment in a broad population of adult patients,” the researchers wrote in a poster presentation detailing the analyses’ findings.
That poster was presented by Zilbrysq’s developer UCB at the Muscular Dystrophy Association’s MDA Clinical and Scientific Conference, held March 3-6 in Orlando, Florida, and virtually. The poster was titled “Response rates with zilucoplan among generalized myasthenia gravis patients in an interim analysis of RAISE-XT, a Phase 3 open-label extension study.” The study was funded by UC Pharma.
In an abstract accompanying the poster, the researchers noted that “responder rates had improved” for both the patients treated with Zilbrysq all along and those who switched to the therapy.
Zilbrysq approved last year in US, Japan, EU
Zilbrysq is a small molecule designed to block the activation of the immune system’s complement cascade, which is implicated in the autoimmune attacks that characterize gMG. The therapy works by targeting the C5 complement protein.
A self-administered, under-the-skin (subcutaneous) therapy, Zilbrysq was approved last year in the U.S., Japan, and the European Union for adults with gMG who are positive for antibodies targeting the acetylcholine receptor (AChR) — the most common type of MG-causing antibody.
The regulatory approvals were backed largely by data from the Phase 3 RAISE clinical trial (NCT04115293), in which 174 adults with AChR-positive gMG were randomly assigned to receive daily subcutaneous injections of Zilbrysq, at a dose of 0.3 mg/kg, or a placebo for 12 weeks, or about three months.
The results showed that the treatment’s use was associated with significant reductions in disease severity relative to the placebo, with more Zilbrysq-treated patients achieving clinically meaningful improvements in scores on the MG Activities of Daily Living (MG-ADL) and the Quantitative MG (QMG) scales relative to the placebo after the 12 weeks.
MG-ADL is a standard patient-reported measure of MG symptom severity and their impact on daily life, while QMG is a standardized clinician-reported measure of disease severity.
Participants from RAISE, as well as a small group of people who completed an earlier 12-week Phase 2 clinical trial (NCT03315130), could then enroll in RAISE-XT, which is evaluating the long-term safety and exploratory efficacy of once-daily, self-administered Zilbrysq (0.3 mg/kg). RAISE-XT is slated to run through 2026.
The OLE enrolled 200 adults at study sites in North America, Europe, and Asia. In all, 105 participants had initially been assigned to receive Zilbrysq in the main clinical trials, while 95 were on the placebo and then switched to active treatment. As of the analyses’ cut-off date in September 2022, the participants had received Zilbrysq for a median of 1.2 years.
Rapid improvements seen for patients given a placebo in earlier trial
In the poster, the researchers reported efficacy data after 48 weeks, or about 11 months, in RAISE-XT. For those patients originally assigned to Zilbrysq, the timeframe spanned a total of 60 weeks of treatment spanning from the initial trial to the OLE.
For patients on Zilbrysq in the main trials, the MG-ADL scores were found to continue to improve through to week 24, or about six months, with gains then sustained through to week 60.
Moreover, patients on the placebo in the initial trials began to see a rapid clinical response within a week of starting Zilbrysq that were then sustained throughout the extension study, the results showed.
In this interim analysis, [Zilbrysq] demonstrated improved MG-ADL and QMG responder rates, sustained up to 60 weeks of treatment, with a favorable safety profile.
According to the scientists, these findings also were mirrored in other clinical scales of disease severity, including QMG, although the data were not shown on the poster.
At the start of RAISE-XT, or the study’s baseline, 74.2% of Zilbrysq-treated patients were considered MG-ADL treatment responders, meaning they had achieved at least a 3-point reduction. Responder rates had increased to 87% after 60 weeks of treatment. Likewise, a baseline QMG responder rate (at least a 5-point reduction) of 59.8% rose to 84.6% in RAISE-XT.
Further, 19.4% of Zilbrysq-treated patients were found to have minimal symptom expression (MSE) at RAISE-XT baseline, defined as an MG-ADL score of 0 or 1. By week 60, this status had been achieved by 35.2% of patients.
For patients who started off on the placebo, the baseline MG-ADL responder rate of 52.2% rose to 85.7% at week 60, and the baseline QMG responder rate of 37.1% increased to 77.1%.
While 7.8% of the patients on the placebo achieved MSE during the main trials, 38.8% achieved it by week 60 in RAISE-XT.
Zilbrysq was well tolerated with no new safety concerns identified. The most common treatment-emergent side effects included MG worsening, COVID-19, headache, diarrhea, and cold-like symptoms.
“In this interim analysis, zilucoplan demonstrated improved MG-ADL and QMG responder rates, sustained up to 60 weeks of treatment, with a favorable safety profile,” the researchers concluded in the abstract.
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