Alexion announces positive results from phase III study of Ultomiris.

The study met, with high statistical significance, its primary endpoint of change from baseline in the Myasthenia Gravis-Activities of Daily Living Profile (MG-ADL) total score, a patient-reported assessment, at Week 26, and for the subset of patients who have completed 26 weeks in the extension study to date, the positive treatment effect was maintained through a total of 52 weeks. Ultomiris was well tolerated with a safety profile consistent with that observed in Phase III studies in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Based on these results, Alexion plans to make regulatory filings in the U.S., European Union and Japan in late 2021/early 2022.

“The treatment landscape for people living with gMG has advanced and expanded rapidly in recent years, empowering both patients and caregivers. However, as a clinician and scientist, I know the work is not done,” said Professor James F. Howard, M.D., Department of Neurology at The University of North Carolina, Chapel Hill, USA, and lead primary investigator in the Phase 3 study. “These Phase III Ultomiris results reinforce the critical role complement inhibition plays in treating gMG. I am encouraged by the opportunity this could provide for more patients to be treated early with a mechanism of action designed to preserve neuromuscular function.”

About the Phase III Study : This global Phase III randomized, double-blind, placebo-controlled, multicenter 26-week study evaluated the safety and efficacy of Ultomiris in adults with gMG who were not previously treated with a complement inhibitor medicine. The study enrolled 175 patients across North America, Europe, Asia-Pacific and Japan. To enter the study, participants were required to have a confirmed MG diagnosis at least 6 months prior to the screening visit with a positive serologic test for anti-AChR antibodies, MG-ADL total score of at least 6 at study entry and Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV at screening. There was no requirement for prior treatment failure, and patients could stay on stable standard of care medicines, with a few exceptions, for the duration of the study.

Patients were randomized 1:1 to receive Ultomiris or placebo for a total of 26 weeks. Patients received a single weight-based loading dose on Day 1, followed by regular weight-based maintenance dosing beginning on Day 15, every 8 weeks. The primary endpoint of change from baseline in the Myasthenia Gravis-Activities of Daily Living Profile (MG-ADL) total score at Week 26 was assessed along with multiple secondary endpoints evaluating improvement in disease-related and quality of life measures. The study met its primary endpoint, with a statistically significant change in MG-ADL score from baseline through Week 26 for patients receiving Ultomiris compared to those receiving placebo (Ultomiris: -3.1, placebo: -1.4, treatment difference: -1.6, p<0.001).></0.001).>

In the prospectively-defined secondary endpoints of change from baseline through Week 26 in Quantitative Myasthenia Gravis (QMG) total score – a physician-administered assessment of MG clinical severity – as well as the proportion of patients who achieved an improvement of at least 5 points in QMG, Ultomiris also demonstrated clinically meaningful and statistically significant improvements (p<0.001 and p="0.005," respectively). nearly three times as many patients receiving ultomiris experienced an improvement of at least 5 points in their qmg score compared to patients receiving placebo (30.0% vs 11.3%). these improvements in mg-adl and qmg scores were observed as early as week 1 and were sustained through week 26.></0.001>

Additional secondary endpoints assessing qualify of life measures, such as Revised 15-Component Myasthenia Gravis Quality of Life (MG-QOL15r) score (p=0.064) and Neuro-QOL Fatigue score (p=0.373), did not meet statistical significance at Week 26. The proportion of patients who achieved an improvement of at least 3 points in MG-ADL score (Ultomiris: 56.7%, placebo: 34.1%, nominal p=0.005), was not considered statistically significant based on hierarchical testing.

During the randomized controlled period, adverse events were comparable between the Ultomiris and placebo groups. The most frequently observed adverse events were headache (Ultomiris: 18.6%; placebo: 25.8%), diarrhea (Ultomiris: 15.1%; placebo: 12.4%) and nausea (Ultomiris: 10.5%; placebo: 10.1%). The most frequently observed serious adverse events were MG crisis (Ultomiris: 1.2%) and MG worsening (placebo: 3.4%). Through 52 weeks (26 weeks randomized controlled period + 26 weeks of open-label extension), there were four patient deaths in the Ultomiris group – three of them were due to COVID-19 and none were considered related to treatment with Ultomiris. No cases of meningococcal infection were observed through 52 weeks.

Patients who completed the randomized controlled period were eligible to continue into an open-label extension period evaluating the safety and efficacy of Ultomiris for up to two years, which is ongoing . At the time of this preliminary analysis of the open-label extension period, 75 patients had completed 26 weeks of treatment, for a total of 52 weeks of treatment. Among the patients who received Ultomiris in the randomized controlled period, the treatment effects were maintained through an additional 26 weeks of treatment, demonstrating sustained efficacy for a total of 52 weeks. In addition, patients who received placebo in the randomized controlled period and switched to Ultomiris at the beginning of the open-label extension showed immediate and sustained improvement in MG-ADL and QMG scores in a similar magnitude and time course to that observed in the Ultomiris group during the randomized controlled period.