Ultomiris shows sustained disease control in NMOSD analysis
Findings were similar in patients with or without prior rituximab use
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Ultomiris (ravulizumab-cwvz) was associated with sustained disease control in people with neuromyelitis optica spectrum disorder (NMOSD), regardless of whether they had been previously treated off-label with rituximab.
That’s according to a new analysis of data from the Phase 3 CHAMPION-NMOSD clinical trial (NCT04201262), whose results supported Ultomiris’ approvals for treating adults with NMOSD who have disease-driving self-reactive antibodies against the AQP4 protein.
“These results support consideration of [Ultomiris] in patients with [AQP4-related] NMOSD who have previously received [rituximab], further validating the role of complement [blockage] in the management of NMOSD,” the researchers wrote. Future studies, including real-world analyses, may help clarify “long-term outcomes after treatment transitions.”
The study, “Safety and efficacy of ravulizumab in patients with NMOSD previously treated with rituximab: A post hoc analysis of the CHAMPION-NMOSD trial,” was published in the Multiple Sclerosis Journal. It was funded by Alexion, AstraZeneca Rare Disease, the developer of Ultomiris.
Complement activation plays key role in NMOSD
NMOSD is an autoimmune disorder that causes damaging inflammation in the central nervous system, particularly the spinal cord and optic nerves, which relay signals between the eyes and the brain. Most cases are driven by anti-AQP4 antibodies, and these autoimmune attacks can activate the complement cascade, a part of the immune system, further driving inflammation and nerve cell damage.
Patients often experience relapses, or periods when symptoms suddenly worsen or new ones appear. These relapses can result in cumulative damage and disability.
Rituximab (sold as Rituxan, among others, with biosimilars available) promotes the death of CD20-positive immune B cells, which are involved in antibody-driven disease activity, and is sometimes used off-label in NMOSD. Although it has been shown to reduce relapses, rituximab is not effective in all patients and has been associated with infection risks.
“These safety considerations highlight the clinical need for therapies with alternative mechanisms of action,” the researchers wrote.
Ultomiris is one such therapy. Designed to suppress complement-driven cell damage by blocking the complement protein C5, it is approved for adults with NMOSD who are positive for anti-AQP4 antibodies. The therapy is given by infusion into the bloodstream, with maintenance doses administered every eight weeks.
Among U.S.-approved NMOSD therapies, the CHAMPION-NMOSD trial, which tested Ultomiris in adults with AQP4-related NMOSD, recruited the largest proportion of patients previously treated with rituximab.
With this in mind, a team of researchers conducted a post hoc analysis of CHAMPION-NMOSD data to assess whether Ultomiris’ safety and efficacy differed based on prior rituximab exposure. A post hoc analysis is conducted after a trial’s main analysis and is not part of the study’s original primary analysis plan. The researchers noted that no formal hypothesis testing was performed. In other words, the analysis described results in the two groups but was not designed to prove differences between them.
Analysis compared patients by prior rituximab use
All 58 CHAMPION-NMOSD participants who were treated with Ultomiris were included in the analysis. A total of 21 patients (36.2%) had been previously treated with rituximab, while the remaining 37 (63.8%) had not and were considered rituximab-naïve. Participants treated with rituximab within three months before screening were not included in CHAMPION-NMOSD.
Participants were in the study for a mean of about 168 weeks, or slightly more than three years. Among those previously treated with rituximab, the mean time from last rituximab dose to first Ultomiris dose was 7.2 months.
The researchers evaluated relapse rates before and after starting Ultomiris, as well as safety outcomes.
Before entering the trial, 12 of the 21 rituximab-exposed patients (57.1%) had experienced a relapse between their first rituximab dose and the start of Ultomiris. After treatment with Ultomiris began, no physician-confirmed relapses were reported during the trial, regardless of whether patients had been previously treated with rituximab.
Safety findings were generally similar between groups. Adverse events were reported in 95.2% of rituximab-exposed participants and 94.6% of rituximab-naïve participants. Serious adverse events were reported in 28.6% and 24.3%, respectively, but most were deemed unrelated to Ultomiris.
Common adverse events included COVID-19, headache, urinary tract infection, upper respiratory tract infection, back pain, diarrhea, joint pain, common cold, and fever. Urinary tract infections, which were all nonserious, were more common in patients previously treated with rituximab (33.3% vs. 8.1%).
All trial participants were vaccinated against meningococcal infections, because complement blockers such as Ultomiris can increase the risk of such infections. Still, two meningococcal infections were reported, one in each group.
Meningococcal infections resolved with treatment
Despite receiving their last rituximab dose 13 months before starting Ultomiris, the rituximab-exposed patient who developed a meningococcal infection still showed lower-than-normal B-cell counts two weeks before developing the infection.
Both patients were treated promptly with antibiotics and intensive care and recovered fully without lasting complications.
Among 19 participants who received their first meningococcal vaccination after being treated with rituximab, the average time from last rituximab dose to first meningococcal vaccination was 5.58 months. Most received vaccination within six months of their last rituximab dose.
Overall, these results “support consideration of [Ultomiris] for patients previously treated with [rituximab] and may inform future research aimed at advancing personalized treatment strategies for patients with NMOSD,” the researchers concluded.
