Last updated May 17, 2023, by Marta Figueiredo, PhD
 Fact-checked by Inês Martins, PhD
What is Ultomiris for neuromyelitis optica?
Ultomiris (ravulizumab-cwvz) is an experimental infusion therapy designed to lessen the inflammatory response underlying neuromyelitis optica spectrum disorder (NMOSD).
It is being investigated for adults who are positive for antibodies against the aquaporin-4 (AQP4) water channel, the most common target of self-reactive antibodies in NMOSD.
Regulatory applications seeking the therapy’s approval for this indication are under review by health authorities in the U.S. and Japan. In Europe, Ultomiris was approved in May 2023 for adults with NMOSD who test positive for anti-AQP4 antibodies.
The therapy was developed by Alexion Pharmaceuticals, which was acquired by AstraZeneca in 2021 and is now known as Alexion, AstraZeneca Rare Disease.
Ultomiris is widely approved for disorders sharing some underlying immune-related mechanisms with NMOSD, including generalized myasthenia gravis, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria.
How does Ultomiris work in neuromyelitis optica?
In NMOSD, the immune system produces antibodies that wrongly attack and damage healthy cells in the nervous system. The most common target of these self-reactive antibodies is AQP4, a water channel protein found at the surface of neuron-supporting cells called astrocytes.
The complement cascade, a set of blood proteins that are part of the immune system’s first line of defense, plays a central role in driving the autoimmune attack.
When antibodies like those against AQP4 bind to their target, they can trigger the activation of the complement cascade, which works like a chain reaction. The first activated complement protein activates the next, which activates the next and so on, ultimately driving a powerful inflammatory reaction.
One of the latest steps in complement activation is the cleavage, or split, of the terminal complement component 5 (C5) into two subunits — C5a and C5b — that go on to promote further inflammation. In NMOSD patients positive for anti-AQP4 antibodies, C5a and C5b contribute to inflammation and astrocyte destruction.
Ultomiris is an antibody-based therapy designed to bind to C5 and prevent this cleavage, thereby suppressing the activation of the complement cascade that helps drive autoimmune damage in NMOSD. By doing so, the therapy is expected to help control symptoms.
The medication works in essentially the same way as Soliris (eculizumab), an older treatment approved for NMOSD patients with anti-AQP4 antibodies. Both Ultomiris and Soliris were developed by Alexion.
The newer therapy was created by introducing a small change to Soliris’ chemical structure. This change makes Ultomiris more stable and long-acting in the body than Soliris, allowing for less frequent dosing. Maintenance doses of Ultomiris are given every eight weeks, compared with the every-other-week regimen of Soliris.
How will Ultomiris be administered in neuromyelitis optica?
In clinical trials of NMOSD, Ultomiris was administered directly into the bloodstream. On the first day, patients were given an initial infusion, or loading dose, that ranged from 2,400-3,000 mg based on body weight.
Then, weight-based maintenance doses (3,000-3,600 mg) were administered on day 15 and once every eight weeks (about once every two months) thereafter.
Ultomiris in neuromyelitis optica clinical trials
Alexion’s application to the U.S. Food and Drug Administration is supported by data from a Phase 3 clinical trial called CHAMPION-NMOSD (NCT04201262).
CHAMPION-NMOSD
Initiated in December 2019, the ongoing CHAMPION-NMOSD trial is evaluating Ultomiris’ safety and effectiveness in NMOSD adult patients carrying anti-AQP4 antibodies. All participants had experienced at least one relapse in the year prior to enrollment and were recruited at 36 sites across 11 countries.
A total of 58 patients were enrolled and treated for up to 2.5 years. Treatment consisted of a weight-based loading dose (2,400-3,000 mg) on day 1, then weight-based maintenance doses (3,000-3,600 mg) on day 15 and once every eight weeks thereafter.
Because three therapies were already approved for NMOSD at the time of the study, no participant received a placebo. Instead, trial data were compared with those of an external group of 47 patients who received a placebo in the Phase 3 PREVENT trial (NCT01892345), the study that supported Soliris’ approvals for AQP4-associated NMOSD.
Inclusion criteria were similar between the CHAMPION-NMOSD and PREVENT studies, and patients in the external control group had comparable demographic and clinical features to those given Ultomiris.
CHAMPION-NMOSD’s main goal was to assess the time to first on-trial relapse and associated relapse risk reduction in Ultomiris-treated patients compared with the external placebo group.
Patients given Ultomiris were followed for a median of 17 months, while those in the external PREVENT group were followed for a median of about eight months. In both groups, some patients were followed for more than two years.
Results showed there were no confirmed relapses among Ultomiris-treated patients, while 20 patients in the external group experienced relapses. This represented a significant drop, by 98.6%, in the risk of relapse with Ultomiris relative to a placebo.
A 97.9% reduction in relapse risk was also observed among patients receiving Ultomiris without additional immunosuppressants, when compared with those given a placebo in PREVENT in the absence of such medications.
In addition, all patients treated with Ultomiris were free from relapses at 48 weeks (nearly one year) versus 63% of those in the external placebo group.Â
CHAMPION-NMOSD also met two key secondary goals. It showed that Ultomiris-treated patients had significantly fewer relapses per year than would be expected in an NMOSD population. Ultomiris was also associated with a significantly lower chance of clinically important worsening in walking skills — with 3.4% of patients experiencing such motor worsening versus 23.4% of those given a placebo in PREVENT.
Changes in quality of life and overall disability — as assessed with the expanded disability status scale — also favored Ultomiris, but group differences failed to reach statistical significance.
Safety-related findings were generally consistent with those reported in previous Soliris trials in NMOSD patients and Ultomiris trials for other approved indications.
Open-label extension
After completing CHAMPION-NMOSD’s primary treatment period — which ended in March 2022 — 56 participants chose to enroll in the study’s long-term extension period, in which they will continue to receive Ultomiris for up to two additional years.
Common side effects of Ultomiris
The most common side effects of Ultomiris reported in NMOSD clinical trials included:
- COVID-19 infection
- joint pain.
Back pain, headache, and urinary tract infection were also reported in more than 10% of patients who received Ultomiris, but these occurred at a similar or higher rate in patients given a placebo. Most side effects related to treatment were mild to moderate in nature.
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