Ultomiris (ravulizumab-cwvz) for myasthenia gravis

Last updated Nov. 1, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What is Ultomiris for myasthenia gravis?

Ultomiris (ravulizumab-cwvz) is a complement inhibitor that’s approved for adults with generalized myasthenia gravis (gMG) who are positive for antibodies targeting the acetylcholine receptor (AChR), which is the most common type of MG-causing antibody.

The therapy, which is administered via intravenous infusions, or into the bloodstream, is designed to ease the severity of gMG symptoms and their impact on daily activities.

Originally developed by Alexion Pharmaceuticals, which was acquired by AstraZeneca in 2021, Ultomiris is also approved for atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, and neuromyelitis optica spectrum disorder.

Therapy Snapshot

How does Ultomiris work?

In myasthenia gravis (MG), the body’s immune system erroneously launches an attack against molecules that play a key role in the communication between nerve and muscle cells, ultimately leading to symptoms such as muscle weakness.

This autoimmune attack is driven by self-reactive antibodies, most commonly anti-AChR antibodies, that, among other functions, can activate a part of the immune system called the complement cascade when bound to their target.

The complement cascade consists of a group of proteins that normally exist in the blood in an inactive state. When antibodies like those targeting AChR bind to their target, however, the complement system becomes activated in a manner that resembles a series of dominoes or a Rube Goldberg machine. When the first complement protein is activated, it activates the next, which activates the next and so on, ultimately driving a powerful inflammatory reaction.

One of the steps in the complement cascade is the cleavage of a complement protein called C5 into two subunits, C5a and C5b, that go on to promote further complement activation. Ultomiris is an antibody-based therapy designed to bind to C5 and prevent this cleavage, thereby inhibiting complement activation.

The treatment’s mechanism of action is virtually identical to that of Soliris (eculizumab), a previously approved gMG therapy also developed by Alexion. Ultomiris was created by introducing a small change to the chemical structure of Soliris to make the therapy more stable and long-acting in the body, thereby allowing for less frequent dosing. Maintenance doses of Soliris are given every two weeks, whereas Ultomiris is given every eight weeks.

Who with myasthenia gravis can take Ultomiris?

Ultomiris was approved by the U.S Food and Drug Administration in April 2022 for adults with gMG who are positive for anti-AChR antibodies, representing about 80% of cases.

However, because Ultomiris is associated with an increased risk of serious meningococcal infections, which can become rapidly life-threatening or fatal if not detected and treated early, the medication is only available in the U.S. through a restricted access program called Ultomiris and Soliris REMS (Risk Evaluation and Mitigation Strategy).

The REMS program ensures that only certified healthcare professionals and pharmacies can prescribe and dispense the therapy. Prescribers who enroll in the program must inform patients of the potential risks of treatment and assess their vaccination status for meningococcal vaccines, making sure they meet current recommendations before receiving treatment.

Ultomiris was also approved in the European Union in September 2022 as an add-on to standard therapy for adults with gMG who are positive for antibodies targeting AChR. Approvals for the therapy have also been issued in Japan and Canada.

Who should not take Ultomiris?

Starting treatment with Ultomiris is not recommended for patients with serious unresolved infections caused by Neisseria meningitidis, the bacteria that causes a serious illness called meningococcal disease.

The prescribing information for Ultomiris carries a boxed warning for serious meningococcal infections, as life-threatening and fatal infections have occurred in patients treated with complement inhibitors. Patients should be monitored for early signs and symptoms of these infections and be evaluated immediately if an infection is suspected.

The boxed warning also notes Ultomiris should not be administered to patients who aren’t vaccinated against meningococcal bacteria, unless the risks of delaying treatment outweigh the potential risk of a meningococcal infection.

How is Ultomiris administered in myasthenia gravis?

Ultomiris is given via an infusion directly into the bloodstream that’s administered only by a healthcare provider.

Patients receive an initial infusion called a loading dose, followed by maintenance doses for as long as the patient is on treatment. The first maintenance dose is administered two weeks after the loading dose and subsequent doses are given every eight weeks thereafter.

Dosing of Ultomiris varies according to body weight.

• For gMG patients weighing 40 kg to less than 60 kg (88-132 pounds), the loading dose is 2,400 mg, and maintenance doses are 3,000 mg.
• For those weighing 60 kg to less than 100 kg (132-220 pounds), the loading dose is 2,700 mg, and maintenance doses are 3,300 mg.
• For those weighing 100 kg (220 pounds) or more, the loading dose is 3,000 mg, and maintenance doses are 3,600 mg.

With the exception of the first maintenance dose, Ultomiris can occasionally be given within seven days of the scheduled infusion dates. However, subsequent doses should be administered following the regular dosing schedule. Patients who miss a dose of the therapy should contact their healthcare providers immediately.

Supplemental doses of Ultomiris might be required for patients undergoing plasma exchange, called plasmapheresis, or given intravenous immunoglobulin, known as IVIG. These MG treatments work by decreasing antibody levels in the body and may also affect the levels of Ultomiris’ active agent.

The effectiveness of Ultomiris may also be reduced by neonatal Fc receptor blockers, a class of medications that includes the approved gMG therapies Vyvgart (efgartigimod alfa-fcab) and Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc). Close monitoring is recommended in these cases.

Ultomiris in clinical trials

The approvals of Ultomiris for adults with gMG were supported by data from an international Phase 3 clinical trial called CHAMPION MG (NCT03920293), which was completed in 2024.

CHAMPION MG trial

Sponsored by Alexion, CHAMPION MG enrolled 175 adults with gMG and anti-AChR antibodies at multiple centers worldwide. None of the participants had been treated with a complement inhibitor previously, but most were receiving immunosuppressive therapies and could continue to do so during the trial.

Participants were randomly assigned to take Ultomiris at the now-approved weight-based dosage or a placebo for 26 weeks (about six months). The study’s main goal was to assess the effect of treatment on the MG Activities of Daily Living (MG-ADL) scale, a patient-reported assessment of symptom severity. Scores range from 0 to 24, with higher values indicating worse symptoms.

The results showed Ultomiris significantly outperformed a placebo at easing MG symptoms. After 26 weeks, the average MG-ADL score decreased by 3.1 points for those on Ultomiris compared with 1.4 points for those on the placebo. The scores for patients on Ultomiris started improving as soon as one week after treatment, analyses indicated.

Average scores on a clinician-reported measure of disease severity, the Quantitative MG (QMG) scale, also dropped significantly more in patients treated with Ultomiris than in those given a placebo after 26 weeks (2.8 vs. 0.8 points), with improvements being seen as early as one week following the start of treatment.

On this scale, three times as many patients on Ultomiris experienced an improvement of at least five points by week 26 (30% vs. 11.3%), indicating a substantial easing of symptoms.

Additional trial analyses also indicated Ultomiris tended to have stronger effects in patients who had been living with MG for no more than two years. The medication was also found to be effective at easing symptoms in specific muscle domains, most notably eye-related symptoms.

Open-label extension

Participants who completed the initial 26-week placebo-controlled portion of the CHAMPION-MG trial had the option to enter into the study’s open-label extension, where all were given Ultomiris for up to four years.

Data spanning 60 weeks, or a little more than one year, from CHAMPION-MG and the extension study showed that improvements in MG-ADL and QMG scores seen after 26 weeks were largely sustained among participants who had been on Ultomiris. Those who were previously on a placebo and switched to Ultomiris during the open-label extension also reached similar scores on these measures as patients who had been on Ultomiris from the start.

Final data from the 161 patients who entered the extension study and received Ultomiris for up to around three years showed that improvements in MG-ADL and QMG scores were maintained in both groups of patients.

Common side effects of Ultomiris

The most common side effects of Ultomiris reported in clinical trials of adults with gMG were:

• diarrhea
• upper respiratory tract infections.

Serious meningococcal infections

Ultomiris carries a boxed warning noting the therapy can increase the risk of serious meningococcal infections, which can rapidly become life-threatening or fatal if they are not recognized and treated quickly. These bacterial infections have been observed in both vaccinated and unvaccinated patients treated with complement inhibitors. Treatment with Ultomiris should not be started in patients who have an unresolved serious infection caused by the bacteria Neisseria meningitidis. The therapy should also be used with caution in those with any other systemic infection.

Patients should be vaccinated according to current recommendations, and should receive a meningococcal vaccine for bacteria belonging to serogroups A, C, W, Y, and B at least two weeks before starting treatment with Ultomiris, unless the risks of delaying treatment outweigh the potential risk of infection. If urgent treatment with Ultomiris is required in patients who are not up to date on their meningococcal vaccines, prophylactic (preventive) antibacterial treatment should be provided to reduce the risk of infection, and the recommended vaccines should be given as soon as possible afterward.

Vaccination reduces the risk of meningococcal infection, but does not completely eliminate it, so proper monitoring and prompt treatment is required if an infection develops. Interruption of Ultomiris may also be considered in cases of serious meningococcal infections.

Other infections

Serious infections caused by other species of Neisseria bacteria, including disseminated gonococcal infections, have also been reported in people given complement inhibitors.

Because Ultomiris dampens the activity of the immune system, patients receiving the therapy may be more susceptible to infections, particularly those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae. Vaccination to prevent infections caused by S. pneumoniae and H. influenzae should be administered according to current recommendations. Notably, even patients who develop antibodies following vaccination against these bacteria are at an increased risk of developing infections while receiving Ultomiris, so caution is advised.

Infusion-related reactions

Infusion-related reactions were reported in about 1% to 7% of patients given Ultomiris in clinical trials. These may include lower back pain, abdominal pain, changes in blood pressure, limb discomfort, bad taste, drowsiness, and allergic reactions such as anaphylaxis. These reactions generally do not necessitate stopping treatment, but infusions may be paused to provide supportive management, especially if there are signs of heart-related changes or breathing difficulty.

Use in pregnancy and breastfeeding

There are no available data on using Ultomiris during pregnancy, but animal studies have suggested the therapy may cause harm to the developing fetus.

It’s also not known if Ultomiris can be found in human milk, or whether it has a negative effect on milk production or on the breastfed infant. However, because many antibody-based therapies can be found in human milk, it’s recommended female patients not breastfeed while on Ultomiris and for at least eight months following their last dose.

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