Ultomiris (ravulizumab) for myasthenia gravis
Fact-checked by
What is Ultomiris for myasthenia gravis?
Ultomiris (ravulizumab-cwvz) is a complement inhibitor approved in the U.S. to treat adults with generalized myasthenia gravis (gMG) who are positive for antibodies targeting the acetylcholine receptor (anti-AChR) — the most common type of MG-causing antibody.
The therapy was originally developed by Alexion Pharmaceuticals, which was acquired by AstraZeneca in 2021.
Ultomiris also is approved for the treatment of adults and children with two other rare diseases, atypical hemolytic uremic syndrome, called aHUS, and paroxysmal nocturnal hemoglobinuria, known as PNH.
Therapy Snapshot
| Brand Name: | Ultomiris |
| Chemical Name: | Ravulizumab-cwvz |
| Usage: | Treatment of generalized myasthenia gravis |
| Administration: | Into-the-vein (intravenous) infusion |
How does Ultomiris work?
In 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 like muscle weakness. This autoimmune attack is driven by self-reactive antibodies, most commonly anti-AChR. A group of immune proteins known as the complement cascade also play a role in this autoimmune attack.
The complement cascade consists of a group of proteins that normally exist in the blood in an inactive state. When an antibody like anti-AChR binds to its target, it can trigger the activation of the complement cascade, which works a bit like 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 complement activation is a protein called C5 that gets cleaved, or split, into two subunits — C5a and C5b — that go on to promote further inflammation. Ultomiris is an antibody-based therapy designed to bind to C5 and prevent this cleavage, thereby inhibiting the activation of the complement cascade that helps drive autoimmune damage in gMG.
The treatment’s mechanism of action is virtually identical to that of Soliris (eculizumab), an older approved gMG therapy also developed by Alexion. Ultomiris was created by introducing a small change to the chemical structure of the C5-binding antibody that makes up Soliris. The change was designed 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 MG can take Ultomiris?
In the U.S., Ultomiris is approved to treat adults with gMG who are positive for anti-AChR, representing about 80% of cases. It also has been approved in the European Union as an add-on to standard therapy for the same group of patients. Approvals for the therapy also have been issued in Japan and Canada.
Ultomiris is only available in the U.S. through a restricted access program called Ultomiris REMS (Risk Evaluation and Mitigation Strategy) due to the risk of serious meningococcal infections associated with the treatment. Patients must be carefully monitored for signs of meningococcal infections, as these can become rapidly life-threatening or fatal if not detected and treated early.
Who should not take Ultomiris?
Ultomiris should not be used by anyone who has an ongoing infection with Neisseria meningitidis, the bacteria that causes a serious illness called meningococcal disease.
The therapy also should not be administered to patients who aren’t vaccinated against Neisseria meningitidis, unless the risks of delaying treatment outweigh the potential risk of a meningococcal infection.
How is Ultomiris administered in MG?
Ultomiris is given via an infusion directly into the bloodstream. Patients are administered 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 given 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 to less than 60 kg (88 to less than 132 pounds), the loading dose is 2,400 mg and maintenance doses are 3,000 mg.
- For those weighing 60 to less than 100 kg (132 to less than 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.
Supplemental doses of Ultomiris might be required for patients treated with plasma exchange, called plasmapheresis, or intravenous immunoglobulin, known as IVIG. These MG treatments work by decreasing antibody levels in the body and may also affect Ultomiris’ active agent.
Ultomiris’ effectiveness also may be reduced by neonatal Fc receptor blockers, a class of medications that includes the approved gMG therapy Vyvgart (efgartigimod). Close monitoring is recommended in these cases.
Ultomiris in clinical trials
The approval of Ultomiris for treating gMG in the U.S. was supported by data from a Phase 3 clinical trial called CHAMPION MG (NCT03920293).
CHAMPION MG trial
The CHAMPION MG trial enrolled 175 adults with gMG at multiple centers worldwide. About three-quarters of participants were white and around half were women. All were positive for anti-AChR and none had been treated with a complement inhibitor previously.
Participants were randomly assigned to take Ultomiris or a placebo for 26 weeks (about half a year). The study’s main goal was to assess the effect of treatment on the score of the MG Activities of Daily Living (MG-ADL), a patient-reported assessment of symptom severity. Scores on the MG-ADL can 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 placebo. MG-ADL scores for patients on Ultomiris started improving as soon as one week after treatment, analyses indicated.
For scores on a clinician-reported measure of disease severity, the Quantitative MG (QMG), three times as many patients on Ultomiris than on a placebo experienced an improvement of at least five points. This was considered to indicate a substantial easing of symptoms. Patients on Ultomiris generally tended to report better outcomes related to fatigue and health-related quality of life. However, the difference in relation to a placebo was not statistically significant.
Additional trial analyses also indicated that Ultomiris tended to have stronger effects in patients who had been living with MG for no more than two years. The medication also was found to be effective at easing symptoms in specific muscle domains, most notably eye-related symptoms.
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. Data from a subset of 79 trial participants showed that improvements in MG-ADL scores seen after 26 weeks were largely sustained after a year on the therapy. Improvements in MG-ADL scores also were seen in patients who switched from a placebo to Ultomiris during the open-label extension. Similar findings were reported in a more recent analysis comprising data from 161 patients gathered up to 60 weeks, or about 14 months.
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.
Infections
Ultomiris carries a boxed warning for serious meningococcal infections and sepsis, which can rapidly become life-threatening if they are not recognized and treated quickly.
Patients should be vaccinated according to current guidelines, and should receive a meningococcal vaccine at least two weeks before starting treatment with Ultomiris unless the risks of delaying treatment outweigh the potential risk of infection. Vaccination reduces the risk of meningococcal infection in gMG patients, but it does not completely eliminate the risk of such infections, so proper monitoring is required.
Infusion-related reactions
Infusion-related reactions were reported in about 1% of patients given Ultomiris in clinical trials. These may include lower back pain, changes in blood pressure, limb discomfort, dysgeusia (bad taste), drowsiness, and allergic reactions such as anaphylaxis. These reactions generally do not require discontinuing 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 is no available data on using Ultomiris during pregnancy or breastfeeding. Animal studies have suggested the therapy may cause harm to the developing fetus. It’s recommended that female patients not breastfeed while on Ultomiris or for at least eight months following its last dose.
Myasthenia Gravis News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Ultomiris
The U.S. Food and Drug Administration (FDA) approved Ultomiris in 2022 to treat adults with generalized myasthenia gravis (gMG) who are positive for antibodies targeting the acetylcholine receptor. In addition to gMG, Ultomiris is approved in the U.S. for the treatment of atypical hemolytic uremic syndrome, or aHUS, and paroxysmal nocturnal hemoglobinuria, known as PNH.
Some generalized myasthenia gravis (gMG) patients may see results as early as one week after starting treatment with Ultomiris. The CHAMPION MG trial showed that, in adults with gMG who had never received a complement inhibitor, Ultomiris could rapidly improve scores on different measures of disease severity within one week. However, each patient is unique and may respond differently to a given treatment; thus, a discussion with their healthcare team can help gMG patients better understand how Ultomiris may help in their particular case.
Neither hair loss nor weight gain has been reported in clinical trials as side effects of Ultomiris treatment in patients with generalized myasthenia gravis. Patients are advised to speak with their healthcare provider if they experience any unusual symptoms while on the medication.
There are no clinical data on the use of Ultomiris in pregnant patients. However, a similar compound, an anti-C5 antibody, caused harm to the developing fetus in animal models. Patients who are pregnant or are planning to become pregnant should discuss this issue with their healthcare providers.
Ultomiris has been reported to have no or a negligible impact on a person’s ability to drive and use machines. Nevertheless, it’s recommended that patients be careful before attempting to drive or use any machines until they know how Ultomiris affects them. Patients prescribed Ultomiris should talk with their healthcare team regarding the treatment’s potential impact on activities such as driving.
Related Articles
