Ultomiris (Ravulizumab) for Myasthenia Gravis

Last updated Sept. 27, 2022, by Marisa Wexler, MS

✅ Fact-checked by Joana Carvalho, PhD


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.

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 early 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.

Its 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 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 has also been approved for the same indication in the EU.

The medication has also been approved in Japan to treat adults with gMG who are positive for anti-AChR and whose symptoms are difficult to control with other treatments, such as intravenous immunoglobulin (IVIG) or plasma exchange.

Ultomiris has also been approved to treat atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH), two other disorders associated with complement impairment.

Ultomiris is only available in the U.S. through a restricted access program called ULTOMIRIS REMS.

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?

Ultomiris is administered via an infusion directly into the bloodstream. Patients are given 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.

Ultomiris must be diluted in an appropriate solution before use and administered immediately following preparation. If not given immediately, the medication should be stored in the fridge no more than 24 hours. The medication is supplied in single-dose vials of three strengths: 300 mg/30 mL; 300 mg/3 mL; and 1,100 mg/11 mL

Ultomiris in clinical trials

CHAMPION-MG

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). The study enrolled 175 adults with gMG at multiple centers worldwide. About three-quarters of participants were white and around half were female. 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 Myasthenia Gravis (QMG), three times as many patients on Ultomiris than on a placebo experienced an improvement of at least five points, which 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, but the difference in relation to a placebo was not statistically significant.

Participants who completed the initial 26-week placebo-controlled portion of the CHAMPION-MG trial had the option to enter in the study’s open-label extension, where all were given Ultomiris. Data from a subset of 79 trial participants showed improvements in MG-ADL scores seen after 26 weeks were largely sustained after a year on the therapy. Improvements in MG-ADL scores were also seen in patients who switched from a placebo to Ultomiris during the open-label extension.

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.

Interactions with other treatments

MG is driven by self-reactive antibodies, and many MG treatments work by decreasing antibody levels in the body. However, the active agent in Ultomiris is also an antibody and may be affected by these treatments.

Supplemental doses of Ultomiris are required for patients treated with plasmapheresis (plasma exchange) or intravenous immunoglobulin (IVIG). Its effectiveness 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.

Use in pregnancy and breastfeeding

There are 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.

 


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