Myasthenia Gravis

Ultomiris® (ravulizumab-cwvz) is a prescription medicine indicated for the treatment of adult patients who have generalized myasthenia gravis (gMG) with anti-acetylcholine receptor (anti-AChR) antibodies.¹ MG is a rare neuromuscular disease characterized by generalized fatigability and muscle weakness.^2,3 It develops when the body produces auto-antibodies against specific proteins found in muscles, such as nicotinic acetylcholine receptor (n-AChR).^3,4 The abnormal autoimmune reaction leads to complement activation, formation of the terminal complement complex, and destruction of the post-synaptic membrane. As a result, nerve impulse transmission at the neuromuscular level and muscle contraction are compromised.^3-5

The US Food and Drug Administration (FDA) initially approved Ultomiris in 2018. This medicine has been used for the treatment of adult and pediatric patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).¹ In April 2022, Ultomiris was approved for the treatment of patients with anti-AChR antibody-positive gMG, who account for approximately 80% of individuals with MG. Ultomiris is currently under review for approval in the European Union and Japan.⁶

Ultomiris Mode of Action and Use

The active ingredient of Ultomiris is ravulizumab-cwvz, a humanized monoclonal antibody developed by Alexion Pharmaceuticals, which is now a part of Alexion, AstraZeneca Rare Disease.^5,7 Ravulizumab-cwvz was re-engineered from eculizumab with the goal of developing a longer-acting antibody, so that fewer infusions would be required to treat gMG.⁷ Like eculizumab, ravulizumab-cwvz binds with high affinity and specificity to complement protein C5, preventing C5 cleavage and disruption of the neuromuscular junction.^5,7 Ravulizumab-cwvz, however, has been designed so that therapeutic serum concentrations are maintained for 8 weeks, and it is the first long-acting C5 inhibitor approved for the treatment of gMG.^5,6 The exact mode of action of ravulizumab-cwvz requires further elucidation; however, it is thought to reduce the deposition of the terminal complement complex C5b-9 at the neuromuscular junction.¹ 

Ultomiris is administered intravenously. For the treatment of gMG, a loading dose is followed by a maintenance dosing regimen started 2 weeks after the initial dose. Depending on the patient’s weight, a maintenance dose may be administered once every 4 or 8 weeks.¹ Ultomiris may induce infusion-related reactions; therefore, patients should be closely monitored during infusions.¹ 

The use of Ultomiris has been associated with an increased risk for the development of meningococcal infections, which can be life-threatening. If not previously vaccinated, patients must receive meningococcal vaccines at least 2 weeks before starting Ultomiris infusions. Patients who have unresolved infections caused by Neisseria meningitiditis should not start treatment with Ultomiris.¹

The most common adverse reactions observed in patients who have gMG treated with Ultomiris are diarrhea and upper respiratory tract infections.¹

Get full prescribing information for Ultomiris at MPR

Approval for Treatment of Generalized Myasthenia Gravis

The approval of Ultomiris to treat gMG followed positive results of a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, CHAMPION-MG (NCT03920293),⁸ which evaluated the safety and efficacy of ravulizumab-cwvz in 175 adult patients with anti-AChr antibody-positive gMG.⁵ Patients were randomized in a 1:1 ratio to receive intravenous infusions of ravulizumab-cwvz or placebo. A loading dose of ravulizumab-cwvz or placebo was administered on day 1, and maintenance doses were administered on day 15 and every 8 weeks thereafter according to patient weight. Of the 175 patients, 162 continued treatment for the entire 26-week duration of the trial. The primary endpoint was the change from baseline to week 26 in scores on the patient-reported Myasthenia Gravis–Activities of Daily Living (MG-ADL) scale. One of the secondary endpoints was the change in the clinician-reported Quantitative Myasthenia Gravis (QMG) total score. Baseline values for these scores indicated mild to moderate impairment and mild to moderate severity of disease.⁵ 

The differences between the primary endpoint and the QMG secondary endpoint in the Ultomiris group vs those in the placebo group were statistically significant. The improvements were observed within the first week of Ultomiris administration and were maintained throughout the duration of the trial, supporting the early and sustained effect of ravulizumab-cwvz.⁵ 

The safety profile for ravulizumab-cwvz was similar to that for placebo, with no significant differences detected between types of adverse events in the 2 groups. After completing the 26-week trial, patients may enter an extension trial to receive open-label treatment with ravulizumab-cwvz for up to 4 years.⁵

References

1. ULTOMIRIS® (ravulizumab-cwvz) injection. Highlights of prescribing information. Revised April 2022.

2. Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of myasthenia gravis. Neurol Clin. 2018;36(2):311-337. doi:10.1016/j.ncl.2018.01.011

3. Beloor Suresh A, Asuncion RMD. Myasthenia gravis. StatPearls [Internet]. Updated August 29, 2021. Accessed April 29 , 2022.

4. Myasthenia gravis. National Organization for Rare Disorders (NORD). Accessed April 29, 2022.

5. Vu T, Meisel A, Mantegazza R, et al. Terminal complement inhibitor ravulizumab in generalized myasthenia gravis. NEJM Evid. 2022;1(5). doi:10.1056/EVIDoa2100066

6. ULTOMIRIS® (ravulizumab-cwvz) approved in the US for adults with generalized myasthenia gravis. News release. Alexion; April 28, 2022.

7. McKeage K. Ravulizumab: first global approval. Drugs. 2019;79(3):347-352. doi:10.1007/s40265-019-01068-2

8. Safety and Efficacy Study of Ravulizumab in Adults With Generalized Myasthenia Gravis. ClinicalTrials.gov. NCT03920293. Accessed April 29, 2022.

Reviewed by Harshi Dhingra, MD, on 4/29/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.