Subcutaneous zilucoplan – the end of necessary “trips” to the hospital for myasthenia gravis patients?

Therapy options for MG

Myasthenia gravis is a rare autoimmune disease occurring globally at a rate of 150–300/million people. It is characterized by fluctuating muscle weakness and fatigue following exertion, including life-threatening exacerbations in the form of myasthenic crises (respiratory muscle failure requiring intubation).

First-line treatment according to international guidelines includes acetylcholinesterase inhibitors, followed by corticosteroids or nonsteroidal immunosuppressants. Thymectomy is an option for some patients. Approximately 15–20% of patients will experience at least one myasthenic crisis during their lifetime. Despite treatment, 50% are unable to achieve disease compensation. Therefore, new treatment options are needed.

In the past decade, research has focused on the complement cascade, as one of the fundamental pathogenic mechanisms of MG involves antibodies against acetylcholine receptors (AChR), which activate complement. During this activation, component C5 is cleaved into C5a and C5b. C5b subsequently binds to C6–C9, forming the terminal membrane attack complex. In MG patients, deposits of these complexes lead to damage to the postsynaptic membrane of the neuromuscular junction and disruption of neuromuscular signal transmission. Antibodies against acetylcholine also prevent its binding to AChR. AChR is the most common target of autoantibodies in MG, and 80–88% of patients have AChR-positive generalized disease. Inhibition of C5 cleavage, therefore, represents an effective therapeutic mechanism for AChR-positive MG patients.

C5 inhibitors like eculizumab and ravulizumab are approved treatments, demonstrating rapid onset of action, sustained efficacy, and good tolerability. However, their intravenous administration poses a limitation.

In December 2023, the European Medicines Agency (EMA) approved subcutaneously administered zilucoplan.

Zilucoplan: A complement C5 inhibitor for MG

Zilucoplan is a complement C5 inhibitor for subcutaneous (s.c.) administration once daily, allowing patients to self-administer. It binds to C5 with high affinity and specificity, preventing its cleavage. Additionally, it inhibits the binding of C5b to C6. Unlike eculizumab and ravulizumab, subcutaneous administration offers patients greater freedom and independence. A previous randomized 12-week Phase II study with 44 MG patients (MGFA Class II–IV) demonstrated that zilucoplan administered once daily at doses of 0.1 or 0.3 mg/kg significantly improved QMG (Quantitative Myasthenia Gravis) scores compared to placebo. The higher dose had faster and stronger effects and was selected for further evaluation.

Study methodology and progression

The Phase III RAISE study involved a randomized, double-blind, placebo-controlled trial with patients from 75 specialized centers in Europe, North America, and Japan. Participants aged 18–74 with diagnosed MG (MGFA Class II–IV), positive AChR antibodies, MG-ADL (Myasthenia Gravis Activities of Daily Living) score ≥ 6, and QMG score ≥ 12 were included. They were required to be vaccinated against meningococcus B and could use corticosteroids or nonsteroidal immunosuppressants with stable doses 30 days prior to zilucoplan administration. Participants self-administered 0.3 mg/kg zilucoplan or placebo daily using pre-filled syringes into the abdomen, thigh, or upper arm.

Study findings

After 12 weeks, patients receiving zilucoplan demonstrated statistically and clinically significant improvements in MG-ADL scores (−4.39) compared to placebo (−2.3; p = 0.0004). Zilucoplan also significantly improved QMG scores, with a reduction of 6.19 versus 3.25 in the placebo group (p < 0.0001). Similarly, zilucoplan showed significant benefits in reducing MGC scores (−8.62 versus −5.42; p = 0.0023). Quality of life for patients was also significantly improved based on MG-QoL 15r scores (−5.65 versus −3.16; p = 0.013). Differences between the groups in all monitored parameters were evident in favor of zilucoplan treatment from Week 1. By Week 12, 14% of patients on zilucoplan had minimal symptoms compared to 6% on placebo.

Treatment-emergent adverse events (TEAEs) were reported by 77% of zilucoplan patients and 70% of the control group, with the most common being injection site bruising (16% versus 9%). The incidence of severe adverse events was similar in both groups. Treatment was discontinued due to adverse events in 5% of zilucoplan patients and 2% of placebo patients. The incidence of infections was higher in the treated group (27% versus 18%). There were no occurrences of meningococcal infection or anaphylactic reactions.

Conclusion

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Source: Howard J. F. Jr., Bresch S., Genge A. et al.; RAISE Study Team. Safety and efficacy of zilucoplan in patients with generalized myasthenia gravis (RAISE): a randomized, double-blind, placebo-controlled, phase 3 study. Lancet Neurol 2023 May; 22 (5): 395–406, doi: 10.1016/S1474-4422(23)00080-7.