By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration has approved a once-daily subcutaneously administered drug for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. Zilucoplan is macrocyclic peptide that inhibits the cleavage of complement 5 (C5) to C5a and C5b.1 Two previously approved complement inhibitors, ravulizumab-cwvz and eculizumab, require periodic intravenous infusion. Zilucoplan was given an orphan designation and is distributed by UCB, Inc. as Zilbrysq.
INDICATIONS
Zilucoplan is indicated for the treatment of gMG in adult patients who are AChR antibody positive.1
DOSAGE
The recommended dose is administered subcutaneously once daily based on body weight.1 For patients weighing less than 56 kg, the dose is 16.6 mg; for 56 kg to < 77 kg, the dose is 23 mg; and for 77 kg and above, the dose is 32.4 mg. Zilucoplan is available as 16.6 mg/0.416 mL, 23 mg/0.574 mL, and 32.4 mg/0.81 mL in single-dose prefilled syringes.
POTENTIAL ADVANTAGES
Approximately three-fourths of patients (73% vs. 46% for placebo) experienced ≥ 3 point reduction in gMG symptoms without rescue medication.2 A 2-point reduction is considered clinically meaningful. Zilucoplan is self-administered subcutaneously and does not require intravenous infusion as with eculizumab and ravulizumab-cwvz.
POTENTIAL DISADVANTAGES
Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors.1 For this reason, all the complement inhibitors are only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Patients also may have increased susceptibility to infections caused by encapsulated bacteria (e.g., Neisseria meningitidis, Streptococcus pneumoniae). Pancreatitits (1.9%) and pancreatic cysts (1.4%) have been reported with zilucoplan.1 The most frequently reported adverse reactions (vs. placebo) are injection site reactions (29% vs. 16%), upper respiratory tract (14% vs. 7%), diarrhea (11% vs. 2%), increase in lipase (6.9% vs. 0%), and increase in amylase (4.7% vs. 1.1%).1
COMMENTS
The efficacy of zilucoplan was established in a randomized, double-blind, placebo-controlled, 12-week study.1,2 Participants had clinical classification II to IV gMG and were anti-AChR antibody positive. They were randomized to zilucoplan (n = 86) or placebo (n = 88). The primary efficacy endpoint was change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL). This is an eight-item questionnaire that includes chewing, swallowing, breathing, brushing teeth or hair, arising from chair, double vision, and eyelid droop.3 Each task is scored from 0 to 3. Secondary outcomes include the Quantitative Myasthenia Gravis (QMG) total score, which is a 13-item categorical grading system that includes assessment of muscle weakness (4-point scale and range from 0-39), and proportion of study participants with improvements of at least 3 and 5 points in the MG-ADL total score and QMG total score, respectively, at week 12 without rescue therapy. At week 12, zilucoplan significantly improved MG-ADL total score compared to placebo, -4.39 vs. -2.30 (mean difference of -2.09; 95% confidence interval, -3.24, -0.95) as well as QMG total score, -6.19 vs. -3.25 (mean difference -2.94 [-4.39, -1.49]). The proportion of responders with at least a 3-point improvement in MG-ADL was 73.1% vs. 46.1%, and those with at least a 5-point improvement in QMG total was 58% vs. 33%. Benefit was noted starting within a week.2
CLINICAL IMPLICATIONS
MG is a rare, chronic autoimmune, neuromuscular disease.4 It can manifest at any age but generally is more common in younger women and older men. The disease causes weakness in the skeletal muscles affecting body movement in the arms and legs. Certain muscles that control eye/eyelid movement, facial expression, chewing, talking, and swallowing also may be involved. It is caused by autoantibodies that alter or destroy the receptors for acetycholine. An enlarged thymus gland may be associated with MG. Currently, there is no cure for MG. Treatment includes thymectomy, anticholinesterases (e.g., pyridostigmine), and immunosuppressives including corticosteroids, azathioprine, mycophenolate, and tacrolimus. For those who test positive for AChR antibodies, (estimated to be 80% to 88%), targeted therapy with a complement inhibitor is more likely to be effective.5 Currently, there are two monoclonal antibodies, eculizumab and ravulizumab-cwvz, that require periodic intravenous infusion. Zilucoplan is a macrocyclic peptide that can be self-administered by subcutaneous injection. There are no comparative studies between zilucoplan and either monoclonal antibody. A systemic review, meta-analysis, and network meta-analysis suggest that the complement inhibitors seem to have similar efficacy.6 The cost of zilucoplan was not available at the time of this review.
REFERENCES
- UCB, Inc. Zilbrysq prescribing information. October 2023. https://www.zilbrysq.com/
- Howard JF Jr, Bresch S, Genge A, et al. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): A randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol 2023;22;395-406.
- Conquer Myasthenia Gravis. MG Activities of Daily Living (MG-ADL) Scale. Last updated Sept. 29, 2022. https://www.myastheniagravis.org/mg-activities-of-daily-living-mg-adl-scale/#:~:text=The%20MG%2DADL%20scale%20assesses,use%20this%20tool%20as%20well.
- National Institute of Neurological Disorders and Stroke. Myasthenia Gravis. Last reviewed Jan. 23, 2023. https://www.ninds.nih.gov/health-information/disorders/myasthenia-gravis#
- Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: Results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol 2020;77:582-592.
- Sacca F, Pane C, Ezequiel Espinosa P, et al. Efficacy of innovative therapies in myasthenia gravis: A systematic review, meta-analysis and network meta-analysis. Eur J Neurol 2023;30:3854-3867.
