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Encouraging results zilucoplan in myasthenia gravis

Presented by
Prof. James Howard & Dr Josep Gamez
AAN 2019
Positive data of a randomised trial of zilucoplan in patients with generalised myasthenia gravis supports its potential therapeutic role [1]. Another important finding on the subject of myasthenia gravis: preoperative intravenous immunoglobulin to prevent myasthenic crisis is not always justified [2].

Prof. James Howard (University of North Carolina School of Medicine, USA) presented the results of a phase 2 trial of zilucoplan [1]. He explained zilucoplan is a subcutaneously self-administered small molecule complement inhibitor, targeting complement 5a (C5a) to C6. By inhibiting C5 activation, zilucoplan prevents formation and assembly of the membrane attack complex in myasthenia gravis. The 44 patients included in the trial had Quantitative Myasthenia Gravis (QMG) scores ≥12. They were randomised 1:1:1 to placebo, zilucoplan 0.1 mg/kg/day, or 0.3 mg/kg/day for 12 weeks. The 0.3 mg/kg group experienced a mean reduction of 6 points in QMG score (placebo corrected change -2.8; P=0.05) in addition to a reduction of 3.4 points in MG-ADL score (placebo-corrected change -2.3; P=0.04).

Zilucoplan had a favourable safety and tolerability profile, consistent with prior clinical trials. Prof. Howard went on to present results from the long-term open-label extension (OLE), in which 43 patients entered. The 14 patients in the placebo group switched to zilucoplan 0.3 mg/kg. The change from baseline in QMG score after 24 weeks was significant in both the original treatment arm (P<0.0001) and the original placebo arm (P=0.01). This was also true for the change in MG-ADL scores (P<0.0001 and P=0.0004, respectively). Based on these results, zilucoplan will be further evaluated in a registrational phase 3 trial.

Additionally, results of a prospective, randomised, double-blind, single-centre study suggest that preoperative intravenous immunoglobulin (IVIg) to prevent myasthenic crisis in myasthenia gravis patients is unjustified under certain conditions [2]. The results of this prospective study were presented by Dr Josep Gamez (Vall d’Hebron University Hospital, Spain). The 47 participants were scheduled for surgery under general anaesthesia, and were randomised 1:1 to treatment with IVIg at 0.4 mg/kg/day for 5 days, or saline solution under the same conditions. Primary outcome was the occurrence of myasthenic crisis. Only 1 patient, who received placebo, presented with myasthenic crisis requiring non-invasive ventilation (but not reintubation) for 6 days. There were no differences between groups in the univariate analysis, nor risk factors for myasthenic crisis in the multivariate analysis. Dr Gamez observed: “In our series no myasthenic crisis may be expected if preoperative QMG score <8 and preoperative FVC >70%”. He concluded: “IVIg need not be administered to patients before thymectomy and other surgical procedures if there is a good preoperative functional status; and in multidisciplinary units with neurologists, anaesthetists, and surgeons experienced in myasthenia gravis patient care.”

1. Howard JF, et al. AAN 2019, emerging science 008.
2. Gamez J, et al. AAN 2019, Plen02.003.

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