New Study to Assess Complement Inhibitor Iptacopan in Generalized Myasthenia Gravis

An ongoing randomized, double-blind, placebo-controlled, multicenter phase 3 study (NCT06517758) will look to measure the efficacy and safety of investigational iptacopan (Novartis) in patients with anti-acetylcholine receptor antibody-positive (AChR+) general myasthenia gravis (gMG) on stable standard of care (SOC) treatment.

Iptacopan, a medication used to treat paroxysmal nocturnal hemoglobinuria (PNH), is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. The 6-month trial will assess the change in myasthenia gravis activities of daily living score (MG-ADL) total score from baseline to month 6 as the primary outcome measure.¹

The study design, presented at the 2025 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 29 to November 1, in San Francisco, California, enrolls patients (n = 146) aged 18 to 75 years who are diagnosed with class II-IV gMG (according to the Myasthenia Gravis Foundation of America). Eligible patients must also have a baseline MG-ADL score of at least 6, with greater then 50% due to non-ocular symptoms, and inadequate disease control on one or more non-steroidal immunosuppressant treatments or frequent plasmapheresis, plasmaexchange, or intravenous immunoglobulin (IVIG) therapy.

Led by Srikanth Muppidi, MD, a neuromuscular neurologist and professor at Standford University, the study will randomize patients 1:1 to receive iptacopan or placebo during the 6-month double-blind core period. After the trial concludes, those on the placebo treatment will have the option to switch to iptacopan in the open-label extension for up to 60 months. In addition to evaluating the change in MG-ADL score from baseline to month 6, the trial also includes assessments of Quantitative Myasthenia Gravis (QMG), and MG Composite (MGC), among others.

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Another trial conducted in 2023 also analyzed iptacopan, with the focus surrounding iptacopan as an alternative complement pathway inhibitor for IgA nephropathy (IgAN). All told, results showed that iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN.²

The study, a randomized, double-blind, parallel-group adaptive phase 2 trial (NTC03373461), evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Additionally, other efficacy, safety, and biomarker parameters were assessed.

Senior author Jonathan Barratt, MD, PhD, leader of the Renal Research Group within the College of Life Sciences at the University of Leicester, and his colleagues observed a statistically significant dose-response effect. By the third month of treatment, investigators recorded a 23% reduction in UPCR in the iptacopan 200 mg bid (80% confidence interval 8-34%) group. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). Notably, a sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed

The trial enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m² and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period.

References
1. Muppidi S, Bril V, Howard J, et al. Efficacy and Safety of Iptacopan in Patients with Generalized Myasthenia Gravis: study Design. Presented at: 2025 AANEM; October 29 to November 1; San Francisco, California. Abstract 169
2. Zhang H, Rizk D, Perkovic V, et al. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Kidney Int. 2024 Jan;105(1):189-199. doi: 10.1016/j.kint.2023.09.027.