Regulatory Decision Summary for Soliris

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, severely disabling autoimmune inflammatory disorder of the central nervous system that predominately affects the optic nerves and spinal cord. The typical manifestations of NMOSD are characterized by recurrent relapses of optic neuritis or transverse myelitis, which result in a stepwise accumulation of potentially irreversible relapse-related neurologic disability, including blindness, paralysis, and/or death. The diagnosed prevalence of NMOSD has been estimated at 0.5 to 4.4 per 100,000 worldwide inhabitants.

Authorization of Soliris (eculizumab for injection) in this submission was based upon a randomized, double-blind, placebo-controlled event driven trial that enrolled 143 patients with NMOSD who were anti-AQP4 antibody positive. Patients had a history of at least 2 relapses in last 12 months or 3 relapses in the last 24 months, with at least 1 relapse in the 12 months prior to screening, and had an Expanded Disability Status Scale (EDSS) score ≤7 (consistent with the presence of at least limited ambulation with aid). A total of 96 patients were randomized to receive Soliris treatment and 47 were randomized to receive placebo. Randomization was stratified using two variables:

1. EDSS score at randomization; and
2. patients prior immunosuppressive therapy (IST) and IST status at randomization.

Patients could continue to receive a stable dose of the ISTs they were taking at the time of screening (with the exception of protocol-specified disallowed medications), but no new ISTs and no change in IST dosage were permitted during the study.

The primary endpoint was the time-to-first on-trial relapse as adjudicated by an independent committee who were blinded to treatment. On-trial relapse was defined as a new onset of neurologic symptoms or worsening of existing neurologic symptoms with an objective change (i.e., clinical sign) on neurologic examination that persisted for more than 24 hours as confirmed by the treating physician who was blinded to treatment. A key secondary endpoint was the adjudicated on-trial Annualized Relapse Rate (ARR), which was computed for each patient as the number of relapses divided by the time in years.

Soliris resulted in a 94.2% reduction in the risk of an adjudicated on-trial relapse (hazard ratio: 0.058 [95% CI; 0.017, 0.197]; p<0.0001). The treatment effect was consistent regardless of background IST status (i.e., use of any IST at baseline versus no IST use at baseline). Furthermore, Soliris resulted in a 95.5% reduction in adjudicated ARR ratio (hazard ratio: 0.045 [95% CI; 0.013, 0.151]; p<0.0001). Additionally, patients treated with Soliris compared to placebo, experienced clinically meaningful reductions in the annualized rates of relapse-associated hospitalization (0.04 versus 0.31), and the annualized rate of relapse-associated with acute relapse treatment, including intravenous (IV) methylprednisolone (0.07 versus 0.42) or plasma exchange (0.02 versus 0.19).

The most frequently reported treatment-emergent adverse events (TEAEs) (≥5% of subjects in either treatment group and at a higher rate than placebo) were upper respiratory tract infection, headache, nasopharyngitis, urinary tract infection, back pain, diarrhoea and influenza. The majority of TEAEs were mild or moderate in severity. There were no discontinuations due to a TEAE in the Soliris group.

The recommended dose of Soliris is 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. View the Soliris Product Monograph for details.