C. Lathia,1 X. Gao,1 N. Kassir,2 S. M. Mouksassi,2 B. Jayaraman,2 J. Marier,2 J. Wang,1 C. Bedrosian1; 1Alexion Pharmaceuticals Inc., Cheshire, CT, 2Pharsight, a Certara Company, Montreal, QC, Canada
BACKGROUND: Complement activation at the neuromuscular junction is the primary cause of acetylcholine receptor (AChR) loss and impaired neuromuscular transmission in acquired autoimmune myasthenia gravis (MG). Data from a Phase II eculizumab (Ec) study (14 pts) lend substantial support that complete and sustained terminal complement blockade is associated with clinical improvement and may be required to prevent clinical deterioration or myasthenic crisis in refractory generalized MG (gMG). The objectives of this project were: 1) develop a population PK/PD model using data from the Phase II trial with an Ec dose regimen of 600 mg weekly for 4 weeks, 900 mg at week 5 and 900 mg every 2 weeks (600 /900 mg) and 2) perform simulations to support the Phase III dose regimen (900/1200 mg, with the same schedule as Phase II).
METHODS: Population PK analysis was performed using nonlinear mixed-effect modeling. Simulations were done to determine the probabilities of minimum concentrations (Cmin) of Ec >50 µg/mL (minimum threshold for complete terminal complement blockade).
RESULTS: A one-compartment model parameterized by clearance and volume of distribution fitted Ec PK well. The 600/900 mg dosing scheme resulted in Cmin >50 µg/mL in 87% of patients suggesting that some patients remain at risk of clinical deterioration or crisis. A dosing scheme of 900/1200 mg is expected to result in Cmin >50 µg/mL in 95% patients. Safety of Ec with the Phase III dose regimen is expected to be similar to Phase II based on safety data from other indications for which Ec is approved or in development for.
CONCLUSION: The 900/1200 mg dosing scheme for the Phase III study in refractory gMG patients is expected to result in concentrations above the minimum target for complete complement blockade, minimizing risk of clinical deterioration.