Jun Chen1, Feng Yang1, Hanbin Li2, Rajendra Pradhan1, Stephan Ortiz1
1Alexion, AstraZeneca Rare Disease, 2QuanTx Consulting
Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a chronic and progressive disease of uncontrolled terminal complement activation that leads to intravascular haemolysis, thrombosis, organ damage and increased risk of premature mortality, imposing significant burden on patients. Treatment of PNH with the complement C5 inhibitors eculizumab and ravulizumab, now as current standard of care, effectively inhibits terminal complement activity, resulting in control of intravascular haemolysis, a reduction in thrombotic events, and lower mortality and morbidity. Danicopan, a complement Factor D inhibitor, has been approved as add-on therapy to C5 inhibitors (ravulizumab or eculizumab) for the treatment of extravascular hemolysis (EVH) in patients with PNH. Danicopan has demonstrated a favourable benefit–risk profile through 72 weeks, providing sustained control of terminal complement activity, IVH, and csEVH in the Phase 3 ALPHA study.1,2 Objectives: Population Pharmacokinetic (PPK) and Pharmacokinetic-Pharmacodynamic (PK-PD) analyses were conducted based on data from healthy participants and patients with PNH, to quantify the relationship between danicopan plasma concentrations and alternative pathway (AP) activity. PK-PD model simulations were conducted to support the approved danicopan dose regimen. Methods: The PPK modeling analysis used danicopan plasma concentration data from 316 healthy participants in 11 Phase 1 trials and 91 participants with PNH from two Phase 2 trials and one Phase 3 trial. AP activity data from 69 patients with PNH in the Phase 3 study were used in the PK-PD analysis. The PPK and PK-PD modeling analyses were performed in NONMEM® Version 7.5 using the first-order conditional estimation. Impact of covariates on the PK and PK-PD, including demographics, baseline disease characteristics, food and concomitant medications, were evaluated. Standard diagnostic plots were used throughout model development to assess each model’s ability to describe the observed data. PK-PD model simulations were performed to support the selected dose. Steady state danicopan PK exposure and AP activities were simulated for the selected danicopan regimens of 150 mg tid and 200 mg tid. Covariates were sampled from the PNH population in the pivotal Phase 3 trial. Results: Danicopan pharmacokinetic data was modeled using a two-compartment model with linear elimination from the central compartment, with absorption characterized by a zero-order release followed by first order absorption. Apparent clearance (CL/F) in patients with PNH was estimated to be 63 L/hr, with elimination half-life of 7.9 hr. Danicopan CL/F and Vc/F increased in participants with higher body weight. CL/F reduced by 22.7% in females and by 41.3% in subjects with severe renal impairment. At therapeutic doses of 150 mg tid to 200 mg tid, danicopan exposures at steady state is approximately dose proportional. The relationship between danicopan plasma concentration and AP activity was described using an inhibitory Emax model. Maximum reduction of AP activity was to 3.05% from the baseline value of 29.1%. IC50 and IC90 were estimated to be 12 ng/mL and 108 ng/mL, respectively. Model simulations in PNH patients on C5 inhibitors indicated that danicopan regimens of 150 mg tid or 200 mg tid achieved trough concentrations above the IC90, resulting in an overall 90% AP inhibition. AP activities at trough were predicted to be reduced to 4.7% and 4.0% for the 150 mg and 200 mg tid dose regimens, respectively. Conclusions: Danicopan dosing regimens of 150 mg tid or 200 mg tid effectively achieved the IC90 of 108 ng/mL, resulting in a substantial reduction of AP activity (<10% remaining AP activity) in patients with PNH concurrently using C5 inhibitors (ravulizumab or eculizumab). The PK-PD analyses confirmed that the selected danicopan dose regimens for patients with PNH are appropriate.
1. Kulasekararaj, A.G., et al., Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab. Blood, 2021. 138(20): p. 1928-1938. 2. Lee, JW et al., Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematology. 2023 Dec;10(12):e955-e965
Reference: PAGE 33 (2025) Abstr 11368 [www.page-meeting.org/?abstract=11368]
Poster: Drug/Disease Modelling - Other Topics