Background: PNH is a rare, life-threatening disease caused by uncontrolled terminal pathway activation leading to intravascular hemolysis (IVH). The C5 inhibitors eculizumab (ECU) and ravulizumab (RAV) prevent IVH by inhibiting terminal complement; however, some C5 inhibitor-treated patients may experience persistent anemia due to extravascular hemolysis (EVH) caused by C3 fragment deposition and opsonization driven by constitutive activation of the alternative pathway (AP). Inhibition of factor D (FD), the rate limiting enzyme of the AP, acts on the complement cascade upstream of C3. Danicopan (ALXN2040, ACH-4471) is a first-in-class oral small molecule FD inhibitor. In vitro studies with RBCs collected from PNH patients have shown that danicopan not only inhibited hemolysis but also prevented deposition of C3 fragments on PNH RBCs. In a 24-week Phase 2 study of ECU-treated PNH patients with transfusion-dependent anemia (hemoglobin [Hgb] <10 g/dL), danicopan add-on resulted in clinically significant improvements in Hgb, near transfusion-independence, improvements in FACIT-Fatigue scores, and was generally well-tolerated; 96% of treatment-emergent adverse events were mild-to-moderate in severity and did not result in discontinuation.

The purpose of this randomized, double-blind, pivotal Phase 3 trial (NCT04469465; EudraCT 2019-003829-18) is to evaluate the efficacy of oral danicopan add-on therapy in PNH patients with clinically evident EVH (CE-EVH) on an approved C5 inhibitor.

Study Design and Methods: This study consists of a 12-week double-blind placebo-controlled treatment period 1 followed by a 12-week danicopan+C5 inhibitor treatment period 2 and a long-term extension up to 1-year. Patients (target enrollment, N=84) will be randomized to danicopan or matched placebo TID in a 2:1 ratio for the 12-week treatment period 1. Patients randomized to placebo for treatment period 1 will switch to danicopan at week 12 (Figure). Eligible adult patients must be receiving a stable regimen of ECU or RAV (no change in drug/dose/interval for ≥24 weeks), and have CE-EVH, defined by anemia (Hgb ≤9.5 g/dL), absolute reticulocyte count ≥120 x 109/L, and ≥1 transfusion within 6 months before study entry. The starting dose of danicopan is 150 mg TID. Patients with alanine aminotransferase (ALT) or direct bilirubin values >1.5 × upper limit of normal (ULN) will start at 100 mg TID. Doses may be escalated in 50-mg increments, with ≥4 weeks between escalations, to a maximum of 200 mg TID based on safety and clinical effect at protocol-specified time points. Exclusion criteria include major organ transplant or hematopoietic stem cell transplantation (HSCT), aplastic anemia requiring HSCT, complement deficiency, or ALT >2 × ULN.

The primary efficacy endpoint is change in Hgb at week 12. Secondary endpoints are proportion of patients not requiring a transfusion through week 12, change from baseline in FACIT-Fatigue scores, and change from baseline in absolute reticulocyte count at week 12. Other secondary endpoints (at weeks 12 and 24) include RBC units transfused, Hgb stabilization, laboratory markers (including bilirubin, LDH, and PNH clone size), and patient-reported outcomes (EQ-5D-3L, EORTC-QLQ-C30, WPAI, and health resource utilization). Primary and secondary efficacy analyses will be performed on the intent-to-treat population; safety analyses will include all patients who received ≥1 dose of study drug.

Danicopan has the potential to be the first oral PNH therapy, and offers an opportunity to enhance the well-characterized efficacy of C5 inhibitors without compromising safety. This Phase 3, pivotal trial will be the largest clinical evaluation of danicopan to date. More importantly, the trial has the potential to generate robust data to demonstrate the efficacy and safety of add-on, oral danicopan to C5 inhibitor therapy in PNH patients with clinically evident hemolysis.

Disclosures

Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang:Alexion: Current Employment, Current equity holder in publicly-traded company. Nishimura:Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Chugai: Consultancy. Ramirez-Santiago:Alexion: Current Employment, Current equity holder in publicly-traded company.

Author notes

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Asterisk with author names denotes non-ASH members.