Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Inhibition of FD proteolytic activity by danicopan. FD participates in C3 convertase generation by cleavage of factor B at 2 steps in the AP cascade: generation of the initial C3 convertase [C3(H2O)Bb] following spontaneous AP activation (tick-over) in the fluid phase and the production of surface-bound C3 convertase (C3bBb), which mediates dramatic amplification of the initial activation (amplification loop) and activation of the terminal pathway (cleavage of C5 into C5a and C5b by C5 convertase [ie, C3bBb3b]), leading to opsonization of target surfaces by C3b, release of the anaphylatoxins C3a and C5a, and formation of MAC. An erythrocyte is shown to depict the membrane-bound events. Regulatory proteins not shown here can promote (properdin and FH-related proteins) or attenuate (factor H, factor I, multiple membrane-bound proteins, including CD55 and CD59) AP activity. Eculizumab acts directly at the terminal pathway by preventing its activation via binding to C5; danicopan acts upstream by preventing AP activation via inhibition of proteolytic activity of FD. Although the C5 inhibitor is able to block MAC formation regardless of the initiation pathway of complement activation, it has no effect on C3 fragment deposition. FD inhibitor is able to block C3 fragment deposition and MAC formation when the complement activation is initiated via AP, such as in the case of PNH; it should be able to exert the same, although not complete, inhibitory effect when complement activation is initiated via CP or LP through blocking the amplification loop.

Figure 2.

Effect of danicopan on laboratory markers. Mean (and standard deviation [SD]) change from baseline (BL) for Hgb (primary end point) (A), reticulocytes (B), total bilirubin (C), direct bilirubin (D), LDH (E), and FACIT-Fatigue score (F). P values represent change from baseline to week 24.

Figure 3.

Effect of danicopan on blood transfusions. Per-patient transfusion occurrences and units 52 weeks prior to the start of danicopan and during treatment with danicopan. *Patient A was excluded from the table because of a religious objection to receiving transfusions; baseline Hgb = 5 g/dL.†−24 weeks up to the first dose of study medication.

Figure 4.

Effect of danicopan on complement biomarkers and GPI-deficient cell population. Serum, plasma, and whole blood samples were collected at day 1 prior to dosing danicopan (baseline [BL]) and at the indicated time points during the study and subjected to measurement of CP activity (A), AP activity with AP hemolysis assay (B), plasma Bb concentration (C), and the population size of GPI-deficient granulocytes, GPI-deficient erythrocytes, and C3d+ GPI-deficient erythrocytes (D), as described in Methods. Arithmetic mean and standard derivation (SD) are shown for all, with the range shown at each time point. LLN, lower limit of normal; NHS, normal human serum.