In patients with paroxysmal nocturnal hemoglobinuria (PNH) and clinically significant extravascular hemolysis (cs-EVH), treatment with the oral factor D inhibitor danicopan plus C5 inhibitors (C5i) ravulizumab and eculizumab showed efficiency and safety through 72 weeks in the continual control of terminal complement activity, intravascular hemolysis (IVH), and cs-EVH. This is according to the long-term data from the phase III ALPHA trial, published in Blood, in which danicopan demonstrated a favorable benefit-risk profile and no new safety signals.1
“Today, patients with PNH who also have cs-EVH have many options including C3 inhibitor monotherapy (pegcetacoplan), factor B inhibitor monotherapy (iptacopan), and danicopan add-on therapy to C5i,” said corresponding author Jong Wook Lee, MD, PhD, of Hanyang University Seoul Hospital in South Korea. However, it is “critical” to consider the risks and benefits of these options “before initiating treatment, particularly as it relates to the risk of losing complete IVH control. As such, danicopan as add-on therapy provides a safe and efficacious option for patients with cs-EVH who may need proximal inhibition to improve their symptoms while maintaining control of terminal complement activity and IVH with ravulizumab or eculizumab, and without risking the severe consequences of breakthrough IVH.”
The primary analysis of the randomized, double-blind, placebo-controlled trial demonstrated the efficiency of danicopan versus placebo as add-on treatment to ravulizumab and eculizumab in 63 patients (around 75% of the overall enrollment target) with PNH, severe cs-EVH, low hemoglobin (Hb), elevated absolute reticulocyte count (ARC), and fatigue.2 The drug combination showed clinically significant superiority versus placebo in the primary endpoint — a change in Hb concentration from baseline to week 12 — and key secondary endpoints.
Ultimately, the researchers enrolled 86 participants (≥18 years) with PNH and cs-EVH (anemia [Hb ≤9.5 g/dL] with ARC ≥120 x 109/L) who were taking ravulizumab or eculizumab for six months or more. Participants were randomly assigned 2:1 to receive oral danicopan 150 mg, increased to 200 mg based on clinical response, three times daily or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period. Of the participants, 82 completed the first 12-week treatment period. Participants receiving placebo switched to danicopan during the following 12-week open-label treatment period. Eighty participants entered the two-year long-term extension.
Treatment with danicopan improved Hb concentrations from baseline at week 12 (mean change =2.8 g/dL), meeting the primary endpoint. For participants switching from placebo to danicopan at week 12, improvements in Hb occurred by week 24 (mean change = 2.3 g/dL).
For secondary endpoints, the authors reported “similar trends” favoring danicopan in the proportion of participants achieving a Hb increase of 2 g/dL or more and transfusion avoidance, and improvements in ARC and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores.
Of the 84 participants exposed to danicopan, 73.8% reached a maximum dose of 200 mg, and the mean adherence to the drug stood at 97.1%. Further, 98.8% of participants experienced one or more treatment-emergent adverse event with danicopan. Serious adverse events (bilirubin increase, pancreatitis) occurred in one patient during the initial treatment cycle, and one patient reported a headache during the second treatment cycle.
Danicopan provides a benefit as add-on therapy to C5i “by addressing cs-EVH, while maintaining control of terminal complement activity and IVH as evidenced by increased Hb, reduced ARC, maintenance of low lactate dehydrogenase, and improvements in transfusion avoidance and fatigue score,” Dr. Lee said. “Even if there would be a missed dose of danicopan or increased complement activity, for example due to an infection, the fact that there is maintained control of terminal complement activity and IVH with the C5i, the risk for breakthrough IVH is very low, as shown in this long-term dataset and with a large number of patients.”
Limitations to the study include the lack of a predefined endpoint of breakthrough hemolysis (BTH). Researchers reported BTH as a safety event based on their clinical judgment. Other limitations included the small number of participants and exclusion of pediatric patients.
“These long-term data underscore the importance of dual-inhibition treatment in patients with cs-EVH, and more real-world data will be informative in clinical practice,” Dr. Lee concluded.
Any conflicts of interest declared by the authors can be found in the original article.
References
- Kulasekararaj A, Griffin M, Piatek C, et al. Long-term efficacy and safety of danicopan as add-on therapy to ravulizumab or eculizumab in PNH with significant EVH [published online ahead of print, 2024 Dec. 19]. doi: 10.1182/blood.2024026299.
- Lee JW, Griffin M, Kim JS, 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 Haematol. 2023;10(12):e955-e965.