Long-term efficacy and safety of danicopan as add-on therapy to ravulizumab or eculizumab in PNH with significant EVH

Abstract

Treatments for paroxysmal nocturnal hemoglobinuria, particularly those involving the inhibition of complement protein C5 through agents such as ravulizumab or eculizumab, have demonstrably revolutionized patient care, leading to substantial improvements in clinical outcomes and a significant enhancement in overall survival rates for individuals afflicted with this rare and debilitating blood disorder. Despite these profound advancements in controlling intravascular hemolysis, a subset of patients continues to experience clinically significant anemia. This persistent anemia is primarily attributed to a phenomenon known as clinically significant extravascular hemolysis, often abbreviated as cs-EVH. This condition is specifically defined by a hemoglobin level equal to or below 9.5 grams per deciliter (≤9.5 g/dL) coupled with an absolute reticulocyte count equal to or greater than 120 × 10^9 per liter (≥120 × 10^9/L), indicating ongoing red blood cell destruction despite C5 inhibition.

To address this unmet clinical need, the phase 3 ALPHA trial was meticulously designed to evaluate the efficacy and safety of a novel oral therapeutic agent, danicopan. Danicopan operates as a factor D inhibitor, targeting an earlier step in the alternative complement pathway than C5 inhibitors, thereby offering a distinct mechanism to potentially mitigate extravascular hemolysis. During the initial 12-week double-blind treatment period, referred to as Treatment Period 1 (TP1), eligible participants were randomly assigned to receive either oral danicopan at a dosage of 150 mg three times daily or a placebo, in addition to their ongoing treatment with either ravulizumab or eculizumab. Following this double-blind phase, participants who had been assigned to the placebo arm seamlessly transitioned to receive danicopan during the subsequent 12-week open-label Treatment Period 2 (TP2). All participants, including those who had originally received danicopan in TP1, continued on danicopan during a comprehensive 2-year long-term extension (LTE) phase, designed to gather extensive data on sustained efficacy and safety.

The study commenced with a total of 86 participants who were randomized into the treatment arms. Of these, 82 individuals successfully progressed into Treatment Period 2, and a robust 80 participants continued their involvement into the long-term extension phase, underscoring high patient retention and commitment to the study. The predefined primary end point of the trial was successfully met, demonstrating a statistically significant and clinically meaningful improvement in hemoglobin levels from baseline at week 12 in the danicopan-treated group. Specifically, a least squares mean change of 2.8 g/dL in hemoglobin was observed, which represents a substantial amelioration of anemia. For those participants who transitioned from placebo to danicopan at week 12, a comparable and significant improvement in mean hemoglobin levels was subsequently observed by week 24, reinforcing the therapeutic benefit of danicopan regardless of initial assignment.

Consistent and beneficial trends were also noted across several key secondary end points, further supporting the positive impact of danicopan. These included the proportion of participants achieving a clinically relevant increase of at least 2 g/dL in hemoglobin, a significant improvement in the absolute reticulocyte count, a higher proportion of participants achieving transfusion avoidance (indicating reduced reliance on blood transfusions), and improvements in scores on the Functional Assessment of Chronic Illness Therapy-Fatigue scale, reflecting a reduction in patient-reported fatigue levels. Critically, these observed improvements in both hematological parameters and patient-reported outcomes were robustly maintained throughout the study, extending reliably up to week 72, indicating the sustained efficacy of the treatment.

In terms of safety, the long-term data collected across all treatment phases revealed no new or unexpected safety signals, affirming the favorable safety profile of danicopan when administered in conjunction with C5 inhibitors. The rate of breakthrough hemolysis, a key measure of disease control, was recorded at 6 events per 100 patient-years, signifying effective and sustained suppression of complement-mediated hemolysis. These comprehensive and long-term data collectively provide compelling evidence for the sustained efficacy and a well-tolerated safety profile of danicopan administered as an add-on therapy to ravulizumab or eculizumab. This combination treatment offers continued control over terminal complement activity, effectively managing both intravascular hemolysis and the persistent challenges posed by clinically significant extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria. The successful completion of this trial contributes significantly to the understanding and management of PNH, demonstrating a valuable therapeutic advancement.

Conflict of Interest Statement

The individuals involved in this research have disclosed various financial relationships with pharmaceutical and biotechnology companies, ensuring transparency regarding potential conflicts of interest.

A.K. has reported numerous financial engagements with companies active in the pharmaceutical sector. These include receiving honoraria, indicating compensation for speaking engagements or similar activities, from Alexion, AstraZeneca Rare Disease, Amgen, Agios, Celgene/Bristol Myers Squibb (BMS), Novartis, Pfizer, Roche, Samsung, and Sobi. Furthermore, A.K. has contributed their expertise as a board member or as a participant on advisory boards for Alexion, AstraZeneca Rare Disease, Amgen, BioCryst, Celgene/BMS, Novartis, Regeneron, and Roche. Additionally, A.K. has provided consulting services, for which fees were received, to Alexion, AstraZeneca Rare Disease, Celgene/BMS, Novo Nordisk, Janssen Pharmaceuticals, Pfizer, Roche, Samsung, Sobi, and Novartis.

M.G. has also disclosed financial relationships, having received honoraria from Alexion, AstraZeneca Rare Disease, Sobi, and Pfizer. M.G. has served as an advisory board member, offering strategic guidance, for Alexion, AstraZeneca Rare Disease, Amgen, BioCryst, Novartis, Pfizer, and Sobi. Consulting services have been provided to BioCryst and Regeneron Pharmaceuticals, and M.G. has also received educational grant support from Apellis.

C. Piatek has engaged in consulting activities for Alexion, AstraZeneca Rare Disease. Their expertise has also been sought for board or advisory committees, participating in discussions for Annexon Biosciences, Apellis, Alexion, AstraZeneca Rare Disease, Rigel, Sanofi, and Sobi. C. Piatek has served on a speakers’ bureau for Sobi, and has secured research funding from multiple entities, including Argenx, Alexion, AstraZeneca Rare Disease, Celgene, Oscotec, Rigel, Sanofi, and Incyte.

J.S. has reported receiving honoraria and consulting fees from several pharmaceutical companies, namely Alexion, AstraZeneca Rare Disease, Apellis, BMS, CTI Bio, GlaxoSmithKline, Incyte, Novartis, and Sanofi.

J.-i.N. has received research grants from Alexion, AstraZeneca Rare Disease. In an advisory capacity, J.-i.N. is a board member for Alexion, AstraZeneca Rare Disease, Chugai, and Roche, and has also received honoraria from Alexion, AstraZeneca Rare Disease.

C. Patriquin has received honoraria for participation in speaker bureaus and/or for providing consulting services to Alexion, AstraZeneca Rare Disease, Apellis, Amgen, BioCryst, Novartis, Roche, Sanofi, Sobi, and Takeda. Furthermore, C. Patriquin has served as a clinical site investigator, overseeing research at study sites, for Alexion, AstraZeneca Rare Disease and Apellis.

H.S. has disclosed financial support including travel support, honoraria, and research support that was directed to their institution from Alexion, AstraZeneca Rare Disease, Novartis, and Sobi. Additionally, H.S. has received honoraria, specifically channeled to the University of Ulm, from Alexion, AstraZeneca Rare Disease, Apellis, Roche, Sanofi, and Sobi.

W.B. has provided consulting services to Alexion, AstraZeneca Rare Disease, Novartis, Roche, Sanofi, and Sobi. W.B. has also been a recipient of research funding from Alexion.

J.P. has a broad range of financial relationships, having received honoraria from and serving as an advisory board member for Alexion, Amgen, Apellis, AstraZeneca, Blueprint Medicines, BMS, Boehringer Ingelheim, Gilead, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Sobi. J.P. has also received travel support from Alexion, Blueprint Medicines, Boehringer Ingelheim, Novartis, Pfizer, Roche, and Sobi. Beyond industry engagements, J.P. has served in a leadership or fiduciary role for the Lichterzellen Foundation, and has received other forms of support from Apellis, Blueprint Medicines, Novartis, and Roche.

A.G. has reported receiving honoraria from Alexion, AstraZeneca Rare Disease, Novartis, Roche, and Sobi. A.G. also serves as an advisory board member for Alexion, AstraZeneca Rare Disease, Novartis, Roche, and Sobi.

Y.P., P.L., and G.F. are employees of Alexion, AstraZeneca Rare Disease, indicating direct employment and financial ties to the company.

F.S.d.F. has received honoraria and research support, specifically directed to Saint-Louis Hospital in Paris, France, from Alexion, AstraZeneca Rare Disease, Novartis, Samsung, and Sobi.

A.R. has engaged in consulting activities and received honoraria from Alexion, AstraZeneca Rare Disease, Roche, and Novartis. Additionally, A.R. has received research funding from Alexion, AstraZeneca Rare Disease and Roche.

J.W.L. has received research grants from Alexion, AstraZeneca Rare Disease and Achillion. J.W.L. is also a member of an advisory board and has received honoraria from Alexion, AstraZeneca Rare Disease. Furthermore, J.W.L. serves as a consultant to Kyowa Kirin, Novartis, and Sanofi.