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

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.

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Journal
Blood
Published
2024-12-19
DOI
https://doi.org/10.1182/blood.2024026299
Citations
21
Primary Topic
Complement system in diseases
Type
article
Field-Weighted Citation Impact
5.05

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article

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

Jun‐ichi Nishimura, Caroline Piatek, Jens Panse, Jamile M. Shammo et al.
21 citations
Blood
Complement system in diseases
5.05
article

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

Jun‐ichi Nishimura, Caroline Piatek, Jens Panse, Jamile M. Shammo, Anna Gayà, Morag Griffin, Wilma Barcellini, Gleb Filippov, Austin Kulasekararaj, Antonio M. Risitano, Hubert Schrezenmeier, Flore Sicre de Fontbrune, Jong Wook Lee, Christopher J. Patriquin, Peng Liu, Yogesh Patel
article en
21 citations

Abstract

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.

BloodVol. 145(8)
Northwestern University (US), University of Southern California (US), King's College London (GB), University of Toronto (CA), Universität Ulm (DE), Leeds Teaching Hospitals NHS Trust (GB), German Red Cross (DE), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), King's College Hospital NHS Foundation Trust (GB), Azienda Ospedaliera S.Giuseppe Moscati (IT), Hospital Clínic de Barcelona (ES), AstraZeneca (Brazil) (BR), Alexion Pharmaceuticals (United States) (US), Immungenetics (Germany) (DE), Hanyang University Seoul Hospital (KR), Hôpital Saint-Louis (FR), AstraZeneca (United States) (US), Technische Hochschule Ulm (DE), University of Naples Federico II (IT), RWTH Aachen University (DE), The University of Osaka (JP)
Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Alexion Pharmaceuticals, Celgene, Regeneron Pharmaceuticals, BioCryst, Agios Pharmaceuticals, Incyte, Argenx, Apellis Pharmaceuticals, Novo Nordisk, Universität Ulm, Swedish Orphan Biovitrum, Samsung, Chugai Pharmaceutical, Janssen Pharmaceuticals
Good health and well-being
Openalex Percentile: Top 4%
Complement system in diseases
5.05
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