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. 2025 Jul 24;6(4):e70095.
doi: 10.1002/jha2.70095. eCollection 2025 Aug.

Safety, Efficacy, and Patient-Reported Outcomes From a Phase 2 Randomized Trial of Pozelimab and Cemdisiran Combination in Patients With Paroxysmal Nocturnal Hemoglobinuria

Jun-Ho Jang  1 , Raymond Siu Ming Wong  2 , Christopher Hartford  3 , Rodrigo Pavani  4 , Lisa Aurand  4 , Quang Nguyen  4 , Kosalai Mohan  4 , Karoline Meagher  3 , Steven Sherman  3 , Diana Rofail  3 , Lorah Perlee  4 , Amal Souttou  4 , Richard J Kelly  5
Affiliations

Safety, Efficacy, and Patient-Reported Outcomes From a Phase 2 Randomized Trial of Pozelimab and Cemdisiran Combination in Patients With Paroxysmal Nocturnal Hemoglobinuria

Jun-Ho Jang et al. EJHaem. .

Abstract

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, life-threatening disease associated with chronic intravascular hemolysis due to uncontrolled complement activation. PNH results in anemia with an increased risk of thrombosis, and often causes severe fatigue, and decreased physical function and health-related quality of life (QoL). We investigated the efficacy, safety, and patient-reported outcomes data of the combination of pozelimab (a fully human monoclonal antibody) and cemdisiran (an N-acetylgalactosamine-conjugated small interfering ribonucleic acid) from a Phase 2 trial (NCT04811716) in patients with PNH who transitioned from pozelimab monotherapy.

Methods: In this randomized, open-label, Phase 2 study, patients were randomized (1:1) to one of two treatment arms; both arms received subcutaneous cemdisiran 200 mg every 4 weeks (Q4W) plus subcutaneous pozelimab 400 mg either Q4W (Arm 1) or every 2 weeks (Arm 2).

Results: Twenty-four patients were treated with combination dosing. During the 28-week open-label treatment period (OLTP), 20 patients (83.3%) maintained control of lactate dehydrogenase (≤ 1.5 × upper limit of normal) at all timepoints. The majority of patients (92%) did not require a blood transfusion. While most patients (66.7%) experienced treatment-emergent adverse events, the majority of these events were mild to moderate in severity. No meningococcal infections, thrombotic events, or deaths were reported. The combination therapy maintained improvements in patient-reported fatigue, physical functioning, and QoL throughout the OLTP.

Conclusion: Combination treatment maintained adequate hemolysis control and was generally well tolerated. Administration of pozelimab Q2W did not improve disease control as compared to pozelimab Q4W.

Trial registration: ClinicalTrials.gov/NCT04811716.

Keywords: complement; hemolysis; quality of life.

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Conflict of interest statement

Jun‐Ho Jang has received research funding from Alexion, Novartis, Regeneron Pharmaceuticals, Inc., AbbVie, Allovir, Janssen, Bristol Myers Squibb, Sanofi, Samsung Bioepis, and Roche Pharmaceuticals; and honoraria from Bristol Myers Squibb, Sanofi, Alexion, Janssen, Samsung Bioepis, Novartis, Astella, and Vifor Pharma. Raymond Siu Ming Wong has received research funding from Amgen, Apellis, Gilead, Novartis, Regeneron Pharmaceuticals, Inc., AbbVie, Acerta, Bayer, Roche, UCB, and Daiichi Sankyo; and honoraria from Bristol Myers Squibb, Sanofi, Apellis, Alexion, Pfizer, Spark Therapeutics, and Astella. Christopher Hartford, Rodrigo Pavani, Lisa Aurand, Quang Nguyen, Karoline Meagher, Steven Sherman, Diana Rofail, Lorah Perlee, and Amal Souttou are employees of and stockholders in Regeneron Pharmaceuticals, Inc. Kosalai Mohan was an employee of Regeneron Pharmaceuticals, Inc. at the time the study was conducted. Richard J. Kelly has received consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Astellas, F. Hoffmann‐La Roche Ltd, Florio, Jazz Pharmaceuticals, Novartis, Otsuka, and Sobi.

Figures

FIGURE 1
FIGURE 1
Study design. (a) Arm 1: pozelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W. (b) Arm 2: pozelimab 400 mg SC Q2W + cemdisiran 200 mg SC Q4W. Patients completed the FACIT‐Fatigue scale (score range 0–52), the EORTC‐QLQ‐C30 physical function (score range 0–100) assessment, and the EORTC‐QLQ‐C30 GHS/QoL assessment at baseline and intermittently throughout the OLTP. All baseline values and assessments were collected prior to patients receiving their first treatment dose. EORTC, European Organisation for Research and Treatment of Cancer; EOT, end of treatment; FACIT‐Fatigue, Functional Assessment of Chronic Illness Therapy‐Fatigue; GHS, global health status; OLEP, open‐label extension period; OLTP, open‐label treatment period; Q2W, every 2 weeks; Q4W, every 4 weeks; QLQ‐C30, Quality‐of‐Life Questionnaire Core 30; R, randomization; SC, subcutaneous.
FIGURE 2
FIGURE 2
Change from baseline in LDH over time in patients with PNH (full analysis set). LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks, ULN, upper limit of normal.
FIGURE 3
FIGURE 3
Mean hemoglobin from baseline through Week 28 in patients with PNH (full analysis set). PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.
FIGURE 4
FIGURE 4
Mean FACIT‐Fatigue scores from baseline to Week 28 in patients with PNH (full analysis set). FACIT‐Fatigue, Functional Assessment of Chronic Illness Therapy‐Fatigue; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.Mean FACIT‐Fatigue scores from baseline to Week 28 in patients with PNH (full analysis set). FACIT‐Fatigue, Functional Assessment of Chronic Illness Therapy‐Fatigue; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.
FIGURE 5
FIGURE 5
Mean physical functioning scores from baseline to Week 28 in patients with PNH (full analysis set). PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.Mean physical functioning scores from baseline to Week 28 in patients with PNH (full analysis set). PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.
FIGURE 6
FIGURE 6
Mean GHS/QoL scores from baseline to Week 28 in patients with PNH (full analysis set). GHS, global health status; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; QoL, quality of life; SE, standard error.Mean GHS/QoL scores from baseline to Week 28 in patients with PNH (full analysis set). GHS, global health status; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; QoL, quality of life; SE, standard error.
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