Pozelimab and Cemdisiran Combination Therapy in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy

A Single Arm, Open-Label Study to Assess the Safety, Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy

The primary objective of the study is to evaluate the safety and tolerability of pozelimab and cemdisiran combination therapy in participants with PNH who switch from eculizumab therapy

The secondary objectives of the study are:

• To evaluate the effect of the combination treatment on the following parameters of intravascular hemolysis: lactate dehydrogenase (LDH) control, breakthrough hemolysis, and inhibition of CH50
• To evaluate the effect of the combination treatment on the stability of LDH during the transition period from eculizumab monotherapy to combination with pozelimab and cemdisiran
• To evaluate the effect of the combination treatment on red blood cell (RBC) transfusion requirements
• To evaluate the effect of the combination treatment on hemoglobin levels
• To evaluate the effect of the combination treatment on clinical outcome assessments (COAs) measuring fatigue and health related quality of life (HRQoL)
• To assess the concentrations of total pozelimab and eculizumab in serum; and total cemdisiran and C5 protein in plasma
• To assess the immunogenicity of pozelimab and cemdisiran
• To assess safety after dose intensification
• To evaluate the long-term safety and efficacy of the combination treatment in an optional open-label extension period (OLEP)

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Drug: Pozelimab; Drug: Cemdisiran

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Regeneron Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Diagnosis of paroxysmal nocturnal hemoglobinuria confirmed by a history of high-sensitivity flow cytometry from prior testing
2. Treated with stable (ie, no change in dose or frequency) eculizumab therapy at the labeled dosing regimen or a higher dose and/or more frequently administered than labeled for at least 12 weeks prior to screening visit

Key Exclusion Criteria:

1. History of bone marrow transplantation or receipt of an organ transplant
2. Body weight <40 kg at screening
3. Current plans for modification of the following background concomitant medications, as applicable, during screening and treatment period: erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, anticoagulants, iron supplements, and folic acid as described in the protocol
4. Any use of complement inhibitor therapy other than eculizumab in the 12 weeks prior to the screening visit or planned use during the study
5. Known hypocellular bone marrow based on a history of reduced age-adjusted bone marrow cellularity and/or bone marrow cellularity ≤25%
6. No documented meningococcal vaccination within 5 years prior to screening visit unless it is documented that vaccination has been administered during the screening period and prior to initiation of study treatment
7. Unable to take antibiotics for meningococcal prophylaxis, if required by local standard of care
8. Any active, ongoing infection or a recent infection requiring ongoing systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or during the screening period
9. Documented positive polymerase chain reaction (PCR) or equivalent test based on regional recommendations for COVID-19 or suspected SARS-CoV-2 infection as described in the protocol
10. Documented history of active, uncontrolled, ongoing systemic autoimmune diseases
11. Recent, unstable medical conditions, excluding PNH and PNH-related complications, within the past 3 months prior to screening visit as described in the protocol
12. Anticipated need for major surgery during the study

NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pozelimab+Cemdisiran	Drug: Pozelimab; Intravenous (IV) loading dose (once) followed after 30 minutes by sub-cutaneous (SC) administration; Other Names: REGN3918; Drug: Cemdisiran; SC administration; Other Names: ALN-CC5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
OLTP: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Up to Day 225

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OLTP: Percent Change in Lactate Dehydrogenase (LDH) From Pre-treatment to End-of-treatment Period		Screening (Day 1) through Day 225
OLTP: Percent Change in LDH From Pre-treatment Through Day 29		Screening (Day 1) through Day 29
OLTP: Percentage of Participants Who Were Transfusion-free From Baseline Through Week 32		Baseline through Week 32
OLTP: Percentage of Participants Who Were Transfusion-free From Week 4 Through Week 32		Week 4 through Week 32
OLTP: Rate of Red Blood Cell (RBC) Transfusions From Baseline Through Week 32	The rate of units of transfusion for a participant was calculated based on the duration of treatment exposure of the participant.	Baseline through Week 32
OLTP: Rate of RBC Transfusions From Week 4 Through Week 32	The rate of units of transfusion for a participant was calculated based on the duration of treatment exposure of the participant.	Week 4 through Week 32
OLTP: Number of RBC Units Transfused From Baseline Through Week 32		Baseline through Week 32
OLTP: Number of RBC Units Transfused From Week 4 Through Week 32		Week 4 through Week 32
OLTP: Percentage of Participants With Breakthrough Hemolysis From Baseline Through Week 32	Breakthrough hemolysis was defined as having an LDH ≥ 2 x upper limit of normal (ULN) and having signs or symptoms.	Baseline through Week 32
OLTP: Percentage of Participants With Breakthrough Hemolysis From Week 4 Through Week 32	Breakthrough hemolysis was defined as having an LDH ≥ 2 x ULN and having signs or symptoms.	Week 4 through Week 32
OLTP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Day 1 Through Week 32	Adequate control was defined as LDH ≤ 1.5 x ULN from Day 1 through Week 32.	Day 1 through Week 32
OLTP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Week 8 Through Week 32	Adequate control was defined as LDH ≤ 1.5 x ULN from Week 8 through Week 32.	Week 8 through Week 32
OLTP: Number of Participants With Adequate Control of Hemolysis at Each Visit	Adequate control at a visit was defined as having LDH ≤1.5 x ULN at that visit.	Days 1, 8, 15, 29, 43, 57, 71, 85, 113, 141, 169, 197, 225
OLTP: Number of Participants With Normalization of Their LDH at Each Visit	Normalization was defined as LDH ≤ 1.0 x ULN at that visit.	Days 1, 8, 15, 29, 43, 57, 71, 85, 113, 141, 169, 197, 225
OLTP: Average LDH From Baseline Through Week 32	The trapezoidal rule was used to calculate area under the curve (AUC). Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.	Baseline through Week 32
OLTP: Average LDH From Week 8 Through Week 32	The trapezoidal rule was used to calculate AUC. Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.	Week 8 through Week 32
OLTP: Percentage of Participants With Hemoglobin Stabilization From Baseline Through Week 32	Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 grams per deciliter (g/dL).	Baseline through Week 32
OLTP: Percentage of Participants With Hemoglobin Stabilization From Week 4 Through Week 32	Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 g/dL.	Week 4 through Week 32
OLTP: Change From Baseline in Hemoglobin Levels		Baseline, Week 32
OLTP: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score	The FACIT-Fatigue is a 13-item, self-reported measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire is part of the FACIT measurement system, a compilation of questions measuring health-related quality of life (QoL) in participants with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a Likert scale ranging from 0 (not at all) to 4 (very much). Total scores range from 0 to 52, with higher scores indicating a higher quality of life.	Baseline, Week 32
OLTP: Change From Baseline in Health Related Quality of Life (HRQoL) as Measured by the Global Health Status Subscale of the European Organization for Research and Treatment of Cancer (EORTC)- Quality of Life Cancer Patients Questionnaire (QLQ) - 30 Scale	EORTC-QLQ-C30 is a 30-item self-reported questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. The GHS subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.	Baseline, Week 32
OLTP: Change From Baseline in Physical Function (PF) Scores on the EORTC QLQ-C30	EORTC-QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a PF scale. PF subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.	Baseline, Week 32
OLTP: Change From Baseline in Total Complement Hemolytic Activity Assay (CH50)	This assay assessed the activity of the classical pathway of complement to measure C5 activity.	Baseline through Week 32
OLTP and OLEP: Concentration of Total Pozelimab in Serum		Pre-dose Days 28, 56, 84, 112, 140, 168, 196, 224, 392, 588; Post-dose Day 28
OLTP: Concentration of Total Eculizumab in Serum		Pre-dose Days 0, 14, 28, 56, 84, 112, 140, 168, 196, 224
OLTP and OLEP: Concentration of Total Cemdisiran in Plasma		Pre-dose and Post-dose Days 0, 84, 196, 224, 588
OLTP and OLEP: Concentration of Total C5 in Plasma		Pre-dose Days 0, 7, 14, 28, 56, 84, 112, 140, 168, 196, 224, 392, 588
OLTP: Number of Participants With Pozelimab Anti-drug Antibodies (ADA)		Baseline through Week 32
OLTP: Number of Participants With Cemdisiran ADA		Baseline through Week 32
OLTP: Number of Participants Who Received Dose Intensification With TEAEs		Baseline through Week 32
OLEP: Number of Participants With TEAEs		Day 1 through Week 52 of the OLEP
OLEP: Percent Change in LDH From Day 1 Through Week 24 of the OLEP		Day 1 through Week 24 of the OLEP
OLEP: Percent Change in LDH From Day 1 Through Week 52 of the OLEP		Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants Who Were Transfusion-free From Day 1 Through Week 24 of the OLEP		Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants Who Were Transfusion-free From Day 1 Through Week 52 of the OLEP		Day 1 through Week 52 of the OLEP
OLEP: Rate of RBC Transfusions From Day 1 Through Week 24 of the OLEP	The rate of units of transfusion for a participants was calculated based on the duration of treatment exposure of the participant.	Day 1 through Week 24 of the OLEP
OLEP: Rate of RBC Transfusions From Day 1 Through Week 52 of the OLEP	The rate of units of transfusion for a participants was calculated based on the duration of treatment exposure of the participant.	Day 1 through Week 52 of the OLEP
OLEP: Number of RBC Units Transfused From Day 1 Through Week 24 of the OLEP		Day 1 through Week 24 of the OLEP
OLEP: Number of RBC Units Transfused From Day 1 Through Week 52 of the OLEP		Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants With Breakthrough Hemolysis From Day 1 Through Week 24 of the OLEP	Breakthrough hemolysis was defined as having an LDH ≥ 2 x ULN and having signs or symptoms.	Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants With Breakthrough Hemolysis From Day 1 Through Week 52 of the OLEP	Breakthrough hemolysis was defined as having an LDH ≥ 2 x ULN and having signs or symptoms.	Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Day 1 Through Week 24 of the OLEP	Adequate control was defined as LDH ≤ 1.5 x ULN.	Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Day 1 Through Week 52 of the OLEP	Adequate control was defined as LDH ≤ 1.5 x ULN.	Day 1 through Week 52 of the OLEP
OLEP: Number of Participants Who Maintained Adequate Control of Hemolysis at Each Visit in OLEP	Adequate control was defined as LDH ≤ 1.5 x ULN at that visit.	Baseline, Days 57, 113, 169, 225, 281, 365 of the OLEP
OLEP: Number of Participants With Normalization of Their LDH at Each Visit in OLEP	Normalization was defined as LDH ≤ 1.0 x ULN at that visit.	Baseline, Days 57, 113, 169, 225, 281, 365 of the OLEP
OLEP: Average LDH From Day 1 Through Week 24 of the OLEP	The trapezoidal rule was used to calculate AUC. Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.	Day 1 through Week 24 of the OLEP
OLEP: Average LDH From Day 1 Through Week 52 of the OLEP	The trapezoidal rule was used to calculate AUC. Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.	Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants With Hemoglobin Stabilization From Day 1 Through Week 24 of the OLEP	Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 g/dL.	Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants With Hemoglobin Stabilization From Day 1 Through Week 52 of the OLEP	Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 g/dL.	Day 1 through Week 52 of the OLEP
OLEP: Change From Baseline in Hemoglobin Levels		Day 1 and Week 24 of the OLEP
OLEP: Change From Baseline in Hemoglobin Levels		Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in FACIT-Fatigue Score	The FACIT-Fatigue is a 13-item, self-reported measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire is part of the FACIT measurement system, a compilation of questions measuring health-related quality of life (QoL) in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a Likert scale ranging from 0 (not at all) to 4 (very much). Total scores range from 0 to 52, with higher scores indicating a higher quality of life.	Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in HRQoL as Measured by the Global Health Status Subscale of the EORTC-QLQ-30 Scale	EORTC-QLQ-C30 is a 30-item self-reported questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. GHS subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.	Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in PF Scores on the EORTC QLQ-C30	EORTC-QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a PF scale. PF subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.	Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in CH50	This assay assessed the activity of the classical pathway of complement to measure C5 activity.	Baseline, Week 16, Week 32, Week 52 of the OLEP
OLEP: Number of Participants With Pozelimab ADA		Day 1 through Week 52 of the OLEP
OLEP: Number of Participants With Cemdisiran ADA		Day 1 through Week 52 of the OLEP

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Summary is available on TrialSummaries.com

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2021
• Primary Completion (Actual): May 5, 2022
• Study Completion (Actual): May 4, 2023

Study Registration Dates

• First Submitted: April 23, 2021
• First Submitted That Met QC Criteria: May 12, 2021
• First Posted (Actual): May 17, 2021

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 27, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: PNH
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Anemia, Hemolytic; Anemia; Myelodysplastic Syndromes; Hemic and Lymphatic Diseases; Hemoglobinuria, Paroxysmal
• Other Study ID Numbers: R3918-PNH-20105; 2020-005006-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• IPD Sharing Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes