Pozelimab and Cemdisiran Combination Treatment in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Have Received Pozelimab Monotherapy

A Randomized, Open-label, Two-arm Study to Evaluate the Safety, Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran Combination Treatment in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Received Pozelimab Monotherapy

The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens of pozelimab and cemdisiran combination therapy during the open-label treatment period (OLTP)

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 total complement hemolysis activity (CH50)
• To evaluate the effect of the combination treatment on hemoglobin levels
• To evaluate the effect of the combination treatment on red blood cell (RBC) transfusion requirements
• To evaluate the effect of the combination treatment on clinical outcome assessments (COAs) measuring fatigue and health related quality of life
• To assess the concentrations of total pozelimab in serum and total complement component (C) 5 and cemdisiran in plasma
• To assess immunogenicity to pozelimab and cemdisiran
• To evaluate the long-term safety and efficacy of pozelimab and cemdisiran in an optional open-label extension period (OLEP)
• To assess safety after treatment intensification with pozelimab and cemdisiran

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hong Kong
  • New Territories
    • Hong Kong, New Territories, Hong Kong, 550540
      • Prince of Wales Hospital
• Hungary
  • Nagyvárad Tér 1
    • Budapest, Nagyvárad Tér 1, Hungary, 1907
      • D l Pesti Centrumk rh z Orsz gos Hematol giai s Infektol giai Int zet
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 3722
    • Yonsei University College of Medicine, Severance Hospital
  • Seoul, Korea, Republic of, 7985
    • Ewha Womans University Medical Centre
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 06351
      • Samsung Medical Center
• Malaysia
  • Sarawak
    • Miri, Sarawak, Malaysia, 98000
      • Hospital Miri
    • Sibu, Sarawak, Malaysia, 96000
      • Hospital Sibu
  • Terengganu
    • Kuala Terengganu, Terengganu, Malaysia, 20400
      • Hospital Sultanah Nur Zahirah
• Taiwan
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taoyuan City, Taiwan, 333
    • Chang Gung Memorial Hospital
• United Kingdom
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS97TF
      • St. James's University Hospital

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

1. Participants with PNH who are receiving treatment with pozelimab monotherapy in the R3918- PNH-1868 study (NCT04162470)

Key Exclusion Criteria:

1. Documented, positive polymerase chain reaction (PCR) or equivalent test based on regional recommendations for COVID-19 or suspected SARS-CoV-2 infection as defined in the protocol
2. Participants with documented history of liver cirrhosis or participants with liver disease with evidence of currently impaired liver function; or participants with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) as described in the protocol
3. Significant protocol deviation(s) in the parent study based on the investigator's judgment as described in the protocol
4. Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the participant unsuitable for enrollment or would jeopardize the safety of the participant
5. Known hypersensitivity to cemdisiran or any component of cemdisiran formulation

NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pozelimab Q4W + Cemdisiran	Drug: Pozelimab; Administered Sub-cutaneous (SC) per protocol; Other Names: REGN3918; Drug: Cemdisiran; Administered SC per protocol; Other Names: ALN-CC5
Experimental: Pozelimab Q2W + Cemdisiran	Drug: Pozelimab; Administered Sub-cutaneous (SC) per protocol; Other Names: REGN3918; Drug: Cemdisiran; Administered SC per protocol; Other Names: ALN-CC5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)	Open Label Treatment Period (OLTP)	Through Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change of Lactate Dehydrogenase (LDH) From Pre-treatment to End-of-treatment Period	OLTP Pre-treatment (mean of LDH values prior to combination dosing); End-of-treatment (mean of LDH value at week 24- through week 28); percentage of change in Upper Limit of Normal (xULN).	End of treatment period, approximately 28 Weeks
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1) Through Week 28	OLTP Adequate control of hemolysis is defined as LDH values ≤1.5 × Upper limit of normal (ULN) from baseline (day 1) to week 28	Baseline (Day 1) through Week 28
Percentage of Participants Maintaining Adequate Control of Hemolysis From Week 4 Through Week 28	OLTP	Week 4 through Week 28
Percentage of Participants With Adequate Control of Hemolysis at Each Visit Day 1 Through Week 28	OLTP; Adequate control at a visit is defined as having LDH <=1.5 x ULN at that visit	Day 1 through Week 28
Percentage of Participants With Normalization of LDH at Each Visit From Baseline (Day 1) Through Week 28	OLTP; Normalization of LDH was defined as LDH ≤1.0 × ULN at each visit	Baseline (Day 1) through Week 28
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLTP Baseline (Day 1) Through Week 28	OLTP	Baseline (Day 1) through Week 28
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLTP Week 4 Through Week 28	OLTP	Week 4 through Week 28
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1) Through Week 28	OLTP Breakthrough hemolysis is defined as an increase in LDH with concomitant signs or symptoms associated with hemolysis: • An increase in LDH occurs when: LDH ≥2 × ULN if pre-treatment LDH is ≤1.5 × ULN or; LDH ≥2 × ULN after initial achievement of LDH ≤1.5 × ULN if pre-treatment LDH is >1.5 × ULN Signs or symptoms should correspond to those known to be associated with intravascular hemolysis due to Paroxysmal nocturnal hemoglobinuria (PNH) limited to the following: new onset or worsening fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral icterus, erectile dysfunction, chest pain, confusion, dysphagia, anemia including hemoglobin value significantly lower (ie, ≥2g/dL decrease) compared to patient's known baseline hemoglobin values, and thrombotic event.	Baseline (Day 1) through Week 28
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1) Through Week 28	OLTP Hemoglobin stabilization was defined as participants who did not receive an RBC transfusion and had no decrease in hemoglobin level of ≥2 grams per deciLiter (g/dL).	Baseline (Day 1) through Week 28
Change in Hemoglobin Levels From Baseline (Day 1) Through Week 28	OLTP	Baseline (Day 1) to Week 28
Percentage of Participants With Transfusion Avoidance From Baseline (Day 1) Through Week 28	OLTP Not requiring a red blood cell (RBC) transfusion as per protocol algorithm	Baseline (Day 1) to Week 28
Rate of Red Blood Cells (RBCs) Transfused From Baseline (Day 1) to Week 28	OLTP Rate of RBCs transfused is defined as number of events per person-years of treatment. For each participant, the participant-years are the time from first dose date to week 28 (or early terminations visit if subject discontinued the study early) in the OLTP.	Baseline (Day 1) to Week 28
Number of Per-Protocol RBC Units Transfused From Baseline (Day 1) Through Week 28	OLTP	Baseline (Day 1) to Week 28
Change in Total Complement Hemolysis Activity Assay (CH50) From Baseline (Day 1) Through Week 28	OLTP	Baseline (Day 1) to Week 28
Change in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline (Day 1) Through Week 28	OLTP FACIT fatigue is a 13-item scale and for each item 4 is not at all fatigued to 0 very much fatigued. Higher FACIT-Fatigue scores indicate less fatigue (scores range from 0-52). A 5-point change is considered clinically meaningful.	Baseline (Day 1) to Week 28
Change in Global Health Status/Quality of Life Scale (GHS/QoL) on the European Organization for Research and Treatment of Cancer: Quality-of-Life Questionnaire Core 30 Items (EORTC QLQ-C30) From Baseline (Day 1) Through Week 28	OLTP EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.	Baseline (Day 1) to Week 28
Change in Physical Function (PF) Scores on the EORTC QLQ-C30 From Baseline (Day 1) Through Week 28	OLTP; EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.	Baseline (Day 1) to Week 28
Concentrations of Total Pozelimab in Serum on Week 28	OLTP	On Week 28
Concentrations of Cemdisiran in Plasma on Week 28	OLTP	On Week 28
Concentrations of Total C5 on Week 28	OLTP	On Week 28
Number of Participants With Pozelimab Anti-Drug Antibody (ADA) Responses Over Time	OLTP and OLEP	Up to Week 52 (OLTP [ Week 0 - Week 28] + OLEP [Week 28 - Week 52])
Number of Participants With Cemdisiran Anti-Drug Antibody (ADA) Responses Over Time	OLTP and OLEP	Up to Week 52 (OLTP [ Week 0 - Week 28] + OLEP [Week 28 - Week 52])
Percentage of Participants With TEAEs for Participants Who Received Treatment Intensification	OLTP No participants received dose intensification during the study; Therefore, assessment of the safety of pozelimab + cemdisiran combination therapy in participants requiring dose intensification was not conducted.	Through Week 28
Change of LDH From Baseline (Day 1e) to Week 24e	Optional Open-Label Extension Period (OLEP)	Baseline (Day 1e) to Week 24e
Percent Change of LDH From OLEP Baseline (Day 1e) to Week 24e	OLEP; Percentage of change for units per liter (U/L)	Baseline (Day 1e) to Week 24e
Change of LDH From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Percent Change of LDH From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1e) Through Week 24e	OLEP	Baseline (Day 1e) through Week 24e
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1e) Through Week 52e	OLEP	Baseline (Day 1e) through Week 52e
Percentage of Participants With Adequate Control of Hemolysis at Each Visit From Baseline (Day 1e) Through Week 52e	OLEP Adequate control at a visit is defined as having LDH <=1.5 x ULN at that visit	Baseline (Day 1e) through Week 52e
Percentage of Participants With Normalization of LDH at Each Visit From Baseline (Day 1e) Through Week 52e	OLEP	Baseline (Day 1e) through week 52e
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLEP Baseline (Day 1e) Through Week 52e	OLEP	Baseline (Day 1e) through Week 52e
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1e) Through Week 24e	OLEP	Baseline (Day 1e) through Week 24e
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1e) Through Week 52e	OLEP	Baseline (Day 1e) through Week 52e
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1e) Through Week 24e	OLEP Participants who did not receive RBC transfusion and had no decrease in hemoglobin levels	Baseline (Day 1e) through Week 24e
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1e) Through Week 52e	OLEP Participants who did not receive RBC transfusion and had no decrease in hemoglobin levels	Baseline (Day 1e) through Week 52e
Change in Hemoglobin Levels From Baseline (Day 1e) to Week 24e	OLEP	Baseline (Day 1e) to Week 24e
Change in Hemoglobin Levels From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Percentage of Participants With Per-Protocol Transfusion Avoidance From Baseline (Day 1e) Through Week 24e	OLEP Not requiring a RBC transfusion as per protocol algorithm	Baseline (Day 1e) through Week 24e
Percentage of Participants With Per-Protocol Transfusion Avoidance From Baseline (Day 1e) Through Week 52e	OLEP Not requiring a RBC transfusion as per protocol algorithm	Baseline (Day 1e) to Week 52e
Rate of RBCs Transfused From Baseline (Day 1e) to Week 24e	OLEP	Baseline (Day 1e) to Week 24e
Rate of RBCs Transfused From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Number of Units of RBCs Transfused From Baseline (Day 1e) to Week 24e	OLEP	Baseline (Day 1e) to Week 24e
Number of Units of RBCs Transfused From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Change in CH50 From Baseline (Day 1e) to Week 16e	OLEP	Baseline (Day 1e) to Week 16e
Change in CH50 From Baseline (Day 1e) to Week 24e	OLEP	Baseline (Day 1e) to Week 24e
Change in CH50 From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Percent Change in CH50 From Baseline (Day 1e) to Week 16e	OLEP	Baseline (Day 1e) to Week 16e
Percent Change in CH50 From Baseline (Day 1e) to Week 24e	OLEP	Baseline (Day 1e) to Week 24e
Percent Change in CH50 From Baseline (Day 1e) to Week 52e	OLEP	Baseline (Day 1e) to Week 52e
Change in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline (Day 1e) to Week 52e	OLEP; The FACIT-Fatigue is a 13-item, self-administered assessment of 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 QoL in participants with cancer and other chronic illnesses. The FACIT-Fatigue items are measured with a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating less fatigue. A 5-point change is considered clinically meaningful.	Baseline (Day 1e) to Week 52e
Change in GHS/QoL on the EORTC QLQ-C30 From Baseline (Day 1e) to Week 52e	OLEP; EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.	Baseline (Day 1e) to Week 52e
Change in PF Scores on the EORTC QLQ-C30 From Baseline (Day 1e) to Week 52e	OLEP; EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.	Baseline (Day 1e) to Week 52e
Percentage of Participants With TEAEs Up to Week 52	OLEP	Up to Week 52
Concentrations of Total Pozelimab in Serum on Week 52	OLEP	On Week 52
Concentrations of Total C5 on Week 52	OLEP	On Week 52
Concentrations of Cemdisiran in Plasma on Week 52	OLEP	On Week 52

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 29, 2021
• Primary Completion (Actual): October 25, 2022
• Study Completion (Actual): October 18, 2023

Study Registration Dates

• First Submitted: March 19, 2021
• First Submitted That Met QC Criteria: March 19, 2021
• First Posted (Actual): March 23, 2021

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 3, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: PNH
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urination Disorders; Urological Manifestations; Hematologic Diseases; Bone Marrow Diseases; Anemia, Hemolytic; Anemia; Myelodysplastic Syndromes; Proteinuria; Hemoglobinuria; Hemoglobinuria, Paroxysmal
• Other Study ID Numbers: R3918-PNH-2092; 2020-005005-17 (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