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	Measure Description	Time Frame
Incidence and severity of treatment emergent adverse events (TEAEs)	Open Label Treatment Period (OLTP)	Through day 225

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change of LDH	OLEP	Day 1 to Week 24
Change of LDH	OLEP	Day 1 to Week 52
Percent change of LDH	OLEP	Day 1 to Week 52
AUC of LDH over time	OLEP	Day 1 through Week 52
Change in hemoglobin levels	OLEP	Day 1 to Week 24
Change in hemoglobin levels	OLEP	Day 1 to Week 52
Change in CH50	OLEP	Day 1 to Week 16
Change in CH50	OLEP	Day 1 to Week 24
Change in CH50	OLEP	Day 1 to Week 52
Change in GHS/QoL on the EORTC QLQ-C30	OLEP	Day 1 to Week 52
Change in PF scores on the EORTC QLQ-C30	OLEP	Day 1 to Week 52
Concentrations of total pozelimab in serum	OLEP	Up to Week 52
Concentrations of total C5	OLEP	Up to Week 52
Concentrations of cemdisiran in plasma	OLEP	Up to Week 52
Incidence of pozelimab anti-drug antibody (ADA) responses over time	OLEP	Up to Week 52
Incidence of cemdisiran anti-drug antibody (ADA) responses over time	OLEP	Up to Week 52
Percent change in LDH from pre-treatment to end-of-treatment period	OLTP	Screening through Day 225
Percent change in LDH from pre-treatment	OLTP	Screening through Day 29
Proportion of participants who are transfusion-free	OLTP Not requiring a RBC transfusion as per protocol algorithm	Baseline through Day 225
Proportion of participants who are transfusion-free	OLTP Not requiring a RBC transfusion as per protocol algorithm	Day 29 through Day 225
Rate of RBCs transfused	OLTP	Baseline through Day 225
Rate of RBCs transfused	OLTP	Day 29 through Day 225
Number of units of RBCs transfused	OLTP	Baseline through Day 225
Number of units of RBCs transfused	OLTP	Day 29 through Day 225
Proportion of participants with breakthrough hemolysis	OLTP	Baseline through Day 225
Proportion of participants with breakthrough hemolysis	OLTP	Day 29 through Day 225
Proportion of participants who maintain adequate control of hemolysis	OLTP	Post Baseline (on Day 1) through Day 225
Proportion of participants who maintain adequate control of hemolysis	OLTP	Day 57 through Day 225
Proportion of participants with adequate control of hemolysis at each visit	OLTP	Post Baseline (on Day 1) through Day 225
Proportion of participants with normalization of their LDH at each visit	OLTP	Post Baseline (on Day 1) through Day 225
Area under the curve (AUC) of LDH over time	OLTP	Baseline through Day 225
AUC of LDH over time	OLTP	Day 57 through Day 225
Proportion of participants with hemoglobin stabilization	OLTP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels meeting pre-specified criteria	Baseline through Day 225
Proportion of participants with hemoglobin stabilization	OLTP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels meeting pre-specified criteria.	Day 29 through Day 225
Change in hemoglobin levels	OLTP	Baseline to Day 225
Change in fatigue as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale	OLTP The FACIT-Fatigue is a 13-item, self-reported PRO 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 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). Scores range from 0 to 52, with higher scores indicating a higher quality of life.	Baseline to Day 225
Change 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	OLTP EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small. A change of 10 - 20 points is considered a moderate change.	Baseline to Day 225
Change in physical function (PF) scores on the EORTC QLQ-C30	OLTP	Baseline to Day 225
Change in total CH50	OLTP	Baseline to Day 225
Concentrations of total pozelimab and eculizumab in serum	OLTP	Up to Day 225
Concentrations of total cemdisiran in plasma	OLTP	Up to Day 225
Change from baseline in concentration of total C5	OLTP	Up to Day 225
Incidence of pozelimab anti-drug antibody (ADA) responses over time	OLTP	Up to Day 225
Incidence of cemdisiran anti-drug antibody (ADA) responses over time	OLTP	Up to Day 225
Incidence and severity of TEAEs for participants who receive dose intensification	Intensified OLTP	Through Day 225
Incidence and severity of TEAEs in participants treated with pozelimab and cemdisiran combination therapy	Optional Open-Label Extension Period (OLEP)	Through Week 52
Change of LDH	OLEP	Day 1 to Week 24
Proportion of participants who are transfusion-free	OLEP Not requiring an RBC transfusion as per protocol algorithm	Day 1 through Week 24
Proportion of participants who are transfusion-free	OLEP Not requiring an RBC transfusion as per protocol algorithm	Day 1 through Week 52
Rate of RBCs transfused	OLEP	Day 1 through Week 24
Rate of RBCs transfused	OLEP	Day 1 through Week 52
Number of units of RBCs transfused	OLEP	Day 1 through Week 24
Number of units of RBCs transfused	OLEP	Day 1 through Week 52
Proportion of participants with breakthrough hemolysis	OLEP	Day 1 through Week 24
Proportion of participants with breakthrough hemolysis	OLEP	Day 1 through Week 52
Proportion of participants who maintain adequate control of their hemolysis	OLEP	Day 1 through Week 24
Proportion of participants who maintain adequate control of their hemolysis	OLEP	Day 1 through Week 52
Proportion of participants with adequate control of hemolysis at each visit	OLEP	Day 1 through Week 24
Proportion of participants with adequate control of hemolysis at each visit	OLEP	Day 1 through Week 52
Proportion of participants with normalization of LDH at each visit	OLEP	Day 1 through Week 24
Proportion of participants with normalization of LDH at each visit	OLEP	Day 1 through Week 52
AUC of LDH over time	OLEP	Day 1 through Week 24
Proportion of participants with hemoglobin stabilization	OLEP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels meeting pre-specified criteria.	Day 1 through Week 24
Proportion of participants with hemoglobin stabilization	OLEP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels meeting pre-specified criteria.	Day 1 through Week 52
Change in fatigue as measured by FACIT-Fatigue scale	OLEP	Day 1 to Week 52

Collaborators and Investigators

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

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): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: PNH
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hemoglobinuria; 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