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

Paroxysmal Nocturnal Hemoglobinuria Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04888507
• Other study ID #: R3918-PNH-20105
• Secondary ID: 2020-005006-25
• Status: Completed
• Phase: Phase 2
• Start date: July 8, 2021
• Est. completion date: May 4, 2023

Study information

• Verified date: June 2023
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: May 4, 2023
• Est. primary completion date: May 5, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemoglobinuria
• Hemoglobinuria, Paroxysmal
• Paroxysmal Nocturnal Hemoglobinuria

Intervention

Drug:
• Pozelimab
Intravenous (IV) loading dose (once) followed after 30 minutes by sub-cutaneous (SC) administration
• Cemdisiran
SC administration

Locations

Country	Name	City	State
United Kingdom	Regeneron Study Site	Leeds

Sponsors (1)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of treatment emergent adverse events (TEAEs)	Open Label Treatment Period (OLTP)	Through day 225
Secondary	Percent change in LDH from pre-treatment to end-of-treatment period	OLTP	Screening through Day 225
Secondary	Percent change in LDH from pre-treatment	OLTP	Screening through Day 29
Secondary	Proportion of participants who are transfusion-free	OLTP Not requiring a RBC transfusion as per protocol algorithm	Baseline through Day 225
Secondary	Proportion of participants who are transfusion-free	OLTP Not requiring a RBC transfusion as per protocol algorithm	Day 29 through Day 225
Secondary	Rate of RBCs transfused	OLTP	Baseline through Day 225
Secondary	Rate of RBCs transfused	OLTP	Day 29 through Day 225
Secondary	Number of units of RBCs transfused	OLTP	Baseline through Day 225
Secondary	Number of units of RBCs transfused	OLTP	Day 29 through Day 225
Secondary	Proportion of participants with breakthrough hemolysis	OLTP	Baseline through Day 225
Secondary	Proportion of participants with breakthrough hemolysis	OLTP	Day 29 through Day 225
Secondary	Proportion of participants who maintain adequate control of hemolysis	OLTP	Post Baseline (on Day 1) through Day 225
Secondary	Proportion of participants who maintain adequate control of hemolysis	OLTP	Day 57 through Day 225
Secondary	Proportion of participants with adequate control of hemolysis at each visit	OLTP	Post Baseline (on Day 1) through Day 225
Secondary	Proportion of participants with normalization of their LDH at each visit	OLTP	Post Baseline (on Day 1) through Day 225
Secondary	Area under the curve (AUC) of LDH over time	OLTP	Baseline through Day 225
Secondary	AUC of LDH over time	OLTP	Day 57 through Day 225
Secondary	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
Secondary	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
Secondary	Change in hemoglobin levels	OLTP	Baseline to Day 225
Secondary	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
Secondary	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
Secondary	Change in physical function (PF) scores on the EORTC QLQ-C30	OLTP	Baseline to Day 225
Secondary	Change in total CH50	OLTP	Baseline to Day 225
Secondary	Concentrations of total pozelimab and eculizumab in serum	OLTP	Up to Day 225
Secondary	Concentrations of total cemdisiran in plasma	OLTP	Up to Day 225
Secondary	Change from baseline in concentration of total C5	OLTP	Up to Day 225
Secondary	Incidence of pozelimab anti-drug antibody (ADA) responses over time	OLTP	Up to Day 225
Secondary	Incidence of cemdisiran anti-drug antibody (ADA) responses over time	OLTP	Up to Day 225
Secondary	Incidence and severity of TEAEs for participants who receive dose intensification	Intensified OLTP	Through Day 225
Secondary	Incidence and severity of TEAEs in participants treated with pozelimab and cemdisiran combination therapy	Optional Open-Label Extension Period (OLEP)	Through Week 52
Secondary	Change of LDH	OLEP	Day 1 to Week 24
Secondary	Change of LDH	OLEP	Day 1 to Week 52
Secondary	Percent change of LDH	OLEP	Day 1 to Week 24
Secondary	Percent change of LDH	OLEP	Day 1 to Week 52
Secondary	Proportion of participants who are transfusion-free	OLEP Not requiring an RBC transfusion as per protocol algorithm	Day 1 through Week 24
Secondary	Proportion of participants who are transfusion-free	OLEP Not requiring an RBC transfusion as per protocol algorithm	Day 1 through Week 52
Secondary	Rate of RBCs transfused	OLEP	Day 1 through Week 24
Secondary	Rate of RBCs transfused	OLEP	Day 1 through Week 52
Secondary	Number of units of RBCs transfused	OLEP	Day 1 through Week 24
Secondary	Number of units of RBCs transfused	OLEP	Day 1 through Week 52
Secondary	Proportion of participants with breakthrough hemolysis	OLEP	Day 1 through Week 24
Secondary	Proportion of participants with breakthrough hemolysis	OLEP	Day 1 through Week 52
Secondary	Proportion of participants who maintain adequate control of their hemolysis	OLEP	Day 1 through Week 24
Secondary	Proportion of participants who maintain adequate control of their hemolysis	OLEP	Day 1 through Week 52
Secondary	Proportion of participants with adequate control of hemolysis at each visit	OLEP	Day 1 through Week 24
Secondary	Proportion of participants with adequate control of hemolysis at each visit	OLEP	Day 1 through Week 52
Secondary	Proportion of participants with normalization of LDH at each visit	OLEP	Day 1 through Week 24
Secondary	Proportion of participants with normalization of LDH at each visit	OLEP	Day 1 through Week 52
Secondary	AUC of LDH over time	OLEP	Day 1 through Week 24
Secondary	AUC of LDH over time	OLEP	Day 1 through Week 52
Secondary	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
Secondary	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
Secondary	Change in hemoglobin levels	OLEP	Day 1 to Week 24
Secondary	Change in hemoglobin levels	OLEP	Day 1 to Week 52
Secondary	Change in fatigue as measured by FACIT-Fatigue scale	OLEP	Day 1 to Week 52
Secondary	Change in GHS/QoL on the EORTC QLQ-C30	OLEP	Day 1 to Week 52
Secondary	Change in PF scores on the EORTC QLQ-C30	OLEP	Day 1 to Week 52
Secondary	Change in CH50	OLEP	Day 1 to Week 16
Secondary	Change in CH50	OLEP	Day 1 to Week 24
Secondary	Change in CH50	OLEP	Day 1 to Week 52
Secondary	Concentrations of total pozelimab in serum	OLEP	Up to Week 52
Secondary	Concentrations of total C5	OLEP	Up to Week 52
Secondary	Concentrations of cemdisiran in plasma	OLEP	Up to Week 52
Secondary	Incidence of pozelimab anti-drug antibody (ADA) responses over time	OLEP	Up to Week 52
Secondary	Incidence of cemdisiran anti-drug antibody (ADA) responses over time	OLEP	Up to Week 52