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

Study Overview
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Brief Summary
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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)

Official Title
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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

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: Pozelimab
* Drug: Cemdisiran


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of paroxysmal nocturnal hemoglobinuria confirmed by a history of high-sensitivity flow cytometry from prior testing 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: History of bone marrow transplantation or receipt of an organ transplant Body weight <40 kg at screening 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 Any use of complement inhibitor therapy other than eculizumab in the 12 weeks prior to the screening visit or planned use during the study Known hypocellular bone marrow based on a history of reduced age-adjusted bone marrow cellularity and/or bone marrow cellularity ≤25% 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 Unable to take antibiotics for meningococcal prophylaxis, if required by local standard of care 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 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 Documented history of active, uncontrolled, ongoing systemic autoimmune diseases Recent, unstable medical conditions, excluding PNH and PNH-related complications, within the past 3 months prior to screening visit as described in the protocol Anticipated need for major surgery during the study NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 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 | 
| Change of LDH | OLEP | Day 1 to Week 52 | 
| Percent change of LDH | OLEP | Day 1 to Week 24 | 
| Percent change of LDH | OLEP | Day 1 to Week 52 | 
| 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 | 
| AUC of LDH over time | OLEP | Day 1 through Week 52 | 
| 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 hemoglobin levels | OLEP | Day 1 to Week 24 | 
| Change in hemoglobin levels | OLEP | Day 1 to Week 52 | 
| Change in fatigue as measured by FACIT-Fatigue scale | 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNH