Efficacy and Safety of the Combination of Pozelimab and Cemdisiran Versus Continued Eculizumab or Ravulizumab Treatment in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

Study Overview
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Brief Summary
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The primary objective of the study is: To evaluate the effect of pozelimab and cemdisiran combination therapy on hemolysis, as assessed by lactate dehydrogenase (LDH), after 36 weeks of treatment, in patients with PNH who switch from eculizumab or ravulizumab therapy versus patients who continue their eculizumab or ravulizumab therapy The secondary objectives of the study are to: Evaluate the effect of pozelimab and cemdisiran combination treatment versus anti-C5 standard-of-care treatment (eculizumab or ravulizumab) on the following: Transfusion requirements and transfusion parameters Measures of hemolysis: LDH control, breakthrough hemolysis, and inhibition of CH50 Hemoglobin levels Fatigue as assessed by Clinical Outcome Assessments (COAs) Health-related quality of life (HRQoL) as assessed by COAs Safety and tolerability To assess the concentrations of total pozelimab and either total eculizumab or total ravulizumab in serum and total cemdisiran and total C5 protein in plasma To assess the immunogenicity of pozelimab and cemdisiran

Official Title
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A Randomized, Open-Label, Eculizumab and Ravulizumab Controlled Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Are Currently Treated With Eculizumab or Ravulizumab

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: Cemdisiran
* Drug: Eculizumab
* Drug: Pozelimab
* Drug: Ravulizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of PNH confirmed by a history of high-sensitivity flow cytometry from prior testing Treated with eculizumab or ravulizumab prior to screening visit as described in the protocol Note: Biosimilars are not permitted, unless approved by the Sponsor Key Exclusion Criteria: Patients with a screening LDH >1.5 × ULN who have not taken their C5 inhibitor within the labeled dose interval at the dose prior to the screening LDH assessment Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant Body weight < 40 kilograms at screening visit Any use of complement inhibitor therapy other than eculizumab or ravulizumab in the 26 weeks prior to the screening visit or planned use during the study with the exception of study treatments Not meeting meningococcal vaccination requirements for eculizumab or ravulizumab according to the current local prescribing information (where available) and at a minimum documentation of meningococcal vaccination within 5 years prior to screening visit. Any contraindication for receiving Neisseria meningitidis vaccination. Positive for hepatitis B, and/ or hepatitis C as described in the protocol History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer Participation in another interventional clinical study (except R3918-PNH-2021) or use of any experimental therapy within 30 days before screening visit or within 5 half-lives of that investigational product, whichever is greater, with the exception of eculizumab or ravulizumab. Patients with functional or anatomic asplenia 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pozelimab and Cemdisiran<br>Randomized 1:1 | Drug: Cemdisiran<br>* Administered per protocol<br>* Other names: ALN-CC5;Drug: Eculizumab<br>* Administered per protocol<br>* Other names: Soliris;Drug: Pozelimab<br>* Administered per protocol<br>* Other names: REGN3918;Drug: Ravulizumab<br>* Administered per protocol<br>* Other names: Ultomiris;|
| Experimental: Anti-C5 standard-of-care<br>Randomized 1:1 | Drug: Eculizumab<br>* Administered per protocol<br>* Other names: Soliris;Drug: Ravulizumab<br>* Administered per protocol<br>* Other names: Ultomiris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in lactate dehydrogenase (LDH) |  | From baseline to week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with transfusion avoidance | Patients who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values | Day 1 through week 36 | 
| Proportion of patients with transfusion avoidance | Patients who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values | Week 4 through week 36 | 
| Proportion of patients with breakthrough hemolysis | Patients with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol | Day 1 through week 36 | 
| Proportion of patients with breakthrough hemolysis | Patients with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol | Week 4 (day 29) through week 36 | 
| Proportion of patients with hemoglobin stabilization | Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol | Day 1 through week 36 | 
| Proportion of patients with hemoglobin stabilization | Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol | Week 4 (day 29) through week 36 | 
| Proportion of patients with adequate control of LDH | Proportion of patients with adequate control of LDH as defined in the protocol | Day 1 through week 36 | 
| Proportion of patients with adequate control of LDH | Proportion of patients with adequate control of LDH as defined in the protocol | Week 8 (day 57) through week 36 | 
| Proportion of patients with normalization of LDH | Proportion of patients with normalization of LDH as defined in the protocol | Day 1 through week 36 | 
| Proportion of patients with normalization of LDH | Proportion of patients with normalization of LDH as defined in the protocol | Week 8 (day 57) through week 36 | 
| Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale | The FACIT-Fatigue is a 13 item, self-administered clinical outcome assessment (COA) 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). Scores range from 0 to 52, with higher scores indicating greater fatigue. | From baseline to week 36 | 
| Change in Physical Function (PF) score on the European organization for research and treatment of cancer quality-of-Life questionnaire Core 30 Items (EORTC-QLQ-C30) | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as not at all and 4 as very much. | From baseline to week 36 | 
| Change in global health status (GHS)/QoL scale score on the EORTC-QLQ-C30 | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 7 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, sleep and financial difficulties). Participants rate items on a 4-point scale, with 1 as not at all and 4 as very much. | From baseline to week 36 | 
| Rate of RBCs transfused per protocol algorithm | Per protocol algorithm | Day 1 through week 36 | 
| Rate of RBCs transfused per protocol algorithm | Per protocol algorithm | Week 4 through week 36 | 
| Number of units of RBCs transfused per protocol algorithm | Per protocol algorithm | Day 1 through week 36 | 
| Number of units of RBCs transfused per protocol algorithm | Per protocol algorithm | Week 4 through week 36 | 
| Change in hemoglobin levels | Per protocol algorithm | From baseline to week 36 | 
| Incidence and severity of treatment emergent serious adverse events (SAEs) | Treatment period and safety follow up period | Up to 88 weeks | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest | Treatment period and safety follow up period | Up to 88 weeks | 
| Incidence and severity TEAEs leading to treatment discontinuation | Treatment period and safety follow up period | Up to 88 weeks | 
| Change in total CH50 |  | From baseline to week 36 | 
| Percent change in total CH50 |  | From baseline to week 36 | 
| Concentration of total C5 in plasma | Treatment period and safety follow up period | Through week 62 | 
| Concentrations of total pozelimab in serum | Treatment period and safety follow up period | Through week 62 | 
| Concentrations of total cemdisiran in plasma | Treatment period | Through week 32 | 
| Concentrations of total eculizumab in serum | Treatment period | Through week 40 | 
| Concentrations of total ravulizumab in plasma | Treatment period | Through week 44 | 
| Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab | Treatment period and safety follow up period | Through week 62 | 
| Incidence of treatment emergent ADAs to cemdisiran | Treatment period and safety follow up period | Through week 62 | 

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