A C5 Inhibitor-controlled Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Are Complement Inhibitor Treatment-Naive or Have Not Recently Received Complement Inhibitor Therapy

Study Overview
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Brief Summary
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The study is researching a clinical treatment combination with two experimental drugs called pozelimab and cemdisiran. The study is focused on patients with paroxysmal nocturnal hemoglobinuria (PNH). The aim of the study is to see how safe and effective the pozelimab + cemdisiran combination is for patients with PNH and how the combination compares with 2 existing treatments, one called ravulizumab and the other called eculizumab. The pozelimab + cemdisiran combination may be referred to as study drugs. Ravulizumab and eculizumab may also be called the comparator drug. The study is looking at several research questions, including: How effective is the pozelimab + cemdisiran combination compared to ravulizumab? How effective is pozelimab + cemdisiran combination compared to eculizumab? What side effects may happen from taking the study drugs? How much study drugs are in your blood at different times? Whether the body makes antibodies against the study drugs (which could make the study drugs less effective or could lead to side effects)

Official Title
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A Randomized, Open-Label, C5 Inhibitor-Controlled Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Are Complement Inhibitor Treatment-Naive or Have Not Recently Received Complement Inhibitor Therapy

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes or monocytes as described in the protocol Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms as described in the protocol LDH level ≥2 × ULN at the screening visit Key Exclusion Criteria: Prior treatment with eculizumab within 3 months prior to screening, ravulizumab within 6 months prior to screening, or other complement inhibitors within 5 half-lives of the respective agent prior to screening Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant Body weight <40 kilograms at screening visit Planned use of any complement inhibitor therapy other than study drugs during the treatment period Not meeting meningococcal vaccination requirements for ravulizumab (Cohort A) or eculizumab (Cohort B) 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 Unable to take antibiotics for meningococcal prophylaxis (if required by local ravulizumab [Cohort A] or eculizumab [Cohort B] prescribing information, where available, or national guidelines/local practice or if necessary when vaccination is less than 2 weeks from study treatment initiation) 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 history of active, uncontrolled, ongoing systemic autoimmune diseases 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: Cohort A<br>Randomized 1:1 | Drug: Ravulizumab<br>* Administered Intravenous (IV) per the protocol<br>* Other names: Ultomiris;Drug: Pozelimab<br>* Administered IV and subcutaneous (SC) per the protocol<br>* Other names: REGN3918;Drug: Cemdisiran<br>* Administered SC per the protocol<br>* Other names: ALN-CC5;|
| Experimental: Cohort B<br>Randomized 1:1 | Drug: Pozelimab<br>* Administered IV and subcutaneous (SC) per the protocol<br>* Other names: REGN3918;Drug: Cemdisiran<br>* Administered SC per the protocol<br>* Other names: ALN-CC5;Drug: Eculizumab<br>* Administered IV per the protocol<br>* Other names: Soliris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in lactate dehydrogenase (LDH) | Cohort A | From baseline to week 26 | 
| Transfusion avoidance | Cohort B Not requiring a red blood cell (RBC) transfusion per the protocol | From post-baseline day 1 through week 26 | 
| Maintenance of adequate control of hemolysis | Cohort B LDH ≤1.5 × ULN | From week 8 through week 26, inclusive | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance of adequate control of hemolysis | Cohort A LDH ≤1.5 × ULN | From week 8 through week 26, inclusive | 
| Breakthrough hemolysis | Cohort A and B LDH ≥2 × ULN per the protocol | From post-baseline day 1 through week 26 | 
| Adequate control of hemolysis | Cohort A and B LDH ≤1.5 × ULN | From week 8 through week 26, inclusive | 
| Hemoglobin stabilization | Cohort A and B Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level per the protocol | From day 1 (post-baseline) through week 26 | 
| Normalization of LDH | Cohort A and B LDH ≤1.0 × ULN per the protocol | Between week 8 through week 26, inclusive | 
| Transfusion avoidance | Cohort A Not requiring an RBC transfusion as per protocol algorithm based on post-baseline hemoglobin values. | Day 1 through week 26 | 
| Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale | Cohort A and B FACIT-Fatigue Scale 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 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 26 | 
| Change in physical function (PF) scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) | Cohort A and B 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. | Change from baseline to week 26 | 
| Change in global health status (GHS)/QoL scale score on the EORTC-QLC-C30 | Cohort A and B 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 26 | 
| Percent change in LDH | Cohort B | From baseline to week 26 | 
| Rate of RBC transfused | Cohort A and B Per protocol algorithm | Post-baseline Day 1 through week 26 | 
| Number of units of RBC transfused | Cohort A and B Per protocol algorithm | Post-baseline Day 1 through week 26 | 
| Time to first LDH ≤1.5 × ULN | Cohort A and B | Up to Week 26 | 
| Time to first LDH ≤1.0 × ULN | Cohort A and B | Up to Week 26 | 
| Percentage of days with LDH ≤1.5 × ULN | Cohort A and B | Between week 8 and week 26, inclusive | 
| Change in hemoglobin levels | Cohort A and B | From baseline to week 26 | 
| Incidence and severity of treatment emergent serious adverse events (SAEs) | Cohort A and B | Up to 26 weeks | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest | Cohort A and B | Up to 26 weeks | 
| Incidence and severity of TEAEs leading to treatment discontinuation | Cohort A and B | Up to 26 weeks | 
| Change in total CH50 | Cohort A and B | From baseline to week 26 | 
| Percent change in total CH50 | Cohort A and B | From baseline to week 26 | 
| Concentration of total C5 in plasma | Cohort A and B | Up to 60 weeks | 
| Concentrations of total pozelimab in serum | Cohort A and B | Up to 60 weeks | 
| Concentrations of cemdisiran in plasma | Cohort A and B | Up to 60 weeks | 
| Concentrations of total ravulizumab in serum | Cohort A | Up to 34 weeks | 
| Concentrations of total eculizumab in serum | Cohort B | Up to 30 weeks | 
| Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab | Cohort A and B | Up to 52 weeks | 
| Incidence of treatment emergent ADAs to cemdisiran | Cohort A and B | Up to 52 weeks | 

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