A Study to Examine the Long-term Safety, Tolerability, and Effectiveness of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

Study Overview
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Brief Summary
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This study is researching an experimental treatment combination with two experimental drugs called pozelimab and cemdisiran. The study is focused on patients with paroxysmal nocturnal hemoglobinuria (PNH). The aim of this study is to see how safe and effective the pozelimab + cemdisiran combination is for patients with PNH in the long term. The pozelimab + cemdisiran combination may be referred to as study drugs in this section. This study is looking at several other research questions, including: How effective is the pozelimab + cemdisiran combination? What side effects may happen from taking the study drugs? How much of each study drug is in your blood at different times? Whether the body makes antibodies against the study drugs (which could make the drugs less effective or could lead to side effects)

Official Title
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An Open-Label Extension Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria

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: Patients Entering from the Parent Study 1. Patients with PNH who have completed, without permanent discontinuation, study treatment in the parent study (R3918-PNH-2021[NCT05133531]), including the post-Open-label treatment period (OLTP) transition period, if applicable. Patients Entering with C5 polymorphism Patients with PNH who have a documented C5 polymorphism rendering them refractory to eculizumab or ravulizumab (eg, p.Arg885His, p.Arg885Cys), as described in the protocol Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes or monocytes Active disease, as defined by the presence of 1 or more PNH-related sign or symptom as described in the protocol LDH level ≥2 × upper limit of normal (ULN) at the screening visit Key Exclusion Criteria: Patients Entering from the Parent Study Significant protocol deviation(s) in the parent study based on the investigator's judgment and to the extent that these would (if continued) impact the study objectives and/or safety of the patient Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment or could interfere with the patient participating in or completing the study Patients Entering with C5 polymorphism Prior treatment with complement inhibitors within 5 half-lives of the respective agent prior to screening, except for prior eculizumab or ravulizumab which are not exclusionary Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant No documentation of meningococcal vaccination within 5 years prior to enrollment Positive hepatitis B surface antigen or hepatitis C virus Ribonucleic acid (RNA) during screening Patients with known HIV with history of opportunistic infections in the last 1 year as described in the protocol Known hereditary complement deficiency Documented history of active, uncontrolled, ongoing systemic autoimmune diseases Documented history of liver cirrhosis or patients with liver disease with evidence of current impaired liver function or patients with elevations in Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) (unrelated to PNH or its complications) as described in the protocol 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PNH Transition Patients<br>Patients with PNH who completed treatment/ protocol requirements (as applicable) in the parent study (R3918-PNH-2021 [NCT05133531]) Note: Dose of pozelimab may be administered intravenously [IV] as needed or as warranted in some circumstances and with sponsor approval for patients who experience breakthrough hemolysis, an increase in lactate dehydrogenase (LDH), a type III hypersensitivity reaction, or reintroduction of study treatment after a period of treatment interruption. | Drug: Pozelimab<br>* Administered subcutaneously (SC) every 4 weeks (Q4W)<br>* Other names: REGN3918;Drug: Cemdisiran<br>* Administered SC Q4W<br>* Other names: ALN-CC5;|
| Experimental: C5 Polymorphism Patients<br>Patients who have not been treated in either parent study but who have a documented complement component 5 (C5) variation rendering them refractory to eculizumab/ravulizumab. Note: Loading dose of pozelimab administered IV on Day 1. | Drug: Pozelimab<br>* Administered subcutaneously (SC) every 4 weeks (Q4W)<br>* Other names: REGN3918;Drug: Cemdisiran<br>* Administered SC Q4W<br>* Other names: ALN-CC5;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent serious adverse events (SAEs) | An SAE is any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires in-patient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect. Is an important medical event | Up to week 108 | 
| Severity of treatment-emergent SAEs |  | Up to week 108 | 
| Incidence of treatment emergent adverse events of special interest (AESIs) | An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it | Up to week 108 | 
| Severity of treatment emergent AESIs |  | Up to week 108 | 
| Incidence of adverse events (AEs) leading to permanent treatment discontinuation | Any untoward medical occurrence in a patient administered a study drug which may or may not have a causal relationship with the study drug. | Up to week 108 | 
| Severity of adverse events (AEs) leading to permanent treatment discontinuation | Any untoward medical occurrence in a patient administered a study drug which may or may not have a causal relationship with the study drug. | Up to week 108 | 
| Percent change from baseline in lactate dehydrogenase (LDH) |  | Baseline to week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) |  | Post-baseline through week 36 | 
| Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) |  | Post-baseline through week 48 | 
| Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) |  | Post-baseline through week 76 | 
| Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) |  | Post-baseline through week 108 | 
| Adequate control of hemolysis (LDH ≤1.5 × ULN) |  | Post-baseline through week 108 | 
| Transfusion avoidance | Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values | Post-baseline through week 36 | 
| Transfusion avoidance | Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values | Post-baseline through week 48 | 
| Transfusion avoidance | Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values | Post-baseline through week 76 | 
| Transfusion avoidance | Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values | Post-baseline through week 108 | 
| Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) |  | Post-baseline through week 36 | 
| Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) |  | Post-baseline through week 48 | 
| Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) |  | Post-baseline through week 76 | 
| Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) |  | Post-baseline through week 108 | 
| Hemoglobin stabilization | Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL | Post-baseline through week 36 | 
| Hemoglobin stabilization | Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL | Post-baseline through week 48 | 
| Hemoglobin stabilization | Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL | Post-baseline through week 76 | 
| Hemoglobin stabilization | Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL | Post-baseline through week 108 | 
| Percent change in LDH |  | From baseline to week 48 | 
| Percent change in LDH |  | From baseline to week 76 | 
| Percent change in LDH |  | From baseline to week 108 | 
| Change in fatigue | Measured by the FACIT-Fatigue scale The FACIT-F 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 5-point 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 fatigue | Measured by the FACIT-Fatigue scale The FACIT-F 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 4-point 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 48 | 
| Change in fatigue | Measured by the FACIT-Fatigue scale The FACIT-F 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 4-point 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 76 | 
| Change in fatigue | Measured by the FACIT-Fatigue scale The FACIT-F 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 4-point 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 weeks 108 | 
| Change in physical function (PF) scores on the EORTC QLQ-C30 | EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 36 | 
| Change in PF scores on the EORTC QLQ-C30 | EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 48 | 
| Change in PF scores on the EORTC QLQ-C30 | EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 76 | 
| Change in PF scores on the EORTC QLQ-C30 | EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 108 | 
| Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 | GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 36 | 
| Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 | GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 48 | 
| Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 | GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 76 | 
| Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 | GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). 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 change. A change of 10 - 20 points is considered a moderate change. | From baseline to week 108 | 
| Normalization of LDH |  | From post-baseline through week 108 | 
| Rate of red blood cell (RBC) transfusion | Per protocol algorithm | Post-baseline through week 36 | 
| Rate of RBC transfusion | Per protocol algorithm | Post-baseline through week 48 | 
| Rate of RBC transfusion | Per protocol algorithm | Post-baseline through week 76 | 
| Rate of RBC transfusion | Per protocol algorithm | Post-baseline through week 108 | 
| Number of units of RBC transfusion | Per protocol algorithm | Post-baseline through week 36 | 
| Number of units of RBC transfusion | Per protocol algorithm | Post-baseline through week 48 | 
| Number of units of RBC transfusion | Per protocol algorithm | Post-baseline through week 76 | 
| Number of units of RBC transfusion | Per protocol algorithm | Post-baseline through week 108 | 
| Percentage of days with LDH ≤1.5x upper limit of normal (ULN) |  | Post-baseline through week 36 | 
| Percentage of days with LDH ≤1.5x ULN |  | Post-baseline through week 48 | 
| Percentage of days with LDH ≤1.5x ULN |  | Post-baseline through week 76 | 
| Percentage of days with LDH ≤1.5x ULN |  | Post-baseline through week 108 | 
| Change in hemoglobin levels |  | From baseline to week 36 | 
| Change in hemoglobin levels |  | From baseline to week 48 | 
| Change in hemoglobin levels |  | From baseline to week 76 | 
| Change in hemoglobin levels |  | From baseline to week 108 | 
| Change in total complement hemolytic activity assay (CH50) |  | Through week 108 | 
| Percent change in CH50 |  | Through week 108 | 
| Concentrations of total pozelimab in serum |  | Through week 108 | 
| Concentrations of cemdisiran in plasma |  | Through week 24 | 
| Incidence of treatment-emergent anti-drug antibodies to pozelimab |  | Through week 108 | 
| Incidence of treatment-emergent anti-drug antibodies to cemdisiran |  | Through week 108 | 
| Concentration of total complement component 5 (C5) in plasma |  | Through week 108 | 
| Percent change of concentration of total C5 in plasma |  | Through week 108 | 

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