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)
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Intravenous (IV) loading dose (once) followed after 30 minutes by sub-cutaneous (SC) administration
SC administration
Regeneron Study Site
Leeds, United Kingdom
OLTP: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: Up to Day 225
OLTP: Percent Change in Lactate Dehydrogenase (LDH) From Pre-treatment to End-of-treatment Period
Time frame: Screening (Day 1) through Day 225
OLTP: Percent Change in LDH From Pre-treatment Through Day 29
Time frame: Screening (Day 1) through Day 29
OLTP: Percentage of Participants Who Were Transfusion-free From Baseline Through Week 32
Time frame: Baseline through Week 32
OLTP: Percentage of Participants Who Were Transfusion-free From Week 4 Through Week 32
Time frame: Week 4 through Week 32
OLTP: Rate of Red Blood Cell (RBC) Transfusions From Baseline Through Week 32
The rate of units of transfusion for a participant was calculated based on the duration of treatment exposure of the participant.
Time frame: Baseline through Week 32
OLTP: Rate of RBC Transfusions From Week 4 Through Week 32
The rate of units of transfusion for a participant was calculated based on the duration of treatment exposure of the participant.
Time frame: Week 4 through Week 32
OLTP: Number of RBC Units Transfused From Baseline Through Week 32
Time frame: Baseline through Week 32
OLTP: Number of RBC Units Transfused From Week 4 Through Week 32
Time frame: Week 4 through Week 32
OLTP: Percentage of Participants With Breakthrough Hemolysis From Baseline Through Week 32
Breakthrough hemolysis was defined as having an LDH ≥ 2 x upper limit of normal (ULN) and having signs or symptoms.
Time frame: Baseline through Week 32
OLTP: Percentage of Participants With Breakthrough Hemolysis From Week 4 Through Week 32
Breakthrough hemolysis was defined as having an LDH ≥ 2 x ULN and having signs or symptoms.
Time frame: Week 4 through Week 32
OLTP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Day 1 Through Week 32
Adequate control was defined as LDH ≤ 1.5 x ULN from Day 1 through Week 32.
Time frame: Day 1 through Week 32
OLTP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Week 8 Through Week 32
Adequate control was defined as LDH ≤ 1.5 x ULN from Week 8 through Week 32.
Time frame: Week 8 through Week 32
OLTP: Number of Participants With Adequate Control of Hemolysis at Each Visit
Adequate control at a visit was defined as having LDH ≤1.5 x ULN at that visit.
Time frame: Days 1, 8, 15, 29, 43, 57, 71, 85, 113, 141, 169, 197, 225
OLTP: Number of Participants With Normalization of Their LDH at Each Visit
Normalization was defined as LDH ≤ 1.0 x ULN at that visit.
Time frame: Days 1, 8, 15, 29, 43, 57, 71, 85, 113, 141, 169, 197, 225
OLTP: Average LDH From Baseline Through Week 32
The trapezoidal rule was used to calculate area under the curve (AUC). Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.
Time frame: Baseline through Week 32
OLTP: Average LDH From Week 8 Through Week 32
The trapezoidal rule was used to calculate AUC. Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.
Time frame: Week 8 through Week 32
OLTP: Percentage of Participants With Hemoglobin Stabilization From Baseline Through Week 32
Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 grams per deciliter (g/dL).
Time frame: Baseline through Week 32
OLTP: Percentage of Participants With Hemoglobin Stabilization From Week 4 Through Week 32
Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 g/dL.
Time frame: Week 4 through Week 32
OLTP: Change From Baseline in Hemoglobin Levels
Time frame: Baseline, Week 32
OLTP: Change From Baseline in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score
The FACIT-Fatigue is a 13-item, self-reported 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 participants 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). Total scores range from 0 to 52, with higher scores indicating a higher quality of life.
Time frame: Baseline, Week 32
OLTP: Change From Baseline 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
EORTC-QLQ-C30 is a 30-item self-reported questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. The GHS subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.
Time frame: Baseline, Week 32
OLTP: Change From Baseline in Physical Function (PF) Scores on the EORTC QLQ-C30
EORTC-QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a PF scale. PF subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.
Time frame: Baseline, Week 32
OLTP: Change From Baseline in Total Complement Hemolytic Activity Assay (CH50)
This assay assessed the activity of the classical pathway of complement to measure C5 activity.
Time frame: Baseline through Week 32
OLTP and OLEP: Concentration of Total Pozelimab in Serum
Time frame: Pre-dose Days 28, 56, 84, 112, 140, 168, 196, 224, 392, 588; Post-dose Day 28
OLTP: Concentration of Total Eculizumab in Serum
Time frame: Pre-dose Days 0, 14, 28, 56, 84, 112, 140, 168, 196, 224
OLTP and OLEP: Concentration of Total Cemdisiran in Plasma
Time frame: Pre-dose and Post-dose Days 0, 84, 196, 224, 588
OLTP and OLEP: Concentration of Total C5 in Plasma
Time frame: Pre-dose Days 0, 7, 14, 28, 56, 84, 112, 140, 168, 196, 224, 392, 588
OLTP: Number of Participants With Pozelimab Anti-drug Antibodies (ADA)
Time frame: Baseline through Week 32
OLTP: Number of Participants With Cemdisiran ADA
Time frame: Baseline through Week 32
OLTP: Number of Participants Who Received Dose Intensification With TEAEs
Time frame: Baseline through Week 32
OLEP: Number of Participants With TEAEs
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Percent Change in LDH From Day 1 Through Week 24 of the OLEP
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Percent Change in LDH From Day 1 Through Week 52 of the OLEP
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants Who Were Transfusion-free From Day 1 Through Week 24 of the OLEP
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants Who Were Transfusion-free From Day 1 Through Week 52 of the OLEP
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Rate of RBC Transfusions From Day 1 Through Week 24 of the OLEP
The rate of units of transfusion for a participants was calculated based on the duration of treatment exposure of the participant.
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Rate of RBC Transfusions From Day 1 Through Week 52 of the OLEP
The rate of units of transfusion for a participants was calculated based on the duration of treatment exposure of the participant.
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Number of RBC Units Transfused From Day 1 Through Week 24 of the OLEP
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Number of RBC Units Transfused From Day 1 Through Week 52 of the OLEP
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants With Breakthrough Hemolysis From Day 1 Through Week 24 of the OLEP
Breakthrough hemolysis was defined as having an LDH ≥ 2 x ULN and having signs or symptoms.
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants With Breakthrough Hemolysis From Day 1 Through Week 52 of the OLEP
Breakthrough hemolysis was defined as having an LDH ≥ 2 x ULN and having signs or symptoms.
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Day 1 Through Week 24 of the OLEP
Adequate control was defined as LDH ≤ 1.5 x ULN.
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants Who Maintained Adequate Control of Hemolysis From Day 1 Through Week 52 of the OLEP
Adequate control was defined as LDH ≤ 1.5 x ULN.
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Number of Participants Who Maintained Adequate Control of Hemolysis at Each Visit in OLEP
Adequate control was defined as LDH ≤ 1.5 x ULN at that visit.
Time frame: Baseline, Days 57, 113, 169, 225, 281, 365 of the OLEP
OLEP: Number of Participants With Normalization of Their LDH at Each Visit in OLEP
Normalization was defined as LDH ≤ 1.0 x ULN at that visit.
Time frame: Baseline, Days 57, 113, 169, 225, 281, 365 of the OLEP
OLEP: Average LDH From Day 1 Through Week 24 of the OLEP
The trapezoidal rule was used to calculate AUC. Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Average LDH From Day 1 Through Week 52 of the OLEP
The trapezoidal rule was used to calculate AUC. Individual mean LDH is defined as AUC divided by (last assessment date of LDH - first assessment date of LDH) of specific period.
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Percentage of Participants With Hemoglobin Stabilization From Day 1 Through Week 24 of the OLEP
Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 g/dL.
Time frame: Day 1 through Week 24 of the OLEP
OLEP: Percentage of Participants With Hemoglobin Stabilization From Day 1 Through Week 52 of the OLEP
Hemoglobin stabilization was defined as not receiving an RBC transfusion and having no decrease in hemoglobin level of ≥ 2 g/dL.
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Change From Baseline in Hemoglobin Levels
Time frame: Day 1 and Week 24 of the OLEP
OLEP: Change From Baseline in Hemoglobin Levels
Time frame: Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in FACIT-Fatigue Score
The FACIT-Fatigue is a 13-item, self-reported 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). Total scores range from 0 to 52, with higher scores indicating a higher quality of life.
Time frame: Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in HRQoL as Measured by the Global Health Status Subscale of the EORTC-QLQ-30 Scale
EORTC-QLQ-C30 is a 30-item self-reported questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. GHS subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.
Time frame: Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in PF Scores on the EORTC QLQ-C30
EORTC-QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a PF scale. PF subscale scores ranged from 0 to 100 with higher scores indicating better quality of life.
Time frame: Day 1 and Week 52 of the OLEP
OLEP: Change From Baseline in CH50
This assay assessed the activity of the classical pathway of complement to measure C5 activity.
Time frame: Baseline, Week 16, Week 32, Week 52 of the OLEP
OLEP: Number of Participants With Pozelimab ADA
Time frame: Day 1 through Week 52 of the OLEP
OLEP: Number of Participants With Cemdisiran ADA
Time frame: Day 1 through Week 52 of the OLEP
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