Clinical trial NCT04888507: Pozelimab and Cemdisiran Combination Therapy in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2021-05-17
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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)


Eligibility criteria: Key Inclusion Criteria:

1. Diagnosis of paroxysmal nocturnal hemoglobinuria confirmed by a history of high-sensitivity flow cytometry from prior testing
2. 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:

1. History of bone marrow transplantation or receipt of an organ transplant
2. Body weight \<40 kg at screening
3. 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
4. Any use of complement inhibitor therapy other than eculizumab in the 12 weeks prior to the screening visit or planned use during the study
5. Known hypocellular bone marrow based on a history of reduced age-adjusted bone marrow cellularity and/or bone marrow cellularity ≤25%
6. 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
7. Unable to take antibiotics for meningococcal prophylaxis, if required by local standard of care
8. 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
9. 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
10. Documented history of active, uncontrolled, ongoing systemic autoimmune diseases
11. Recent, unstable medical conditions, excluding PNH and PNH-related complications, within the past 3 months prior to screening visit as described in the protocol
12. Anticipated need for major surgery during the study

NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply.

Primary outcomes:
measure: Incidence and severity of treatment emergent adverse events (TEAEs)
timeFrame: Through day 225
Secondary outcomes:
measure: Percent change in LDH from pre-treatment to end-of-treatment period
timeFrame: Screening through Day 225
measure: Percent change in LDH from pre-treatment
timeFrame: Screening through Day 29
measure: Proportion of participants who are transfusion-free
timeFrame: Baseline through Day 225
measure: Proportion of participants who are transfusion-free
timeFrame: Day 29 through Day 225
measure: Rate of RBCs transfused
timeFrame: Baseline through Day 225
measure: Rate of RBCs transfused
timeFrame: Day 29 through Day 225
measure: Number of units of RBCs transfused
timeFrame: Baseline through Day 225
measure: Number of units of RBCs transfused
timeFrame: Day 29 through Day 225
measure: Proportion of participants with breakthrough hemolysis
timeFrame: Baseline through Day 225
measure: Proportion of participants with breakthrough hemolysis
timeFrame: Day 29 through Day 225
measure: Proportion of participants who maintain adequate control of hemolysis
timeFrame: Post Baseline (on Day 1) through Day 225
measure: Proportion of participants who maintain adequate control of hemolysis
timeFrame: Day 57 through Day 225
measure: Proportion of participants with adequate control of hemolysis at each visit
timeFrame: Post Baseline (on Day 1) through Day 225
measure: Proportion of participants with normalization of their LDH at each visit
timeFrame: Post Baseline (on Day 1) through Day 225
measure: Area under the curve (AUC) of LDH over time
timeFrame: Baseline through Day 225
measure: AUC of LDH over time
timeFrame: Day 57 through Day 225
measure: Proportion of participants with hemoglobin stabilization
timeFrame: Baseline through Day 225
measure: Proportion of participants with hemoglobin stabilization
timeFrame: Day 29 through Day 225
measure: Change in hemoglobin levels
timeFrame: Baseline to Day 225
measure: Change in fatigue as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale
timeFrame: Baseline to Day 225
measure: 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
timeFrame: Baseline to Day 225
measure: Change in physical function (PF) scores on the EORTC QLQ-C30
timeFrame: Baseline to Day 225
measure: Change in total CH50
timeFrame: Baseline to Day 225
measure: Concentrations of total pozelimab and eculizumab in serum
timeFrame: Up to Day 225
measure: Concentrations of total cemdisiran in plasma
timeFrame: Up to Day 225
measure: Change from baseline in concentration of total C5
timeFrame: Up to Day 225
measure: Incidence of pozelimab anti-drug antibody (ADA) responses over time
timeFrame: Up to Day 225
measure: Incidence of cemdisiran anti-drug antibody (ADA) responses over time
timeFrame: Up to Day 225
measure: Incidence and severity of TEAEs for participants who receive dose intensification
timeFrame: Through Day 225
measure: Incidence and severity of TEAEs in participants treated with pozelimab and cemdisiran combination therapy
timeFrame: Through Week 52
measure: Change of LDH
timeFrame: Day 1 to Week 24
measure: Change of LDH
timeFrame: Day 1 to Week 52
measure: Percent change of LDH
timeFrame: Day 1 to Week 24
measure: Percent change of LDH
timeFrame: Day 1 to Week 52
measure: Proportion of participants who are transfusion-free
timeFrame: Day 1 through Week 24
measure: Proportion of participants who are transfusion-free
timeFrame: Day 1 through Week 52
measure: Rate of RBCs transfused
timeFrame: Day 1 through Week 24
measure: Rate of RBCs transfused
timeFrame: Day 1 through Week 52
measure: Number of units of RBCs transfused
timeFrame: Day 1 through Week 24
measure: Number of units of RBCs transfused
timeFrame: Day 1 through Week 52
measure: Proportion of participants with breakthrough hemolysis
timeFrame: Day 1 through Week 24
measure: Proportion of participants with breakthrough hemolysis
timeFrame: Day 1 through Week 52
measure: Proportion of participants who maintain adequate control of their hemolysis
timeFrame: Day 1 through Week 24
measure: Proportion of participants who maintain adequate control of their hemolysis
timeFrame: Day 1 through Week 52
measure: Proportion of participants with adequate control of hemolysis at each visit
timeFrame: Day 1 through Week 24
measure: Proportion of participants with adequate control of hemolysis at each visit
timeFrame: Day 1 through Week 52
measure: Proportion of participants with normalization of LDH at each visit
timeFrame: Day 1 through Week 24
measure: Proportion of participants with normalization of LDH at each visit
timeFrame: Day 1 through Week 52
measure: AUC of LDH over time
timeFrame: Day 1 through Week 24
measure: AUC of LDH over time
timeFrame: Day 1 through Week 52
measure: Proportion of participants with hemoglobin stabilization
timeFrame: Day 1 through Week 24
measure: Proportion of participants with hemoglobin stabilization
timeFrame: Day 1 through Week 52
measure: Change in hemoglobin levels
timeFrame: Day 1 to Week 24
measure: Change in hemoglobin levels
timeFrame: Day 1 to Week 52
measure: Change in fatigue as measured by FACIT-Fatigue scale
timeFrame: Day 1 to Week 52
measure: Change in GHS/QoL on the EORTC QLQ-C30
timeFrame: Day 1 to Week 52
measure: Change in PF scores on the EORTC QLQ-C30
timeFrame: Day 1 to Week 52
measure: Change in CH50
timeFrame: Day 1 to Week 16
measure: Change in CH50
timeFrame: Day 1 to Week 24
measure: Change in CH50
timeFrame: Day 1 to Week 52
measure: Concentrations of total pozelimab in serum
timeFrame: Up to Week 52
measure: Concentrations of total C5
timeFrame: Up to Week 52
measure: Concentrations of cemdisiran in plasma
timeFrame: Up to Week 52
measure: Incidence of pozelimab anti-drug antibody (ADA) responses over time
timeFrame: Up to Week 52
measure: Incidence of cemdisiran anti-drug antibody (ADA) responses over time
timeFrame: Up to Week 52
Other outcomes:
Locations:
city: Leeds
country: United Kingdom
facility: Regeneron Study Site
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: