Efficacy and Safety of the Combination of Pozelimab and Cemdisiran Versus Continued Eculizumab or Ravulizumab Treatment in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (ACCESS 2)

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

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

Study Overview

• Status: Terminated
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Drug: Cemdisiran; Drug: Eculizumab; Drug: Pozelimab; Drug: Ravulizumab

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Whittier, California, United States, 90603
      • Regeneron Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

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

1. 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
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
3. Body weight < 40 kilograms at screening visit
4. 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
5. 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.
6. Any contraindication for receiving Neisseria meningitidis vaccination.
7. Positive for hepatitis B, and/ or hepatitis C as described in the protocol
8. 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
9. 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.
10. Patients with functional or anatomic asplenia

Note: Other protocol-defined Inclusion/ Exclusion Criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pozelimab and Cemdisiran; Randomized 1:1	Drug: Cemdisiran; Administered per protocol; Other Names: ALN-CC5; Drug: Eculizumab; Administered per protocol; Other Names: Soliris; Drug: Pozelimab; Administered per protocol; Other Names: REGN3918; Drug: Ravulizumab; Administered per protocol; Other Names: Ultomiris; ALXN1210
Experimental: Anti-C5 standard-of-care; Randomized 1:1	Drug: Eculizumab; Administered per protocol; Other Names: Soliris; Drug: Ravulizumab; Administered per protocol; Other Names: Ultomiris; ALXN1210

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2022
• Primary Completion (Actual): July 12, 2023
• Study Completion (Actual): July 12, 2023

Study Registration Dates

• First Submitted: November 12, 2021
• First Submitted That Met QC Criteria: November 12, 2021
• First Posted (Actual): November 23, 2021

Study Record Updates

• Last Update Posted (Actual): August 16, 2023
• Last Update Submitted That Met QC Criteria: August 14, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: PNH
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab; Ravulizumab
• Other Study ID Numbers: R3918-PNH-2022; 2020-002761-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• IPD Sharing Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No