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A Phase 2/3 Study Evaluating the Efficacy and Safety of Pozelimab in Patients with CD55 Deficiency with Hyperactivation of Complement, Angiopathic Thrombosis, and Protein-Losing Enteropathy (CHAPLE Disease)

45 Pages Posted: 27 Jul 2023

See all articles by Ahmet Ozen

Ahmet Ozen

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Voranush Chongsrisawat

Chulalongkorn University - Department of Pediatrics

Asena Pinar Sefer

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Burcu Kolukisa

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Jessica J. Jalbert

Regeneron Pharmaceuticals Inc

Jutta L. Miller

Regeneron Pharmaceuticals Inc

Karoline A. Meagher

Regeneron Pharmaceuticals Inc

Taylor Brackin

Regeneron Pharmaceuticals Inc

Hagit Baris Feldman

Tel Aviv Sourasky Medical Centre - Genetic Institute

Orly Eshach Adiv

Hillel Yaffe Medical Center - Pediatric Gastroenterology and Nutrition Unit

Safa Baris

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Elif Karakoc-Aydiner

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Sevgi Bilgic Eltan

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Melek Yorgun Altunbaş

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases

Rabia Ergelen

Marmara University - Department of Radiology

Ivan J. Fuss

Government of the United States of America - Mucosal Immunity Section

Heather Moorman

Government of the United States of America - Molecular Development of the Immune System Section

Mary Magliocco

Government of the United States of America - Molecular Development of the Immune System Section

Helen Matthews

Government of the United States of America - Molecular Development of the Immune System Section

Beatriz E. Marciano

Government of the United States of America - Molecular Development of the Immune System Section

Narissara Suratannon

Chulalongkorn University - Center of Excellence in Clinical Virology

Pantipa Chatchatee

Chulalongkorn University - Center of Excellence for Allergy and Clinical Immunology

Kanya Suphapeetiporn

Chulalongkorn University - Center of Excellence for Medical Genomics

Caryn F. Trbovic

Regeneron Pharmaceuticals Inc

Michael E. Burczynski

Regeneron Pharmaceuticals Inc

Umesh Chaudhari

Regeneron Pharmaceuticals Inc

Lorah Perlee

Regeneron Pharmaceuticals Inc

Olivier A. Harari

Regeneron Pharmaceuticals Inc

George D. Yancopoulos

Regeneron Pharmaceuticals Inc

Michael J. Lenardo

Government of the United States of America - Molecular Development of the Immune System Section

The Pozelimab CHAPLE Working Group

Independent

More...

Abstract

Background: CHAPLE is an ultra-rare genetic disorder characterized by intestinal lymphatic damage and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an investigational antibody blocking complement component 5 (C5).

Methods: This open-label, single-arm, historically-controlled study evaluated ten patients with CHAPLE disease (ClinicalTrials.gov, NCT04209634) treated weekly with subcutaneous pozelimab (following loading). The primary endpoint was proportion of patients achieving serum albumin normalization with improvement or no worsening in clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial edema severity, and peripheral edema severity) at week 24. Secondary/exploratory efficacy endpoints and safety are also reported.

Findings: All patients (100%) experienced serum albumin normalization and improvement/no worsening in clinical outcomes. Complete inhibition of complement activity (CH50) was achieved. Seven patients (70%) experienced adverse events; none were severe, and only one experienced adverse events considered related to pozelimab.

Interpretation: Pozelimab inhibits complement overactivation and resolves the clinical and pathophysiological manifestations of CHAPLE disease.

Trial Registration: ClinicalTrials.gov, NCT04209634.

Funding: Regeneron Pharmaceuticals, Inc. and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Declaration of Interest: AO is a consultant and steering committee member for Regeneron, Pharmaceuticals, Inc.; received sample analysis support for a prior collaborative study (https://doi.org/10.1038/s41590- 020-00830-z) from Regeneron, Pharmaceuticals, Inc.; and has a pending patent on C5 inhibitor treatment in CHAPLE disease. VC, NS, PC, and KS received support to conduct the study and provision of the investigational product from Regeneron Pharmaceuticals, Inc. APS, BK, SB, EK-A, MYA., RE, H Moorman, MM, H Matthews, and BEM have nothing to disclose. JJJ, JLM, TB, CFT, MEB, UC, and LP are Regeneron Pharmaceuticals, Inc. employees/stockholders. KAM is a Regeneron Pharmaceuticals, Inc. employee/stockholder and has both pending and issued patents with Regeneron Pharmaceuticals, Inc. HBF and OEA are consultants and advisory board members for Regeneron, Pharmaceuticals, Inc. IJF is an associate on a cooperative research and development agreement (CRADA) between Merck Pharmaceuticals and the NIH. OAH and GDY are Regeneron Pharmaceuticals, Inc. employees/stockholders and have a pending patent on C5 inhibitor treatment in CHAPLE disease. MJL received support for a federally-approved CRADA to support the clinical trial and has a pending patent on C5 inhibitor treatment in CHAPLE disease.

Ethical Approval: The study protocol was approved by the local institutional review boards and/or ethics committees prior to study initiation. All patients or legally-authorized representatives provided written informed consent prior to study enrollment. This study was conducted in accordance with the principles of the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, and was consistent with Good Clinical Practices of the International Conference on Harmonisation and applicable regulatory requirements. Monitoring and site supervision were performed with oversight by the sponsor.

Keywords: Complement inhibitor deficiency, CD55 deficiency, decay accelerating factor, protein-losing enteropathy, primary intestinal lymphangiectasia, historical-controlled trial, ultra-orphan disease, anti-C5 monoclonal antibody

Suggested Citation

Ozen, Ahmet and Chongsrisawat, Voranush and Sefer, Asena Pinar and Kolukisa, Burcu and Jalbert, Jessica J. and Miller, Jutta L. and Meagher, Karoline A. and Brackin, Taylor and Feldman, Hagit Baris and Adiv, Orly Eshach and Baris, Safa and Karakoc-Aydiner, Elif and Eltan, Sevgi Bilgic and Altunbaş, Melek Yorgun and Ergelen, Rabia and Fuss, Ivan J. and Moorman, Heather and Magliocco, Mary and Matthews, Helen and Marciano, Beatriz E. and Suratannon, Narissara and Chatchatee, Pantipa and Suphapeetiporn, Kanya and Trbovic, Caryn F. and Burczynski, Michael E. and Chaudhari, Umesh and Perlee, Lorah and Harari, Olivier A. and Yancopoulos, George D. and Lenardo, Michael J. and Group, The Pozelimab CHAPLE Working, A Phase 2/3 Study Evaluating the Efficacy and Safety of Pozelimab in Patients with CD55 Deficiency with Hyperactivation of Complement, Angiopathic Thrombosis, and Protein-Losing Enteropathy (CHAPLE Disease). Available at SSRN: https://ssrn.com/abstract=4485593 or http://dx.doi.org/10.2139/ssrn.4485593

Ahmet Ozen

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Voranush Chongsrisawat

Chulalongkorn University - Department of Pediatrics ( email )

Asena Pinar Sefer

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Burcu Kolukisa

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Jessica J. Jalbert

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Jutta L. Miller

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Karoline A. Meagher

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Taylor Brackin

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Hagit Baris Feldman

Tel Aviv Sourasky Medical Centre - Genetic Institute ( email )

Orly Eshach Adiv

Hillel Yaffe Medical Center - Pediatric Gastroenterology and Nutrition Unit ( email )

Safa Baris

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Elif Karakoc-Aydiner

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Sevgi Bilgic Eltan

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Melek Yorgun Altunbaş

Marmara University - Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases ( email )

Rabia Ergelen

Marmara University - Department of Radiology ( email )

Ivan J. Fuss

Government of the United States of America - Mucosal Immunity Section ( email )

Heather Moorman

Government of the United States of America - Molecular Development of the Immune System Section ( email )

Mary Magliocco

Government of the United States of America - Molecular Development of the Immune System Section ( email )

Helen Matthews

Government of the United States of America - Molecular Development of the Immune System Section ( email )

Beatriz E. Marciano

Government of the United States of America - Molecular Development of the Immune System Section ( email )

Narissara Suratannon

Chulalongkorn University - Center of Excellence in Clinical Virology ( email )

Pantipa Chatchatee

Chulalongkorn University - Center of Excellence for Allergy and Clinical Immunology ( email )

Kanya Suphapeetiporn

Chulalongkorn University - Center of Excellence for Medical Genomics ( email )

Caryn F. Trbovic

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Michael E. Burczynski

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Umesh Chaudhari

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Lorah Perlee

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Olivier A. Harari (Contact Author)

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

George D. Yancopoulos

Regeneron Pharmaceuticals Inc ( email )

Tarrytown
United States

Michael J. Lenardo

Government of the United States of America - Molecular Development of the Immune System Section ( email )

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