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A prospective phase 2 clinical trial of a C5a complement inhibitor for acute GVHD with lower GI tract involvement

Bone Marrow Transplantation volume 58, pages 991–999 (2023)Cite this article

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Abstract

Involvement of lower gastrointestinal tract (LGI) occurs in 60% of patients with graft-versus-host-disease (GVHD). Complement components C3 and C5 are involved in GVHD pathogenesis. In this phase 2a study, we evaluated the safety and efficacy of ALXN1007, a monoclonal antibody against C5a, in patients with newly diagnosed LGI acute GVHD receiving concomitant corticosteroid. Twenty-five patients were enrolled; one was excluded from the efficacy analysis based upon negative biopsy. Most patients (16/25, 64%) had acute leukemia; 52% (13/25) had an HLA-matched unrelated donor; and 68% (17/25) received myeloablative conditioning. Half the patients (12/24) had a high biomarker profile, Ann Arbor score 3; 42% (10/24) had high-risk GVHD per Minnesota classification. Day-28 overall response was 58% (13/24 complete response, 1/24 partial response), and 63% by Day-56 (all complete responses). Day-28 overall response was 50% (5/10) in Minnesota high-risk and 42% (5/12) in high-risk Ann Arbor patients, increasing to 58% (7/12) by Day-56. Non-relapse mortality at 6-months was 24% (95% CI 11–53). The most common treatment-related adverse event was infection (6/25, 24%). Neither baseline complement levels (except for C5), activity, nor inhibition of C5a with ALXN1007 correlated with GVHD severity or responses. Further studies are needed to evaluate the role of complement inhibition in GVHD treatment.

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Fig. 1: Eligibility, randomization, and follow-up.
Fig. 2: Baseline levels of C5 and C5a stratified by response at Day 28.
Fig. 3

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Alexion will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods like data de-identification, pseudonymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at https://alexionclinicaltrials.com/Disclosure-and-Transparency-Policy. Link to Data Request Form (https://alexion.com/contact-alexion/medical-information).

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Acknowledgements

The authors would like to thank the investigators from the study sites: Zaid Al-Kadhimi (Emory University Hospital, Atlanta, GA, USA), George Liwei Chen (Roswell Park Cancer Institute, Buffalo, NY, USA), Iskra Pusic (Washington University School of Medicine, St. Louis MO, USA), Michele Donato (John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA), and Stéphane Vigouroux (Centre F. Magendie, Hospital Haut-Leveque, France). The authors thank John Levine, James Ferrara, (Icahn School of Medicine at Mount Sinai, New York, NY), and Susan Abraham (University of Texas MD Anderson Cancer Center, Houston, TX) for contributions to the biomarker analyses. The authors also thank from Alexion Pharmaceuticals: Richard Riese, Susan Faas, and Mittie Doyle for contributions to study design, Kaushik Patra and Fanny O’Brien for extensive review of the data, and Rima Saliba for providing statistical guidance. This study was supported by research funding from Alexion Pharmaceuticals Inc. Medical writing support was provided by Bioscript Group, Macclesfield, UK, funded by Alexion Pharmaceuticals Inc.

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Authors and Affiliations

  1. Clinical Research Division Fred Hutch, University of Washington School of Medicine, Seattle, Washington, USA

    Rohtesh S. Mehta

  2. City of Hope, Duarte, CA, USA

    Haris Ali

  3. Alexion, AstraZeneca Rare Disease, New Haven, CT, USA

    Yang Dai, Bert Yao, Kevin Anderson & Arshad Mujeebuddin

  4. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bethany Overman, Richard Champlin, Elizabeth Shpall & Amin Alousi

  5. Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Voravit Ratanatharathorn

  6. Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Saar Gill

  7. University Paris VII Head of Hematology Transplantation APHP Hospital Saint Louis, Paris, France

    Gerard Socié

  8. Université Grenoble Alpes, Grenoble, France

    Jean Yves Cahn

  9. University of Minnesota, Minneapolis, MN, USA

    Shernan G. Holtan

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Contributions

RSM, interpreted the data and wrote the manuscript. BO, helped manage clinical trial as research nurse and reviewed manuscript critically for important intellectual content. AM, KA, YD, BY helped design the study, interpret the data, and reviewed the manuscript. AA, helped design the study, interpreted the data and wrote the manuscript. JYC, ES, SH, HA, RC helped enroll patients, interpret the data, and review the manuscript. VR, SG, GS helped design the study, enrolled patients, interpreted data, and reviewed the manuscript. All authors contributed to the manuscript content, approved the final version of the manuscript and agreed to be accountable for questions related to the accuracy and integrity of the work.

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Correspondence to Amin Alousi.

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Competing interests

RSM received research funding from CSLBehring, Kadmon and Incyte. HA has received consulting fees from Incyte and BMS. YD, and AM are employees and stockholders of Alexion Pharmaceuticals Inc (now Alexion, Astrazeneca Rare Disease). BY and KA were employees and stockholders of Alexion Pharmaceuticals Inc during the development phase of this manuscript. GS received a research grant from Alexion Pharamceuticals. SH has received consulting fees/honoraria from Incyte, Generon and served participated in a Data Safety Monitoring Board/Advisory Board for CSl Behring. JYC declares receiving honoraria for participating in an Advisory Board for Alexion Pharmaceuticals. BO, VR, SG, RC, and ES declare no competing interests. AA has received research support, and honoraria for participating in an Advisory Board for Alexion Pharmaceuticals.

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Mehta, R.S., Ali, H., Dai, Y. et al. A prospective phase 2 clinical trial of a C5a complement inhibitor for acute GVHD with lower GI tract involvement. Bone Marrow Transplant 58, 991–999 (2023). https://doi.org/10.1038/s41409-023-01996-4

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