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FDA approves axatilimab for the treatment of chronic graft-versus-host disease

On August 14, 2024, the U.S. Food and Drug Administration (FDA) approved axatilimab as a treatment for chronic graft-versus-host disease (cGvHD) in adult and pediatric patients weighing at least 40kg who have failed on two or more prior lines of systemic therapy.1 

cGvHD is a serious and potentially life-threatening complication of allogeneic stem cell transplantation (alloSCT) which occurs when donor-derived hematopoietic cells mount an immune response against recipient tissues.2 This can lead to multi-organ damage, immunosuppression-related systemic toxicities, and fibrotic manifestations, making cGvHD a major cause of late morbidity in patients undergoing alloSCT.3 Traditionally, immunosuppressive agents combined with corticosteroids were used for its management, however, this therapeutic approach is associated with significant toxicity and risk of death resulting from infectious disease.2 Despite the recent approvals of several novel agents (ibrutinib, belumosudil, and ruxolitinib), therapy failure remains high, underscoring the need for alternative therapeutic options for patients.4

Axatilimab is a monoclonal antibody targeting the colony-stimulating factor-1 receptor (CSF-1R). This agent works by modulating the activity of macrophages, which play a critical role in the pathogenesis of cGvHD.4 By inhibiting CSF-1R, axatilimab reduces inflammation and fibrosis, which are key drivers of the disease.

The approval of axatilimab is supported by data from the Phase I/II AGAVE-201 trial (NCT04710576),5 evaluating the safety and efficacy of the drug in adult and pediatric patients with recurrent or refractory cGvHD who have received at least two prior lines of therapy. In this open-label, randomized study, patients were assigned to one of three study arms, with each arm receiving a different dose of axatilimab intravenously (0.3 mg/kg every two weeks, 1 mg/kg every two weeks, or 3 mg/kg every four weeks) for up to two years. 5 In the 79 patients who received the recommended dose of the agent (0.3 mg/kg every two weeks), encouraging efficacy was observed. The study met its primary endpoint, with an overall response rate (ORR) of 75% (95% CI: 64-84) at Cycle 7 Day 1. 1

The median time to first response in patients receiving the recommended dosage was 1.5 months (range: 0.9 to 5.1), and the median duration of response – the duration from first response to progression, death, or new systemic therapies for cGvHD – was 1.9 months (95% CI: 1.6-3.5). In 60% (95% CI: 43-74) of responders, no death or initiation of new systemic therapy occurred for at least 12 months following response.1

The safety profile of the agent was manageable, with the most common adverse events (AEs) being increased levels of aspartate aminotransferase (AST), unspecified pathogen infection, increased levels of alanine aminotransferase (ALT), decreased phosphate, decreased hemoglobin, viral infection, increased gamma glutamyl transferase (GGT), musculoskeletal pain, increased lipase, fatigue, increased amylase, increased calcium, increased creatine phosphokinase (CPK), increased alkaline phosphatase (ALP), nausea, headache, diarrhea, cough, bacterial infection, pyrexia, and dyspnea.1

The study’s results demonstrate the encouraging efficacy of axatilimab in patients with cGvHD and provide proof of concept for CSF-1R targeting in patients with this condition. The drug was generally well tolerated and there is potential for its combination with additional agents to target nonoverlapping pathways.4 The approval of axatilimab provides an alternative treatment option for patients with persistent and progressive cGvHD, hence addressing a significant unmet medical need. 

References

  1. U.S. Food and Drug Administration. FDA approves axatilimab-csfr for chronic graft-versus-host disease. Available here. (Last accessed 15/08/2024).
  2. Ferrara L, Levine J, Reddy P, et al. Graft-versus-Host Disease. Lancet. 2009;373(9674), 1550. 
  3. Arora M, Cutler C, Jagasia M, et al. Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016 March;22(3):449-55. 
  4. Kitko C, Arora M, DeFilipp Z, et al. Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study. JCO. 2023;41, 1864-1875.
  5. ClinicalTrials.gov. A Study of Axatilimab at 3 Different Doses in Participants with Chronic Graft Versus Host Disease (cGVHD) (AGAVE-201). Available here. (Last accessed 15/08/2024).

Written by Natalie Markova

Edited by Anya Dragojlovic Kerkache & Sol Yohannes