Axatilimab

Axatilimab (^Niktimvo®) is a high-affinity humanized IgG4 monoclonal antibody that recognizes the ligand-binding domain on CSF-1R and has been shown to bind to known CSF-1R variants (V32G, A245S, P247H and V279M). Axatilimab blocks the binding of both colony-stimulating factor 1 (CSF-1) and interleukins-34 ligand and effectively inhibits ligand-induced monocyte activation without antibody-mediated receptor internalization or activation.

Chronic GvHD is characterized by dysregulated inflammation, chronic tissue damage and impaired remodelling. This immunological dysreaction is driven by CSF-1R)-dependent monocytes (colony-stimulating factor 1 receptor) leading to profibrotic (M2) macrophage differentiation, persistent inflammation and tissue damage, and accelerated maladaptive tissue repair and fibrosis. Due to the key role of CSF-1R-driven signaling in macrophage biology and preclinical results, the benefit of CSF-1R-targeted therapy in cGVHD patients has now been demonstrated (Kitko CL et al. 2023).

The FDA approval is based on data from the global AGAVE-201 study, which evaluated the safety and efficacy of axatilimab in 241 adult and pediatric patients with refractory chronic GvHD who had received at least two prior lines of systemic therapy. The study met the primary endpoint in all cohorts receiving axatilimab. The results of the study demonstrated durable responses in all organs studied and in all patient subgroups. Of the patients receiving axatilimab at the approved dose of 0.3 mg/kg every two weeks (n=79), 75 achieved an overall response rate (ORR) within the first six months of treatment. The median time to response was 1.5 months. In addition, response persisted in 60 of the patients after 12 months of treatment (from first response to new systemic therapy or death based on the Kaplan-Meier estimate). The study also achieved an important exploratory endpoint: the majority (56%) of patients achieved an improvement in the modified Lee Symptom Scale (mLSS) score of =7 points. Organ-specific complete and partial responses were observed in all organs studied that were affected by chronic GvHD, including the lower gastrointestinal tract, upper gastrointestinal tract, esophagus, joints/fascia, mouth, lungs, liver, eyes and skin.

The Biologics License Application (BLA) for axatilimab for the treatment of chronic GvHD after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing at least 40 kg was reviewed by the FDA as part of a priority review process. The FDA grants priority review status to drug applications that, if approved, would provide new treatment options for a serious condition and significantly improve the safety or effectiveness of treatment.

Embryo-fetal toxicity: Due to its mechanism of action, axatilimab may cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus. Women of childbearing age are advised to use effective contraceptive methods during treatment with axatilimab and for 30 weeks after the last dose.

Because serious adverse reactions may occur in an infant, women should be instructed not to breastfeed during treatment and for 30 days after the last dose of axatilimab.

Women of childbearing age should be advised to use effective contraceptive methods during treatment with axatilimab and for 30 weeks after the last dose.

The overall response was documented in 74% of patients with 0.3mg axatilimab, 67% with a 1mg dose and 50% with a 3mg dose.

Eye diseases: periorbital edema

Skin and subcutaneous disorders: itching

Vascular disorders: hypertension

Immunogenicity: Anti-drug antibody-related adverse reactions

Serious adverse reactions occurred in 44 of the patients taking axatilima (n=79). The most common (=15%) adverse reactions including laboratory abnormalities were elevated aspartate aminotransferase (AST) levels, infections (unspecified pathogen), elevated alanine aminotransferase (ALT) levels, low phosphate levels, low hemoglobin levels, viral infection, increased gamma-glutamyl transferase (GGT) levels, musculoskeletal pain, increased lipase levels, fatigue, increased amylase levels, increased calcium levels, increased creatine phosphokinase (CPK) levels, increased alkaline phosphatase (ALP) levels, nausea, headache, diarrhea, cough, bacterial infection, fever and shortness of breath.

1. Bachier CR. et al. (2019) ASH Annual Meeting 2019; Abstract 2109; Epidemiology and Real-World Treatment of Chronic Graft-Versus-Host Disease Post Allogeneic Hematopoietic Cell Transplantation: A U.S. Claims Analysis.
2. Kitko CL et al. (2023) Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study. J Clin Oncol 41:1864-1875.
3. Mohty M (2024) CSF1R Blockade for Refractory Chronic Graft-versus-Host Disease. N Engl J Med 391:1055-1059
4. Sarantopoulos S (2024) Targeting CSF1R in Chronic GVHD - Lessons in Translation. N Engl J Med 391:1053-1055.
5. Wolff D et al. (2024) AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med 391:1002-1014