An Innovative Approach to Treating Chronic Graft-Versus-Host Disease

An Innovative Approach to Treating Chronic Graft-Versus-Host Disease

Axatilimab, an investigational monoclonal antibody, has demonstrated promising results in the treatment of recurrent/refractory chronic graft-versus-host disease (cGVHD), according to findings from the phase II AGAVE-201 trial. These results, presented at the American Society of Hematology annual meeting by Daniel Wolff, MD, PhD, indicate that axatilimab achieved rapid and durable responses in patients with cGVHD. This innovative therapeutic strategy shows great potential in addressing the unmet need for well-tolerated, rapidly acting agents that provide long-lasting responses in this patient population.

Chronic GVHD, a multi-organ inflammatory disease, often leads to significant morbidity in a large proportion of patients. Current treatment options for cGVHD have limitations, and there is a pressing need for new therapies that not only improve patient outcomes but also enhance their quality of life. Axatilimab, a high-affinity anti-colony-stimulating factor-1 receptor (CSF-1R) monoclonal antibody, specifically targets monocytes and macrophages, which play a crucial role in cGVHD inflammation and fibrosis.

The AGAVE-201 trial included 241 patients with active cGVHD who had received at least three prior lines of therapy. The highest overall response rate (ORR) of 74% was observed in patients treated with a low dose of axatilimab (0.3 mg/kg every 2 weeks) within the first 6 months. Importantly, these responses were sustainable, with 60% of patients maintaining their response for 12 months or longer. The ORR for patients treated with higher doses (1.0 mg/kg every 2 weeks and 3.0 mg/kg every 4 weeks) was 67% and 50%, respectively.

Axatilimab demonstrated organ-specific responses, with significant improvements observed in fibrosis-dominated organs such as the esophagus, joints and fascia, lung, and skin. In the low-dose cohort, the median failure-free survival was 17.3 months, and over half of the patients reported a clinically meaningful improvement in symptom burden. These positive outcomes highlight the potential of axatilimab to address the complex nature of cGVHD and provide relief to patients suffering from this debilitating condition.

In addition to its efficacy, axatilimab also demonstrated a favorable safety profile. The low-dose cohort had the least toxicity, with only 6.3% of patients experiencing an adverse event leading to treatment discontinuation. This is in contrast to the higher dose cohorts, where discontinuation rates were higher (22.2% for 1.0 mg/kg and 17.7% for 3.0 mg/kg). Notably, periorbital edema, a known side effect of axatilimab, was more prevalent in the higher dose groups but occurred at a minimal rate (2.5%) in the low-dose group.

The trial results revealed an interesting inverse dose response, with the lowest dose of axatilimab demonstrating the highest overall response rate. Dr. Wolff explained that this may be due to the prolonged depletion of monocytes and macrophages at higher doses, which subsequently increases the level of CSF-1 in the circulation. Once monocytes reappear, they are stimulated by the excessive CSF-1, which is not present at lower doses. Although this is a plausible explanation, further research is warranted to fully understand this inverse dose response phenomenon.

Based on the promising results from the AGAVE-201 trial, Syndax Pharmaceuticals and Incyte, the developers of axatilimab, plan to submit a biologics license application to the FDA by the end of 2023. If approved, this innovative therapy would represent a significant milestone in addressing the unmet needs of patients with cGVHD, providing a new treatment option that offers rapid and durable responses with a favorable safety profile.

Axatilimab has shown tremendous potential in the treatment of recurrent/refractory cGVHD, offering rapid and durable responses to patients who have previously exhausted multiple lines of therapy. The findings from the phase II AGAVE-201 trial highlight the efficacy and safety of this high-affinity anti-CSF-1R monoclonal antibody. With its unique mechanism of action, axatilimab represents a promising therapeutic strategy that has the potential to improve the quality of life for patients with cGVHD. Continued research and development in this field are crucial to further unlock the therapeutic benefits of axatilimab and provide hope to patients battling this challenging disease.


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