Chronic graft-versus-host disease (cGVHD) is a debilitating condition that affects up to 50% of patients who have undergone hematopoietic stem cell transplantation. It is characterized by multi-organ inflammation and fibrosis, leading to significant morbidity and decreased quality of life. Despite recent advances in treatment options, there is a clear need for new therapies that are both effective and well-tolerated. In the phase II AGAVE-201 trial, the investigational drug axatilimab has shown promising results in achieving rapid and durable responses in patients with recurrent/refractory cGVHD.
Unveiling the Potential of Axatilimab
Axatilimab, a high-affinity anti-CSF-1R monoclonal antibody, targets monocytes and macrophages, which play a crucial role in the inflammation and fibrosis seen in cGVHD. In the study conducted by Daniel Wolff, MD, PhD, the overall response rate (ORR) was found to be highest in patients treated with the lowest dose of axatilimab at 0.3 mg/kg every 2 weeks, with an ORR of 74% within the first 6 months. Furthermore, the response to therapy was rapid, with a median time of 1.7 months, and 60% of patients maintained this response for 12 months or longer.
The AGAVE-201 trial included patients who had received at least three prior lines of therapy and had active cGVHD. Among the three dose levels tested, the 0.3 mg/kg cohort demonstrated the highest ORR, followed by 1.0 mg/kg and 3.0 mg/kg cohorts, with ORRs of 67% and 50%, respectively. These results suggest that axatilimab may represent a new therapeutic strategy for cGVHD. Notably, the lowest dose of axatilimab also had the least toxicity, highlighting the importance of conducting sufficiently powered studies to ensure the safety and efficacy of treatments in this vulnerable patient population.
One of the key findings of the AGAVE-201 trial was the observation of organ-specific responses across all involved organs. The most significant responses were seen in fibrosis-dominated organs, such as the esophagus, joints and fascia, lung, and skin. This suggests that axatilimab may have a particularly beneficial effect on fibrotic manifestations of cGVHD. Moreover, more than half of the patients in the 0.3 mg/kg cohort reported a clinically meaningful improvement in symptom burden, further supporting the efficacy of axatilimab in reducing the overall impact of cGVHD on patients’ lives.
In terms of safety, axatilimab demonstrated a generally favorable profile. The low-dose cohort experienced the lowest rates of adverse events (AEs) leading to treatment discontinuation at 6.3%, compared to 22.2% and 17.7% in the higher dose cohorts. However, it is important to note that one patient in the low-dose group had a fatal AE, whereas several fatal AEs were reported in the higher dose groups. Additionally, periorbital edema was a notable side effect observed in the higher dose groups, but only affected a small percentage of patients in the low-dose cohort.
Interestingly, the AGAVE-201 trial revealed an inverse dose response to axatilimab, with lower doses showing more favorable outcomes. According to Daniel Wolff, this may be attributed to the prolonged depletion of monocytes and macrophages at higher doses, which leads to an increase in circulating CSF-1. The excessive stimulation of reappearing monocytes by the elevated CSF-1 levels may account for the decreased response observed in higher dose groups. However, further research is needed to fully understand this phenomenon and its implications.
Based on the encouraging results from the AGAVE-201 trial, developers Syndax Pharmaceuticals and Incyte plan to submit a biologics license application to the FDA by the end of 2023. If approved, axatilimab could potentially become a novel and valuable treatment option for patients with recurrent/refractory cGVHD, addressing the unmet need for effective, well-tolerated therapies.
The phase II AGAVE-201 trial has provided compelling evidence of the efficacy of axatilimab in the treatment of recurrent/refractory cGVHD. The study demonstrated rapid and durable responses, particularly at lower doses of axatilimab, with favorable organ-specific responses and symptom reduction. With its unique mechanism of action, targeting monocytes and macrophages, axatilimab offers a potentially new therapeutic strategy for cGVHD. However, further research is needed to elucidate the optimal dosing regimen and fully understand the inverse dose response observed in this study. Overall, the results of the AGAVE-201 trial offer hope for improving the lives of patients affected by this debilitating condition.
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