Syndax and Incyte Report Positive Topline Results from Pivotal Trial Chronic GVHD

Rare Daily Staff

Syndax Pharmaceuticals and Incyte reported positive topline data from the pivotal AGAVE-201 trial of axatilimab, an anti-CSF-1R antibody, in adult and pediatric patients with chronic graft-versus-host disease following two or more prior lines of therapy.

The trial achieved its primary endpoint across all cohorts, with patients treated with axatilimab at three different doses demonstrating overall response rates within the first six months of treatment of 74 percent in the highest dose, 67 percent in a mid-range dose, and 50 percent in the lowest dose. Responses were achieved across key patient subgroups, including those with prior exposure to ruxolitinib, belumosudil and/or ibrutinib.

Based on these results and pending agreement from the U.S. Food and Drug Administration, Syndax and Incyte intend to submit a Biologics License application to the FDA by end of the this year.

“Axatilimab is the first investigational chronic GVHD treatment to target inflammation and fibrosis through the inhibition of disease associated macrophages, and the AGAVE-201 data demonstrates the potentially pronounced impact this mechanism, alone or in combination with standard of care therapies already available for the management of this disease, may have on patients suffering from chronic GVHD,” said Michael Metzger, CEO of Syndax. “These results underscore our belief that axatilimab could provide a valuable and highly differentiated therapeutic option for this devastating disease.”

Chronic graft-versus-host disease (GVHD), an immune response of the donor-derived hematopoietic cells against recipient tissues, is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation which can last for years. Chronic GVHD is estimated to develop in approximately 40 percent of transplant recipients, and affects approximately 14,000 patients in the United States. Chronic GVHD typically manifests across multiple organ systems, with skin and mucosa being commonly involved, and is characterized by the development of fibrotic tissue.

Axatilimab is an investigational monoclonal antibody that targets colony stimulating factor-1 receptor, or CSF-1R, a cell surface protein thought to control the survival and function of monocytes and macrophages. In pre-clinical models, inhibition of signaling through the CSF-1 receptor has been shown to reduce the number of disease-mediating macrophages along with their monocyte precursors, which has been shown to play a key role in the fibrotic disease process underlying diseases such as chronic GVHD and IPF.

The AGAVE-201 pivotal study enrolled a total of 241 patients across 121 sites in 16 countries. Patients enrolled in the trial had received a median of four prior systemic therapies with 74 percent having previously received ruxolitinib, 23 percent having previously received belumosudil and 31 percent having previously received ibrutinib. Fifty four percent of these patients had at least four organs involved at baseline including 45 percent with lung involvement.

Among responders treated with highest dose of axatilimab, 60 percent of patients maintained a response at 12 months. The median duration of response in this population has not been reached. Additionally, 55 percent of patients in this group experienced a clinically meaningful improvement in symptoms.

The most common adverse events were consistent with the on-target effects of CSF-1R inhibition and with what was previously observed with axatilimab treatment. In the overall population, adverse events in greater than 20 percent of patients include an increase in aspartate aminotransferase, blood creatine phosphokinase, lipase, blood lactate dehydrogenase, alanine aminotransferase and fatigue. Serious adverse events in the overall population occurred in 101 (42.3 percent) patients, with 37 (15.5 percent) patients experiencing adverse events leading to discontinuation of study treatment.

Axatilimab was granted Orphan Drug designation by the FDA for the treatment of patients with chronic GVHD and IPF. In September 2021, Syndax and Incyte entered into an exclusive worldwide co-development and co-commercialization license agreement for axatilimab. Axatilimab is being developed under an exclusive worldwide license from UCB entered into between Syndax and UCB in 2016.

Photo: Michael Metzger, CEO of Syndax