Syndax Pharmaceuticals, Inc. (Nasdaq: SNDX) and Incyte (Nasdaq: INCY) reported that results from the Phase 1/2 trial of axatilimab, Syndax’s anti-CSF-1R antibody, in patients with recurrent or refractory chronic graft-versus-host disease (cGVHD) following two or more prior lines of therapy, were published in the Journal of Clinical Oncology (Press release, Syndax, DEC 5, 2022, View Source [SID1234624802]).
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A total of 40 patients with refractory disease who received a median of four prior systemic therapies, some of which included ibrutinib, ruxolitinib and belumosudil, were treated in the Phase 1/2 dose escalation trial. Thirty-nine patients were evaluable for response as of the data cutoff. All study participants were treated for a median duration of 29 weeks, with all responding patients treated for a median duration of 38 weeks at the time of data cut-off. Results showed:
Overall response rate by cycle 7 day 1 was 82% (18/22) in the Phase 2 cohort (1mg/kg every two weeks) and 67% (26/39) among all evaluable patients treated in the dose escalation study. Best ORR (complete response + partial response) observed at any point during the study in all patients treated was 69% (27/39).
Median duration of response for Phase 2 responding patients was not reached; 33% of patients experiencing sustained response lasting 20 weeks or longer.
A decrease in glucocorticoids doses was observed in 52% of responding patients.
Responses were observed across a range of organ systems with difficult to treat manifestations such as lung (5/16), skin (5/35), and joints and fascia (19/31).
A clinically meaningful disease improvement using the Lee Symptom Score of at least 7 points was seen in 58% (21/36) of all evaluable patients.
Axatilimab was well tolerated with a favorable safety profile in this refractory population. The most common adverse events were consistent with on-target effects of CSF-1R inhibition. In the Phase 1 cohort, two dose limiting toxicities were reported, both at the 3 mg/kg every two weeks dose. There were no ≥Grade 3 on-target toxicities of CSF-1R blockade seen in the Phase 2 cohort. There was no incidence of cytomegalovirus or other viral reactivation, and no apparent increases in risk for infection. Serious adverse events occurred in 40% (16/40) of patients, with seven (18%) patients discontinuing the study intervention due to adverse events, four (10%) of which were deemed treatment-related.
"We believe axatilimab is well positioned to potentially be a first- and best-in-class anti-CSF-1R antibody for cGVHD," said Kate Madigan, M.D., Chief Medical Officer of Syndax. "The robust, durable responses and multi-organ clinical benefit observed in this Phase 1/2 trial in refractory patients support the potential for axatilimab to serve as an effective intervention in this underserved population."
"The results of this Phase 1/2 dose finding study are very encouraging regarding the ability of axatilimab to provide meaningful clinical responses in chronic GVHD patients that have been refractory to multiple prior therapies" said Carrie Kitko, M.D., Medical Director of the Pediatric Stem Cell Transplant Program at the Vanderbilt-Ingram Cancer Center, and the corresponding author of the Phase 1/2 publication. "Combining both anti-inflammatory and anti-fibrotic effects through the targeting of disease associated macrophages would be particularly exciting for this patient population that would benefit from a reduction in sclerotic and fibrotic manifestations of chronic GVHD. In the past simply stopping further progression of those manifestations was considered a "win", but some of these patients are actually having improvements in joint range of motion and skin tightening."
The article, titled "Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a Phase 1/2 study," is available online.
About Chronic Graft-Versus-Host Disease
Chronic graft-versus-host disease, 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% of transplant recipients, and affects approximately 14,000 patients in the U.S.1,2 Chronic GVHD typically manifests across multiple organ systems, with skin and mucosa being commonly involved, and is characterized by the development of fibrotic tissue.3
About Axatilimab
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 cGVHD and IPF. Phase 1/2 data of Axatilimab in cGVHD demonstrating its broad activity and tolerability was last presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Axatilimab was granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of patients with cGVHD 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.
Enrollment in the Company’s global pivotal Phase 2 AGAVE-201 Phase 2 study evaluating the efficacy, safety, and tolerability of axatilimab in patients with recurrent or refractory active cGVHD who have received at least two prior lines of systemic therapy is complete, and topline data is expected mid-2023. Additionally, a Phase 1 combination trial of ruxolitinib and axatilimab, led by Incyte, is in preparation and expected to initiate by end of the first quarter of 2023, and a Phase 2b trial of axatilimab in patients with idiopathic pulmonary fibrosis led by Syndax is expected to begin in the fourth quarter of 2022.
For more information about AGAVE-201, visit View Source