Data from the the pivotal Phase 2 AGAVE-201 trial (NCT04710576) featured in the Plenary Scientific Session at the 65th Annual Meeting of the American Society of Hematology, held in San Diego, CA, December 9 – 12, 2023 shows that  axatilimab*/**, an anti-CSF-1R## antibody, in adult and pediatric patients with refractory chronic graft-versus-host disease (GVHD) who had received at least two prior lines of systemic therapy, met its primary endpoint across all dose cohorts with 74% of patients at the 0.3 mg/kg dose achieving a complete or partial response within the first six months of treatment.

Chronic graft-versus-host disease (cGVHD), 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]

cGVHD adversely affects patients health related quality of life (hrQoL), impaired functional status, continued need for immunosuppressive medications, and increased non-relapse mortality [4][5]

Building on previous outcomes
The study results from the Phase 2 AGAVE-201 trial, which build on previously announced topline data, show that the trial met the primary endpoint across all cohorts receiving axatilimab, at doses of 0.3 mg/kg every two weeks, 1.0 mg/kg every two weeks and 3.0 mg/kg every four weeks.

Participating patients who received axatilimab at 0.3 mg/kg every two weeks achieved the highest overall response rate (ORR) of 74% within the first six months of treatment (95% CI; 63-83). Patients in this cohort experienced a median time to response to axatilimab of 1.7 months (0.9-8.1), and 60% of patients maintained a response at 12 months (measured from first response to new systemic therapy or death, based on the Kaplan Meier estimate).

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The recommended dose of axatilimab for future trials in chronic GVHD is 0.3 mg/kg every two weeks.

“The data presented at the American Society of Hematology Annual Meeting represent a significant step forward in expanding the treatment options for patients with refractory chronic GVHD,” said Pablo J. Cagnoni, M.D., President and Head of Research and Development, Incyte.

“An unmet (medical) need remains for treatments that are well tolerated and efficacious for patients with refractory chronic GVHD, and the data presented today show that axatilimab could provide a valuable option. We look forward to working with our partners at Syndax as we move axatilimab towards regulatory filing,” Cagnoni added.

Secondary endpoints
The AGAVE-201 trial also met key secondary endpoints in the 0.3 mg/kg dose, with 55% of patients achieving a ≥7-point improvement in the modified Lee Symptom Scale (mLSS) score (a 30-item scale developed to measure the symptoms of cGVHD) [4] Organ-specific responses, including complete responses (CRs), were seen across all organs involved at baseline, including lower gastrointestinal (GI), upper GI, esophagus, joints/fascia, mouth, lungs, liver, eyes and skin. Additionally, responses were notable in fibrosis-dominated organs, including the esophagus (78%), joints and fascia (76%), lungs (47%) and skin (27%).

“The additional positive data from AGAVE-201 further strengthen axatilimab’s strong safety and efficacy profile as a well-differentiated treatment option for patients with refractory chronic GVHD,” noted Michael A. Metzger, Chief Executive Officer of Syndax.

“As a potentially first-in-class anti-CSF-1R antibody targeting inflammation and fibrosis through the inhibition of disease associated macrophages, we have more conviction than ever that axatilimab is poised to transform the treatment paradigm for chronic GVHD. Axatilimab has the potential to positively impact patients with this devastating disease and we are working diligently with Incyte to bring this agent to market,” Metzger further noted.

The AGAVE-201 pivotal trial enrolled 241 patients with relapsed and refractory cGVHD who had received two or more prior systemic therapies, with 74% having previously received ruxolitinib (Jakafi®; Incyte) , 31% having previously received ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) and 23% having previously received belumosudil (Rezurock®; Kadmon Pharmaceuticals). Patients were enrolled across 121 sites in 16 countries.

Adverse events
The most common treatment-emergent adverse events (TEAEs) were consistent with the on-target effects of CSF-1R inhibition and with what was previously observed with axatilimab treatment. TEAEs in greater than 20% of patients in the overall population (n=239) include increases in aspartate aminotransferase, blood creatine phosphokinase, lipase, lactate dehydrogenase, and alanine aminotransferase.

In the overall trial population, 33% of patients experienced at least one grade ≥3 TEAE, with 15.5% experiencing adverse events leading to discontinuation of treatment. For patients who received axatilimab at 0.3 mg/kg (n=79), grade ≥3 TEAEs occurred in 17.7% of patients, with 6.3% experiencing TEAEs leading to discontinuation of treatment.

“Approximately 50% of chronic GVHD patients are refractory to first-line treatment and 25% of patients require at least four lines of treatment, representing a great need for additional effective treatment options,” said Daniel Wolff, M.D., Ph.D., Head, Senior Physician, and Professor at University Hospital Regensburg.

“Full results from the AGAVE-201 trial show rapid durable responses documented in all organs and patient subgroups, with significant symptom burden reduction reported by most of these heavily-pretreated patients. I am pleased that the results of the AGAVE-201 trial showed potential advances for patients who had not responded to previous lines of treatments and look forward to further research to underscore the efficacy of axatilimab patients with chronic GVHD,” Wolff said.

Based on these results and pending agreement from the U.S. Food and Drug Administration (FDA), Syndax and Incyte expect to submit a Biologics License Application (BLA) to the FDA by year-end 2023.#

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Note: * 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 graft-versus-host disease (GVHD) and idiopathic pulmonary fibrosis (IPF). [6]

** Phase 1 / 2 data of axatilimab in chronic GVHD demonstrating its broad activity and tolerability were last presented at the 63rd American Society of Hematology Annual Meeting and data were published in the Journal of Clinical Oncology. Axatilimab was granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of patients with chronic GVHD and IPF.

*** The global Phase 2 AGAVE-201 dose-ranging trial evaluated the efficacy, safety, and tolerability of axatilimab in 241 adult and pediatric patients with recurrent or refractory active chronic GVHD whose disease had progressed after two prior therapies. Patients were randomized to one of three treatment groups that investigated a distinct dose of axatilimab administered at 0.3 mg/kg every two weeks, 1.0 mg/kg every two weeks or 3.0 mg/kg every four weeks. The trial’s primary endpoint is the proportion of patients in each dose group who achieved an objective response as defined by 2014 NIH Consensus Criteria for chronic GVHD by cycle 7 day 1. Secondary endpoints include duration of response, percent reduction in daily steroids dose, organ specific response rates and validated quality-of-life assessments using the Modified Lee Symptom Scale.

# In September 2021, Syndax Pharmaceuticals 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.

## Colony-Stimulating Factor-1 Receptor (CSF-1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts.

Clinical trials
A Study of Axatilimab at 3 Different Doses in Participants With Chronic Graft Versus Host Disease (cGVHD) (AGAVE-201) – ClinicalTrials.gov ID NCT04710576
A Phase 1/​2 Study to Evaluate SNDX- 6352 in Participants With Active cGVHD – ClinicalTrials.gov ID NCT03604692

Highlights of prescribing information
Ruxolitinib (Jakafi®; Incyte) [Prescribing Information]
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) [Prescribing Information]
Belumosudil (Rezurock®; Kadmon Pharmaceuticals/Sanofi) [Prescribing Information]

References
[1] SmartAnalyst 2020 SmartImmunology Insights chronic GVHD report.
[2] Bachier, CR. et al. 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.
[3] Kantar 2020 GVHD Expert Interviews N=32 interviews.
[4] Teh C, Onstad L, Lee SJ. Reliability and Validity of the Modified 7-Day Lee Chronic Graft-versus-Host Disease Symptom Scale. Biol Blood Marrow Transplant. 2020 Mar;26(3):562-567. doi: 10.1016/j.bbmt.2019.11.020. Epub 2019 Nov 20. PMID: 31759158; PMCID: PMC7031026.
[5] Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017 Jan 5;129(1):30-37. doi: 10.1182/blood-2016-07-686642. Epub 2016 Nov 7. PMID: 27821503; PMCID: PMC5216262.
[6] Kitko CL, Arora M, DeFilipp Z, Zaid MA, Di Stasi A, Radojcic V, Betts CB, Coussens LM, Meyers ML, Qamoos H, Ordentlich P, Kumar V, Quaranto C, Schmitt A, Gu Y, Blazar BR, Wang TP, Salhotra A, Pusic I, Jagasia M, Lee SJ. 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. 2023 Apr 1;41(10):1864-1875. doi: 10.1200/JCO.22.00958. Epub 2022 Dec 2. PMID: 36459673; PMCID: PMC10082302.

Featured image courtesy © 2022 – 2023 American Society of Hematology (ASH). Used with permission.

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