Safety, Tolerability, and Efficacy of Axatilimab, a CSF-1R Humanized Antibody, for Chronic Graft-Versus-Host Disease after 2 or More Lines of Systemic Treatment
Authors: Lee Stephanie J. , Arora Mukta , Defilipp Zachariah , Abu Zaid Mohammad Issam , Di Stasi Antonio , Radojcic Vedran , Meyers Michael L. , Qamoos Hope , Ordentlich Peter , Quaranto Christine , Schmitt Aaron , Gu Yu , Salhotra Amandeep , Pusic Iskra , Kitko Carrie Lynn 
Published: November 2021

Abstract
Background: Axatilimab (Axa) is an IgG4 humanized monoclonal antibody with high affinity binding to CSF-1R. Axa blocks CSF1 and IL-34 binding and activation of CSF-1R signaling, a key pathway involved in the expansion and infiltration of donor-derived macrophages that mediate chronic graft-versus-host disease (cGVHD). We previously reported preliminary phase (Ph) 1 data demonstrating clinical activity and safety of Axa in patients with active cGVHD (Arora, ASH 2020). Here, we provide updated results, including Ph 2 clinical data, for doses chosen to move forward in a global, randomized pivotal study, AGAVE-201 (SNDX-6352-504).
Methods: SNDX-6352-0503 is a Ph 1/2 study evaluating safety, tolerability, and efficacy of Axa in pts ≥6 years of age with active cGVHD despite ≥2 prior lines of systemic therapy. Ph 1 evaluated Axa at doses of 0.15mg/kg (n=1), 0.5mg/kg (n=1), 1mg/kg (n=3), and 3mg/kg (n=6) Q2W and 3mg/kg Q4W (n=6). The Ph 2 dose expansion evaluated Axa at 1mg/kg Q2W (n=23) with a primary objective of overall response rate (CR+PR) at 6 months. The data cutoff was 28 Jun 2021.
Results: Forty pts (17 Ph 1 and 23 Ph 2) were enrolled and received at least 1 dose of axatilimab. Median age was 59 y (range, 16-73). Pts had received a median of 4 prior lines of treatment (range, 1-11), including ibrutinib (n=25), ruxolitinib (n=21), and belumosudil (n=8). Pts had a median of 4 involved organ systems at baseline (range, 1-9). At the time of the data cut, 22 pts (Ph 1, n=6; Ph 2, n=16) were continuing study treatment. Reasons for discontinuation included progression (n=5, 13%), physician decision (n=5, 13%), adverse events (AEs) (n=4, 10%; grade [Gr]) 3 periorbital edema, Gr 3 hypersensitivity reaction, Gr 4 CPK increased, Gr 5 fall (n=1 each), other (n=2, 5%), and withdrawal of consent (n=2, 5%).
Thirty-eight pts were evaluable for response across Ph 1 & Ph 2. Overall response rate was 66% (n=25/38) and similar in pts previously treated with ibrutinib (n=16/24; 67%), ruxolitinib (n=13/20; 65%), and belumosudil (n=4/7; 57%). Response rates were similar for moderate severity cGVHD (60% [6/10]) vs severe cGVHD (70% [19/27]). A 7-point improvement in the normalized Lee Symptom score was seen in 54% (n=19/35) of pts (Fig 1).
Focusing on the 32 pts treated at 2 of the doses selected to move forward (1mg/kg Q2W [n=26] and 3 mg/kg Q4W [n=6]), AEs related to Axa occurred in 66% (n=21/32) of pts with 13% (n=4/32) of pts experiencing grade ≥3 related-AEs. At the 1mg/kg Q2W dose, 62% (n=16/26) of pts experienced a related-AE with 8% (n=2/26) of pts experiencing grade ≥3 related-AEs (hypersensitivity, septic arthritis; both grade 3). Related-AEs, regardless of grade, in the 32 pts demonstrate a trend toward dose dependency (1mg/kg Q2W vs 3 mg/kg Q4W) with a higher proportion having elevations in AST (23% vs 50%), CPK (12% vs 67%), ALT (12% vs 33%), lipase (12% vs 50%), and incidence of periorbital edema (8% vs 50%) in the 3mg/kg Q4W cohort (Table 1). Transient elevated circulating enzyme levels have not been associated with hepatotoxicity or any other end-organ damage and are likely due to CSF-1R blockade on Kupffer cells, which are liver macrophages that mediate clearance of these enzymes. Importantly, the risk of infection was low, and no cases of viral reactivation were reported (cytomegalovirus, Epstein-Barr, and/or herpes simplex virus).
Of the 32 pts treated at 1mg/1kg Q2W or 3mg/kg Q4W, 30 pts were considered evaluable for response (2 pts had not undergone a postbaseline assessment at the time of the data cut). A best overall response rate (CR+PR) of 70% (75% [18/24] 1mg/kg Q2W; 50% [3/6] 3mg/kg Q4W) as defined by the 2014 NIH cGVHD Consensus Criteria was observed. Responses were noted in difficult-to-treat organ manifestations, with 31% (n=4/13) experiencing a response in lung, 19% (n=5/27) in skin, and 57% (n=13/23) in joints and fascia. Median time to first response was 0.95 months (Fig 2).
Conclusions: Axa is a novel agent targeting a pathway different than other cGVHD treatments. Data from this Ph 1/2 study demonstrate the safety and clinical activity of Axa in heavily pre-treated pts with active cGVHD, particularly those with fibrotic manifestations. A randomized pivotal study (AGAVE-201) has started enrolling a similar pt population, evaluating doses of 1 mg/kg Q2W and 3mg/kg Q4W, along with a lower dose of 0.3mg/kg Q2W.
Figure 1 Figure 1.

Disclosures
Lee: Syndax: Research Funding; Takeda: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kadmon: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Amgen: Research Funding. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Abu Zaid: Syndax: Consultancy, Research Funding; Pieris: Current equity holder in publicly-traded company; Pharamcyclic: Research Funding; Incyte: Research Funding. Di Stasi: Syndax Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Alabama at Birmingham: Current Employment. Radojcic: Syndax Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Allakos: Membership on an entity's Board of Directors or advisory committees. Meyers: Nuvalent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Patents & Royalties. Qamoos: Syndax Pharmaceuticals: Current Employment. Ordentlich: Novartis: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Patrys Lmtd: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Twenty-eight Seven Therapeutics: Consultancy; Cymabay Therapeutics: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Viking Therapeutics: Current equity holder in publicly-traded company. Quaranto: Syndax Pharmaceuticals, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Schmitt: Syndax Pharmaceuticals, LLC: Current Employment, Current holder of stock options in a privately-held company; Fractyl Laboratories Inc. (Now Fractyl Health): Ended employment in the past 24 months. Gu: Syndax: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Ended employment in the past 24 months. Pusic: Syndax: Other: Advisory Board. Kitko: Horizon: Membership on an entity's Board of Directors or advisory committees; Co-investigator on two NIH grants as part of the cGVHD consortium: Research Funding; PER: Other: PER - CME educational talks about GVHD; Vanderbilt University Medical Center: Current Employment.