Advancing Chronic Graft-Versus-Host Disease Treatment: Insights from the AGAVE-201 Study of Axatilimab

SAN ANTONIO—Each year, more than 5,000 Americans develop graft-versus-host disease (GVHD), and for many, the condition becomes chronic (cGVHD) and harder to treat.

Corey Cutler, MD, MPH, director of the Stem Cell Transplantation Program at Dana-Farber Cancer Institute and president-elect of the American Society for Transplantation and Cellular Therapy (ASTCT), said, "When we look at patients who are diagnosed with chronic GVHD, about half of them actually end up in the steroid refractory patient segment. So, really, 50% plus of our patients will end up getting second-line and third-line therapy. So it really is still a big deal," at the Tandem Meetings, Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood and Marrow Transplant Research (CIBMTR), in San Antonio.

The results of the AGAVE-201 trial of axatilimab, presented by a team of researchers led by Zachariah DeFilipp, MD, director of BMT Research at Massachusetts General Hospital, Boston, found that axatilimab, an investigational high-affinity anti-CSF-1R monoclonal antibody, targets CSF-1R–dependent monocytes and macrophages, which are key contributors to the inflammation and fibrosis characteristic of cGVHD.

The phase II, open-label, multicenter trial was designed to evaluate axatilimab’s safety and efficacy in patients with recurrent or refractory cGVHD. Three doses (0.3, 1.0, and 3.0 mg/kg) were tested, and the lowest dose of 0.3 mg/kg every 2 weeks (Q2W) yielded the most favorable response rates and the best safety profile.

The study enrolled 241 participants, with demographics and baseline characteristics consistent across cohorts. Patients were age 53 on average, predominantly men (63%), and primarily White (83%). The eligibility criteria required participants to be at least 2 years old with two or more prior lines of systemic therapy, showcasing the study’s focus on a population with significant treatment history and challenging disease profiles.

On the primary endpoint of overall response rate (ORR) in the first 6 cycles, the response was best with the lowest dose, with approximately 74% of patients assigned to the 0.3-mg/kg Q2W dosing regimen achieving a response compared to 67% with the 1-mg/kg dose and 50% with the 3-mg/kg dose.

The low-dose cohort also documented a rapid median time to first response, 1.5 months, indicating axatilimab’s potential for quick efficacy. Subgroup and organ-specific responses for the 0.3 mg/kg dose further underscored the drug’s effectiveness across various patient groups and in organs typically affected by fibrosis due to cGVHD. Details on the other two doses were not provided.

Axatilimab’s efficacy was pronounced in organs predominantly affected by fibrosis, a hallmark of cGVHD. Patients on the 0.3 mg/kg every 2 weeks (Q2W) dosing regimen demonstrated significant response rates across various organs, with the highest number of responses observed in fibrosis-dominated tissues, such as in patients with joints and fascia involvement (n=55; 76% response), patients with lung involvement (n=32; 47%), and patients with skin involvement (n=64; 27%). Researchers also documented an impressive 89% response rate in the nine patients with lower gastrointestinal (GI) manifestations (8 responses), highlighting axatilimab’s potential to address severe complications of cGVHD.

The organ-specific analysis revealed that 82% of patients with upper GI involvement (n=11) and 78% of patients with esophageal cGVHD (n=23) responded to treatment. Moreover, the skin and lungs, critical areas of concern in cGVHD due to their impact on patient quality of life, showed meaningful improvement. Notably, 66% of patients experienced improvements in skin and joint tightening severity, while 44% had reductions in sclerotic cGVHD manifestations. These findings suggest a broad applicability of axatilimab across the diverse manifestations of cGVHD.

Axatilimab’s safety profile was manageable, with the 0.3 mg/kg Q2W dose associated with a lower incidence of Grade ≥3 treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) compared to higher doses. Common TEAEs included fatigue, headache, and Covid-19, with most being low-grade and reversible.

Another significant aspect of the AGAVE-201 study was its exploration of corticosteroid dose reductions, a critical consideration given the long-term side effects associated with steroid therapy. Among patients who received concomitant corticosteroids, 11% were able to discontinue steroids within the first six cycles of axatilimab, and 41% of patients achieved a corticosteroid dose reduction by cycle 6, indicating a substantial steroid-sparing effect of axatilimab.

The mean daily corticosteroid dose showed a consistent downward trend from baseline through cycle 6, decreasing from 18.8 mg to 12.9 mg. This reduction is particularly noteworthy as it suggests that axatilimab may enable a reduction in steroid dependency, potentially mitigating the adverse effects associated with long-term corticosteroid use, such as increased risk of infections, bone density loss, and cardiovascular issues.

The AGAVE-201 researchers concluded that axatilimab, particularly with the 0.3 mg/kg Q2W dosing regimen, is highly effective in treating recurrent/refractory cGVHD, offering rapid and durable responses across all tested organs and patient subgroups. The significant reduction in symptom burden, combined with a manageable safety profile, positions axatilimab as a promising therapeutic option for cGVHD patients.

Yet, why is the low dose better than higher doses? According to Cutler, there are a couple of different theories about this.

"The first theory is that the patients who receive the highest doses have the highest side effect rates that lead to more discontinuations. So, you are actually treating fewer people or giving them fewer doses of drug because of the side effect profile. And, if you give people less drug, they are less likely to respond. That’s one theory," he said. "The second possibility is that the drug depletes…macrophages…We think in GVHD, there’s an abnormal segment of those cells that are circulating that are instrumental in causing the disease. We think axatilimab targets the activated or pathogenic portion of the monocyte macrophage group. However, if you go into higher doses of the compound, it’s quite possible that you’re actually now deleting normal or healthy monocytes and macrophages, and those are cells that are important for infection fighting and to help tissue remodeling. So, it’s possible that the drug is depleting cell subsets that we actually want."

There also could be an issue with the FDA, which generally likes to be sure there isn’t an even lower dose of a drug that is effective—and perhaps with fewer side effects. The FDA has been known to require companies with this type of dose response to do an additional trial that includes an even lower dose.

According to Cutler, the main downside to axatilimab is that it is parenterally administered.

"Patients must go to a clinic to receive it. At the moment, that would be the transplant center, but we do feel confident that this is a drug that can be administered in the community setting. However, it is still a trip to a doctor’s office, having an IV placed, and getting an infusion…The three drugs that are currently FDA approved are all pills. So, patients clearly are going to prefer orally administered drugs. The other thing is we don’t have an algorithm of how to sequence these compounds. And it takes time to break into the market," he said.

The AGAVE 201 study was funded by Syndax Pharmaceuticals, Inc., and Incyte Corporation.

DeFilipp reported serving as a consultant for Incyte Corporation, Inhibrx, MorphoSys, Ono Pharmaceuticals, PharmaBiome AG, and Sanofi; receiving honoraria from Incyte Corporation and MorphoSys; and receiving research funding from Incyte Corporation, Regimmune, and Taiho Oncology.

DeFilipp Z, et al "Safety and efficacy of axatilimab in patients with chronic graft-versus-host disease (AGAVE-201)" Presented at the 2024 Tandem Meetings; February 21–24, 2024; San Antonio, TX, USA (Abstract #36).