Axatilimab Presents a New Treatment Horizon for Chronic GVHD


In an interview with Targeted Oncology, Daniel Wolff, MD, discussed findings from the phase 2 AGAVE-201 trial evaluating axatilimab as a potential treatment option for patients with chronic graft-vs-host disease.

Daniel Wolff, MD

Daniel Wolff, MD

Treatment of chronic graft-vs-host disease (GVHD) has relied on corticosteroids as the first-line option for over 3 decades, and clinical manifestations of the disease can stay for years and impact patients’ day-to-day lives. However, some researchers are seeking to turn the tide for chronic GVHD treatment.

At a plenary scientific session at the 2023 American Society of Hematology (ASH) Annual Meeting, Daniel Wolff, MD, presented findings from the phase 2 AGAVE-201 trial (NCT04710576).

The trial is evaluating axatilimab, an investigational monoclonal antibody targeting colony stimulating factor-1 receptor, a protein thought to affect the survival and function of monocytes and macrophages.1 The promising results from the trial potentially present a new landscape for the treatment of chronic GVHD.

“The axatilimab story shows that exploring new pathways in animal models translates into identification of targets, which could be used for treatment and could lead to a much better response than expected using traditional immunosuppressive agents,” Wolff, head, senior physician, and professor at University Hospital Regensburg, Germany, said in an interview with Targeted OncologyTM.

In the interview, Wolff discussed the study’s background and elaborated on the findings presented at ASH.

Targeted Oncology: Can you provide some background of the study and what prompted it?

Wolff: Chronic graft-vs-host disease is a disease now known for almost 50 years, and we have not really had progress for the first 30 years. We just used agents which were applied in organ transplantation with a pretty low success rate, leaving a significant proportion of patients badly injured in a way that they were cured not they were not healthy. They just exchanged 1 deadly disease for chronic disease.

Thanks to very talented teams and a very talented colleague in Australia, Kelli MacDonald [PhD, group leader and principal research fellow, Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia], we identified not only T or B cells, which are usually targeted, but also monocytes and macrophages are involved in inflammation and fibrosis. [MacDonald] showed in an animal model that blocking that pathway would prevent fibrosis. It was macrophages and monocytes that were targeted by antibodies for totally other reasons. It was first explored, this pathway in oncology, and then the 2 things came together. [First,] the acknowledgement that these macrophages [and] monocytes may be relevant. Second, there is an antibody [called axatilimab] available which was intended to be used in a totally different medication, but it’s available for clinical trial use.

The idea was initially to perform a small phase 1 or 2 trial, a classical dose-finding trial, and those patients, heavily pretreated, showed a very nice response and incredibly low toxicity. Then the question was, could we recreate [or] replicate that study in significantly larger cohorts just to identify [the] optimal dose regarding safety and response?

Could you describe how the trial was designed?

[AGAVE-201] is 1 of the biggest phase 2 trials ever done in chronic graft-vs-host disease in terms of numbers. Looking at it in retrospect, we are kind of happy that the trial was designed in the way it [was]. It compared 3 different doses with 2 scheduled and explored axatilimab.

One specific issue with this trial was that there was hardly any selection of patients in terms that those patients who are seen typically seen in this situation were included. So, it was not a selected population. The only selection criteria were [patients must have had] at least 2 lines [of previous treatment] and had active chronic graft-vs-host disease. There were hardly any exclusion criteria.

There was no problem to recruit [to] the trial, even with those large numbers, number 1, because many sites were involved, [and] number 2, many patients needed an efficient treatment. They failed or didn’t have good options available.

Can you summarize the findings?

The results [were] quite astonishing, in a way, [because] high responses were seen across all 3 cohorts. The surprise was that the lowest dose was accompanied with the highest response rates, between 60-70%. An additional 15% [were] stable, meaning there were hardly any patients or a very small proportion of patients progressing. This response was quick, which is unusual in this population being treated for years and responding within 2 months or less is something which was a big surprise. Responses, in fact, lasted, and when we looked at who would be the patient benefiting from the treatment, there was no predictor of failure. Basically, regardless of how severe the GVHD was, which organ was involved, the pretreatment, age, didn’t play a role. Basically, the response rate was pretty equal across all the sub-cohorts treated, which we actually didn’t expect to happen. 

Can you talk about some of the safety findings?

What was reassuring of the low-dose cohort, we have some pretty low toxicities, and those responses lasted. Sixty percent of patients have a long-lasting response and didn’t need any additional treatment. There were only, in the low-dose cohort, 2 patient [deaths], which was reassuring in a way that some other agents used have been associated with higher mortality due to the infection complications, which was not observed in that way with axatilimab.

Those toxicities were quite dose-dependent, meaning the low-dose cohort which responded best had a low toxicity profile, and only 6% terminated their treatment because of [adverse] effects. Only 1 patient died of a consequence of treatment. This patient was severely ill before with lung disease, so that was something where I thought back, in retrospect, the treatment came too late. The other patient dying was also something who was severely sick with lung disease and had a preceding infection. 

There was 1 specific [adverse] effect which increased at higher doses, [which was] periorbital edema, which is reversible. There is another [adverse] effect, which is not just an [adverse] effect, but an effect on circulating enzymes derived from the liver in a way that those counts go up, but there’s not toxicity. But the clearance of those enzymes in the blood is reduced due to the fact that those cells [that] usually clear those enzymes in the blood are diminished by the antibody.

With a low toxicity profileand high response rates, it also shows that you need high patient numbers to identify the optimal dose, because the way we usually do things is we go for the maximum tolerated dose. But that didn't turn out to be the case in chronic GVHD using this antibody, and we would never have found out this inverse relationship between dose and response without this sufficiently powered trial.

1. Axatilimab. Syndax. Accessed December 18, 2023. 
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