MAXPIRe Failure Closes IPF Chapter for Axatilimab; CSF-1R Monotherapy Hypothesis Unvalidated in Fibrosis

Syndax's Axatilimab Misses Primary Endpoint in IPF Phase 2 Trial

Syndax Pharmaceuticals announced that its MAXPIRe Phase 2 trial of axatilimab in idiopathic pulmonary fibrosis (IPF) did not meet its primary endpoint of the annualized rate of decline in forced vital capacity (FVC). The 26-week, randomized, double-blind, placebo-controlled trial enrolled 145 patients across 62 sites in 14 countries. Despite the primary endpoint not being met, axatilimab was well tolerated with a safety profile comparable to placebo, showing no new safety signals. Consequently, Syndax does not plan further development of axatilimab for IPF, but its development for chronic graft-versus-host disease (cGVHD) continues, where it is already FDA approved.

• The MAXPIRe Phase 2 trial, evaluating axatilimab in 145 patients with idiopathic pulmonary fibrosis (IPF), failed to achieve its primary endpoint, which was the annualized rate of decline in forced vital capacity (FVC). This outcome leads Syndax to discontinue further development of axatilimab for IPF, despite initial promising scientific rationale for the indication.
• Despite not meeting the efficacy endpoint, axatilimab demonstrated a favorable safety and tolerability profile in the MAXPIRe trial. The drug was comparable to placebo, with no new safety signals observed, and low rates of treatment-emergent adverse events leading to discontinuation, supporting its continued development in other indications.
• While development for IPF is halted, axatilimab's progress in chronic graft-versus-host disease (cGVHD) remains unaffected. The drug is already FDA approved for cGVHD and is advancing in multiple ongoing trials, including combination studies with ruxolitinib and steroids, with results anticipated later this year and in early 2028.

MAXPIRe Phase 2: Axatilimab's Efficacy and Safety in IPF

Several recent randomized controlled trials have evaluated novel therapeutic agents in idiopathic pulmonary fibrosis (IPF), spanning phosphodiesterase inhibition, autotaxin inhibition, and anti-connective tissue growth factor strategies. The studies below represent a cross-section of late-phase clinical evidence, with forced vital capacity (FVC) change as the predominant efficacy endpoint.

Navigating the Unmet Needs in Idiopathic Pulmonary Fibrosis Treatment

Despite the availability of approved antifibrotic therapies, the management of idiopathic pulmonary fibrosis (IPF) remains constrained by fundamental limitations in both therapeutic efficacy and patient monitoring. Current treatments slow but do not arrest or reverse fibrotic progression, and a significant proportion of patients experience disease advancement even under active therapy.

• Treatments slow but do not stop disease progression. Pirfenidone and nintedanib, the currently approved antifibrotic agents, reduce the rate of forced vital capacity (FVC) decline and lower the risk of acute exacerbations, but cannot relieve IPF-associated symptoms nor improve overall survival rates. Fibrosis remains largely irreversible under existing therapeutic options.

• Management of progressive disease on antifibrotic therapy lacks evidence-based guidance. Optimal management of patients who progress despite treatment remains undefined. Evidence-based guidance for continuation, switching, or combination of antifibrotics is lacking — a gap the PROGRESSION-IPF trial is designed to address by evaluating combination therapy with pirfenidone and nintedanib versus switching or continuing monotherapy in patients with progressive IPF.

• Adverse event burden leads to dose reductions and discontinuations. Gastrointestinal events — particularly diarrhea, nausea, and vomiting — are the most frequent adverse events associated with nintedanib, reported in 72.3% of patients in the INBUILD trial. Adverse events led to treatment discontinuation in 22.0% of nintedanib-treated patients in that trial. Low body surface area has been identified as a statistically significant predictor of dose reduction and/or discontinuation of nintedanib in IPF patients. Liver enzyme elevations, and rare cases of severe hepatotoxicity, further complicate long-term management.

• Reliable predictive biomarkers for disease progression and treatment response are lacking. While biomarkers such as KL-6, SP-D, MMP-7, TIMPs, CCL18, and emerging markers including HE4, GDF15, and PRDX4 have been investigated, no single circulating biomarker is currently in clinical use for guiding treatment decisions. The identification of robust predictive biomarkers of prognosis and treatment response represents a significant unmet need, with development of transformational therapies for IPF challenged in part by this absence.

• FVC alone is insufficient for disease monitoring in certain patient populations. In combined pulmonary fibrosis and emphysema (CPFE), baseline and follow-up FVC values failed to predict radiological progression, while DLCO decline at year 1 was significantly more frequent in patients with progression (p = 0.039). Baseline DLCO was identified as an independent predictor of mortality (HR = 0.934, 95% CI: 0.902–0.966, p < 0.001), underscoring the need for multidimensional assessment strategies beyond spirometry alone.

• Acute exacerbations carry high mortality and lack clear treatment protocols. Acute exacerbation of IPF (AE-IPF) is defined as acute worsening of dyspnea within one month in an IPF patient, excluding other causes such as left heart failure and pulmonary embolism. Corticosteroids remain the primary treatment strategy, though controversy persists regarding dosing and tapering. Corticosteroids combined with intravenous cyclophosphamide have been shown to be detrimental to prognosis in AE-IPF, and no clear conclusions can be drawn about the effectiveness and safety of other proposed interventions.

Axatilimab's Continued Development and Promise in cGVHD

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Consistent Safety Profile of Axatilimab Across Clinical Studies

FDA approval of axatilimab on August 14, 2024, for chronic GVHD after failure of at least two prior lines of systemic therapy was based on the AGAVE-201 Study (NCT04710576), which evaluated axatilimab 0.3 mg/kg administered intravenously every 2 weeks in an open-label, single-arm cohort of 79 patients. The safety data from this approval provide the published basis for characterizing axatilimab's tolerability profile.

• Common adverse reactions identified in the AGAVE-201 cohort included infection, increased transaminases, decreased phosphate, decreased hemoglobin, musculoskeletal pain, increased lipase, fatigue, increased amylase, increased calcium, increased creatine phosphokinase, increased alkaline phosphatase, nausea, headache, diarrhea, cough, fever, and dyspnea.

• Efficacy context for the safety population: The overall response rate through Cycle 7 Day 1 was 75% (95% CI: 64, 84), with all responses being partial responses; 60% (95% CI: 43, 74) of responding patients remained alive without new systemic therapy for at least 12 months from response, providing a durability frame within which the safety profile was observed.

• Postmarket safety requirement: The FDA issued a postmarket requirement to evaluate safety with long-term use, indicating that the long-term tolerability profile of axatilimab requires further characterization beyond the AGAVE-201 data.

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Axatilimab's IPF Setback: A Lesson in Fibrosis Targeting

The recent announcement regarding axatilimab's Phase 2 trial in idiopathic pulmonary fibrosis (IPF) not meeting its primary endpoint sends a clear signal about the persistent challenges in developing effective treatments for this devastating lung disease. Axatilimab, a humanized monoclonal antibody targeting the colony-stimulating factor 1 receptor (CSF-1R), was hypothesized to modulate macrophage-driven fibrosis, a mechanism supported by preclinical evidence and the known activity of existing IPF therapies like nintedanib, which also inhibits CSF-1R. However, the trial's outcome suggests that a single-target approach, even one addressing a biologically relevant pathway, may not be sufficient to overcome the profound complexity and pathway redundancy characteristic of IPF.

This setback for IPF stands in stark contrast to axatilimab's success in chronic graft-versus-host disease (cGVHD), where it is already FDA approved. In cGVHD, CSF-1R-dependent macrophages are recognized as key drivers of fibrosis, and axatilimab has demonstrated significant efficacy and a favorable safety profile in heavily pre-treated patients. This divergence highlights a critical lesson: while a therapeutic mechanism may be highly effective in one fibrotic condition, its translation to another, seemingly similar, disease is not guaranteed. The distinct biological contexts, macrophage subsets involved, and the interplay of various fibrotic pathways likely contribute to these differing outcomes.

For the pharmaceutical industry, this event underscores the high development risk associated with IPF. Future strategies may need to move beyond isolated pathway modulation, exploring multi-kinase inhibitors that target several IPF-related processes or combination approaches that address the disease's multifaceted pathology. Furthermore, a deeper understanding of patient stratification and the specific roles of various macrophage phenotypes in IPF progression will be crucial. While the pursuit of novel antifibrotic therapies continues, the path forward for IPF appears to demand more nuanced, potentially combinatorial, and highly targeted approaches to truly impact patient outcomes.