Target engagement and drug delivery in PAH: lessons from inhaled imatinib

The development of new therapeutic agents remains one of the most complex and uncertain endeavors in biomedical science. This challenge is reflected in the high attrition rates observed across the drug discovery pathway, with only a small proportion of compounds progressing successfully from preclinical evaluation to regulatory approval. Lengthy development timelines, often spanning more than a decade, further underscore the formidable barriers to therapeutic innovation. In an effort to mitigate failure, contemporary strategies have increasingly prioritized targets supported by robust pharmacological or genetic validation, repurposed drugs with established safety profiles, and adopted innovative trial methodologies, including adaptive designs, to improve efficiency and signal detection. Despite these advances, uncertainty remains intrinsic to drug development. Sotatercept provides a compelling illustration of both promise and unpredictability. Initially developed for aplastic anemia, its trajectory shifted following insights into impaired bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH), with relative overactivity of transforming growth factor–β (TGF-β) pathways. Sotatercept, a ligand trap for the TGF-β superfamily ligand, activin A, was repurposed to restore signaling balance in favor of BMP pathways. This strategy proved successful, with phase 3 trials demonstrating clinically meaningful benefit and subsequent regulatory approval for PAH in multiple jurisdictions.1,2 However, the attempt to extend this therapeutic concept to cibotercept, another activin A ligand trap, was unsuccessful; a phase 2 trial was terminated prematurely due to the development of pericardial effusions,3 underscoring the fragility of translational success even within shared mechanistic frameworks. Imatinib offers a further instructive example. Originally developed as a BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia, its inhibition of platelet-derived growth factor receptor (PDGFR) signaling generated interest in PAH, where vascular smooth muscle proliferation is a central pathological feature. Early phase 2 data were encouraging4 and were largely replicated in a subsequent phase 3 trial,5 which demonstrated improvements in hemodynamics and six-minute walk distance among patients who tolerated therapy. However, two major issues precluded regulatory approval. First, serious bleeding events, namely, intracranial and subdural hemorrhage, occurred in a subset of patients receiving concomitant anticoagulation. Although thrombocytopenia is a recognized adverse effect of imatinib, such bleeding complications have not been observed in other clinical indications, and subsequent regulatory and trial decisions reflected an abundance of caution rather than definitive attribution of causality. Second, the high rate of treatment discontinuation raised concerns regarding tolerability in this population, with adverse effects including nausea, periorbital oedema, and fluid retention, likely related to systemic exposure. These observations prompted contraindication of anticoagulant use in later studies and motivated exploration of alternative delivery strategies, including the development of an inhaled formulation intended to maximize pulmonary exposure while minimize systemic toxicity. IMPACHT,6 reported in the current issue of the Journal by Hill and colleagues, was a phase 2 b study evaluating inhaled imatinib (AV-101) in patients with PAH receiving at least two background therapies. The trial failed to demonstrate statistically significant improvements in either primary or secondary endpoints. At doses of 10, 35, and 70 mg, placebo-adjusted changes in pulmonary vascular resistance (PVR) were 42.8, −5.5, and −57.0 dyn·s·cm−5, respectively. These findings have led to the cessation of further development of inhaled imatinib for PAH. The modest hemodynamic effects contrast sharply with the reductions in PVR observed with sotatercept (−145.8 and −239.5 dyn·s·cm−5 at doses of 0.3 and 0.7 mg, respectively) and with the -379 dyn·s·cm−5 reduction reported in the phase 3 trial of oral imatinib in patients on broadly comparable background therapy. Importantly, these contemporary positive trials suggest that the neutral findings of IMPACHT do not reflect a ceiling of therapeutic response in a maximally treated population. Rather, post hoc analyses of IMPACHT have centered on two critical questions: whether sufficient drug exposure was achieved within the pulmonary vasculature to elicit a therapeutic effect, and whether PDGFR inhibition represents an optimal target in PAH. The dose range studied was modelled to approximate lung exposure expected from an oral imatinib dose of 400 mg daily. However, direct confirmation of pulmonary drug concentrations is not feasible, and in the absence of validated surrogates, such as radiotracer displacement, actual lung exposure remains ­uncertain. Insufficient pulmonary exposure therefore represents one plausible explanation for the negative findings. Importantly, these results do not invalidate PDGFR as a therapeutic target, but rather highlight the challenges of achieving adequate and appropriately distributed target inhibition in humans. Systemic exposure, as measured by plasma imatinib area under the curve, was less than 10% of that achieved with oral dosing. On the one hand, this was associated with an absence of systemic toxicities such as thrombocytopenia or leukopenia. On the other hand, it raises the possibility that systemic, and specifically bone marrow, exposure may be necessary to achieve a meaningful hemodynamic response. Beyond PDGFR, imatinib inhibits c-kit, a pathway implicated in pulmonary vascular remodeling.7 Demonstrating anti-remodeling effects in humans is inherently challenging; however, recent studies using advanced hemodynamic monitoring suggest that the benefits of imatinib persist well beyond systemic drug clearance, with gradual attenuation over approximately 40 days, consistent with a disease-modifying effect.8-10 Whether this reflects direct vascular antiproliferative activity or requires inhibition of bone marrow–derived c-kit–positive progenitor cells remains unresolved. Even rationally designed therapeutic strategies may falter when confronted with the complexity of human disease. Several lessons emerge. First, establishing target engagement across a range of safe and tolerated doses in patients is essential. Second, modifying the route of administration to reduce systemic exposure may inadvertently eliminate tissue exposure required for efficacy, underscoring the importance of mechanistic understanding. Third, inhaled delivery of PAH-specific therapies can be highly effective, as exemplified by treprostinil,11 and remains an attractive approach under active investigation for other agents, including seralutinib.12 How, then, should IMPACHT reshape perspectives on imatinib as a therapeutic option in PAH? While the present data diminish enthusiasm for further investment in this preparation and dose of inhaled imatinib, early safety and efficacy signals observed with oral imatinib in carefully selected patients not receiving anticoagulation continue to raise the possibility that generic oral imatinib could, if appropriately evaluated, represent a cost-effective, disease-modifying approach. This possibility, though challenging, merits continued exploration within carefully designed clinical trials. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. Please see the ICMJE disclosure forms, which have been provided as supplementary material.