PDGF Pathway in PAH: Setbacks and Promise, With Olivier Sitbon, MD, PhD

The platelet-derived growth factor (PDGF) pathway remains a legitimate target in pulmonary arterial hypertension (PAH) despite a difficult history with oral tyrosine kinase inhibitors, according to Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Pulmonary Hypertension Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Speaking in a symposium at the European Respiratory Society (ERS) International Congress, held in Barcelona from September 5-9, Sitbon traced 2 decades of PDGF-directed drug development in PAH, from early kinase inhibitors through the antibody and prodrug programs now in testing. Earlier this year, another PDGF-pathway kinase inhibitor, seralutinib, missed its primary end point in a phase 3 trial.

"PDGF is a growth factor. It's involved in the pathophysiology, involved in many cells that contribute to the development of lesions we see in PAH, in particular smooth muscle cells, endothelial cells, progenitors, also immune cells. That's a real target," Sitbon said.

Sorafenib, the first PDGF-pathway agent tested in PAH, was abandoned early because of excessive toxicity. Imatinib (Gleevec) followed, producing major hemodynamic improvement in a phase 2 trial that led to the phase 3 IMPRES trial.¹

IMPRES showed imatinib improved 6-minute walk distance versus placebo, but adverse events, including gastrointestinal toxicity, facial edema, and subdural hematoma, drove more discontinuations in the imatinib arm than placebo. The drug's PAH development program was ultimately discontinued.

An inhaled dry-powder formulation, AV-101, was tested against placebo across 3 doses in the phase 2b/3 IMPAHCT trial.² Results were neutral on the primary end point of pulmonary vascular resistance, and the phase 3 portion was halted.

A newer approach uses IKT-001, an oral prodrug of imatinib designed to release the drug systemically while limiting direct gastrointestinal exposure. Inhibikase Therapeutics is testing 300-mg and 500-mg once-daily doses against placebo in the adaptive phase 3 IMPROVE-PAH trial, which began enrolling in 2026.³

Sitbon also pointed to a nontyrosine kinase inhibitor strategy: REGN13335, an anti-PDGF-B monoclonal antibody from Regeneron, is being tested against placebo in the phase 2 ILLUMINATE trial in adults with PAH.⁴ He said its more selective mechanism could avoid the safety issues seen with tyrosine kinase inhibitors.

References

1. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128-1138.

2. Hill NS, Gillies H, Chakinala MM, et al. Phase 2b trial of inhaled imatinib for treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2026;212(4):802-812.

3. Inhibikase Therapeutics. Inhibikase Therapeutics Advancing IKT-001 to Global Phase 3 Study in Pulmonary Arterial Hypertension. Press release. November 20, 2025.

4. ClinicalTrials.gov. Study of REGN13335 in Adult Participants With Pulmonary Arterial Hypertension (ILLUMINATE). NCT07318597.