Frespaciguat Misses 6MWD End Point in PH-COPD: Gabor Kovacs, MD, PhD

Inhaled frespaciguat did not significantly improve 6-minute walk distance (6MWD) at week 24 versus placebo in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD) in the phase 2a INSIGNIA PH-COPD trial, according to Gabor Kovacs, MD, PhD, a pulmonologist at the Medical University of Graz in Austria, who presented the results at the CHEST 2026 Annual Meeting, held October 18-21, 2026, in Phoenix, Arizona.

Kovacs discussed the primary analysis of INSIGNIA PH-COPD (NCT05612035), with HCPLive, which randomized 128 patients 2:1 to frespaciguat 380 µg, an investigational inhaled soluble guanylate cyclase stimulator, or placebo once daily via dry-powder inhaler for 24 weeks.1,2 Baseline mean pulmonary vascular resistance was 6.2 Wood units (standard deviation [SD], 2.6), mean forced expiratory volume in 1 second was 54.3% predicted (SD, 15.5), and 72 of 128 patients (56.3%) used supplemental oxygen.

"What we learned from this trial that this drug frespaciguat was pulmonary selective. It did not harm the patients. It was a very important result of the study. It did not meet the primary end point. So that is why, as I mentioned, we need to learn and analyze which is really the best end point," Kovacs said.

Kovacs said 6MWD improved by about 11 m with frespaciguat and 4 m with placebo at week 24, a difference of about 7 m without statistical significance. He reported nominally significant improvements in 6MWD at an earlier timepoint and in N-terminal pro-B-type natriuretic peptide, along with a reduced risk of clinical worsening, an exploratory endpoint (hazard ratio, 0.35). Clinical worsening events were not adjudicated and consisted mainly of COPD exacerbations, he noted.

Adverse events were generally more frequent with placebo than with frespaciguat, Kovacs said. Prior PH-targeted therapies have produced neutral or negative results in PH-COPD, which he attributed partly to worsened ventilation-perfusion mismatch from agents not selective for well-ventilated lung regions.

There is no direct path to phase 3 after the negative primary end point, Kovacs said, and investigators will analyze the data to identify more appropriate endpoints for future PH-COPD trials. Full results have not been published or peer reviewed.

Relevant disclosures for Kovacs include Actelion, Janssen, Bayer, GSK, MSD, Boehringer Ingelheim, Novartis, Chiesi, Vitalaire, Ferrer, and Merck.

References

1. Kovacs G, Waxman AB, Criner GJ, et al. Efficacy and safety of frespaciguat in pulmonary hypertension associated with chronic obstructive pulmonary disease: results from the phase 2a INSIGNIA PH-COPD study. Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ.

2. MK-5475-013 INSIGNIA-PH-COPD: a study of the efficacy and safety of MK-5475 in adults with PH-COPD. ClinicalTrials.gov identifier: NCT05612035. Accessed October 20, 2026. https://clinicaltrials.gov/study/NCT05612035