News - June 30, 2020

Multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF)

HFA Discoveries 2020 webinar presented by James Udelson (Boston, MA, USA)

Soluble guanylate cyclase (sGC) deficiency has been considered to play an important role in the pathophysiology of HFpEF, particularly in patients with a metabolic, inflammatory phenotype. Therefore, sGC stimulation may address multiple aspects of HFpEF pathophysiology, including hemodynamics and blood flow, myocardial compliance, microvascular inflammation, fibrosis, as well as effects on kidneys and skeletal muscles.

Praliciguat is an sGC stimulator, resulting in amplification of endogenous nitric oxide signaling. Preclinical data in a rat model of HFpEF demonstrated benefit of praliciguat; it lowered NT-proBNP, attenuated cardiac and renal damage, and reduced expression of fibrotic markers.

The CAPACITY HFpEF trial, a fase 2, randomized, double-blind, placebo-controlled, parallel group trial, evaluated the efficacy and safety of praliciguat over 12 weeks in HFpEF patients. HFpEF patients (EF ≥40%) were randomized to 40 mg praliciguat (n=65) or placebo (n=78) for a period of 12 weeks. Inclusion criteria consisted of ≥2 conditions associated with decreased NO signaling (diabetes/prediabetes, hypertension, obesity, advanced age (>70) to enrich the trial population with those with a metabolic, inflammatory profile. Elevated BNP/NT-proBNP was not an inclusion criteria. Primary efficacy endpoint was change in peak VO₂ (mL/kg/min) by cardiopulmonary exercise testing (CPET) and primary safety endpoint was treatment emergent adverse effects.

Main results

• LS mean change in peak VO₂ was 0.04 (--0.49 to 0.56) in the placebo group and -0.26 (-0.83 to 0.31) in the praliciguat group, resulting in no difference between the groups (LS mean difference: -0.30 [-0.95-0.35], P=0.37).
• Secondary endpoints of 6-min walk distance and KCCQ QoL scores were not different between the 2 groups. Also, no difference in NT-proBNP and troponin levels, and measures of echocardiography were observed.
• No serious AEs were reported in the praliciguat group, but almost 10% of patients in the praliciguat group experienced dizziness or hypotension.

Conclusions

In HFpEF patients selected for potential impaired NO-sGC-cGMP signaling who would possibly most benefit, treatment with the sGC stimulator praliciguat did not have an effect on functional capacity, measured by change in peak VO₂, compared to placebo. In addition, symptomatic, functional, echo or biomarker measures were not changed after treatment with praliciguat when compared to placebo.

- Our reporting is based on the information provided at HFA Discoveries-