Key takeaways:

• High-dose PDE9 inhibition increased plasma cyclic guanosine monophosphate levels but not NT-proBNP in patients with HFrEF or HFpEF.
• Data hinted lower-dose treatment may have a larger impact.

PHOENIX — Tovinontrine increased plasma cyclic guanosine monophosphate levels in patients with HF with reduced or preserved ejection fraction but did not change N-terminal pro-B-type natriuretic peptide levels, a speaker reported.

A post hoc analysis of data indicated a possible inverse dose response relationship with lower-dose tovinontrine (Cardurion Pharmaceuticals) causing less plasma cyclic guanosine monophosphate elevation and greater reduction in NT-proBNP, according to research presented at the Heart Failure Society of America Annual Scientific Meeting.

Tovinontrine increased plasma cyclic guanosine monophosphate levels in patients with HF with reduced or preserved ejection fraction. Image: Adobe Stock.

James E. Udelson, MD, chief of the division of cardiology and director of the nuclear cardiology laboratory at Tufts Medical Center and professor at the Tufts University School of Medicine, presented the results of the Cycle-1^REF and Cycle-2^PEF trials of tovinontrine, a phosphodiesterase 9 inhibitor, in patients with HFrEF and HFpEF, respectively.

Tovinontrine breaks down cyclic guanosine monophosphate, and is hypothesized to enhance the natriuretic peptide signaling pathway, which would increase myocardial relaxation, decrease hypertrophy and inhibit fibrosis, Udelson said during the presentation.

“Most people are familiar with the natriuretic peptide signaling system, resulting in the degeneration of cyclic guanosine monophosphate and protein kinase G activation, leading to several good things happening in the myocytes. We take advantage of this system with sacubitril/valsartan (Entresto, Novartis) to upregulate,” Udelson said during the presentation. “Phosphodiesterase 9 puts the brakes on this process by breaking down cyclic guanosine monophosphate. In concept, a phosphodiesterase inhibitor such as tovinontrine would inhibit this process; increase cyclic guanosine monophosphate, which would spill over into the plasma as a signal of its target engagement; and hopefully increase many of these good things happening in the myocyte.”

For the Cycle-1^REF trial, researchers enrolled 529 patients with HFrEF and randomly assigned them to tovinontrine 2.5 mg twice daily, 25 mg twice daily, 50 mg twice daily or placebo (mean age, 69 years; 78% men; 94% white). For Cycle-2^PEF, Udelson and colleagues enrolled 277 patients with HFpEF and randomly assigned to tovinontrine 50 mg twice daily or placebo (mean age, 72 years; 64% men; 92% white).

The primary endpoint for both trials was percent change plasma NT-proBNP from baseline to 12 weeks. The secondary efficacy endpoint for both trials was change in plasma cyclic guanosine monophosphate and the safety endpoint was treatment-related adverse events.

Tovinontrine in patients with HFrEF

In patients with HFrEF, compared with placebo, the highest dose of tovinontrine did not change NT-proBNP at 12 weeks, but there were trends toward improvement in NT-proBNP with the lower doses 2.5 mg group, 14.1%; 95% CI, 27.2 to 1.3; P =.07; 25 mg group, 10.8%; 95% CI, 20.6 to 0.1; P = .05; 50 mg group, 4.4%; 95% CI, 14.9 to 7.5; P = .45), Udelson said.

However, all three doses of tovinontrine increased plasma cyclic guanosinemonophosphate at 12 weeks, and placebo did not, he said. The inverse dose response was evaluated in a post hoc analysis of Cycle-1^REF, and researchers found that modest increases in plasma cyclic guanosine monophosphate may confer greater reductions in NT-proBNP compared with Placebo, Udelson said.

“There was no significant reduction in the high-dose group,” Udelson said during the presentation. “But ... It's almost like a reverse inverse dose response. The 25 mg twice daily group had a borderline significant reduction, and the low-dose group, in which you would not necessarily expect, had the largest point estimate reduction. Note that there were many fewer patients [in the low-dose group] by design, so the confidence intervals were wide and did not quite reach statistical significance.”

Because the primary outcome at the 50 mg twice daily dose did not reach statistical significance, further formal analyses were not conducted and the results of the present study should be considered hypothesis-generating only, Udelson said.

Treatment-related adverse events were generally mild to moderate; serious adverse events were similar compared with placebo; changes in BP were moderate; and renal changes were reversible upon treatment discontinuation, according to the presentation.

“In stable, very well-treated people with HFrEF, the PDE-9 inhibitor engaged the target, increased plasma cyclic guanosine monophosphate did not lower NT-proBNP at the highest dose. Reductions in NT-proBNP were seen at lower dose,” Udelson said during the presentation. “Exploratory submaximal elevations in cyclic guanosine monophosphate were associated with larger reductions in NT-proBNP vs. placebo, which were more commonly seen at the lower tovinontrine doses.”

Tovinontrine in patients with HFpEF

For patients with HFpEF, at 12 weeks, tovinontrine 50 mg twice daily did not decrease placebo-adjusted NT-proBNP from baseline (least squares mean change, 9.4%; 3.1 to 23.4; P = .147) but did increase median cyclic guanosine monophosphate , according to the presentation.

The researchers reported tovinontrine 50 mg twice daily showed a similar safety profile in the Cycle-2^PEF trial and the Cycle-1^REF trial.

It is unknown whether the dose-response relationship observed in Cycle-1^REF carries over to patients with HFpEF, Udelson said.

“High-dose tovinontrine did not change NT-proBNP in both trials,” Udelson said during the presentation. “Tovinontrine led to increases in cyclic guanosine monophosphate in both trials and we saw trends in NT-proBNP reduction in really well-treated participants in the Cycle-1^REF trial where we had a dose range, and the post hoc analysis we believe supports the hypothesis that at a lower tovinontrine dose, causing less intense PDE-9 inhibition and less cyclic guanosine monophosphate elevation, may result in greater reduction in NT-proBNP.”

Cycle-3^REF, a phase 2b trial of tovinontrine in patients with HFrEF, is planned for 2027, according to the presentation.