Cardurion Pharmaceuticals Tovinontrine (CRD-750) CYCLE Trials Performance
Challenge
Heart failure affects approximately 6.7 million adults in the United States, with roughly equal distribution between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Despite significant therapeutic advances in recent decades—including ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors (ARNIs)—heart failure remains responsible for substantial morbidity and mortality, with approximately 50% of patients dying within five years of diagnosis. One in five patients is hospitalized annually, and roughly 25% are readmitted within a month of discharge. The natriuretic peptide signaling (NPS) pathway plays a critical protective role in cardiac function, but phosphodiesterase 9 (PDE9) activity is significantly upregulated in chronic heart failure—reducing the beneficial effects of this pathway precisely when patients need it most. PDE9 selectively degrades cyclic guanosine monophosphate (cGMP), a second messenger molecule essential for natriuretic peptide signaling that mediates improvements in cardiac relaxation, reduced hypertrophy, and inhibited fibrosis through protein kinase G (PKG) activation. There was an urgent need for a novel therapeutic approach that could enhance natriuretic peptide pathway activity in both types of chronic heart failure through selective PDE9 inhibition.
Approach
Cardurion Pharmaceuticals developed tovinontrine (CRD-750), an orally administered phosphodiesterase 9 (PDE9) inhibitor designed to enhance the natriuretic peptide signaling pathway—representing the first clinical-stage PDE9 inhibitor evaluated in patients with chronic heart failure. The compound works by selectively inhibiting PDE9, which preserves cGMP generated by natriuretic peptide receptor activation and prevents its degradation. This mechanism differs fundamentally from existing therapies: while ARNIs like sacubitril/valsartan prevent the breakdown of natriuretic peptides themselves, tovinontrine targets the downstream degradation of cGMP, potentially offering complementary or additive benefit. PDE9 is preferentially localized near the plasma membrane where particulate guanylate cyclase-derived cGMP is produced—positioning it as the primary regulator of natriuretic peptide-stimulated cGMP, particularly in disease states where nitric oxide signaling is depressed.
Cardurion conducted two parallel Phase 2 clinical trials to evaluate tovinontrine efficacy and safety across both phenotypes of chronic heart failure:
CYCLE-1-REF Trial (CRD-750-201):
A Phase 2, randomized, double-blind, placebo-controlled, dose-finding study in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Enrolled approximately 560 patients with NYHA functional class II-III HF, ejection fraction ≤40%, and elevated NT-proBNP (≥600 pg/mL) from multiple global sites.
Patients had at least 6 months duration of HF and history of hospitalization, emergency department visit, or outpatient visit requiring IV or subcutaneous diuresis within 12 months.
Evaluated three doses of tovinontrine compared to placebo over a 12-week treatment period.
Primary endpoint: change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to week 12.
Study was conducted in 2023 and completed enrollment in 2025.
CYCLE-2-PEF Trial (CRD-750-202):
A Phase 2, randomized, double-blind, placebo-controlled clinical study in patients with chronic heart failure with preserved ejection fraction (HFpEF).
Enrolled approximately 300 patients with NYHA functional class II-III HF, ejection fraction >40%, left atrial enlargement, and elevated NT-proBNP.
Evaluated a single dose (50 mg) of tovinontrine compared to placebo over a 12-week treatment period.
Primary endpoint: change in NT-proBNP from baseline to week 12.
Study was conducted in 2023 and completed enrollment in 2025.
The trials were built upon proof-of-concept data from the earlier CARDINAL-HF Phase 2a trial, which demonstrated that the predecessor compound CRD-740 met its primary endpoint by producing statistically significant increases in plasma cGMP after four weeks of treatment in HFrEF patients—confirming high levels of PDE9 inhibition and activation of the natriuretic peptide pathway. Importantly, cGMP increases were observed both in patients on background sacubitril/valsartan therapy and those without, supporting potential for both monotherapy and combination approaches.
Results: The CYCLE trials represent a significant advancement in cardiovascular drug development, as Cardurion became the first company to bring a PDE9 inhibitor into clinical development for chronic heart failure and to complete enrollment in comprehensive Phase 2 programs evaluating this novel mechanism in both HFrEF and HFpEF patient populations:
Novel mechanism validation: Successfully demonstrated clinical proof-of-mechanism for PDE9 inhibition as a therapeutic strategy in heart failure, targeting the clinically validated natriuretic peptide signaling pathway through a fundamentally new approach.
Comprehensive patient population coverage: Evaluated tovinontrine efficacy across the full spectrum of chronic heart failure phenotypes, addressing approximately equal proportions of the HF patient population (HFrEF and HFpEF).
Precedented biomarker endpoint: NT-proBNP reduction has been established as a validated surrogate marker for treatment efficacy in heart failure trials, including in studies of approved therapies like sacubitril/valsartan (Entresto), and has been qualified as a surrogate for clinical endpoints by regulatory authorities.
Potential for combination therapy: The mechanism of action suggests potential complementary effects when combined with existing heart failure therapies, particularly ARNIs, as demonstrated by cGMP elevation in CARDINAL-HF patients already receiving sacubitril/valsartan.
Addressing unmet needs in HFpEF: Particularly significant for the HFpEF population, which has historically had limited effective pharmacological treatment options compared to HFrEF.
These findings position tovinontrine as a potentially transformative therapy that could enhance natriuretic peptide pathway activity through a novel downstream mechanism, with results from the CYCLE trials expected to be presented at a future medical meeting. The successful completion of enrollment marks a critical milestone in advancing PDE9 inhibition from preclinical promise to potential clinical reality for millions of patients living with chronic heart failure.