SNV-801
Heart Failure
The metabolic inotrope. 6 completed randomized controlled trials spanning stable outpatients to cardiogenic shock. +2.0 L/min cardiac output. −18% NT-proBNP. Hemodynamic rescue without arrhythmogenic risk.
Therapeutic rationale
The strongest drug signal of the last decade is already metabolic.
SGLT2 inhibitors are the most important heart failure drug class in a generation. They reduce cardiovascular mortality by 25\u201326% in patients who don't even have diabetes (DAPA-HF, McMurray et al., NEJM 2019). Glucose reduction in these patients is negligible (HbA1c: 0.16\u20130.20%). The benefit cannot be explained by the designed mechanism.
The consistent pharmacological signal across all SGLT2 inhibitor heart failure trials: elevated circulating ketone bodies (Inagaki et al., Clin Ther 2018). The drug was designed to lower glucose. The benefit tracks with the metabolic state shift.
But SGLT2 inhibitors achieve only modest ketone elevations: 0.1\u20130.3 mM. The RCTs of direct ketone intervention show that therapeutic-level elevations (1.0\u20133.5 mM) produce dramatically larger hemodynamic benefits. The dose-response curve is steep and consistent across 6 trials. We are capturing only a fraction of the potential therapeutic effect.
SNV-801 is designed to deliver the full metabolic therapeutic window that SGLT2 inhibitors partially access, via direct oral delivery of sustained, therapeutic-level ketone body exposure.
Clinical evidence
Six RCTs. Full severity spectrum.
From stable outpatients (Berg-Hansen 2024) to cardiogenic shock (Berg-Hansen 2023), with HFrEF, HFpEF, and pulmonary hypertension represented.
Nielsen et al., JACC Heart Failure 2019 (n=16, acute HFrEF)
+2.0 L/min cardiac output at 3.3 mM BHB. +8 percentage points LVEF. Immediate, dose-dependent hemodynamic improvement. The magnitude of effect rivals inotropic agents without the arrhythmogenic risk.
PMID: 30884964
Berg-Hansen et al., Circulation 2024 (n=24, 14-day oral RCT, HFrEF)
−18% NT-proBNP reduction with oral ketone ester. First demonstration that oral metabolic intervention produces clinically meaningful biomarker improvement in chronic heart failure. NT-proBNP is the gold-standard prognostic marker.
PMID: 38533643
Gopalasingam et al., Circulation 2024 (HFpEF + T2D)
−5 mmHg peak pulmonary capillary wedge pressure (PCWP). Direct hemodynamic improvement in HFpEF, the phenotype where no approved drug has shown consistent benefit on filling pressures.
PMID: 39162035
Berg-Hansen et al., JACC 2023 (Cardiogenic shock)
Hemodynamic stabilization with metabolic intervention in cardiogenic shock. Feasibility and safety demonstrated in the most acute, highest-mortality heart failure setting. Conventional inotropes carry significant arrhythmia risk at these severity levels.
Guldbrandsen et al., 2025 (1,3-butanediol)
Oral 1,3-butanediol (ketone precursor) produced hemodynamic benefits in heart failure. Independent confirmation of the oral ketone approach using a different delivery molecule.
PMID: 39719429
Nielsen et al., 2023 (Pulmonary hypertension)
Metabolic intervention improved hemodynamics in pulmonary hypertension, extending the cardiac indication beyond left-sided heart failure to right ventricular dysfunction.
PMID: 37183871
Mechanism of action
Six validated cardiac pathways.
The failing heart upregulates ketone oxidation enzymes, signaling a metabolic demand that existing therapies do not supply. SNV-801 supplies it.
ATP restoration
The failing heart loses metabolic flexibility. Ketone bodies enter the TCA cycle directly, producing 25–30% more ATP per unit oxygen than glucose. The heart preferentially oxidizes ketones when available, and failing hearts upregulate ketone oxidation enzymes, signaling a metabolic demand that existing therapies do not address.
Aubert et al., 2016; Bedi et al., 2016
NAD+ regeneration
Heart failure depletes the NAD+/NADH ratio critical for electron transport chain function. Specific ketone metabolites regenerate NAD+ through direct biochemical pathways, bypassing the metabolic bottleneck in failing cardiomyocytes. This is mechanistically distinct from BHB alone, which consumes NAD+ via BDH1.
Verdin, 2015; Xie et al., 2020
NLRP3 inflammasome inhibition
BHB directly inhibits NLRP3 inflammasome assembly in cardiac tissue, reducing IL-1β-mediated inflammatory signaling that drives adverse remodeling, cardiomyocyte apoptosis, and fibrosis in heart failure.
Youm et al., Nature Medicine 2015
HDAC inhibition (anti-fibrotic)
BHB acts as an endogenous HDAC inhibitor in cardiac fibroblasts, reducing collagen deposition and fibrotic remodeling. Cardiac fibrosis is a major driver of diastolic dysfunction in HFpEF and disease progression in HFrEF.
Shimazu et al., Science 2013
SIRT3 activation
Ketone-driven NAD+ regeneration activates SIRT3 in cardiac mitochondria, enhancing mitochondrial biogenesis, reducing oxidative stress, and improving electron transport chain efficiency.
Pillai et al., 2016
HCA2/GPR109A vasodilation
BHB activates HCA2/GPR109A receptors in vascular endothelium, producing vasodilatory effects that reduce afterload. This complements the direct myocardial metabolic benefits.
Taggart et al., 2005
Strategic positioning
Complementary to SGLT2 inhibitors. Not competitive.
The combination thesis: SGLT2 inhibitor + SNV-801 covers the full ketone dose-response range. SGLT2 inhibitors provide a baseline metabolic shift (0.1\u20130.3 mM). SNV-801 delivers therapeutic-level exposure (target 1.0\u20133.5 mM). The mechanisms are additive, not redundant.
For pharma partners with SGLT2 franchises, SNV-801 represents a natural pipeline extension into the mechanism their own drugs have validated. The ketone hypothesis for SGLT2 benefit is already published (Inagaki 2018, Ferrannini 2016). SNV-801 is the pharmacological realization of that hypothesis.
Safety advantage: metabolic ketosis (euglycemic, BHB 1\u20134 mM) is physiologically distinct from diabetic ketoacidosis (hyperglycemic, BHB >10 mM with concurrent acidosis). Six completed RCTs with no safety signals support the cardiac safety profile.