reviewed april 2026|next review october 2026|88 physicians psi has verified|430569 published studies

Ularitide (Urodilatin)

Ularitide is a synthetic form of urodilatin, a 32-amino acid naturally occurring (the body's own) natriuretic peptide produced by renal tubular cells, which completed the TRUE-AHF Phase III trial for acute heart failure without meeting its primary cardiovascular death endpoint.

Evidence landscape: 430569 published studies

Published studies span natriuretic peptide pharmacology and acute heart failure clinical trials. Phase III human data exists.

23 Human
141 Animal
36 Reviews
430369 Other research

Not FDA-approved. The TRUE-AHF Phase III trial did not meet its primary endpoint for cardiovascular death reduction. Development status is uncertain.

Not available as a therapeutic product. Urodilatin is a naturally occurring (the body's own) kidney-produced peptide. The synthetic form was developed for acute heart failure treatment.

Ularitide is a natriuretic peptide that activates NPR-A receptors. Unlike ANP, it resists degradation by neutral endopeptidase (NEP), providing sustained renal natriuretic activity. The Phase II-to-Phase III trajectory mirrors the serelaxin (relaxin-2) story in cardiology.

PSI Assessment

Acute heart failure is one of the leading causes of hospitalization. Ularitide, a synthetic version of the kidney hormone urodilatin, was developed to harness the body's own natriuretic signaling for vasodilation and fluid removal. Phase II trials showed hemodynamic benefits. The Phase III TRUE-AHF trial enrolled over 2,100 patients and did not meet its primary endpoint for cardiovascular death reduction. Like serelaxin, ularitide joins the list of biologically compelling cardiovascular peptides that did not survive the Phase III confirmation step.

Synthetic kidney hormone. Phase II showed hemodynamic benefit. TRUE-AHF Phase III failed the cardiovascular mortality endpoint. The pharmacology is sound but clinical benefit is unproven.

The mechanism operates through natriuretic peptide receptor A (NPR-A), activating guanylyl cyclase and increasing cyclic GMP. This produces renal vasodilation, promotes sodium and water excretion, inhibits renin and aldosterone secretion, and reduces cardiac preload and afterload. Ularitide's resistance to neutral endopeptidase (NEP) degradation provides longer renal activity than atrial natriuretic peptide (ANP), which was the pharmacological rationale for its development.

What the evidence supports

Ularitide is a synthetic form of urodilatin, a kidney-produced natriuretic peptide with well-characterized pharmacology. Phase II trials demonstrated hemodynamic benefits in acute heart failure patients. The NPR-A receptor mechanism producing vasodilation and natriuresis is pharmacologically validated. NEP resistance provides longer renal activity than ANP. The compound was well tolerated in the large TRUE-AHF Phase III trial.

What is not yet established

Clinical efficacy for reducing cardiovascular mortality after the TRUE-AHF Phase III trial did not meet its primary endpoint. Whether ularitide has a future development path. Whether alternative endpoints or patient subgroups might show benefit from ularitide treatment.

Research Evidence

The findings below cover the Phase II hemodynamic data, the Phase III TRUE-AHF outcome, and the natriuretic peptide pharmacology.

Evidence by condition

Evidence dimensions across acute heart failure and natriuretic peptide biology. The heart failure application reached Phase III but failed the primary endpoint.

Condition	Mechanism	Animal evidence	Human evidence	Replication
Acute Heart Failure
Renal Natriuretic Biology
Diuresis and Natriuresis

Phase II trials demonstrated that ularitide infusion produces hemodynamic improvements in acute heart failure patients, including reduced pulmonary capillary wedge pressure and improved cardiac index.

The Phase II hemodynamic signal provided the rationale for the larger Phase III trial. Hemodynamic improvement does not guarantee mortality benefit, as multiple heart failure drugs have demonstrated.

The TRUE-AHF Phase III trial did not meet its co-primary endpoints: cardiovascular death through day 180 was not reduced, and a hierarchical clinical composite was not improved by ularitide compared to placebo.

The Phase III failure is the definitive clinical data point. Like serelaxin, ularitide demonstrated biological activity without translating to the mortality benefit needed for approval.

Ularitide activates NPR-A with resistance to NEP degradation, providing sustained natriuretic and vasodilatory effects. The pharmacology is well-characterized across multiple studies.

The mechanism is not disputed. The question was always whether natriuretic peptide receptor activation translates to mortality benefit in acute heart failure, and the TRUE-AHF answer was negative.

23 Human|141 Animal|36 Reviews

View all 430569 indexed studies

How Ularitide (Urodilatin) Works

Ularitide is a synthetic form of urodilatin, a naturally occurring (the body's own) 32-amino acid natriuretic peptide. It activates NPR-A, increasing cGMP to produce renal vasodilation, natriuresis, and cardiac preload/afterload reduction.

Mimics a kidney hormone that eliminates excess fluid and relaxes blood vessels.

For a more detailed view of the biology, here is what researchers have observed at the molecular level.

Synthetic urodilatin. Activates NPR-A increasing cGMP. Promotes natriuresis and vasodilation.

What is Ularitide (Urodilatin) being studied for?

Researchers are studying Ularitide (Urodilatin) across several health conditions. Each condition below is labeled with the strength of evidence that exists for that specific use, not for Ularitide (Urodilatin) overall. This means a compound can have human studies for one condition but only animal data for another.

Acute Heart Failure

·Human Trials

Phase II trials showed hemodynamic benefits. TRUE-AHF Phase III trial (n=2,100+) did not meet primary endpoints for cardiovascular death or clinical composite improvement. Well tolerated with hypotension as dose-limiting effect.

Limitations: The Phase III failure is definitive for the clinical program as designed. Whether alternative endpoints, dosing, or patient selection could yield different results is speculative. Development status is uncertain.

Renal Natriuretic Biology

·Animal Studies

Urodilatin physiology is well-characterized. Produced by renal tubular cells, it acts locally to regulate sodium and water excretion. NEP resistance distinguishes it from ANP.

Limitations: Understanding the physiology has not translated to therapeutic benefit in the heart failure setting. The renal natriuretic biology is established but the clinical application failed.

Diuresis and Natriuresis

·Animal Studies

Ularitide promotes sodium and water excretion through NPR-A-mediated cGMP signaling. Hemodynamic improvements documented in Phase II acute heart failure trials.

Limitations: The diuretic and natriuretic effects are pharmacologically confirmed but did not translate to clinical outcome benefit in the Phase III setting.

Safety and Regulatory Status

FDA Status: Not FDA-approved. Phase III TRUE-AHF trial did not meet primary endpoints. Development status is uncertain.

Availability: Not available as a therapeutic product. Urodilatin is a naturally occurring (the body's own) kidney peptide. The clinical program has not advanced since the Phase III result.

Class context: Ularitide was well tolerated in clinical trials. Hypotension was the dose-limiting adverse effect. Like serelaxin, the program failed on efficacy rather than safety.

Ularitide was well tolerated in the TRUE-AHF Phase III trial. Hypotension was the primary safety concern. The program failed on efficacy, not safety.

Peptide Structure

Technical molecular data for researchers and clinicians.

Questions and Comparisons

Questions the evidence raises for a Ularitide (Urodilatin) discussion.

Comparison and Related Research

Ularitide is compared with other natriuretic peptides and cardiovascular peptide therapies.

Related compounds

BNP Relaxin-2 Angiotensin 1-7

Frequently Asked Questions

References

Each citation links to the original study on PubMed, the U.S. National Library of Medicine database.

1.Phase III TRUE-AHF trial evaluating ularitide, a synthetic form of urodilatin, in 2,157 patients with acute heart failure. The primary endpoint of cardiovascular death was not met, and ularitide did not significantly reduce the hierarchical composite clinical outcome. The trial established the safety profile but failed to demonstrate the survival benefit anticipated from earlier-phase data.Packer M et al., 2017 in N Engl J Med. View on PubMed
2.Early clinical evaluation of intravenous urodilatin (ularitide) in patients with decompensated heart failure. The infusion produced significant increases in cardiac output, reductions in pulmonary capillary wedge pressure, and suppression of aldosterone and norepinephrine, establishing the hemodynamic rationale for larger trials.Elsner D et al., 1995 in Eur Heart J. View on PubMed
3.Dose-ranging Phase II study in 221 heart failure patients receiving 24-hour ularitide infusions at three dose levels or placebo. The two higher doses produced significant reductions in pulmonary capillary wedge pressure within hours, with dose-dependent hemodynamic improvements. Symptomatic hypotension was the main dose-limiting side effect.Mitrovic V et al., 2006 in Am Heart J. View on PubMed
4.Comparative study of urodilatin infusion in healthy volunteers and heart failure patients. In both groups, urodilatin induced significant natriuresis and diuresis in a dose-dependent manner. The renal effects were preserved even in the heart failure cohort, distinguishing urodilatin from atrial natriuretic peptide, which often shows blunted renal responses in decompensated states.Kentsch M et al., 1995 in Eur J Clin Invest. View on PubMed

Medical Disclaimer

This content is for educational and informational purposes only and does not constitute medical advice. The information presented reflects published research as indexed by PSI and should not be used to make treatment decisions. Always consult a qualified healthcare provider before starting, stopping, or modifying any treatment.