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phase 3Cardiovascular

Ularitide

Also known as: Urodilatin, CDD/ANP 95-126, INN Ularitide, Simdax (investigational)

Ularitide is a synthetic form of urodilatin, a 32-amino acid natriuretic peptide produced by renal tubular cells that differs from ANP by an N-terminal extension of four amino acids (Thr-Ala-Pro-Arg). Unlike ANP, urodilatin resists degradation by neutral endopeptidase (neprilysin), giving it a longer effective half-life in the kidney. Ularitide was investigated in the phase 3 TRUE-AHF trial for acute decompensated heart failure but failed to meet its primary endpoint of cardiovascular mortality reduction, though it did improve dyspnea.

3 cited references·6 researched benefits

Quick Answer

Ularitide is a synthetic form of urodilatin, a kidney-derived natriuretic peptide related to ANP that promotes natriuresis, diuresis, and vasodilation. It was developed for acute heart failure treatment and tested in the phase 3 TRUE-AHF trial (n=2,157), where it improved dyspnea but failed to reduce cardiovascular mortality compared to placebo. Ularitide resists neprilysin degradation better than ANP, providing a longer renal effect duration with a plasma half-life of approximately 12 minutes.

Key Facts

Mechanism
Ularitide binds to natriuretic peptide receptor A (NPR-A), the same receptor as ANP and BNP, activating particulate guanylate cyclase and elevating intracellular cGMP in vascular smooth muscle, renal tubular, and adrenal cells. This produces vasodilation (reducing preload and afterload), natriuresis and diuresis (promoting sodium and water excretion), and suppression of the renin-angiotensin-aldosterone system. Ularitide's four-amino acid N-terminal extension compared to ANP makes it resistant to degradation by neutral endopeptidase (neprilysin), the enzyme that rapidly breaks down ANP. This gives ularitide a longer duration of action within the kidney, where urodilatin acts as a paracrine regulator of sodium and water handling.
Research Status
phase 3
Half-Life
~12 minutes
Molecular Formula
C₁₄₃H₂₃₅N₄₃O₄₅S₃
Primary Use
Cardiovascular
Table of Contents

Benefits

  • Improves dyspnea in acute decompensated heart failurestrong
  • Promotes natriuresis and diuresis to reduce volume overloadstrong
  • Reduces preload and afterload via vasodilationstrong
  • Resistant to neprilysin degradation, providing longer renal action than ANPmoderate
  • Suppresses RAAS activation in acute heart failuremoderate
  • Failed to reduce cardiovascular mortality in TRUE-AHF trial (negative result)strong

Dosage Protocols

RouteDosage RangeFrequencyNotes
Intravenous infusion7.5–30 ng/kg/minContinuous infusion for 24-48 hoursTRUE-AHF trial used 15 ng/kg/min for 48 hours. Dose-finding studies tested 7.5-30 ng/kg/min. Infusion must be titrated to avoid symptomatic hypotension.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Hypotension (most common dose-limiting effect)common
  • Dizzinesscommon
  • Worsening renal function at higher dosesrare
  • Symptomatic hypotension requiring vasopressor supportserious
  • Headachecommon

Frequently Asked Questions

Why did ularitide fail in the TRUE-AHF trial?
The TRUE-AHF trial (2,157 patients) tested ularitide 15 ng/kg/min for 48 hours in acute decompensated heart failure. While ularitide significantly improved dyspnea (the co-primary endpoint) and reduced NT-proBNP levels, it did not reduce the hierarchical endpoint of cardiovascular death at 6 months. The trial suggested that short-term hemodynamic improvement in acute heart failure does not necessarily translate to long-term mortality benefit — a finding consistent with other vasodilator trials in this population.
How does ularitide differ from ANP and BNP?
Ularitide (urodilatin) is a 32-amino acid peptide derived from the same preproANP precursor as ANP, but with four additional amino acids at the N-terminus (Thr-Ala-Pro-Arg). This extension makes it resistant to neprilysin degradation, unlike ANP which has a half-life of only 2-5 minutes. BNP is a structurally distinct 32-amino acid peptide from a different gene. All three bind the same NPR-A receptor. Urodilatin is uniquely produced by renal tubular cells and acts locally in the kidney as a paracrine natriuretic factor.
Is ularitide still being developed after the TRUE-AHF failure?
The TRUE-AHF results significantly dampened commercial interest in ularitide for acute heart failure. No major new clinical trials have been announced since the 2017 trial results. However, the concept of augmenting natriuretic peptide signaling lives on through neprilysin inhibitors — sacubitril/valsartan (Entresto) works by preventing the breakdown of endogenous ANP, BNP, and urodilatin, and has demonstrated clear mortality benefit in chronic heart failure.

References

  1. 1
    Effect of ularitide on cardiovascular mortality in acute heart failure (TRUE-AHF trial)(2017)PubMed ↗
  2. 2
    Urodilatin (ularitide) in patients with decompensated chronic heart failure: a phase II trial(2007)PubMed ↗
  3. 3
    Urodilatin: physiology and therapeutic potential in acute heart failure(2008)PubMed ↗

Latest Research

Last updated: 2026-02-19