Are there any ongoing clinical trials in the US for the use of Retinoic Acid Receptor (RAR) agonists for control of Aortic Valve (AV) stenosis?

Current Clinical Trials for Retinoic Acid Receptor Agonists in Aortic Valve Stenosis

There are promising preclinical studies but no current registered clinical trials in the US specifically testing Retinoic Acid Receptor (RAR) agonists for aortic valve stenosis control. 1

Background on Aortic Valve Stenosis Treatment

Current management of aortic valve stenosis (AV stenosis) is primarily interventional, with either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) being the mainstays of treatment for severe symptomatic disease 2. Medical therapy options remain limited:

• Current medical therapies:

  • Hypertension management (cautious use of antihypertensives) 3
  • Symptom management until valve replacement
  • No proven medical therapy to slow progression 2

• Failed medical approaches:

  • Statins have been extensively studied but failed to show benefit for prevention of AS progression in randomized controlled trials 2
  • Current guidelines explicitly state: "Statin therapy is not indicated for prevention of hemodynamic progression of AS" (Class III: No Benefit, Level of Evidence: A) 2

Emerging Research on RAR Agonists

Recent preclinical research has identified promising targets for pharmacological intervention in AV stenosis:

• A 2025 study published in Circulation identified ALDH1A1 (aldehyde dehydrogenase 1 family member A1) as the most downregulated gene in valvular interstitial cells from calcified versus control valves 1

• This downregulation promotes transition of valvular cells to an osteoblastic phenotype, contributing to valve calcification 1

• All-trans retinoic acid (a RAR agonist) was shown to:

  • Decrease calcium deposition
  • Attenuate osteoblast activity in valvular cells
  • Inhibit calcification of bioprosthetic valves in animal models
  • Improve echocardiographic parameters in a xenograft sheep model 1

Current Status of Clinical Trials

Despite promising preclinical data:

1. No registered clinical trials are currently testing RAR agonists specifically for AV stenosis in the US
2. The research is still in the translational phase, moving from animal models to potential human applications
3. The most recent evidence (2025) suggests RAR agonists represent "a promising and innovative pharmacological approach to prevent calcification of native aortic valves" but this has not yet translated to clinical trials 1

Other Investigational Approaches

While RAR agonists are not currently in clinical trials for AV stenosis, other medical approaches are being investigated:

• Renin-angiotensin system inhibitors (RASi) have shown some promise in observational studies:

  • May be safe in patients with AV stenosis 4
  • Potentially reduce need for aortic valve replacement 4
  • Associated with modulation of adverse left ventricular remodeling 5
  • However, evidence remains weak and large randomized trials are needed 4

• The TAVI UNLOAD trial (NCT02661451) is investigating whether early TAVR in patients with moderate AS and heart failure with reduced ejection fraction improves outcomes 2

Clinical Implications

For clinicians managing patients with AV stenosis:

1. Current management should follow established guidelines for valve replacement when indicated 2
2. No medical therapy is currently recommended to slow progression of AV stenosis 2
3. RAR agonists represent a promising future direction but remain investigational
4. Patients interested in novel therapies should be referred to academic medical centers conducting research in this area

Conclusion

While preclinical evidence suggests RAR agonists may have potential in preventing or slowing AV stenosis progression, this approach has not yet advanced to clinical trials in the US. The current standard of care remains close monitoring and timely valve replacement when indicated.