At a glance

What is aviptadil?

Aviptadil is a synthetic copy of vasoactive intestinal peptide (VIP), a 28-amino acid signaling molecule that occurs naturally in the human body. It has been developed and tested as a drug, most prominently as a candidate treatment for acute respiratory failure. It is also known by the research code RLF-100 and the trade name Zyesami.

VIP itself is concentrated in the lungs and the gut, where it acts as a messenger between nerves and tissue. Aviptadil is a manufactured version of that same molecule, intended to be given in larger amounts than the body makes on its own.

The history of aviptadil

Aviptadil's story runs from basic physiology to a high-profile pandemic trial. Vasoactive intestinal peptide was first isolated from the small intestine in 1970¹ by Said and Mutt, and Sami Said later focused on its protective role in the lungs. Because VIP is concentrated in lung tissue and helps regulate inflammation and blood flow there, it was proposed as a candidate for acute respiratory distress syndrome (ARDS), a form of severe lung injury.

Interest surged during the COVID-19 pandemic. A synthetic VIP, aviptadil, was taken into clinical trials for critically ill COVID-19 patients with respiratory failure by the companies NRx Pharmaceuticals and Relief Therapeutics, under the names RLF-100 and Zyesami. The program drew wide attention when the companies reported encouraging early results in 2021. Independent testing² followed, and it was found that it’s not effective, as described below.

How does aviptadil work?

Aviptadil works by mimicking vasoactive intestinal peptide, the natural signaling molecule the body uses to relax blood vessels and calm inflammation, particularly in the lungs. VIP binds to two receptors, VPAC1 and VPAC2³, that are common on lung tissue, and activating them relaxes the smooth muscle in blood vessels and airways and triggers signals that lower inflammation.

Those receptors are not limited to the lungs. VPAC1 and VPAC2 sit on T cells and macrophages⁴, and VPAC1 receptors couple to adenylyl cyclase⁵, the enzyme that makes the signaling molecule cAMP.

A 2013 review of VIP's immune effects describes work in mice, where VIP:

• Inhibited TNF, IL-6, and IL-12⁶ and raised IL-10
• Blocked NF-κB movement into the nucleus
• Induced Foxp3-positive regulatory T cells through tolerogenic dendritic cells

These are animal findings, and they do not show the same effects in patients.

Much of the therapeutic rationale centers on a specific lung cell. In laboratory studies, VIP helps protect the alveolar type II cells that produce surfactant, the substance that keeps the tiny air sacs of the lungs open, and it reduces the release of inflammatory molecules. The theory tested in trials was that supplying extra VIP might help shield the lungs during the severe inflammation of ARDS. This describes the proposed mechanism and the underlying biology; whether aviptadil actually improves outcomes in patients is a separate question, addressed next.

Is it FDA-approved?

No. Aviptadil is not approved by the FDA for any use and remains an investigational drug in the United States. During the pandemic it was studied under FDA oversight and received expedited review designations, but the FDA declined⁷ to authorize it for emergency use in COVID-19, and it has not been approved since.

The FDA granted aviptadil Fast Track Designation⁸ for respiratory distress in COVID-19 in 2020, which speeds review but does not signal approval. Later, the agency declined the company's request⁹ for Breakthrough Therapy Designation in November 2021, according to the sponsor's quarterly filing.

One nuance is worth noting for accuracy. A separate combination product that pairs aviptadil with phentolamine, sold as Invicorp, is approved¹⁰ in some other countries, including in Europe, as an injection for erectile dysfunction. That is a different formulation and a different use, and it does not carry over to the United States, where aviptadil has no FDA approval for any indication.

What does the research show?

The strongest research shows that aviptadil has not been proven to work for the condition it was most studied in. It was tested primarily in critically ill COVID-19 patients with acute hypoxemic respiratory failure. The companies developing it reported favorable early findings from a company-sponsored phase 2b/3 study in 2021, but the pivotal independent test was the NIH-funded TESICO trial¹¹, a randomized, placebo-controlled study of 461 patients. According to PubMed, that trial found that aviptadil did not significantly improve a patient's clinical status at 90 days, showed no reduction in mortality, and was stopped early for futility on the recommendation of its independent safety monitoring board.

TESICO's two headline results, up to day 90, were:

In short, the human evidence is real but conflicting, and the best-designed independent study did not confirm a benefit. Outside the respiratory-failure setting, published human evidence is limited. Aviptadil is best understood as an investigational compound whose effectiveness for its studied uses has not been established.

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