Peptide Graded

All peptides / Immunity

Aviptadil

Vasoactive intestinal peptide

Also Vasoactive intestinal peptide, VIP, Zyesami, RLF-100, Invicorp, Aviptadil acetate

Evidence
BSome human evidence
FDA status
In clinical trialsas of 2026-10-26
Route
Intravenous
Studies cited
1 human3 animal or cell

Sold for

Aviptadil drew attention in 2020 and 2021 as a proposed rescue treatment for COVID-19 respiratory failure, promoted by its sponsor as protecting the lung's surfactant-producing cells.

Studies say

A randomized trial of roughly 460 critically ill COVID-19 patients found no benefit on recovery or survival, so the respiratory claim is not supported despite a plausible mechanism (grade B, negative).

Why grade B. For the use it became known for, respiratory failure in COVID-19, the decisive evidence is TESICO, a randomized placebo-controlled trial of about 460 patients that was stopped for futility with no difference in recovery or 90-day mortality. A properly conducted negative randomized trial is grade B evidence against the claimed benefit; the immunology citations are reviews of the natural peptide, not studies of the drug. 4611

FDA. Aviptadil is not approved by the FDA for any use. The FDA declined requests for emergency use authorisation in critical COVID-19 in 2021 and 2022, and the investigational product has not been approved since. A combination of aviptadil with phentolamine (Invicorp) is approved in the United Kingdom and some other countries as an injection for erectile dysfunction, but not in the United States. 7910

Written from 11 cited sources. Last refreshed 2026-10-27. Not physician reviewed.

Evidence checklist

  • Randomised controlled trial TESICO, placebo-controlled, stopped for futilityyes
  • Human study over 100 people About 460 patients in TESICOyes
  • More than one research group Main trial run by the sponsor's networkno
  • Clinical outcomes, not surrogate markers 90-day recovery and mortality measuredyes
  • Human safety data beyond case reports Monitoring board found no new concernsyes

Drawn from the cited studies below. A dash means the sources give no information.

What it is

Aviptadil is the synthetic form of vasoactive intestinal peptide (VIP), a 28-amino-acid peptide first isolated from pig small intestine in 1970 by Said and Mutt, who noted that it dilated blood vessels, lowered blood pressure, increased cardiac output and stimulated breathing. VIP is now known to act as a neurotransmitter throughout the nervous system and as a signalling molecule in the immune system. 16

Two commercial histories attach to the compound. In Europe it has long been combined with phentolamine as Invicorp, an injection for erectile dysfunction. In 2020 NeuroRx (later NRx Pharmaceuticals) and Relief Therapeutics repurposed intravenous aviptadil as RLF-100, later Zyesami, for respiratory failure in COVID-19, and the FDA granted it Fast Track designation that June. 810

How it works

VIP binds two G-protein-coupled receptors, VPAC1 and VPAC2, which signal through adenylyl cyclase and cyclic AMP. The structure of VPAC1 has been worked out in detail: the peptide docks into the receptor's N-terminal domain. 35

In the immune system, VIP acts on T cells and macrophages. It suppresses T cell migration, proliferation and cytokine production through VPAC1, shifts the balance toward Th2-type responses through VPAC2, and in laboratory studies inhibits inflammatory signals including TNF, IL-6 and IL-12. The COVID-19 hypothesis built on this and on VIP's high concentration in the lung, where it is proposed to protect the type II alveolar cells that make surfactant. 46

What human research shows

The sponsor's own phase 2b/3 trial in 2020 and 2021 reported mixed results, and the FDA declined its requests for emergency use authorisation, stating the data did not meet the standard. 79

The independent test came from ACTIV-3b/TESICO, a National Institutes of Health trial published in The Lancet Respiratory Medicine in 2023. Patients with COVID-19 acute hypoxaemic respiratory failure were randomized to intravenous aviptadil or placebo. Enrolment was stopped for futility after about 460 patients. The primary outcome, a six-category recovery scale at 90 days, showed no benefit (odds ratio 1.10, 95% confidence interval 0.79 to 1.54), and 90-day mortality was 37% with aviptadil versus 36% with placebo. 11

A 2023 independent analysis of the sponsor's claims and data, published in PMC, raised questions about how earlier results were presented. 2

StudyModelFinding
ACTIV-3b/TESICO, Lancet Respiratory Medicine 2023Humans, about 460 adults with COVID-19 respiratory failure, randomized double-blind placebo-controlledNo improvement in 90-day recovery (odds ratio 1.10) and no difference in mortality (37% versus 36%); stopped for futility. 11
Said and Mutt 1970, ScienceIsolation from pig small intestineIdentified a 28-amino-acid peptide with vasodilator, hypotensive and respiratory-stimulant activity. 1
VIP immunoregulation review, 2002Review of T cell and macrophage studies, including transgenic and knockout miceVIP suppresses T cell activation through VPAC1 and shifts Th1/Th2 balance through VPAC2. 4
Independent review of aviptadil COVID-19 evidence, 2023Analysis of sponsor trial data and claimsQuestioned the strength of the evidence behind the emergency-use requests. 2

Safety

VIP is a potent vasodilator, so the expected side effects of intravenous aviptadil are low blood pressure, flushing and diarrhoea. In TESICO the data safety monitoring board reported no safety concerns beyond these known effects. 11

The erectile dysfunction combination has decades of use in Europe with local pain and priapism as the recognised risks of the phentolamine component. There are no data on repeated systemic dosing outside intensive care, and compounded or research-chemical aviptadil sold online has no quality oversight. 10

Questions for your clinician

  • What did the TESICO trial find for the COVID-19 use I read about?
  • Is the aviptadil I am being offered a licensed product or a compounded one?
  • What are the risks of the erectile dysfunction combination, such as prolonged erection?

Questions people ask

Is aviptadil FDA-approved?

No. The FDA refused emergency use authorisation for critical COVID-19 and no approval has followed. The erectile dysfunction combination Invicorp is approved in the UK and elsewhere but not in the United States. 7910

Did aviptadil work for COVID-19?

The NIH-run TESICO trial found no benefit on recovery or 90-day survival in about 460 critically ill patients and was stopped early for futility. 11

What is VIP, and why was it thought to help the lungs?

Vasoactive intestinal peptide is a natural neuropeptide that dilates blood vessels and calms inflammatory immune signalling. It is concentrated in the lung and binds receptors on the cells that make surfactant, which is why the sponsor proposed it would protect those cells in COVID-19. The trial did not bear that out. 4611

Why was it fast-tracked if it failed?

Fast Track designation is granted early on the basis of a serious condition and a plausible mechanism; it speeds review but is not a judgement on efficacy. The later randomized data were negative. 811

Citations

  1. Said and Mutt 1970, Science: polypeptide with broad biological activity isolated from small intestine pubmed.ncbi.nlm.nih.gov
  2. PMC 2023: independent analysis of aviptadil COVID-19 evidence pmc.ncbi.nlm.nih.gov
  3. PMC 2021: VIP receptors VPAC1 and VPAC2 pmc.ncbi.nlm.nih.gov
  4. Goetzl 2002, Regulatory Peptides: immunoeffector and immunoregulatory activities of VIP pubmed.ncbi.nlm.nih.gov
  5. Couvineau 2012, Br J Pharmacol: VPAC receptor structure and pharmacology pubmed.ncbi.nlm.nih.gov
  6. Amino Acids 2013: VIP, a neuropeptide with pleiotropic immune functions pubmed.ncbi.nlm.nih.gov
  7. The Pharma Letter: FDA declines EUA for aviptadil in critical COVID-19 thepharmaletter.com
  8. GlobeNewswire 2020: Fast Track designation for RLF-100 (aviptadil) globenewswire.com
  9. NRx Pharmaceuticals 10-Q, Q1 2022: FDA declined emergency use request sec.gov
  10. All Wales Therapeutics and Toxicology Centre: aviptadil/phentolamine (Invicorp) recommendation awttc.nhs.wales
  11. ACTIV-3b/TESICO 2023, Lancet Respiratory Medicine: aviptadil and remdesivir for COVID-19 respiratory failure doi.org

Related