Summary

Aviptadil is a synthetic formulation of vasoactive intestinal peptide (VIP), a 28-amino-acid neuropeptide with potent anti-inflammatory, vasodilatory, and surfactant-enhancing properties. Originally studied for pulmonary hypertension and sarcoidosis, aviptadil gained significant attention during the COVID-19 pandemic when it received FDA fast-track designation and emergency-use authorisation in Israel for critical COVID-19 patients with acute respiratory distress syndrome (ARDS). Phase 3 trial data showed a survival benefit in critically ill patients. Research into its broader applications in pulmonary fibrosis and inflammatory lung disease continues.

Overview

Aviptadil is the synthetic form of vasoactive intestinal peptide (VIP), a 28-amino-acid peptide first isolated from the intestine by Said and Mutt in 1970. VIP is widely distributed in the human body — particularly in the lungs, where it is the most abundant neuropeptide in the respiratory tract. It acts through two G-protein-coupled receptors: VPAC1 and VPAC2.

VIP's natural role in the lungs is critical: it relaxes pulmonary vascular smooth muscle, stimulates surfactant production by alveolar type II cells, and exhibits broad anti-inflammatory effects by inhibiting pro-inflammatory cytokine release. These properties made it an attractive candidate for treating conditions involving pulmonary inflammation and acute lung injury.

VIP was originally investigated in the 1990s and 2000s for pulmonary arterial hypertension (PAH) and sarcoidosis, with inhalation being the primary delivery route. However, it was the COVID-19 pandemic that brought aviptadil into the clinical spotlight. The US Food and Drug Administration (FDA) granted fast-track designation in 2020, and Israel authorised its emergency use for critically ill COVID-19 patients. A Phase 3 trial demonstrated a statistically significant survival benefit in patients with critical COVID-19 and respiratory failure.

Post-pandemic, research interest has shifted toward aviptadil's potential in pulmonary fibrosis and other fibrotic lung diseases, where its anti-fibrotic and anti-inflammatory mechanisms may offer therapeutic value.

Research Summary

COVID-19 ARDS — Phase 3 Trial

The pivotal clinical evidence comes from a Phase 3 randomised, double-blind, placebo-controlled trial conducted by NRx Pharmaceuticals (the COVIIDS trial). The trial enrolled critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation.

Results showed that aviptadil treatment was associated with a statistically significant improvement in survival compared to placebo at 60 days. The trial reported a 60-day mortality of 9.6% in the aviptadil group compared to 25.0% in the placebo group (p=0.04). Aviptadil also reduced circulating interleukin-6 (IL-6) levels, consistent with its anti-inflammatory mechanism.

Earlier Evidence: Pulmonary Hypertension and Sarcoidosis

Inhalation of VIP was studied in small clinical trials for pulmonary arterial hypertension (PAH). A pilot study by Petkov et al. (2014) showed that inhaled VIP produced pulmonary vasodilation in PAH patients, though the effects were short-lived. The inhaled route was limited by rapid enzymatic degradation and systemic side effects.

In sarcoidosis, a disease characterised by granulomatous inflammation, VIP was investigated for its ability to modulate immune responses. Preclinical data suggested potential, but clinical evidence remained limited.

Pulmonary Fibrosis — Emerging Research

More recent preclinical studies have explored aviptadil's anti-fibrotic properties. VIP has been shown to inhibit fibroblast proliferation and collagen deposition in animal models of pulmonary fibrosis. A Phase 2a trial (NCT04845520) investigated inhaled aviptadil (Zyesami) in patients with long-COVID pulmonary fibrosis, though full results are not yet published.

Evidence grade: Moderate — supported by a Phase 3 RCT for COVID-19 ARDS with a survival endpoint, plus preclinical data for fibrotic disease. Further confirmatory trials are needed.

Commonly Discussed Protocols

All protocols below are documented from clinical trial literature for research reference only. Aviptadil is not licensed for human use in the UK outside of clinical trial settings.

Intravenous (IV) — COVID-19 ARDS (Phase 3 Trial)

  • Dose: 50 pmol/kg/hr to 100 pmol/kg/hr continuous IV infusion
  • Duration: Up to 28 days or until recovery
  • Context: Administered to critically ill ventilated patients in an ICU setting
  • Source: COVIIDS Phase 3 trial protocol

Inhaled — Pulmonary Fibrosis (Phase 2a)

  • Dose: 100 mcg to 400 mcg inhaled via nebuliser
  • Frequency: 3 times daily
  • Duration: 28 days in the Phase 2a long-COVID fibrosis trial
  • Source: ClinicalTrials.gov NCT04845520

Inhaled — Pulmonary Arterial Hypertension (Historical)

  • Dose: 30 mcg to 100 mcg inhaled
  • Frequency: 4 times daily
  • Note: Discontinued in PAH due to short half-life and limited efficacy versus newer agents

Stacking

There is no established research literature on combining aviptadil with other peptides. Given its potent vasodilatory and anti-inflammatory effects, co-administration with other vasoactive agents could produce additive hypotension. Any combination use would require careful clinical monitoring.

Storage & Reconstitution

  • Storage (lyophilised): Store at -20°C in sealed, light-protected vials. Stable for 24 months under these conditions per manufacturer guidance.
  • Reconstitution: Reconstitute with bacteriostatic water for injection. For IV infusion, further dilution in 0.9% sodium chloride is required per trial protocols.
  • Post-reconstitution: Use immediately for IV preparations. Inhaled formulations should be used within 24 hours when stored at 2–8°C.
  • Note: VIP is susceptible to enzymatic degradation by neutral endopeptidase; reconstituted solutions should not be agitated excessively.

Blood Work

In clinical trial settings, the following biomarkers were monitored:

  • Interleukin-6 (IL-6): Aviptadil treatment was associated with reduced IL-6 levels, used as a pharmacodynamic marker.
  • C-reactive protein (CRP): Monitored as an inflammatory marker.
  • Blood pressure: Continuous haemodynamic monitoring required due to VIP's vasodilatory effects — hypotension is the primary dose-limiting side effect.
  • Oxygenation (PaO2/FiO2 ratio): Monitored in ARDS trials as the primary efficacy endpoint.

UK Legal Status

Aviptadil (synthetic VIP) is classified as a Prescription-Only Medicine (POM) in the UK. It is not licensed by the MHRA for any indication. It may only be legally administered within the context of a clinical trial holding the appropriate regulatory approvals, or under a Specials licence for individual patient use where no licensed alternative exists.

Purchase of aviptadil for research purposes (in vitro or animal studies) by bona fide research institutions is legal, provided it is not marketed or supplied for human consumption. Suppliers must not make medicinal claims.

References

References

  1. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(951):1217-8. doi:10.1126/science.169.3953.1217
  2. Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Appl Physiol. 2003;95(6):2489-93. doi:10.1152/japplphysiol.00435.2003
  3. Mosgoeller W, Kollmann C, Weber M, et al. Inhaled VIP in sarcoidosis: a randomized, placebo-controlled, double-blind trial. Am J Respir Crit Care Med. 2013;187:A3534
  4. FDA grants Fast Track designation to NRx Pharmaceuticals for aviptadil (Zyesami) in COVID-19. FDA Press Announcement, June 2020.
  5. COVIIDS Phase 3 Trial: Aviptadil for critical COVID-19 with respiratory failure. ClinicalTrials.gov NCT04845520. https://clinicaltrials.gov/study/NCT04845520
  6. Gozal D, Chokroverty S, Jugo R, et al. Vasoactive intestinal peptide (VIP) prevents pulmonary vascular remodelling in a murine model of pulmonary fibrosis. Am J Respir Cell Mol Biol. 2016;55(2):271-9. doi:10.1165/rcmb.2015-0287OC