VIP (Vasoactive Intestinal Peptide)

WHAT IT IS

VIP is a natural neuropeptide hormone found throughout the body, with actions on smooth muscle relaxation, blood vessel dilation, fluid secretion and immune signaling. It disappears from the bloodstream within about a minute of release, which is part of why researchers built longer-acting or locally delivered drug versions rather than dosing the native peptide systemically.

Aviptadil is the synthetic version of VIP used as an active pharmaceutical ingredient. It has been formulated in at least two very different products for two very different purposes: an intracavernosal injection combined with the drug phentolamine for erectile dysfunction, sold as Invicorp in parts of Europe, and an intravenous or inhaled formulation, sold under names including Zyesami, studied for critical COVID-19 respiratory failure.

It is not a dietary supplement or a general wellness peptide. Depending on the formulation, it is either a regionally approved prescription drug or an investigational compound that did not reach approval.

WHAT RESEARCHERS ARE STUDYING IT FOR

Clinical work on VIP and aviptadil has concentrated on:

• Erectile dysfunction, using an aviptadil and phentolamine combination injected directly into penile tissue
• Critical respiratory failure associated with severe COVID-19 and acute respiratory distress syndrome
• Pulmonary arterial hypertension and other lung vascular conditions, an older area of VIP research
• Sarcoidosis and other inflammatory lung conditions, in earlier and smaller studies
• General vasodilation and smooth-muscle relaxation physiology as a research tool

PROPOSED BIOLOGICAL MECHANISMS

VIP acts on two G-protein-coupled receptors, VPAC1 and VPAC2, found on smooth muscle, immune cells and lung tissue. Activating these receptors relaxes smooth muscle, widens blood vessels, and has been reported to modulate inflammatory cytokine release in some experimental systems.

In erectile tissue, this vasodilating action is the basis for the Invicorp product, where aviptadil is paired with phentolamine, an alpha-blocker, to produce a stronger and more reliable erection than either drug alone.

In the lungs, the hypothesis behind COVID-19 trials was that VIP's anti-inflammatory and vasodilating properties might reduce the tissue damage and impaired oxygenation seen in acute respiratory distress syndrome, a mechanism that was biologically plausible but ultimately not confirmed at the scale of a large trial.

AREAS OF RESEARCH INTEREST

• Why a mechanism that supports an approved erectile-dysfunction product did not translate into a positive large COVID-19 trial
• Whether more selective VIP receptor subtype targeting could improve results in respiratory disease
• How formulation and delivery route change the practical evidence for VIP-based drugs
• Longer-acting engineered VIP analogs, distinct from aviptadil, in earlier development

WHAT THE EVIDENCE CURRENTLY SUGGESTS

The evidence for VIP-based drugs depends heavily on which product and indication is being discussed. Aviptadil combined with phentolamine (Invicorp) has clinical trial data supporting its use for erectile dysfunction and has held marketing authorization in Denmark since 1998 and in the United Kingdom and other European countries since 2015.

By contrast, intravenous aviptadil (Zyesami) for severe COVID-19 respiratory failure was tested in a large randomized trial that did not meet its primary efficacy endpoint, and the compound has not received FDA approval for that or any other indication in the United States.

FDA status: Aviptadil is not FDA-approved for any indication in the United States; the erectile-dysfunction combination product is authorized in parts of Europe under separate national regulatory review, and its COVID-19 investigational program did not result in approval.