VIP

Mechanism of action

VIP binds to the two G protein-coupled receptors VPAC1 and VPAC2 and stimulates adenylyl cyclase there. How tightly this activity depends on the peptide structure is shown by an alanine scan of all 28 positions on membranes from cells expressing human recombinant receptors (Nicole et al., 2000): substituting individual amino acids at 14 of the 28 positions increased the binding constant or the EC50 value at the VPAC1 receptor more than tenfold, while modeling describes a central alpha helix from Val5 to Asn24 with disordered termini. The comparison between the two receptors was largely congruent, with the exception of positions 11, 22 and 28; combining those three substitutions produced [Ala11,22,28]VIP, the first highly selective VPAC1 agonist. Pharmacokinetically, VIP is characterized by an exceptionally short systemic residence time: in an early human investigation, the peptide was infused intravenously into four healthy volunteers at graded doses over 30-minute periods; after the infusions ended, plasma levels fell by first-order kinetics with an average disappearance half-time of about one minute, with an apparent metabolic clearance of roughly 9 ml/kg/min and an apparent volume of distribution of about 14 ml/kg (Domschke et al., 1978). The authors concluded that their data do not support a role for VIP as a circulating hormone under physiological conditions. This kinetic profile explains the routes used by the clinically studied products: the authorized combination product is injected locally into the corpus cavernosum, and the intravenous COVID-19 program used multi-hour continuous infusions on three consecutive days (Brown et al., 2023).

State of evidence

The evidence tier here refers exclusively to the regulatory status of a fixed combination. Aviptadil, the nonproprietary name for synthetic VIP, was authorized together with phentolamine by the UK Medicines Control Agency in October 2000 as the product Invicorp (Keijzers, 2001); the Scottish Medicines Consortium assessed this product in 2017 for restricted use within NHS Scotland, with the licensed indication of symptomatic treatment of erectile dysfunction in adult males of neurogenic, vasculogenic, psychogenic or mixed aetiology. That authorization covers neither VIP as a single substance nor systemic use: it applies to a fixed two-drug combination injected locally into the corpus cavernosum. VIP on its own is not approved as a medicine in any country. The largest systemic trial to date was negative: in the randomized, placebo-controlled phase 3 trial TESICO (ACTIV-3b, NCT04843761) of intravenous aviptadil in COVID-19-associated hypoxaemic respiratory failure, the primary six-category endpoint at day 90 did not differ significantly from placebo in the modified intention-to-treat population of 461 participants (odds ratio 1.11; 95% confidence interval 0.80 to 1.55; p = 0.54). Mortality up to day 90 was 38 percent versus 36 percent (hazard ratio 1.04; 0.77 to 1.41; p = 0.78), and the independent monitoring board recommended stopping the aviptadil part of the trial for futility in May 2022 (Brown et al., 2023). Controlled data on further systemic applications, and robust pharmacokinetics beyond the small 1978 investigation, remain lacking. All of the results named here come from studies with pharmaceutically manufactured products under controlled conditions; they cannot be transferred to the efficacy or safety of research-grade material.

Storage and handling

Lyophilized peptides are generally stored cool, dry and protected from light; for long-term storage, temperatures around -20 °C are commonly cited in the literature. After reconstitution, peptide solutions are typically kept refrigerated (2-8 °C) and used within a few days, as stability in solution is limited. Repeated freeze-thaw cycles are considered unfavorable. These are generic handling notes for lyophilized peptides; no product-specific stability data exist for research-grade VIP.

Questions about the research

Is VIP approved as a medicine?

Only in a narrowly defined form. What is authorized is the fixed combination of aviptadil, the nonproprietary name for synthetic VIP, with phentolamine, which received a marketing authorization in the United Kingdom as Invicorp in October 2000 and is injected locally into the corpus cavernosum. VIP as a single substance and any systemic use are not covered by it and are not approved in any country. The intravenous aviptadil program in COVID-19 (development names RLF-100 and Zyesami) did not lead to an authorization after the phase 3 trial TESICO showed no significant benefit over placebo.

What does the very short half-life of VIP mean?

In the only robust human investigation on this point, plasma levels after the end of an intravenous infusion in four volunteers fell with an average disappearance half-time of about one minute (Domschke et al., 1978). Systemically administered VIP therefore disappears from the blood within minutes, which is why the clinically studied products were either injected locally or given as multi-hour continuous infusions. For research, this mainly means that results depend heavily on the route of administration; the data base comes from a very small study and supports no general conclusions.

Sources

1. Domschke et al., Gut 1978DOI: 10.1136/gut.19.11.1049PMID: 730072
2. Nicole et al., J Biol Chem 2000DOI: 10.1074/jbc.M002325200PMID: 10801840
3. Keijzers, Curr Opin Investig Drugs 2001 (Aviptadil, UK approval October 2000)PMID: 11566015
4. Scottish Medicines Consortium 2017: aviptadil/phentolamine mesilate (Invicorp), SMC 1284/17
5. Brown et al., Lancet Respir Med 2023 (TESICO, ACTIV-3b, NCT04843761)DOI: 10.1016/S2213-2600(23)00147-9PMID: 37348524