A tier · strong
Aviptadil is a licensed prescription-only medicine in the UK, but only as one half of the fixed combination Invicorp with phentolamine mesilate for erectile dysfunction (marketing authorisation holder Evolan Pharma AB; accepted for restricted NHS Scotland use on 11 December 2017). As a single agent it is approved in no jurisdiction, and the rigorous NIH trial in COVID-19 respiratory failure randomised 471 participants and returned a day-90 primary-endpoint odds ratio of 1.11 (95% CI 0.80 to 1.55, p=0.54).
vasoactive intestinal peptide
Vasoactive intestinal peptide is a 28-residue amidated neuropeptide that signals through the Gs-coupled VPAC1 and VPAC2 receptors to raise cAMP, relaxing smooth muscle and modulating epithelial and immune function. Aviptadil is synthetic VIP; in the UK it is a licensed medicine only as one component of Invicorp, an intracavernosal combination with phentolamine mesilate for erectile dysfunction. As a single agent, promoted during the pandemic as Zyesami and studied as inhaled or intravenous RLF-100, it is approved nowhere, and the NIH's own randomised trial found no benefit in COVID-19 respiratory failure.
the explanation
VIP is a natural messenger molecule that relaxes blood vessels and airways and dampens inflammation. Aviptadil is the man-made version of it. In Britain it is licensed only as part of a two-drug injection used for erectile dysfunction when tablets have not worked. During COVID-19 it was promoted hard for severe lung disease, but the large government-run trial found it made no difference to survival or recovery, and no regulator has ever approved it for that.
regulatory status
UK prescription-only medicine only inside a combination product; aviptadil monotherapy unapproved worldwide
Aviptadil is a component of Invicorp, a UK-licensed prescription-only intracavernosal injection combining aviptadil with phentolamine mesilate, whose marketing authorisation holder is Evolan Pharma AB and whose licensed indication is the symptomatic treatment of erectile dysfunction in adult males of neurogenic, vasculogenic, psychogenic or mixed aetiology. The Scottish Medicines Consortium accepted it for restricted use within NHS Scotland on 11 December 2017 in men who have failed oral PDE5 inhibitors and other non-injectable formulations, and the All Wales Therapeutics and Toxicology Centre recommended it with equivalent restrictions. Aviptadil as a single agent has never held a marketing authorisation from the MHRA, the FDA or the EMA. The FDA granted Fast Track designation in June 2020, then declined an Emergency Use Authorisation on 4 November 2021 citing insufficient data on the known and potential benefits and risks, declined a further EUA request covering a remdesivir-treated subgroup, and denied Breakthrough Therapy Designation on 10 June 2022 because the request rested on a post-hoc subgroup analysis. Expanded access and Right-to-Try supply, which the sponsor operated and publicised, are neither authorisations nor findings of efficacy. Neither VIP nor aviptadil appears in the WADA 2026 Prohibited List, and neither is a lawful dietary-supplement ingredient in the UK.
how it works · proposed mechanism
VIP's receptor pharmacology is well characterised and uncontroversial: it is a full agonist at two Gs-coupled receptors that raise cAMP in smooth muscle, epithelium and immune cells. The difficulty has never been the receptor. It has been getting a peptide with a one-minute plasma disappearance half-time to the right tissue at a useful exposure, and then showing that the resulting physiology changes a clinical outcome.
VPAC1 and VPAC2, both Gs-coupled
The IUPHAR/BPS Guide to Pharmacology places VPAC1 (VIPR1) and VPAC2 (VIPR2) alongside PAC1 in the VIP and PACAP receptor family, with VPAC1 and VPAC2 coupling to Gs and raising cAMP, and VIP as an endogenous agonist. PAC1 couples both Gs and Gq/G11, which is why VIP and PACAP pharmacology are not interchangeable.
Vasodilation and the licensed erectile-dysfunction use
cAMP-mediated relaxation of cavernosal smooth muscle underlies the one genuine pharmaceutical success: aviptadil combined with the alpha-adrenoceptor antagonist phentolamine mesilate as an intracavernosal injection. A review of that programme reported clinical studies in which the combination was effective in at least 80% of men with erectile dysfunction, including men who had failed other therapies, with a low incidence of penile pain and minimal priapism risk.
The COVID-19 hypothesis that was tested and failed
The pandemic rationale was that VPAC1 is expressed on alveolar type II cells and that VIP supports surfactant production and restrains inflammatory signalling, so aviptadil might protect the alveolus in severe COVID-19. This was a mechanistic hypothesis. It was put to a properly powered randomised trial and did not survive it.
A one-minute pharmacokinetic ceiling
In healthy volunteers, infused VIP fell by first-order kinetics with an average disappearance half-time of about one minute, and the authors concluded the data do not support VIP acting as a circulating hormone under physiological conditions. The same infusion study produced flushing, raised heart rate and blood pressure, and rises in glucose, free fatty acids and calcium — a picture resembling Verner-Morrison (VIPoma) syndrome.
what’s reported
evidence shape
7 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
The grade is carried entirely by a combination product for erectile dysfunction, not by anything in the research-peptide pitch. Aviptadil as a single agent has never been approved by the MHRA, the FDA or the EMA; the FDA declined an Emergency Use Authorisation on 4 November 2021 for insufficient data on benefits and risks, and denied Breakthrough Therapy Designation on 10 June 2022 because the request rested on a post-hoc subgroup analysis. The definitive test was the NIH's own trial: 471 participants randomised, 461 in the modified intention-to-treat analysis, a day-90 primary-endpoint odds ratio of 1.11 (95% CI 0.80 to 1.55, p=0.54), 90-day mortality of 38% with aviptadil versus 36% with placebo (hazard ratio 1.04, 95% CI 0.77 to 1.41), and a day-5 safety composite that was numerically worse with aviptadil at 63% versus 56%. Expanded access and Right-to-Try programmes treated large numbers of desperately ill patients and generated no efficacy evidence whatsoever, a distinction the promotional record consistently blurred. And VIP's roughly one-minute plasma disappearance half-time means the sustained systemic exposure any research-market claim implicitly assumes is essentially unachievable.
key published findings
- In the NIH ACTIV-3b/TESICO trial, 471 participants were randomised to intravenous aviptadil or placebo (461 in the modified intention-to-treat population: 231 aviptadil, 230 placebo); the odds ratio for a better category of the day-90 primary efficacy endpoint was 1.11 (95% CI 0.80 to 1.55, p=0.54), and the authors concluded aviptadil did not significantly improve clinical outcomes up to day 90.
- TESICO 90-day mortality was 38% with aviptadil versus 36% with placebo (hazard ratio 1.04, 95% CI 0.77 to 1.41, p=0.78) — 86 versus 83 deaths.
- The TESICO primary safety composite to day 5 occurred in 146 of 231 (63%) aviptadil recipients versus 129 of 230 (56%) on placebo (odds ratio 1.40, 95% CI 0.94 to 2.08, p=0.10): numerically worse, not statistically significant.
- The FDA declined an Emergency Use Authorisation on 4 November 2021, having reviewed safety data in only 131 randomised aviptadil-treated patients at that point, and denied Breakthrough Therapy Designation on 10 June 2022 because the request rested on a post-hoc subgroup of patients also receiving remdesivir.
- Of the nine registered aviptadil studies, one phase 3 was withdrawn before enrolling anyone (NCT05137795), two were terminated (NCT04360096 and NCT04536350), and the expanded-access protocol (NCT04453839) is listed as no longer available.
- Aviptadil is UK-licensed only within Invicorp (with phentolamine mesilate), authorisation holder Evolan Pharma AB, indicated for erectile dysfunction in adult males and accepted for restricted use in NHS Scotland on 11 December 2017; a review of that programme reported efficacy in at least 80% of treated men, including non-responders to other therapies.
limitations of the evidence
- The only approval anywhere is for a fixed combination containing aviptadil, in an indication (erectile dysfunction, by intracavernosal injection) unrelated to anything the research-peptide market claims for VIP.
- The positive COVID-19 signals that drove promotion were post-hoc subgroup analyses; the pre-specified, independently run NIH trial with a hard mortality endpoint was null.
- Expanded access and Right-to-Try programmes treated many patients but by design produce no controlled efficacy data, and an EUA request, an EUA denial and an approval are three entirely different things — aviptadil only ever reached the first two.
- A plasma disappearance half-time of about one minute means peripheral administration cannot sustain systemic exposure; inhaled delivery was the workaround, and both inhaled trials in the registry were terminated.
- The PubChem aviptadil record depicts the free acid (C147H237N43O43S, 3326.8 Da) while the pharmaceutical peptide is C-terminally amidated, so the tabulated formula and mass here should be treated as approximate rather than definitive.
- The registry contains only 19 studies naming VIP as an intervention, and the visible set is dominated by aviptadil COVID-19 trials, the long-acting VIP analogue PB1046 in pulmonary arterial hypertension and migraine provocation studies — not the intranasal immune-modulation uses promoted in the research-peptide market.
documented safety signals
- In TESICO the primary safety composite of death, serious adverse events, organ failure, serious infection or grade 3-4 adverse events to day 5 was numerically higher with aviptadil (63% versus 56%; odds ratio 1.40, 95% CI 0.94 to 2.08).
- 90-day mortality was 38% with aviptadil versus 36% with placebo, so in the most rigorous trial there was no survival benefit and a point estimate slightly favouring placebo.
- VIP infusion in healthy volunteers produced flushing, increased heart rate and blood pressure, and rises in glucose, free fatty acids and calcium, reproducing features of Verner-Morrison (VIPoma) syndrome — the expected consequence of a systemic vasodilator and secretagogue.
- The FDA explicitly cited insufficient data on the known and potential risks, not only the benefits, when declining the Emergency Use Authorisation.
- The licensed combination is delivered by intracavernosal injection and carries the general hazards of that route; the reviewed programme reported low penile pain and minimal priapism risk relative to alternatives, but this is a clinician-administered or clinician-trained procedure, not a self-directed one.
identity
| full name | Vasoactive intestinal peptide (VIP), a 28-residue C-terminally amidated neuropeptide of the secretin/glucagon superfamily; aviptadil is the synthetic pharmaceutical form |
| category | Other |
| modality | peptide |
| formula | C147H237N43O43S |
| molar mass | 3326.8 g/mol |
| cas | 40077-57-4 |
| half-life | Infused VIP disappears from human plasma by first-order kinetics with an average disappearance half-time of about one minute |
| sequence | His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2 (HSDAVFTDNYTRLRKQMAVKKYLNSILN, C-terminal asparagine amide; UniProt P01282 residues 125-152) |
laboratory handling
| storage | Treat the lyophilised 28-mer as a hygroscopic, oxidation-sensitive peptide: keep the sealed vial frozen and desiccated, protected from light, and let it reach room temperature before opening to prevent condensation onto the powder. The methionine residue makes it vulnerable to oxidation, so exclude air and oxidising agents; reconstituted solutions should be held refrigerated between 2 °C and 8 °C, aliquoted on first reconstitution, and never subjected to repeated freeze-thaw cycles. Adsorption to glass and plastic is significant for peptides of this class, so pre-rinsed or low-binding labware is preferable. |
| solubility | Soluble in water and in aqueous buffers; the peptide is basic overall and dissolves readily in slightly acidic aqueous media. Avoid strongly alkaline conditions, which accelerate deamidation at the asparagine residues, and avoid oxidising conditions because of the single methionine. Sonication and vigorous agitation should be avoided as they promote aggregation and surface denaturation. |
| co-studied with | The only combination with any regulatory standing is the licensed pairing of aviptadil with the alpha-adrenoceptor antagonist phentolamine mesilate in Invicorp, which exists because neither component alone was adequate for the intracavernosal indication; no controlled study supports combining VIP or aviptadil with any other peptide for anti-inflammatory, respiratory or wellbeing purposes. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
7 citedScottish Medicines Consortium · 2017 · official
BJU International 102(8):933-937 · 2008 · review
The Lancet Respiratory Medicine 11(9):791-803 · 2023 · randomized
IUPHAR/BPS Guide to Pharmacology · 2026 · reference
Gut 19(11):1049-1053 · 1978 · clinical study
NRx Pharmaceuticals / Relief Therapeutics announcement, 4 November 2021 · 2021 · press release
NRx Pharmaceuticals announcement, 10 June 2022 · 2022 · press release
Sources marked tertiary or press release are the weakest citations on this page.
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