Evidence Grade B — Strong clinical evidence. 24556 published studies, 12007 human. 122 registered clinical trials.
Medically reviewed by a licensed medical professional
VIP (vasoactive intestinal peptide) is a naturally occurring hormone found throughout the nervous and immune systems. A pharmaceutical version (aviptadil) has been studied for sarcoidosis, pulmonary hypertension, and was investigated under emergency authorisation during COVID-19 for acute respiratory distress. It has no FDA or EMA approval for any condition. Its extremely short half-life (about 2 minutes) is the fundamental barrier to clinical development.
VIP is also known by these brand and alternate names:
24,556 published studies: 12007 human, 7803 animal, 1770 in-vitro, 7466 reviews
VIP (aviptadil) has no marketing authorisation from the FDA or EMA. Phase II studies have been conducted in sarcoidosis (20 patients, inhaled VIP) and pulmonary hypertension (8 patients, inhaled VIP), and aviptadil was investigated under emergency use for COVID-19-associated ARDS.
VIP is a well-characterised endogenous hormone with extensive basic science literature spanning decades. The challenge for clinical development has been its extremely short half-life and the complexity of targeting a hormone with pleiotropic effects across multiple organ systems. No Phase III trials have been completed for any indication.
Research suggests VIP acts through two specific receptors (VPAC1 and VPAC2) distributed across multiple organ systems. Proposed effects include anti-inflammatory activity, bronchodilation, and vasodilation. The very short half-life (approximately 2 minutes) of the native peptide presents significant pharmacological challenges for therapeutic development.
Research suggests VIP has extensive and compelling preclinical evidence from multiple independent laboratories, with proposed anti-inflammatory, bronchodilatory, and vasodilatory effects. However, clinical translation has been consistently disappointing: sarcoidosis data is proof-of-concept only (20 patients), pulmonary hypertension results were not replicated, and two major COVID-19 respiratory distress trials failed their primary endpoints. The 2-minute half-life remains the core problem — the peptide is destroyed almost immediately in the bloodstream. Inhaled delivery appears more promising than intravenous administration. Despite decades of research and compelling biology, no VIP-based therapy has achieved regulatory approval. Long-acting VIP analogues and alternative delivery methods are being explored.
PeptideTrace tracks 122 registered clinical trials for VIP sourced from ClinicalTrials.gov.
ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)
The Volunteering-in-Place Program for Apathetic Assisted Living Residents With ADRD
IBIS Megastudy of Interventions to Encourage HIV Retesting
Impact of Low-intensity Chemotherapy Combined With Short-course Blinatumomab on Allo-HSCT in Adults With Ph- B-ALL
VIP (Vasoactive Intestinal Peptide) is a 28-amino acid basic neuropeptide hormone first isolated from porcine duodenum by Said and Mutt in 1970. Sequence: HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2. Molecular weight: 3,326.8 Da. CAS: 37221-79-7. Molecular formula: C147H237N43O43S. Half-life approximately 2 minutes. Gene: VIP, chromosome 6q25.2. Approximately 70% of VIP is localized in the lungs, binding alveolar type II cells. Its pharmaceutical form is aviptadil (also RLF-100/ZYESAMI). The extremely short half-life poses the greatest challenge for clinical development. Aviptadil received FDA Fast Track designation for COVID-19 ARDS but has not been approved for any indication.
Research suggests VIP binds VPAC1 and VPAC2 receptors (class B GPCRs), coupling to Gs protein, activating adenylate cyclase, increasing cAMP (and cGMP), and activating PKA and PKC. Anti-inflammatory effects include inhibition of TNF-alpha, IL-6, IL-12, suppression of NF-kappaB and AP-1 transcription factors, promotion of T-regulatory cells, and suppression of Th1 responses. As a vasodilator, VIP increases intracellular cAMP/cGMP in smooth muscle, downregulates endothelin, and regulates BMPR type 2. In the lungs, it upregulates surfactant production via the PKC/c-Fos pathway and has bronchodilatory properties.
Sarcoidosis (Prasse et al., 2010; N=20, open-label Phase II): Inhaled VIP for 28 days significantly reduced BAL TNF-alpha (P=0.04), increased BAL CD8+ T cells (P=0.014), and ameliorated chronic cough in 75% (9/12) of patients. Pulmonary hypertension (Petkov et al., 2003; N=8): Acute 100 ug inhaled VIP reduced MPAP from 59+/-8 to 49+/-14 mmHg (P<0.01); chronic 200 ug/day for 24 weeks improved 6-minute walk test (P<0.01). A subsequent Phase II RCT was negative. COVID-19/ARDS: The TESICO trial (Brown et al., Lancet Respir Med 2023; N=461) found OR 1.10 (95% CI 0.79-1.54), P=0.56, definitively negative, stopped for futility. A smaller IV RCT (N=196) also failed. A Phase II inhaled trial (N=80) research suggests shorter time to discharge (7.8 vs 10 days, P=0.049). Safety signals include diarrhea (32.8% with IV), hypotension, and flushing.
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