VIP: Safety Profile & Research Summary

Animal Studies

• Parkinson’s Disease (Rats, Mosley 2019): VIPR2 agonist LBT-3627 at 2.0 mg/kg SC — 43% increase in surviving TH+ neurons (α-Syn model), 53% spared at 6.0 mg/kg (6-OHDA model), 57–61% reduction in reactive microglia. [19]
• Parkinson’s Disease (Mice, Delgado 2003): VIP in MPTP model prevented dopaminergic neuronal loss and microglial activation; blocked iNOS, IL-1β, TNF-α expression. [21]
• IBD/Colitis (Mice, Jayawardena 2017): VIP-SSM single dose reversed severe DSS colitis (P<0.0001 vs DSS); restored occludin and DRA expression. Free VIP required alternate-day dosing. [22]
• PET Imaging (Mice, Zhang 2007/2008): ⁶⁴Cu-VIP analogues in breast/prostate xenografts — tumor:normal uptake ratios 2.17–10.93, >85% ⁶⁴Cu retention in blood. Detected grade IV prostate neoplasia undetectable by FDG-PET. [23]
• Diabetes (Rats, Tsutsumi 2002): VPAC2 agonist BAY 55-9837 stimulated glucose-dependent insulin secretion without hypoglycemia. [13]
• Cardiovascular tolerability (Dogs, Mosley 2019): LBT-3627 at 0.14–1.4 mg/kg SC — transient hemodynamic effects only at doses >experimental threshold; resolved within 4 hours. [19]
• SCN Circadian (Mice, Kudo 2013): 1 µM VIP increased SCN neuronal firing rate (P<0.05), persisting 4–6 hours post-washout. Requires PER1 and Kv3 channels. [16]

Human Clinical Trials

• COVID-19 ARDS Phase 2b/3 (NCT04311697, n=196): IV aviptadil 50/100/150 pmol/kg/hr × 3 days. Failed primary endpoint; 2× survival at 60 days (OR 2.0, p=0.035), 10× survival in ventilated study subjects. IL-6 significantly reduced. [4]
• TESICO (NCT04843761, n=461): IV aviptadil for COVID-19 hypoxemic respiratory failure. No benefit; stopped for futility. 90-day mortality 38% vs 36% placebo. [20]
• Inhaled COVID-19 Phase II (NCT04844580, n=80): Inhaled aviptadil × 5 days. Failed primary (hospital discharge); significant improvement in dyspnea (p=0.033) and CT scores (p=0.028). [27]
• Sarcoidosis Phase II (n=20): Nebulized VIP 50 µg 4x daily × 4 weeks. Reduced TNF-α, increased Tregs in BAL fluid. No systemic immunosuppression. [25]
• Pulmonary Hypertension (n=20): Inhaled VIP 100–200 µg. Decreased PA pressure, increased cardiac output. Temporary effect. [7]
• Septic ARDS Phase I (n=8): IV aviptadil 50–100 pmol/kg/hr × 12 hours. 6/8 survived; tolerability established. [26]
• Tumor Imaging (Various): ¹²³I-VIP and Tc-99m-TP3654 IV. 87% detection in primary colorectal, 100% lymph node metastases. [23]
• India COVID-19 ARDS (n=150): IV aviptadil ascending doses × 3 days. 80% vs 76% survival (not significant). Improved PaO₂/FiO₂. [28]

Regulatory Status

FDA: Orphan compound Designation (ARDS, pulmonary hypertension, sarcoidosis); Fast Track Designation (critical COVID-19).

EMA: Orphan compound Designation (ARDS, sarcoidosis).

CDSCO (India): registered for emergency use in COVID-19 ARDS (2022).

reported tolerability profile: Most common AEs: hypotension (26%), diarrhea (33% — reproduces “pancreatic cholera” syndrome), facial flushing, tachycardia. No compound-related serious AEs or mortality in controlled trials. Contraindicated in refractory hypotension, severe diarrhea, end-stage liver disease, and pregnancy. [4]