Aviptadil

Aviptadil, a synthetic form of VIP, has been granted a marketing approval in India for the treatment of Acute respiratory distress syndrome (ARDS) in patients with severe COVID-19.

Synonyms	Vasoactive Intestinal Octacosapeptide
Molecular Formula	C147H237N43O43S
Molecular Weight	3325.8 g/mol
Chemical Structure
IUPAC Condensed Formula	H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-GIn-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lle-Leu-Asn-OH¹²

VIP is highly expressed in the lung tissue (approximately 70%) and nasal mucosa.

Recently, VIP was shown to block replication of the SARS-CoV-2 virus in human pulmonary epithelial cells (pneumocytes) and monocytes, while also demonstrating clinical improvement on radiographic and laboratory parameters.

In addition to blocking viral replication:

VIP protects the Alveolar Type II (ATII) cell by up-regulating surfactant production, blocking apoptosis, and blocking cytokine effects.
VIP blocks cytokine synthesis and cytopathy in human pneumocytes and up-regulates surfactant production.

Anti-inflammatory action:

Inhibits inflammatory cytokines like IL6 and TNF alpha production.
Reverses CD4/CD8 ratio.
Reduces pulmonary inflammation by reducing production of pro-inflammatory cytokines.
Protects against HCl-induced pulmonary edema.
Inhibits the synthesis & activation of NF-KB, which block the production of TNF-α.

Increases pulmonary surfactant production:

By up regulation of choline phosphate cystidylyltransferase, which increase the incorporation of methyl choline to phosphatidylcholine, the major components of pulmonary surfactant.
Also up regulate c fos protein expression in type ii alveolar cells, which increase the synthesis of surfactant phospholipids & induce surfactant protein A expression.

Inhibits alveolar epithelial cell Apoptosis

Reduces cell death by inhibiting activation induced perforin, granzyme B and caspase activity.
Restores barrier function at the endothelial/alveolar interface.

Preservation of Pulmonary Tissue

Prevents NMDA-induced caspase-3 activation in the lungs.

VIP reduces ischemia-reperfusion injury

COVID-19

SARS CoV-2 attack mainly type II cells and results in the death of alveolar type II (AT 11) cells which produces surfactant, resulting in profound defect in oxygenation, leading to hypoxia.
VIP and pituitary adenylate cyclase activating polypeptide (PACAP) inhibit SARS CoV-2 RNA.
Synthesis in human lung epithelial cell (by 41%) and human primary monocytes (by 33-45%).
It also blocks viral cytopathic effect demonstrated by reduced LDH release (by 40%).

Aviptadil has vasodilating properties which re 50 times more potent than prostacyclin and independent of the endothelium.
In healthy volunteers intravenous Aviptadil reduced systemic vascular resistance due to its potent vasodilatory effects, followed by increase of heart rate and decrease of blood pressure.
Aviptadil alters the ventilation –perfusion distributions but generates no shunt and does not cause hypoxia.

After injection of 1 μg radioactively labelled Aviptadil within 30 minutes about 45% of the radioactivity is found in the lungs.
The half-life of Aviptadil in plasma is about 1-2 minutes. After injection of radio-labelled Aviptadil, radioactivity is almost completely eliminated by the kidneys, 35% within 4 hours, and 90% within 24 hours.

Therapeutic Indication

Aviptadil has been approved by Central Drugs Standard Control Organisation (CDSCO) in India for treatment of Acute respiratory distress syndrome (ARDS) in patients with severe COVID-19 in April 2022.

Aviptadil intravenous infusion is administered by infusion pump in escalating doses for 3 successive days.

Day 1

Aviptadil 0.166 mcg/kg/hr. intravenous infusions over 12- hour (equivalent to 1 vial of Aviptadil Injection).

Day 2

Aviptadil 0.332 mcg/kg/hr. intravenous infusions over 12- hour (equivalent to 2 vials of Aviptadil Injection).

Day 3

Aviptadil 0.498 mcg/kg/hr. intravenous infusions over 12- hour (equivalent to 3 vials of Aviptadil Injection).

Duration of infusion depends on the patient's body weight:

Body weight < 60 kg - 14 hour infusions of Aviptadil at escalating doses on 3 successive days.
Body weight 60 - 90 kg - 12 hour infusions of Aviptadil at escalating doses on 3 successive days.
Body weight > 90 kg - 10 hour infusions of Aviptadil at escalating doses on 3 successive days.

There is no significant drug-drug interaction.
No clinically relevant interaction was observed concomitantly to anti-hypertensive drugs or other cardiovascular drugs.

Limited data regarding Aviptadil safety in pregnancy. Single clinical report suggests that vasoactive intestinal peptide is a safe treatment of severe coronavirus disease 2019 respiratory failure during pregnancy.

Mild transient flushing of the face or trunk occurs commonly.
Rarely associated with discomfort and palpitations or tachycardia in which cases patients may be withdrawn from treatment.
Caution in patients with severe cardiovascular or cerebrovascular conditions.

Patients who are hypersensitive to any component of this product.

Gastrointestinal Disorders- Diarrhoea.
Vascular disorders- Hypotension, cutaneous and facial flushing.
Infusion related reactions.

No case of overdose has been reported.

India

Aviptadil has been approved by Central Drugs Standard Control Organisation in India for treatment of ARDS in patients with severe COVID-19 in April 2022.

USA

VIP was awarded Orphan Drug* Designation for treatment of Acute Respiratory Distress Syndrome in 2001 by USFDA.
Aviptadil was awarded Orphan Drug Designation for treatment of Pulmonary Arterial Hypertension in 2005 by USFDA.
Aviptadil was awarded Orphan Drug Designation for treatment of Sarcoidosis in 2020 by USFDA.

Europe

Aviptadil was awarded Orphan Drug Designation for treatment of Acute Lung Injury in 2006 by EMA.
Aviptadil was awarded Orphan Drug Designation for treatment of Sarcoidosis in 2007 by EMA.

*An orphan drug is defined as one "intended for the treatment, prevention or diagnosis of a rare disease or condition, which is one that affects less than 200,000 persons in the US" (approx. 6 cases per 10,000 population) "or meets cost recovery provisions of the act.

1. A prospective, open label, administratively controlled trial demonstrates a dramatic multi-dimensional treatment effect, consistent with FDA and ICH-10 guidance for acceptance of externally controlled, open label trials in high lethality conditions.

Four out of five Aviptadil treated patients initially on Extracorporeal Membrane Oxygenation (ECMO) were decannulated, compared to 3 of 13 ECMO treated controls (80% vs 23%; P=0.045).
At day 60, a similar 5.5-fold advantage was seen in the cumulative probability of Recovery from Respiratory Failure (55% vs 10%; P=0.002) at 60 days. The hazard ratio is 0.115 (95% CL: 0.0254, 0.5219).

2. A study assessing the safety/effectiveness of VIP in the treatment of ARDS related to sepsis, VIP demonstrated a successful course during intensive care and successfully removal from mechanical ventilation and discharged from intensive care. It also demonstrated a safety profile consistent with previous studies in normal volunteers.

The study showed that VIP is a promising treatment of other infectious conditions that damage the pulmonary epithelium, particularly COVID-19.

3. A randomized double-blind trial assessing the safety and efficacy of intravenous Aviptadil demonstrated that Aviptadil patients treated with high flow nasal cannula were 35% - 46% more likely to recover, return home, and survive to 28 days compared to placebo-treated patients, with a trend level of significance.

Aviptadil patients additionally demonstrated a highly statistically significant and clinically dramatic ten-day reduction in hospitalisation time.

A randomized, double-blind, comparative Phase III clinical trial assessed the efficacy and safety of Intravenous Aviptadil as an add-on to the “Standard of Care” treatment in severe COVID-19 patients with respiratory failure. It was observed that-

An earlier resolution from the respiratory failure, with a median duration of 7 days was noted in the Aviptadil-treated group as compared to 14 days in the placebo group.
A higher proportion of patients on Aviptadil shifted to the milder clinical state (32.43% vs 17.80%; p=0.0410 on Day 3 and 70.27% vs 45.21%; 0.0035 on Day 7) without the requirement of oxygen than the placebo group.
A reduction of severity (based on WHO 7-point ordinal scale) in clinical status were also observed on Day 14 (p = 0.0005 by Wilcoxon rank sum test) & Day 28 (p = 0.0009 by Wilcoxon rank sum test).
Aviptadil reduced the risk of death by 20% (relative risk 0.80; 95% CI: 0.35, 1.66) in ARDS.
Patients treated with Aviptadil demonstrated significant improvement in PaO2/FiO2 ratio vs. placebo from day 2 to over the week (p< 0.05) and beyond. There were 15 deaths in the Aviptadil group and 18 deaths in the placebo group.

In conclusion, the use of Aviptadil was safe and effective in improving the resolution of respiratory failure, shortening the time to recovery, decreasing respiratory distress and preventing death in respiratory failure patients.

Incompatibilities	Not Applicable
Shelf-life	9 months
Packaging information	Vial of 10 ml
Storage and handing instructions	Store in a refrigerator (20C – 80C). Protect from light. Keep out of reach of children. Do not use in case any foreign particulate matter is observed inside the vial. Do not freeze.
Details of manufacturer	Zuventus Healthcare Ltd, Mumbai. Block No. 33/1, Kanchan Pharma House, N. H. No. 08, Aslali, Taluka Daskroi, District Ahmedabad - 382 427. At : 141-142, Gallops Industrial Park, Plot No. G/5 & G/6, Vasna-Chacharvadi, Taluka Sanand, District Ahmedabad - 382 210. Registered Trade Mark of Zuventus.