Emerging Pharmacological Therapy in ARDS

Emerging Pharmacological Therapy in ARDS

Emerging Pharmacological Therapy

in ARDS

Despite considerable advances in our knowledge regarding the pathophysiology of ARDS, insights into the biologic mechanisms of injury and lung repair and advances in supportive care including ventilatory management, lack of direct effective therapy looms large. Unacceptably high mortality & morbidity underlines the need to continue to develop and test therapies for this devastating clinical condition. COVID-19 pandemic has clearly highlighted challenges with ARDS as it causes severe acute respiratory failure and ARDS in 3–5% of infected patients.

Once ARDS is established the main pharmacological therapies are aimed to :

  • Reduce inflammation (methylprednisolone, lisofylline, N-acetylcysteine, macrolides, simvastatin, and neutrophil elastase inhibitors).
  • Reduce interstitial/alveolar edema (surfactant, β2-adrenergic agonists, fluids).
  • Promote pulmonary vasodilation (nitric oxide and prostacyclin).
  • Act on coagulation pathways (aspirin, platelet-activating factor receptor antagonists).
  • Promote repair of epithelial cells (keratinocyte growth factor) and endothelial cells (manipulation of intercellular adhesive junctions).

Aviptadil

With the lack of FDA approved drugs for management of ARDS, Aviptadil comes as a first in class molecule to get DCGI approval for the treatment of Acute respiratory distress syndrome (ARDS) in patients with severe COVID-19 Aviptadil was awarded Orphan Drug Designation for treatment of Acute Lung Injury in 2006 by EMA.

Aviptadil is a synthetic form of Vasoactive Intestinal Peptide (VIP). VIP is highly expressed in the lung tissue (approximately 70%) and nasal mucosa. In addition to blocking the replication of SARS-CoV-2 virus :

  • VIP protects the Alveolar Type II (ATII) cell by upregulating surfactant production, blocking apoptosis, and blocking cytokine effects.
  • VIP blocks cytokine synthesis and cytopathy in human pneumocytes and upregulates surfactant production.

Key effects of Aviptadil on lungs include :

  • Anti-inflammatory action: Inhibits inflammatory cytokines like IL6 and TNF alpha production and inhibits the synthesis & activation of NF-KB, which block the production of TNF-α.
  • Increases pulmonary surfactant production.
  • Inhibits alveolar epithelial cell apoptosis by inhibiting activation induced perforin, granzyme B and caspase activity.
  • Preservation of Pulmonary tissue.
  • VIP reduces ischemia-reperfusion injury.

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

Below are discussed few key emerging pharmacological therapies for ARDS :

A number of medications with a broad base of ‘pleiotropic’ immunomodulatory effects are in clinical trials for the treatment of ARDS or to prevent ARDS development. 

  • Steroids have long been studied as a potential therapy for both early and late phase ARDS, with some studies suggesting potential benefit, via suppression of the pro-inflammatory cytokine response, while other studies demonstrating potential risks due to immune suppression. Recent open-label multicenter study examined the efficacy of high-dose dexamethasone regimen in patients with established moderate to severe ARDS (i.e., P/F ratio < 200 mmHg at 24 h following ARDS diagnosis). It was found that the mean number of ventilator free days was 4.8 days higher and the number of patient deaths was lower (21% versus 36%) following early treatment with dexamethasone.
  • Ulinastatin is a urinary glycoprotein and protease inhibitor with potent antioxidant and anti-inflammatory effects. Ulinastatin injection 12 hourly for 14 days demonstrated improved lung oxygenation and function , reduced duration of mechanical ventilation and reduced hospital stays compared to standard care in phase II trial of ARDS patients.
  • Dilmapimod is a specific p38MAPK inhibitor and potent anti-inflammatory agent. The p38 mitogen-activated protein kinase (MAPK) pathway is activated during cellular stress and drives downstream production of inflammatory cytokines.  Its 24 hour infusion  in trauma patients at risk for ARDS development was well tolerated and reduced the concentrations of the pro-inflammatory cytokines IL-6, IL-8 and soluble tumor necrosis factor receptor 1 (TNFR1).
  • Mesenchymal stromal cell (MSC) therapies have immunomodulatory and pro-reparative effects and show efficacy in preclinical models of ARDS. The MUST-ARDS trial [108] was a phase 1/2 trial conducted in centers in the USA and the UK. The safety and efficacy of MSCs was studied using three different cohorts. To assess acute safety, cohort 1 was treated using 300 million cells and cohort 2 was treated with 900 million cells. Cohort 3 was randomized, double-blinded, and placebo-controlled, with a treatment group (infused 900 million cells) and a control group (placebo). No treatment-related adverse events were observed in any of the cohorts. In cohort 3, use of MSCs was associated with improved 28-day mortality (25% vs. 45%) and ventilation-free days.

International Clinical Evidence of Aviptadil : Key reflections

  • 21 admitted patients with Critical COVID-19 with respiratory failure were treated with 3 successive 12 hour intravenous infusions of Aviptadil at 50/100/150 pmol/kg/hr. Kaplan-Meier analysis demonstrates a 4-fold advantage in the probability of survival (80% vs. %; P<.0006). A similar 9-fold advantage was seen in the cumulative probability of Recovery from Respiratory failure. Aviptadil also led to 75% reduction in IL-6 and while 80% patients on ECMO were Decannulated with 3 Days Therapy of Aviptadil.
  • 196 patients with PCR+ critical COVID-19 received 3 successive 12-hour intravenous infusions of Aviptadil at 50/100/150 pmol/kg/hr or placebo for 3 successive days. At 28 days, Aviptadil patients treated with HFNC were 35% - 46% more likely to recover, return home, and survive upto 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 hospitalization time.

Indian Clinical Evidence of Aviptadil : Key reflections

12-hour intravenous infusions of Aviptadil over 3 successive days in ascending doses was administered to 76 participants with severe COVID-19 with respiratory failure and acute respiratory distress syndrome while 74 were administered placebo. Aviptadil demonstrated 2.1-fold chance (p=0.0410) of being free of respiratory failure (no oxygen requirement) at Day 3 and 2.6-fold chance (p=0.0035) at day 7 as compared to the placebo group. Furthermore, Aviptadil led to:

  • 41% Patients Showed Increase in PaO : FiO2 by 50 mmHg from Baseline.
  • 20% Reduction in Risk of Death in ARDS.
  • 4 fold More, ventilated patients were Free of Respiratory Failure at Day 3.

Summary

Aviptadil, as a synthetic VIP, holds a promising place in the armamentarium of treatment of SARS COV‑2. Class effect of this drug is already established in the almost similar clinical scenario of ARDS caused by sepsis as well as other related lung injuries in preclinical models. The safety and efficacy of Aviptadil in ARDS management is established through various clinical trials. Aviptadil as a synthetic VIP has already been proved to be an effective option in the treatment of severe respiratory failure due to sepsis and other related lung injuries. 

It is expected that metabolomics profiling and stem cell transplantation offer strong enthusiasm and may completely change the outlook of ARDS management in the near future.

References

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