OP-101

Jeffrey Cleland, Ph.D., Ashvattha Chairman, CEO and President interview with Health Professional Radio, July 1, 2021

"Potential COVID Treatments That Address Brain Inflammation"

Potent Anti-Inflammatory: OP-101

THE NEED

Current anti-inflammatory drugs cause broad immune suppression leading to side effects & secondary infections

OUR SOLUTION

  • Targets cause of hyperinflammation at its source, reactive macrophages attacking lungs and organs

  • Restores the number of macrophages to normal levels, preventing further inflammation from occurring

  • Profound effects of reducing neuroinflammation in multiple animal models

  • Converts reactive proinflammatory macrophages and microglia to normal anti-inflammatory phenotype, preventing further inflammation from occurring

OP-101: A Targeted Selective Anti-Inflammatory Agent

Dexamethasone does appear to be life saving for those sickest patients …but it's a pretty big sledgehammer in terms of what it does to the immune system. Maybe there's something a little more subtle that would be even more effective with less in the way of side-effects.

− Dr. Francis Collins, Director of the NIH

Merad & Martin Nature Rev 2020

Mechanism of Action

  • OP-101 (HD-n-acetyl cysteine) is selectively taken up by reactive macrophages – More potent than steroids across multiple models
  • Mechanism demonstrated in animal models of LPS induced inflammation (ARDS, TB, neuroinflammation, etc.)
  •  After uptake, OP-101 returns macrophage to “normal” shutting down multiple pathways resulting in inflammation.
  • OP-101 also reduces oxidative stress, a process that can damage cells (corticosteroids do not address oxidative stress)

Kannan 2012; Nance 2017

OP-101: Safety Established in Healthy Humans

2x Phase 1, Single Dose – IV Doses Up to 40 mg/kg

SC Doses Up to 8 mg/kg

Study Objectives:

Complete safety, PK metabolism, clearance and safety of single dose administration in adult subjects

Study Results Summary:

  • All doses well tolerated with no clinical adverse events
  • No metabolites detected in urine
  • Complete recovery of the drug in the urine in healthy humans (no cellular uptake)

Excellent Safety Profile to Date

5-10x Therapeutic Window – Predicted Therapeutic Dose = 2-8 mg/kg

OP-101: Phase 2 Trial in Severe COVID-19 Patients

Double Blind, Placebo Controlled Study of OP-101 in Severe COVID-19 Patients

OP-101 Dosed at 2, 4 or 8 mg/kg IV

Key Study Objectives of Stage 1 of Phase 2:

  • Safety and tolerability in severe COVID-19 patients
  • Effect of OP-101 on pro-inflammatory biomarkers (CRP, IL-6, ferritin) (PK/PD evaluation)
  • Assessment of change in clinical status assessment using the 7-point ordinal scale (WHO Blueprint COVID-19 Master Protocol Synopsis) – high flow nasal cannula or ventilator

Exploratory:  Ability to reduce neuroinflammation caused by COVID-19 (demonstrated in preclinical models)

Top-line Study Results of Stage 1 of Phase 2:

  • Overall survival compared to standard of care placebo control (82.4% vs 42.8%)
  • Significant and sustained reduction in pro-inflammatory biomarkers above corticosteroids alone (p < 0.01)
  • Significantly reduced neuronal injury biomarker (p < 0.001) to healthy control levels
  • Well tolerated with no drug related adverse events
  • Shuts down multiple pathways associated with hyperinflammation and cross the blood-brain barrier
  • First therapeutic agent used in COVID that is shown to decrease neuronal injury biomarkers

Timelines:

Expansion of study after dose finding stage (agreed with FDA)

Enrolling 260 patients in Global Stage 1 of Phase 2

Global pivotal data expected in Early 2023

Accelerated approval and expansion into other diseases possible in 2023