Phase 1 and Phase 1/2 Clinical Trials for Treatment of COVID-19-Associated ARDS by AV-001, a Novel Therapeutic Targeting Vascular Endothelium

Background: Acute Respiratory Distress Syndrome (ARDS) is a debilitating, often lethal syndrome and the leading cause of death for patients COVID-19 disease. Patients with moderate-to-severe COVID-19 disease may have ARDS or signs of respiratory failure including hypoxia that fall short of the Berlin definition of ARDS. Hypoxia is defined as a lower than normal concentration of oxygen in arterial blood (SaO2 less than or equal to 94%). Patients with COVID-19 may not experience shortness of breath, but still have significant hypoxia with arterial saturation levels in the SaO2 50%-94% range. Acute Lung Injury (ALI) can be defined by multiple clinical criteria, including being recognized as a less severe form of ARDS, with a PaO2/FiO2 ratio of more than 200 mmHg and less than 300 mmHg. Under the 2012 Berlin definition, the following clinical criteria define ARDS: bilateral pulmonary opacities on radiograph, acute onset, and arterial hypoxemia (PaO2/FiO2 ratio less than 300). Emerging evidence suggests pulmonary endothelial cells contribute to initiation and propagation of ALI/ARDS in COVID-19 by altering vessel barrier integrity, promoting a coagulative state, inducing vascular inflammation (endotheliitis), and mediating inflammatory cell migration. The clinical consensus is that COVID-19-associated ARDS is, in the end, ARDS. Central to the pathogenesis of ALI/ARDS of any cause, including COVID-19, is the accumulation of pulmonary fluid within the interstitium and alveolus, which occurs due to the increased permeability of lung microvasculature and loss of endothelial barrier integrity. Deterioration of vascular barrier function results in compromised gas exchange - and when severe, can be fatal. As such, ALI/ARDS therapeutics aiming to restore endothelial stability and vascular barrier function may be of significant benefit. We have designed a promising new drug, AV-001, for the treatment of COVID-19-associated ARDS and pathogen-induced ARDS. AV-001 is a synthetic Angiopoietin-1 (Angpt1) mimetic, shown to activate the Tie2 tyrosine kinase receptor, a transmembrane protein target highly expressed on the surface of endothelial cells in the vasculature. The Tie2-Angpt signaling axis has been identified as a non-redundant gatekeeper of vascular homeostasis. Tie2 signaling is oppositely modulated by two secreted proteins, Angpt-1 and Angpt-2. Angpt-1 activates Tie2, whereas Angpt-2 is an endogenous, context-specific antagonist of Angpt-1. In patients with COVID-19, pathogen-induced ARDS, or sepsis, Angpt-2 expression is induced, as Angpt-1 and Tie2 expression decline. This contributes to dramatic attenuation of Tie2 signaling, which in turn affects endothelial stability and weakens barrier defense against vascular leakage and inflammation. Circulating levels of Angpt-2 are elevated in patients and predictive of mortality in ALI, ARDS, and sepsis, as well as prognostic for decreased respiratory compliance and ICU admission in COVID-19 patients. There are no clinically approved drugs to treat COVID-19-associated ARDS, ALI/ARDS, vascular leak, or exaggerated Host Vascular Response (HVR). Our novel approach to treating COVID-19-associated hypoxia, ALI, and ARDS involves targeting the vasculature by reinforcing endothelial stability and integrity of the endothelial barrier, and limiting pulmonary edema. Relevance to Topic Area: Our proposed clinical trial program addresses the FY20 PRMRP Respiratory Health Topic Area, and specifically the Area of Encouragement: "Novel and/or ... therapeutics to reduce the incidence and/or severity of ARDS and/or other lung injury secondary to ... infection." Overarching Hypothesis of the Study: The emerging picture of the pathophysiology of COVID-19 shows it extends beyond a serious respiratory disease to include viral sepsis, multi-organ dysfunction, and involvement of vascular endothelial cells. Progression to COVID-19-associated ALI and ARDS is similar to typical ARDS, which involves the maladapted HVR, breakdown of the endothelial barrier, and vascular leak, resulting in pulmonary edema and reduced lung function as measured by hypoxemia. We hypothesize in phase 1 and phase 1/2 clinical studies of AV-001 when administered daily at doses up to 28 µg/kg will be safe and well-tolerated. Further, in phase 1/2 clinical studies in COVID-19 patients, AV-001 will activate the Tie2-angiopoietin signaling axis restoring barrier defense, blocking vascular leak and promoting endothelial stability resulting a reduction in hypoxia, improvement in time to recovery and reducing progression to mechanical ventilation and ICU admission. Overarching Objective: To initially seek Emergency Use Authorization (EUA) for AV-001 for the treatment of severe COVID-19 and COVID-19-associated ARDS and to support future New Drug Application submission the treatment of ARDS. Research activities included in this proposal include two clinical studies designed to characterize the safety and pharmacokinetics of AV-001 in healthy subjects and patients and to characterize the efficacy in patients with ALI (hypoxia, requiring supplemental oxygen) and ARDS. Specific Aim #1: Phase 1 double blind, placebo controlled, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) study in healthy subjects. Study Design: This is a phase 1 SAD and MAD randomized, double-blind, placebo-controlled, single site study in up to 48 healthy subjects. The study will take place at Medpace, Inc. (a CRO specializing in phase 1/2a studies in healthy subjects) in their 60-bed clinical research facility located at the corporate headquarters in Cincinnati, Ohio. Specific Aim #2: Phase 1/2 exploratory, proof-of-concept randomized, double-bind, placebo-controlled multisite study of AV-001 in patients with moderate-to-severe COVID-19 disease. Study Design: This is a randomized, double-blind, placebo-controlled multiple-site multiple ascending dose phase 1/2 study in patients who are hospitalized with moderate-to-severe COVID-19 disease. The purpose of this exploratory proof-of-concept study is to examine the safety, tolerability, efficacy, and target engagement of AV-001 administered daily for up to 28 days to patients with moderate-to-severe COVID-19 disease. Moderate-to-severe COVID-19 patient population includes those who: (1) are hospitalized and meet the ARDS Berlin definition (PaO2/FiO2 under than 300 mmHg) and (2) do not strictly meet Berlin criteria, but are hypoxic and require supplemental oxygen therapy (ordinal scale 5,6). This study can be amended to add cohorts or increase the sample size of existing cohorts to transform into a pivotal study in support of EUA. Clinical Impact: Standard of care for ARDS patients remains limited; current interventions focus primarily on supportive therapy: fluid management and further injury prevention. AV-001 will represent the first targeted therapeutic to treat ARDS. Without accounting for inflation since 2006, treatment with AV-001 resulting in a (modest) 20% improvement in outcomes could potentially save >20,000 lives and $2.3 billion (based on 2005 ICU cost of $3,184/day and mechanical ventilation cost of $3,968/day) annually. AV-001 would well become a new standard of care for treatment of general ARDS, as well as COVID-19-instigated ARDS. Recently Remdesivir received EUA for treatment of patients with severe COVID-19. Vasomune has nonclinical data showing synergy with combination AV-001 and antiviral therapy. Therefore, we do not envision a scenario in which new antiviral therapeutics would prelude use of AV-001 as a standard of care. Military Relevance: Keeping the military combat-ready and fully capable of deterrence globally is of paramount importance. The potential impact on the military readiness is significant. Only a few infected Soldiers can have a devastating medical impact to others in close quarters, especially in naval vessels. Regional outbreaks are also played a role in states that are home to multiple military installations. Even with the advent of a vaccine, it is unlikely to be 100% effective. What is needed is a therapeutic that can treat regional outbreaks of COVID-19 and accelerate time to recovery and decrease progression to mechanical ventilation and the need for ICU admission. Less