A Phase 1 Placebo-Controlled Dose-Escalation Safety and Pharmacokinetic Study of IN-007, a Nebulized, Pan-SARS ACE2-Decoy Therapeutic for Pandemic Preparedness

Background: This research proposal addresses the FY24 JWMRP focus area of "broad spectrum and/or pathogen agnostic approaches to prevent and/or treat endemic or emerging infectious diseases of high operational impact." The project will advance the development of IN-007, a broad-spectrum antiviral to manage infections caused by all viruses that target the ACE2 receptor, including SARS-CoV-2, SARS-CoV-1, the seasonal coronavirus NL63, and emerging novel viruses such as MERS NeoCoV and related PDF-2180-CoV virus in bats. The current Biological Technical Readiness Level (TRL) of the inhaled biologic delivery platform is TRL 6 (two phase 1 studies completed for IN-006, an anti-SARS-CoV-2 mAb). IN-007 is being manufactured under cGMP conditions for the proposed phase 1 study and will be at TRL 5 when funding is available under this JWMRP award, and upon completion of the proposed project will be TRL 6. Viruses that cause SARS, MERS and pandemic influenza efficiently bind host-cell receptors in the airways to infect individuals and rapidly spread through populations. The COVID-19 pandemic shows immune-evasive variants pose a persistent threat to the effectiveness of both vaccines and traditional neutralizing monoclonal antibody (mAb) therapeutics. To address this threat, we are developing a platform of self-administered, inhaled, fast-acting, pan-variant immunodecoy prophylactics and therapeutics that would be effective against a wide range of existing and emerging respiratory pathogens of future pandemic potential. To that end, we have designed IN-007, a molecule comprised of human ACE2 domains linked to an IgG1-Fc, to potently neutralize all pathogens that bind human ACE2 for cellular entry (including every variant of SARS-CoV-2 and SARS-CoV-1). This variant-agnostic approach directly provides an answer for current and future pandemic pathogen preparedness for all ACE2-binding pathogens. Given that three coronaviruses can already transmit among humans (SARS-CoV-1, SARS-CoV-2 and NL63) by binding to ACE2, including two with pandemic potential, it is highly likely that another ACE2-binding pathogen will emerge before long. We have demonstrated that our novel route of administration, brief nebulization via a small, portable, handheld nebulizer provides rapid delivery of biologics like IN-007 to all levels of the respiratory tract at concentrations superior to intravenous administration. Hypothesis and Objective: The hypothesis to be tested in this study is that IN-007 will be a safe and well tolerated therapeutic agent, with sufficient promise to advance to future studies for testing its therapeutic efficacy. Specific Aims: Specific Aim 1: Finalize CRO and Clinical Site Contract Specific Aim 2: Clinical Trial Site Set-Up and Ethics/Regulatory Approval Specific Aim 3: Enroll Subjects and Complete Dose Escalation Specific Aim 4: Produce a Clinical Study Report Study Design: We propose a first in human, double-blind, randomized, ascending-dose safety, tolerability, pharmacokinetic and immunogenicity study. The study will administer IN-007 or saline placebo by nebulization with the Yirdoc NEB-108 vibrating mesh nebulizer. Healthy volunteers in four sequential dose escalation groups will receive (i) a single 30 mg dose, (ii) a single 90 mg dose, (iii) five days of 20 mg twice daily dosing or (iv) five days of 60 mg twice daily dosing. Participants will be closely observed before and after each nebulization for safety parameters that will include vital signs, spirometry (FEV1), oxygenation (SpO_2) and diffusion capacity of carbon monoxide (DLCO). The primary endpoint will be safety, assessed as the number and severity of treatment emergent adverse events of recipients randomized to active study drug versus blinded placebo. Nasal swabs and serum will be obtained at intervals to assess IN-007 pharmacokinetics by ELISA. Serum will be obtained to assess whether anti-drug antibodies are induced. Impact: The proposed study is a key step in the development of IN-007 and will enable progression to clinical efficacy studies. This broad-spectrum anti-coronavirus solution will provide the military with the means to respond effectively to the likely occurrence of future pandemics caused by novel coronaviruses that use ACE2 for cellular entry. IN-007 will also provide a therapeutic alternative to Paxlovid for current SARS-CoV-2 variants, providing a potentially better tolerated and more effective therapy. Moreover, success with this ACE2 decoy will provide proof of concept for other decoy strategies for broad spectrum therapy for families of viruses according to their cellular receptors. Less