AT191: An Inhaled & Precision RNA Therapeutic with Pan-Variant SARS-CoV-2 Efficacy

AT191: An Inhaled & Precision RNA Therapeutic with Pan-Variant SARS-CoV-2 Efficacy is sponsored by NIH. Autonomous Therapeutics Inc. received an SBIR Phase II award to develop a new class of antivirals targeting RNA viruses, including SARS-CoV-2.

AT191: An inhaled & precision RNA therapeutic with pan-variant SARS-CoV-2 efficacy Project Number 1R44AI186871-01A1 Former Number 1R44AI186871-01 PROJECT SUMMARY/ABSTRACT This Phase II SBIR will de-risk a new class of antivirals that can be developed to target any RNA virus from SARS-CoV-2 to influenza.

The effort will specifically translate a lead, platform-derived SARS-CoV-2 candidate (AT191) designed to be self-administered and to prevent hospitalizations or deaths by any SARS-CoV-2 variant. Despite vaccines and 2 blockbuster antivirals marketed to prevent hospitalizations, 900,000 Americans were hospitalized due to SARS-CoV-2 in 2023.

Beyond vaccine hesitancy and durability concerns, existing antivirals only reduce hospitalizations and deaths by 40–50%. SARS-CoV-2 antivirals are further limited by contraindications (e.g. Paxlovid) and safety concerns (e.g. molnupiravir). Moreover, there is a risk that SARS- CoV-2 acquires resistance to all existing classes of antivirals—as occurred with all SARS-COV-2 monoclonal antibodies prior to 2024.

There is a clear unmet need for new classes of antivirals, especially antivirals that can: (i) be used at-home to prevent hospitalizations, and (ii) maintain (variant-proof) efficacy as novel variants emerge. Encrypted RNA (encRNA) is a new class of RNA developed by Autonomous Therapeutics. The plug-and-play platform technology can develop antivirals against any RNA virus and can encode any therapeutic protein.

Unlike state-of-the-art mRNA, each platform-derived encRNA only activates its (broad-spectrum) antiviral payload in targeted virus-infected cells. More specifically, encRNA only translate encoded proteins when bound, transcribed, and amplified by targeted viral RNA polymerase (RdRp) complexes conserved across a viral species. Thus, encRNA remain translationally inactive and safe in uninfected cells (e.g. as prophylactics).

AT191 is our lead, first-in-class encRNA therapeutic candidate developed to confer inhaled and variant-proof efficacy against all variants of SARS-CoV-2 (and SARS-CoV-1). AT191 confers precision and pan-sarbecovirus efficacy—because AT191’s antiviral payload (IFN-β) is only activated and translated by sarbecovirus RdRp.

In Phase I-equivalent studies, we developed: (i) the encRNA platform technology, (ii) the AT191 lead candidate, and (iii) an inhalable lipid nanoparticle (LNP) for encRNA self-administration using marketed nebulizers. We further demonstrated the (iv) variant-proof efficacy of AT191 against every tested SARS-CoV-2 variant in vitro, and the (v) preliminary in vivo safety and efficacy of AT191 in both mice and hamsters.

Here we propose to develop AT191 into a GLP-ready candidate ready for IND-enabling studies. We propose to test the pan-sarbecovirus efficacy (SARS-CoV-1 & 2) of AT191 in vivo and to perform critical CMC, inhalation, dose-timing, and dose-finding studies in hamsters. We will also test safety/efficacy in non-human primates.

The effort will culminate in a pre-IND. If successful in follow-on clinical studies, AT191 could be used at-home as a prophylactic or therapeutic: e.g. for immediate use after exposure to an infected child or family member. Beyond SARS-CoV-2, the same encRNA-LNP platform technology could be used to develop precision and variant-proof candidates for any RNA virus—including viruses for which no safe and effective antivirals exist.

Public Health Relevance Statement PROJECT NARRATIVE More than 1 million Americans have died from COVID-19, and SARS-CoV-2 is likely to remain endemic for decades. In 2023 alone, COVID-19 resulted in the hospitalizations of more than 900,000 Americans.

This project aims to preclinically translate a first-in-class precision RNA antiviral candidate that could protect against all current and future variants of SARS-CoV-2—and thereby de-risk a plug-and-play platform technology that could be applied to any RNA virus from influenza to RSV. No NIH Spending Category available.

2019-nCoV Ablation American Anti-viral Agents Binding Biological Assay Biological Products COVID-19 COVID-19 testing COVID-19 therapeutics Cell Culture Techniques Cells Cessation of life Child Chronic Clinical Clinical Research Colorado Complex Coronavirus DNA-Directed RNA Polymerase Data Death Rate Doctor of Philosophy Dose Evaluation Exposure to Family Family member Future Genetic Transcription Goals Government Hamsters Home Hospitalization In Vitro Individual Infection Influenza Influenza A virus Influenza B Virus Inhalation Inhalation Toxicology Interferon-β Interferons Lead Legal patent Macaca mulatta Marketing Mediating Messenger RNA Molecular Monoclonal Antibodies Mus Nebulizer Nucleosides Paracrine Communication Participant Paxlovid Peer Review Persons Phase Play Population Prodrugs Proteins Publications RNA RNA Viruses RNA-Directed RNA Polymerase Resistance Risk SARS coronavirus SARS-CoV-2 antiviral SARS-CoV-2 variant Safety Sarbecovirus Self Administration Small Business Innovation Research Grant Testing Therapeutic Tissues Translating Translations Transplant Recipients Treatment Efficacy United States National Institutes of Health Vaccines Variant Viral Viral Proteins Virus Virus Diseases commercialization design encryption hospitalization rates in vivo influenzavirus innovation lead candidate lipid nanoparticle manufacture molnupiravir nonhuman primate nonhuman primate models novel pre-clinical prevent prior authorization prophylactic safety testing scaffold seropositive technology platform therapeutic RNA therapeutic candidate therapeutic protein vaccine hesitancy viral RNA virology AUTONOMOUS THERAPEUTICS, INC. [Special Emphasis Panel[ZAI1 LAR-Z (M1)]](https://public.

csr. nih. gov/StudySections/SmallBusinessAndTechnologyTransfer) Administering Institutes or Centers National Institute of Allergy and Infectious Diseases Assistance Listing Number Project Funding Information for 2025 No Sub Projects information available for 1R44AI186871-01A1 Publications are associated with projects, but cannot be identified with any particular year of the project or fiscal year of funding.

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