AT191: an inhaled & precision RNA therapeutic with pan-variant sars-COV-2 efficacy

The National Institute of Allergy and Infectious Diseases awarded Autonomous Therapeutics Inc. $1.981 million on September 10, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to advance a Phase II SBIR project translating AT191, an inhaled encrypted RNA (EncRNA) therapeutic candidate designed to prevent hospitalizations and deaths from SARS-CoV-2 variants.

AT191 is a self-administered antiviral employing a platform-derived, first-in-class EncRNA technology that activates its broad-spectrum antiviral payload only within virus-infected cells. Unlike conventional mRNA therapeutics, AT191 remains translationally inactive in uninfected cells, allowing use as a prophylactic. The therapeutic targets viral RNA polymerase complexes conserved across SARS-CoV-2 variants, conferring variant-proof efficacy. The Phase II effort de-risks this new antiviral class while establishing a plug-and-play platform applicable to any RNA virus, including influenza.

Autonomous Therapeutics Inc., a for-profit biotechnology company, is the recipient. The company is headquartered in the Silver Spring/North Bethesda, Maryland area, where work will be performed. The award obligates $1.981 million through August 31, 2028.

The project addresses an unmet clinical need: despite vaccines and existing antivirals, approximately 900,000 Americans were hospitalized with SARS-CoV-2 in 2023, and existing antivirals reduce hospitalizations and deaths by only 40–50 percent. Existing options carry contraindications and safety concerns, and resistance risk exists across current antiviral classes.

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.