AT191: An inhaled & precision RNA therapeutic with pan-variant SARS-CoV-2 efficacy

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.