LB2. TORC1 Inhibition with RTB101 as a Potential Pan-Antiviral Immunotherapy to Decrease the Incidence of Respiratory Tract Infections Due to Multiple Respiratory Viruses in Older Adults

BACKGROUND: Respiratory tract infections (RTIs) are a leading cause of hospitalization and death in people age ≥65 years. RTIs are caused by multiple viruses, most of which lack effective treatments. An immunotherapy that enhances pan-antiviral innate immunity may reduce RTI incidence in older adults. Inhibition of targets downstream of target of rapamycin complex 1 (TORC1) was reported to upregulate pan-antiviral gene expression and protect mice from a viral RTI (York AG et al. Cell 2015). We evaluated whether TORC1 inhibition increased antiviral gene expression and decreased RTI incidence in older adults. METHODS: A randomized, double-blind, placebo, controlled study was conducted to determine whether the TORC1 inhibitor RTB101 alone or in combination with the TORC1 inhibitor everolimus reduced the incidence of laboratory-confirmed RTIs. The study enrolled 652 older adults at increased risk of RTI-related morbidity and mortality (defined as age ≥85 years, or age ≥65 years with asthma, COPD, type 2 diabetes mellitus, or current smokers). Subjects were treated for 16 weeks during winter cold and flu season with oral RTB101 5 mg or 10 mg once daily (QD), RTB101 10 mg twice daily, RTB101 10 mg + everolimus 0.1 mg QD, or matched placebo. The primary endpoint was the percentage of subjects with ≥1 laboratory-confirmed RTI through Week 16. RESULTS: RTB101 was well tolerated. In the intent-to-treat analysis, RTB101 10 mg QD was observed to: reduce the percentage of subjects with laboratory-confirmed RTIs by 30.6% compared with placebo (P = 0.025); reduce the incidence of RTIs caused by multiple different viruses; and upregulate interferon-stimulated pan-antiviral gene expression in whole blood (P = 0.00001 vs. placebo, Figure 1). Furthermore, RTB101 10 mg QD was observed to reduce the time to alleviation of moderate to severe RTI symptoms by 5 days, and to reduce the rate of all-cause hospitalization (rate ratio 0.439, 90% CI 0.196–0.983, P = 0.047). CONCLUSION: RTB101 10 mg QD was associated with a significant reduction in laboratory-confirmed RTIs due to multiple viral pathogens that lack effective medicines for treatment or prevention. RTB101 was observed to upregulate interferon-stimulated pan-antiviral gene expression, which may underlie the reduction in RTI incidence. [Image: see text] DISCLOSURES: Joan Mannick, MD, resTORbio (Employee, Shareholder), Amelia Tomlinson, PhD, resTORbio (Employee), Sarb Shergill, PhD, resTORbio (Employee), Grace Teo, PhD, resTORbio (Employee), Lloyd Klickstein, MD, PhD, resTORbio (Employee).