INTERIM ANALYSIS of A PHASE i STUDY of PRTX007: SAFETY, PK, and PD RESPONSE

ABSTRACT

Background: PRTX007 is a prodrug of PRX034, a novel TLR7 agonist, for treatment of respiratory viral diseases including SARS-CoV-2. PRX034 activates plasmacytoid dendritic cells to preferentially synthesize poly sub-type interferons while minimizing NFκΒ-mediated proinflammatory factors. Pre-clinical studies have demonstrated decoupling of these two normally linked processes in human PBMCs in vitro and in cynomolgus monkeys in vivo. Antiviral activity is preserved, as demonstrated by inhibition of cytopathicity and viral replication in RNA viruses by conditioned media from PRX034-treated PBMCs. Efficacy and safety have been demonstrated in a murine model of RSV infection. An interim analysis of the first-in-human study in healthy volunteers is presented here. Methods: Phase I, single-center, prospective, randomized, double-blind study of 8 single-ascending dose (SAD) cohorts and 4 multiple-ascending dose (MAD) cohorts of PRTX007 administered orally to healthy adult subjects. Primary objective was safety and tolerability. Secondary objectives were to assess pharmacokinetics (PK) and pharmacodynamics (PD). This interim analysis focuses on the SAD portion of the study over 8 dose levels from 50-600mg. Safety through all SAD cohorts, PK up to the 500 mg cohort, PD up to the 400 mg cohort are presented. The MAD cohort safety data from 3 of 4 planned cohorts are also presented. Results: Treatment-related adverse events (AEs) include mild to moderate headache. Severity or frequency is not dose related, is of short duration and is not associated with systemic symptoms. One participant in the 400 mg cohort had asymptomatic mild sinus tachycardia, attributed to PRTX007. Two subjects in the second MAD cohort at 300 mg had mild increases in ALT that rapidly resolved after treatment. PK analysis demonstrated efficient conversion of PRTX007 to PRX034 with systemic exposure to drug and prodrug increasing proportionally with dose. Duration of systemic exposure to PRX034 at pharmacologically active levels is consistent with activation of innate immune response without counter-regulation (Panel A). Exposure-dependent PD response measured by induction of interferon stimulated genes in the blood is observed at drug AUC > 4,300 hr∗ng/ml (Panel B);duration of induction >24 hours (Panel C). Conclusion: Interim analysis of PRTX007 demonstrates a favorable safety profile with dose-dependent systemic exposure and demonstrated activation of innate immune response.