Safety and Tolerability of the Toll-Like Receptor (TLR)2/6 Agonist INNA-051 in Healthy Adults

RATIONALE: INNA-051 is a Toll-like receptor (TLR) 2/6 agonist delivered via intranasal spray, being developed for treatment of respiratory viral diseases. Pre-clinical studies demonstrate that INNA-051 and analogues are effective against a variety of respiratory viruses including SARS-CoV- 2, influenza, and rhinovirus. INNA-051 induces a tissue-localized innate immune response with cytokine expression and infiltration of innate immune cells into the nasal epithelium that play a key role in viral clearance. The primary objective of this study (ACTRN12621000607875p) was evaluation of safety and tolerability in healthy adults. METHODS: This was a randomized, doubleblind, placebo-controlled, Phase 1 study of single and multiple ascending INNA-051 intranasal doses, with the total dose split evenly across both nostrils. Sixty-four participants ages 18-55 were enrolled, with 5 cohorts (6 active:2 placebo/cohort) receiving single doses of 20μg, 60μg, 150μg, 300μg, or 600μg, and 3 cohorts (6 active:2 placebo/cohort) receiving 4 total doses of 60μg, 150μg, and 300μg administered every third day. Assessments included adverse events, clinical laboratories, peak inspiratory nasal flow (PINF), and peak expiratory flow (PEF).RESULTS: Sixtyfour participants (36 males:28 females) ages 19-55 years were enrolled. Preliminary blinded results demonstrate that INNA-051 was well tolerated across all single and multiple dose cohorts. Adverse events were predominantly mild, limited to the nasopharynx, and resolved within 24-48 hours. Across single dose cohorts, the most frequent events were nasal congestion/blockage (n=20), nasal erythema/inflammation (n=19), rhinorrhea (n=13) and headache (n=11). Except for the 20-μg cohort with only 2 reports of rhinorrhea, all other single dose cohorts had a similar incidence of the other adverse events with no obvious dose relationship. Across all 3 multiple dose cohorts, nasal erythema/inflammation (n=42) was most frequently reported, followed by nasal congestion/blockage (n=26), rhinorrhea (n=9), and headache (n=9), with no dose-dependent relationship. No participants withdrew from the study due to adverse events. There were no clinically significant changes in clinical chemistry and hematology laboratories across all single and multiple dose cohorts. No consistent decrease in post-dose PNIF assessments were observed, and there were no changes in PEF assessments to suggest lower respiratory tract airway response to intranasal INNA- 051.CONCLUSIONS: Intranasal INNA-051 was well tolerated up to single doses of 600μg and multiple doses of 300μg. Mild, self-limited nasal adverse events as described are possible indicators of tissue-localized innate immune response by INNA-051. Investigation of cytokine levels and gene expression of the intranasal epithelium are needed to specifically determine TLR2/6 engagement by INNA-051.