TLR7 agonist ro7020531 triggers immune activation after multiple doses in chronic hepatitis B patients

Abstract

Background: RO7020531 is a double prodrug of the active toll-like receptor 7 (TLR7) agonist RO7011785 and is in clinical development as a component of a curative treatment regimen against chronic hepatitis B (CHB). RO7020531 previously demonstrated activation of TLR7 signaling in healthy volunteers when given as single ascending doses (SAD) and multiple ascending doses (MAD). These new data from this study demonstrate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in virologically suppressed CHB patients. Methods: This first cohort of 10 virologically suppressed CHB patients received 150 mg RO7020531/placebo every other day (QOD) for 6 weeks and were followed up for 6 weeks after the last dose. Safety, tolerability and PK were assessed. PD activity was investigated by changes in protein and metabolite markers (neopterin, IFN-α, IP-10, TNF-α, IL-6, IL-10, IL-12p40) as well as in markers of transcriptional responses (ISG15, OAS-1, MX1 and TLR7). Further cohorts of CHB patients are ongoing. Results: Throughout 6 weeks of dosing, RO7020531 was observed to be safe and with acceptable tolerability. A total of 23 adverse events (AEs) were reported in 7/10 patients, all of which were mild, with the exception of one AE of flu like symptoms of moderate intensity. While no pattern of AEs was observed, transient flu-like symptoms in 2 patients were likely associated with PD effects. The PK characteristics of active TLR7 agonist, RO7011785, in CHB patients were similar to those observed in healthy subjects with no exposure accumulation with the QOD dosing regimen. PD response, consistent with TLR7 activation, was demonstrated across all CHB patients. They exhibited various ranges of maximum fold increase from baseline for the protein, metabolite and transcriptional response markers (1.2- 36.4 fold for IP-10, 1.4- 6.1 fold for neopterin, 5.3 – 270.3 fold for ISG15, 2.5 – 41.5 fold for OAS-1, 5.6 – 87.4 fold for MX1 and 1.62- 6.84 fold for TLR7). A clear positive correlation between exposure and response in most of the PD markers was seen in both healthy subjects and CHB patients. Conclusion: RO7020531 was safe and had acceptable tolerability in 6-week QOD dosing in CHB patients, with evidence of immune activation across all patients. Based on these encouraging data, further CHB patient cohorts are being enrolled to define the optimal dose, which can be used in future studies in combination with other HBV therapies towards a CHB cure regimen.