Safety, pharmacokinetic, pharmacodynamic and viral data after 6-weeks of dosing with TLR7 agonist RO7020531 in chronic hepatitis B patients

Abstract

Background: RO7020531 is a double prodrug of the active toll‐like receptor 7 (TLR7) agonist RO7011785 in clinical development for a curative regimen against chronic hepatitis B (CHB). We present the interim data from 3 CHB patient cohorts on safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and HBsAg dynamics. Methods: Each cohort comprised 10 virologically suppressed CHB patients (2 on placebo: 8 on active drug); 2 cohorts received 150 mg and 1 cohort received 170 mg RO7020531/placebo orally every other day (QOD) for 6 weeks and patients were followed up for further 6 weeks after the last dose. PD activity was investigated by changes in protein and metabolite markers as well as in markers of transcriptional responses. Although 6 weeks of RO7020531 dosing is not aimed to demonstrate efficacy, quantitative HBsAg levels were measured at baseline, end of 6‐week treatment (EOT) and at end of 6‐week follow up. Results: Throughout 6 weeks of dosing, RO7020531 was safe and acceptably tolerated. A total of 87 adverse events (AEs) were reported in 19/30 patients, most of which mild, except of 7 moderate AEs reported in 4 patients and one severe AE (related flu‐ like symptoms after one dose). There were 2 study drug discontinuations. No pattern of AEs was observed, apart from transient flu‐like symptoms in 7 patients. PK parameters of the active metabolite, RO7011785, in CHB patients are consistent between Day 1 to Day 41 and comparable to those in healthy volunteers. PD activity consistent with TLR7 activation was demonstrated and maintained following multiple doses at 150 mg, where more than 70% of the patients had a response in all evaluated biomarkers. Analysis of the PD data following 170 mg dose is ongoing. There was high variability in the HBsAg levels at baseline (1.01‐25,010 IU/mL). The Mean (Standard Deviation) HBsAg log10 decline at EOT was placebo: 0.0102 (0.0642); 150 mg: 0.0243 (0.0845); 170 mg: ‐0.0410 (0.1611) and after 6 weeks of follow‐up was placebo: ‐0.0457 (0.0644); 150 mg: ‐0.0728 (0.1124); 170 mg: ‐0.1392 (0.1508). Conclusion: RO7020531 was safe and acceptably tolerated in 6‐week QOD dosing in CHB patients, with predictable PK and solid evidence of immune activation across all patients Conclusions on HBsAg dynamics could not be made due to the short treatment duration RO7020531 is currently being tested in not‐treated CHB patients. Its clinical benefit in promoting functional cure will be evaluated in combination studies of longer duration