Is alanine aminotransferase flare-up in nucleos(t)ide analogue treatment of chronic hepatitis B a promising, rather than a devastating, sign?

Heo, Nae–Yun

doi:10.3350/cmh.2017.0106

Cited by 3 publications

(1 citation statement)

References 18 publications

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“…Two observed cases of transient ALT elevations are suggestive of immune‐mediated hepatocyte damage, as they were concurrent to HBsAg decline. ( 27,28 ) Apart from ISRs, no other oligonucleotide class effects, such as thrombocytopenia or reduced renal function, were noted with RO7062931. Considering that the vast majority of enrolled study participants were male (93%), it is not possible to adequately generalize the study results to female participants at this time.…”

Section: Discussionmentioning

confidence: 99%

Clinical Study of Single‐Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B

Gane¹,

Yuen

Kim

et al. 2021

Hepatology

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RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver via the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics and pharmacodynamics of RO7062931 in healthy volunteers and virologically suppressed patients with chronic hepatitis B (CHB). Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo.Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg, or placebo every month (QM) for a total of 2 doses (Part 2a), or RO7062931 at 3.0 mg/kg every 2 weeks (Q2W), 3.0 mg/kg every week (QW), or 4.0 mg/kg QW, or placebo for a total 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity.Common AEs included self-limiting injection site reactions and influenza-like illness. Supra-dose proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In CHB patients, RO7062931 resulted in dose-and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log 10 IU/mL) independent of HBeAg status.RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supra-dose proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931. Clinical trial number: NCT03038113.

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Section: Discussionmentioning

confidence: 99%