RG6004 / Roche - LARVOL DELTA

Antisense oligodeoxynucleotides: the certain but limited efficacy and the uncovering mechanisms for the cure of chronic hepatitis B (PubMed, Zhonghua Gan Zang Bing Za Zhi) - "Particularly in the report of phase IIb clinical trial of Bepirovirsen (GSK3228836), approximately 9-10% patients with low baseline serum HBsAg (> 100 IU/ml & < 3 000 IU/ml) achieved functional cure after 24 weeks' of Bepirovirsen treatment. After reviewing the results of other clinical trials, one would be impressed to know that ALG-020572 (Aligos), RO7062931 (Roche) and GSK3389404 (GSK) all failed to sufficiently suppress serum HBsAg expression though the hepatocyte-targeted delivery of these ASOs were enhanced via N-acetyl galactosamine conjugation...Eventually the serum HBsAg declines in most participants and even disappears in a small fraction of patients with low baseline HBsAg level, via attack the infected hepatocytes evidenced by the aberrant elevation of ALT. Nevertheless, the functional cure of CHB remains a challenging issue and more efforts are needed."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Single Ascending Dose Study of Single-Stranded Oligodeoxyribonucleotide RO7062931 in Chinese Healthy Volunteers. (PubMed, Clin Transl Sci) - "PK data suggested that ASGPR saturation had commenced between doses of 2.0 mg/kg and 4.0 mg/kg. Results were broadly consistent with observations in primarily white subjects in the global first in-human study of RO7062931."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Influenza • Pain • Respiratory Diseases • ASGR • MUC4

[VIRTUAL] RO7062931 anti-sense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy (EASL-ILC-I 2020) - P1 | "RO7062931 administered over 4-weeks, at doses of up to 4mg/kg, in CHB patients is safe, well tolerated, and demonstrates target engagement by antiviral activity."

Clinical • P1 data • Hepatitis B • Hepatology • Infectious Disease

Author Reply: Is the HBsAg response to RO7062931 an antisense effect? (PubMed, Hepatology) - "Firstly, Dr Vaillant proposes RO7062931 should have exhibited greater HBsAg reductions, given the efficient RO7062931 liver uptake, rapid turnover of HBsAg, and rapid protein reductions observed with GalNAc-ASOs in other therapeutic indications. We find this reasoning unsatisfactory, primarily as there should be no expectations of similar potency for GalNAc-ASOs targeting different mRNA species."

Journal • Hepatitis B

Letter to the editor: Is the HBsAg response to RO7062931 an antisense effect? (PubMed, Hepatology) - "Exemplary studies (2, 3) illustrate a rapid and uniform ~1 log protein reduction within 15 days in all subjects, occuring with only a single dose and saturating with weekly to monthly dosing from 60mg (0.9 mg/kg) to 90mg (1.4 mg/kg). Given the rapid turnover of HBsAg (4, 5), target engagement with RO7062931 should be accompanied by similar HBsAg responses."

Journal • Hepatitis B • Infectious Disease

Clinical Study of Single Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients with Chronic Hepatitis B. (PubMed, Hepatology) - P1 | "Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931. Clinical trial number: NCT03038113."

Clinical • Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Respiratory Diseases • ASGR • MUC4

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=119; Completed; Sponsor: Hoffmann-La Roche; N=87 ➔ 119

Clinical • Enrollment change • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of RO7062931 in Healthy Chinese Volunteers. (clinicaltrials.gov) - P1; N=41; Completed; Sponsor: Hoffmann-La Roche; N=11 ➔ 41

Clinical • Enrollment change

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=87; Completed; Sponsor: Hoffmann-La Roche; Recruiting ➔ Completed; N=160 ➔ 87

Clinical • Enrollment change • Trial completion

INTERIM RESULTS OF A PHASE 1 STUDY OF RO7062931, A NOVEL LIVER-TARGETED SINGLE-STRANDED OLIGONUCLEOTIDE (SSO) WITH LOCKED NUCLEIC ACID (LNA) THAT TARGETS HBV TRANSCRIPTS. (AASLD 2019) - P1; "RO7062931 was safe and well tolerated in HVs, with a predictable PK profile expected for a GalNAc-conjugated SSO. Study Part 2 in patients with CHB is currently ongoing."

P1 data • ASGR

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=160; Recruiting; Sponsor: Hoffmann-La Roche; Trial completion date: May 2021 ➔ Oct 2019; Trial primary completion date: May 2021 ➔ Oct 2019

Clinical • Trial completion date • Trial primary completion date

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of RO7062931 in Healthy Chinese Volunteers. (clinicaltrials.gov) - P1; N=11; Completed; Sponsor: Hoffmann-La Roche; Recruiting ➔ Completed

Trial completion

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of RO7062931in Healthy Volunteers and Subjects With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=160; Recruiting; Sponsor: Hoffmann-La Roche; Trial completion date: Apr 2019 ➔ May 2021; Trial primary completion date: Apr 2019 ➔ May 2021

Clinical • Trial completion date • Trial primary completion date