RG7907 / Roche - LARVOL DELTA

Piranga: A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (clinicaltrials.gov) - P2 | N=281 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Jul 2024 | Trial primary completion date: Oct 2024 ➔ Jul 2024

Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Piranga: A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (clinicaltrials.gov) - P2 | N=280 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jan 2025 ➔ Jul 2025

Combination therapy • Trial completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Non-HAP CAM-A ALG-006746 and ALG-006780 induce rapid HBsAg reductions in AAV-HBV mice and have favorable pharmacokinetic profiles (EASL-ILC 2024) - "With rapid in vivo HBsAg declines and favorable PK profiles, ALG-006746 and ALG- 006780 are promising CAM-A candidates for further development."

PK/PD data • Preclinical • Hepatitis B • Hepatology • Inflammation

Efficacy, safety and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients. (PubMed, Clin Mol Hepatol) - "Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients...48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient."

Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

CLASS A CAMS INDUCE CELL DEATH THROUGH HBV CORE PROTEIN AGGREGATION AND POTENTIALLY ACTIVATE THE INNATE IMMUNE RESPONSE (AASLD 2023) - "We previously showed that CAM-A RG7907 treatment leads to an unexpected sustained HBsAg reduction and loss of infected hepatocytes via apoptosis in an AAV-HBV mouse model... CAM-A-dependent HBc aggregation drives cell death via activation of host specific pathways such as apoptosis and the inflammatory and innate immunity responses. These results shed light on a previously unknown mechanism of action specific to CAM-A compounds."

Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Solid Tumor

A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (clinicaltrials.gov) - P2 | N=280 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Hepatitis B • Hepatology • Infectious Disease • Inflammation • PD-L1

Evaluation of the drug disposition of RO7049389 with in vitro data and human mass balance supported by physiologically based pharmacokinetic modeling. (PubMed, Br J Clin Pharmacol) - "Metabolic pathways with fractions metabolized - obtained from the in vitro incubation results of 10 μM [ C]RO7049389 and 1 μM M5 with (long-term co-cultured) human hepatocytes in the absence and presence of the cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole - were used to complement the PBPK models, alongside the clinical MB and BA data. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P-glycoprotein (~41%), direct glucuronidation via uridine 5'-diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%). These results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development."

Journal • PK/PD data • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CYP3A4

Class a capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and proliferation. (PubMed, Hepatology) - "Our study unravels a previously unknown mechanism of action for CAM-As such as RG7907 in which HBc aggregation induces cell death, resulting in hepatocyte proliferation and loss of covalently closed circular DNA (cccDNA) or its equivalent, possibly assisted by an induced innate immune response. This represents a promising approach to attain a functional cure for CHB."

Journal • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Solid Tumor

Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection. (PubMed, J Med Chem) - "In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • CYP3A4

[VIRTUAL] Resistance monitoring data from treatment-naive chronic HBV infected patients treated for 28 days with a new class a core protein allosteric modulator RO7049389 monotherapy (EASL-ILC-I 2020) - P1 | "In this study, a low occurrence of polymorphisms within the 24 amino acids in the putative binding pocket of RO7049389 was observed in all sequenced samples. Baseline polymorphisms known to reduce RO7049389 activity were observed in only 1 of the 34 (3%) patients with baseline sequence data, as this was a placebo-treated patient, no conclusion on reduced in vivo susceptibility can be drawn. No mutations known to reduce RO7049389 activity in vitro emerged or were enriched after 28 days of treatment, which is consistent with the robust decline in plasma HBV DNA among all patients who received RO7049389 monotherapy."

Clinical • Monotherapy • Hepatitis B • Hepatology • Infectious Disease

NON-HAP CLASS I CAPSID ASSEMBLY MODULATORS HAVE DISTINCT PROFILES AND A DIFFERENTIATED MECHANISM OF ACTION (AASLD 2022) - "Non-HAP CAM1s such as ALG-005398 and ALG-006162 have a profile that is clearly distinct from known HAP CAM1s such as RG7907. Their underlying mechanisms of action governing in vivo HBsAg reduction are also clearly differentiated. Since optimized non-HAP CAM1s have suitable ADME / tox profiles, they represent an attractive class of molecules for further development as a part of potential functional cure regimens for CHB, offering a potential advantage over HAPs."

Hepatitis B • Hepatology • Infectious Disease • Inflammation • CALM2

HAP CLASS I CAPSID ASSEMBLY MODULATORS CLEAR HEPATITIS B VIRUS-INFECTED HEPATOCYTES THROUGH CORE-DEPENDENT HEPATOCYTE DEATH AND SUBSEQUENT PROLIFERATION (AASLD 2022) - "Here, we present an exploration of the mechanism of action of HAP CAM1s, such as RG7907... HAP CAM1s induce HBc aggregation which triggers a controlled level of hepatocyte apoptosis, limited to HBc-expressing cells. Compensatory hepatocyte proliferation leads to an additional loss of AAV-HBV episomes. The combination of both mechanisms, possibly complemented by an immune response, results in a sustained loss of HBV-positive cells."

Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • CALM2

A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (clinicaltrials.gov) - P2 | N=275 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Aug 2023 ➔ Nov 2024 | Trial primary completion date: Mar 2023 ➔ May 2024

Combination therapy • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation • PD-L1

A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants (clinicaltrials.gov) - P1 | N=192 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Trial completion date: Mar 2025 ➔ Mar 2022 | Trial primary completion date: Mar 2025 ➔ Mar 2022

Trial completion • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Viral nucleic acids suppression activity of RO7049389 plus NUC with/without Peg-IFN in virologically-suppressed and naive chronic hepatitis B patients: 48-week treatment and post-treatment follow up (EASL-ILC 2022) - P1 | "RO7049389+NUC ± Peg-IFN demonstrated potent effect on viral nucleic acids suppression even in treatment naïve patients. HBV DNA was suppressed and maintained 2 log10- copies/ml below baseline after the cessation of RO7049389, which may suggest a certain level of suppression in cccDNA level/ transcriptional activity in treatment naïve patients."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

Hepatitis B virus antigen reduction effect of RO7049389 plus NUC with/without Peg-IFN in chronic hepatitis B patients (EASL-ILC 2022) - P1 | "RO7049389 did not induce obvious HBV antigen reduction in NUC-suppressed patients. RO7049389+Peg-IFN+NUC led to larger HBsAg declines, especially in difficult-to-treat Genotype C patients. HBeAg positivity and high HBsAg baseline levels seemed to positively modulate the ability of RO7049389+Peg-IFN+NUC to reduce HBsAg."

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants (clinicaltrials.gov) - P1 | N=175 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Aug 2022 ➔ Mar 2025 | Trial primary completion date: Aug 2022 ➔ Mar 2025

Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B (clinicaltrials.gov) - P2 | N=275 | Recruiting | Sponsor: Hoffmann-La Roche | N=210 ➔ 275

Combination therapy • Enrollment change • Hepatitis B • Hepatology • Infectious Disease • Inflammation • PD-L1

A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants (clinicaltrials.gov) - P1; N=175; Active, not recruiting; Sponsor: Hoffmann-La Roche; Trial primary completion date: Sep 2021 ➔ Aug 2022

Clinical • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Evaluation of the safety, tolerability, and pharmacokinetics of RO7049389 in healthy Chinese volunteers. (PubMed, Clin Transl Sci) - "In general, the safety profiles were comparable between non-Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non-Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus."

Clinical • Journal • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Mass Balance and Absolute Bioavailability Study of RO7049389 in Healthy Volunteers (clinicaltrials.gov) - P1; N=22; Completed; Sponsor: Hoffmann-La Roche; Active, not recruiting ➔ Completed

Clinical • Trial completion

Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial. (PubMed, Lancet Gastroenterol Hepatol) - P1 | "RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks of treatment in patients with chronic HBV infection. These findings support further clinical development of RO7049389 as a component of novel combination treatment regimens for patients with chronic HBV infection."

Clinical • Journal • P1 data • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Pain • Respiratory Diseases

Mass Balance and Absolute Bioavailability Study of RO7049389 in Healthy Volunteers (clinicaltrials.gov) - P1; N=22; Active, not recruiting; Sponsor: Hoffmann-La Roche; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Mass Balance and Absolute Bioavailability Study of RO7049389 in Healthy Volunteers (clinicaltrials.gov) - P1; N=22; Recruiting; Sponsor: Hoffmann-La Roche; Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants (clinicaltrials.gov) - P1; N=175; Active, not recruiting; Sponsor: Hoffmann-La Roche; Completed ➔ Active, not recruiting; Trial completion date: Oct 2020 ➔ Aug 2022; Trial primary completion date: Oct 2020 ➔ Sep 2021

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease