xalnesiran (RG6346) / Roche, Novo Nordisk - LARVOL DELTA

Efficacy and safety of xalnesiran in combination with the checkpoint inhibitor PD-L1 LNA in virologically suppressed participants with chronic hepatitis B: results from the Piranga phase 2, randomized, controlled, adaptive, open-label platform study (APASL 2025) - P2 | "Here, we report the primary and selected secondary and exploratory endpoint results of xalnesiran (RO7445482), a GalNAc-conjugated small interfering ribonucleic acid (siRNA) targeting HBsAg transcripts, in combination with PD-L1 LNA (RO7191863), a GalNAc-conjugated locked nucleic acid inhibiting the expression of the programmed death-ligand 1. The combination of xalnesiran with the checkpoint inhibitor PD-L1 LNA, either concurrently or sequentially, achieved limited efficacy on HBsAg loss and its durability. Xalnesiran with PD-L1 LNA was generally safe and well-tolerated. Table and Figure:Figure 1."

Checkpoint inhibition • Clinical • Combination therapy • IO biomarker • P2 data • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Oncology

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

Efficacy and safety of xalnesiran with and without an immunomodulator in virologically suppressed participants with chronic hepatitis B: end of study results from the phase 2, randomized, controlled, adaptive, open-label platform study (PIRANGA) (EASL-ILC 2024) - P2 | "Here, we report end of study results, including seroconversion and durability of HBsAg loss, of xalnesiran (RO7445482), an N-acetylgalactosamine (GalNAc)-conjugated small interfering ribonucleic acid (siRNA) targeting HBsAg transcripts with or without an immunomodulator: ruzotolimod (toll-like receptor 7 agonist, RO7020531) or pegylated interferon alfa-2a (Peg-IFN-α). The highest HBsAg loss and seroconversion rates were observed when xalnesiran was combined with an immunomodulator. The continued change in HBsAg loss rate between EOT and 48 wks post-EOT warrants adequate follow-up to confirm sustained functional cure. All treatments were generally safe and well tolerated."

Clinical • Immunomodulating • P2 data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

NUCLEOS(T)IDE ANALOGUE DISCONTINUATION OUTCOMES IN CHRONIC HEPATITIS B PARTICIPANTS TREATED WITH XALNESIRAN COMBINATION THERAPIES WITH AND WITHOUT AN IMMUNOMODULATOR: INTERIM RESULTS FROM THE PHASE 2, RANDOMIZED, CONTROLLED, ADAPTIVE, OPEN-LABEL PLATFORM STUDY (PIRANGA) (AASLD 2023) - P2 | "Here, we report the criteria and the associated outcomes from xalnesiran (a small interfering ribonucleic acid targeting the HBsAg coding region of the HBV genome, RO7445482, RG6346) combination therapies in the PIRANGA phase 2 platform study (NCT04225715, please refer to Abstract #48375)... NUC discontinuation in xalnesiran combination arms was safely managed with close monitoring and pre-specified stopping/restarting criteria."

Clinical • Combination therapy • Immunomodulating • Late-breaking abstract • P2 data • Hepatitis B • Hepatology • Infectious Disease • Inflammation

EFFICACY AND SAFETY OF XALNESIRAN COMBINATION THERAPIES WITH AND WITHOUT AN IMMUNOMODULATOR IN VIROLOGICALLYSUPPRESSED PARTICIPANTS WITH CHRONIC HEPATITIS B: PRIMARY ENDPOINT RESULTS FROM THE PHASE 2, RANDOMIZED, CONTROLLED, ADAPTIVE, OPEN-LABEL PLATFORM STUDY (PIRANGA) (AASLD 2023) - P2 | "Here, we report the primary endpoint results of xalnesiran, a small interfering ribonucleic acid (siRNA) targeting the HBsAg coding region of the HBV genome (RO7445482, RG6346) in combination with nucleos(t)ide analogues (NUC), with or without an immunomodulator: pegylated interferon alfa-2a (Peg-IFN-α, Pegasys®), or ruzotolimod (toll-like receptor 7 agonist, RO7020531, RG7854). Xalnesiran combination therapies of 48 wks treatment duration were generally safe and well tolerated. Higher HBsAg loss rates were observed when xalnesiran was combined with an immunomodulator (PegIFN-α or ruzotolimod)."

Clinical • Combination therapy • Immunomodulating • Late-breaking abstract • P2 data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection. (PubMed, J Hepatol) - P1 | "These favourable safety and pharmacodynamic data support the clinical development of RG6346 as a backbone of a finite antiviral treatment regimen aiming for sustained HBsAg loss in patients with CHB."

Clinical • Journal • P1 data • 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=280 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

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

Study of Safety and Tolerability of DCR HBVS (clinicaltrials.gov) - P1 | N=82 | Completed | Sponsor: Dicerna Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • 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 | 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 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

[VIRTUAL] THE PHARMACOKINETIC AND SAFETY PROFILES OF RO7445482 siRNA ARE SIMILAR BETWEEN ASIAN AND NON- ASIAN HEALTHY VOLUNTEERS AND CHRONIC HEPATITIS B PATIENTS IN A PHASE 1 STUDY (AASLD 2021) - "The current investigation demonstrated similar PK and safety profiles of RO7445482 in Asian and non-Asian subjects . No dose adjustment appears to be needed for Asian compared to non- Asian subjects ."

Clinical • P1 data • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • ASGR

Dicerna Announces Poster Presentations at American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2021 in November (Businesswire) - "Dicerna Pharmaceuticals...announced that two abstracts related to the Company’s clinical development programs have been accepted for poster presentations at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting® taking place Nov. 12-15, 2021....An additional abstract provides results of a subpopulation pharmacokinetic and safety analysis from the Phase 1 trial of RG6346 (RO7445482), an investigational GalXC RNAi therapeutic that Dicerna is developing in collaboration with Roche for the treatment of chronic hepatitis B virus (HBV) infection."

P1 data • PK/PD data • Hepatitis B • Infectious Disease

Study of Safety and Tolerability of DCR HBVS (clinicaltrials.gov) - P1; N=82; Active, not recruiting; Sponsor: Dicerna Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Dicerna Announces First Quarter 2021 Financial Results and Provides a Business Update (Dicerna Press Release) - "Earned $25 Million Milestone Payment in Connection With Roche’s Initiation of GalXC™ RNAi Candidate RG6346 in Phase 2 Combination Trial for Treatment of Chronic Hepatitis B Virus Infection...Research and Development (R&D) Expenses – R&D expenses were $56.0 million for the first quarter 2021, compared to $43.2 million for the same period in 2020."

Commercial • Hepatitis B • Infectious Disease

[VIRTUAL] HBV RNAi INHIBITOR RG6346 IN PHASE 1b-2a TRIAL WAS SAFE, WELL-TOLERATED, AND RESULTED IN SUBSTANTIAL AND DURABLE REDUCTIONS IN SERUM HBsAg LEVELS (AASLD 2020) - "Treatment with RG6346 was safe and consistently induced large and durable reductions of HBsAg regardless of HBeAg status."

Late-breaking abstract • P1/2 data • Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Oncology • Solid Tumor

[VIRTUAL] HBV RNAi INHIBITOR RG6346 IN PHASE 1b-2a TRIAL WAS SAFE, WELLTOLERATED, AND RESULTED IN SUBSTANTIAL AND DURABLE REDUCTIONS IN SERUM HBsAg LEVELS (AASLD 2020) - "Treatment with RG6346 was safe and consistently induced large and durable reductions of HBsAg regardless of HBeAg status."

Late-breaking abstract • P1/2 data • Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Oncology • Solid Tumor

Study of Safety and Tolerability of DCR HBVS (clinicaltrials.gov) - P1; N=56; Recruiting; Sponsor: Dicerna Pharmaceuticals, Inc.; Trial completion date: Jul 2020 ➔ Jul 2022; Trial primary completion date: May 2020 ➔ Jul 2022

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

Dicerna Announces Positive Clinical Data for Investigational Treatments RG6346 for Chronic Hepatitis B Virus and Nedosiran for Primary Hyperoxaluria, and Presents Preclinical Data Applying RNAi Technology in New Tissues (Businesswire) - P1, N=56; NCT03772249; Sponsor: Dicerna Pharmaceuticals, Inc; "Dicerna Pharmaceuticals, Inc....today announced positive data from its Phase 1 proof-of-concept trial of RG6346, an investigational candidate for the treatment of chronic hepatitis B virus (HBV) infection in development in collaboration with Roche....At Day 112, the mean reduction in HBsAg was 1.39 log10 IU/mL (n=4) for the 1.5 mg/kg cohort, 1.80 log10 IU/mL (n=4) for the 3.0 mg/kg cohort, and 1.84 log10 IU/mL (n=2) for the 6.0 mg/kg cohort; two participants have not yet reached Day 112....Under the terms of the agreement between the companies, Roche will be responsible for initiating Phase 2 development of RG6346."

P1 data • Hepatitis B