Dicerna Announces Positive Updated Data From Phase 1 Trial of RG6346 for Treatment of Chronic Hepatitis B Virus (HBV) Infection at AASLD’s The Liver Meeting® Digital Experience™ 2020
Nov 16, 2020
– Data Presentations Show Treatment With Up to Four Monthly Doses of RG6346 Resulted in Substantial and Durable Reductions in HBsAg Levels Lasting Up to One Year After Last Dose –
– RG6346 Was Shown to be Safe and Well Tolerated in This Trial –
In trial participants who were treated with four monthly doses of RG6346 added to nucleos(t)ide (NUC) antiviral therapy (Group C), 11 of 12 (92%) had mean HBsAg reductions from baseline greater than 1.0 log10 IU/mL by Day 112 (one month after last dose). Seven of the 12 participants (58%) also achieved HBsAg levels below 100 IU/mL – a level that is associated with a reduced risk of progression to cirrhosis and hepatocellular carcinoma. Durability of HBsAg reductions was observed up to Day 448 (one year after the last dose). Among participants eligible to continue in long-term follow-up after the dosing period in the longest-observed cohort (1.5 mg/kg; n=3), the mean reduction in HBsAg from baseline was 1.40 log10 IU/mL at Day 448; one of these participants maintained greater than a 2.0 log10 IU/mL reduction in HBsAg level from baseline at Day 448.
“We are pleased by the magnitude and sustainability of HBsAg suppression with RG6346 seen in our latest Phase 1 results, lasting up to one year after the last dose administered,” said
Additional data highlights from Group C participants treated with RG6346 plus NUC therapy (data cutoff
- 75% (9 of 12) experienced HBsAg reductions of ≥1.5 log10 IU/mL.
- At Day 112, the mean reduction in HBsAg was 1.39 (SE 0.19) log10 IU/mL for the 1.5 mg/kg cohort (n=4); 1.80 (SE 0.28) log10 IU/mL for the 3.0 mg/kg cohort (n=4); and 1.64 (SE 0.30) log10 IU/mL for the 6.0 mg/kg cohort (n=4).
- The maximum HBsAg reduction from baseline was 2.7 log10 IU/mL in a participant given 3.0 mg/kg of RG6346.
- 83% (10 of 12) entered conditional follow-up. Participants were eligible to enter the conditional follow-up period if they had HBsAg reductions from baseline of ≥1.0 log10 IU/mL at the end of the treatment period.
- 67% (8 of 12) entered conditional follow-up and had ≥1.0 log10 IU/mL HBsAg reduction from baseline at the last observed time point, which ranged from Day 140 to Day 448.
- Similar mean maximum HBsAg log10 IU/mL reductions were observed independent of hepatitis B e-antigen status (HBeAg levels are an indicator of active HBV replication and high infectivity).
In three of six NUC-naïve participants treated with a single 3.0 mg/kg dose of RG6346 (Group B), transient alanine aminotransferase (ALT) elevations, or flares (defined in the study protocol as more than three times baseline or post-baseline nadir value and more than seven times the upper limit of normal), were observed during the treatment period. These were associated with concomitant viral marker reductions and preserved liver function, suggesting beneficial treatment-induced immune-mediated responses to HBV. No protocol-defined ALT flares were observed in Group C (NUC-suppressed) participants, most likely reflecting therapeutic NUC suppression and further demonstrating RG6346 safety in combination therapy for HBV.
No serious adverse events (SAEs) were reported for participants treated with RG6346, and there were no dose-limiting toxicities or safety-related discontinuations. The most commonly reported adverse events were mild or moderate injection-site events. There were no dose-exposure or regimen-dependent increases in frequency or severity of adverse events, safety lab values, electrocardiogram readings or vital signs.
“The data presented show for the first time the depth of HBsAg reduction achieved by all treated patients during the full RG6346 treatment period, as well as post-dose duration of HBsAg knockdown lasting up to one year,” commented
“We continue to be very encouraged by results seen with RG6346,” said
The results of this Phase 1 trial will be presented live on
About the RG6346 Phase 1 Proof-of-Concept Trial
The RG6346 Phase 1 proof-of-concept trial comprises three groups of adult participants: Group A, composed of 30 healthy volunteers who received single RG6346 doses up to 12.0 mg/kg (completed 2019); Group B, composed of nine participants who were newly diagnosed with chronic HBV and naive to any NUC antiviral therapy, randomized 5:31 to a single 3.0 mg/kg dose of RG6346 or placebo, respectively (completed early 2020); and Group C, composed of 18 participants who were diagnosed with chronic HBV and actively receiving NUC therapy, randomized 2:1 to four monthly doses of 1.5, 3.0 or 6.0 mg/kg of RG6346 or placebo, respectively. The last participant visit in the double-blind period up to Day 112 for Group C occurred in
About Chronic Hepatitis B Virus (HBV) Infection
Hepatitis B virus (HBV) is the world’s most common serious liver infection and affects an estimated 292 million people worldwide.2 According to the
RG6346 is an investigational GalXC™ RNAi therapeutic candidate in development in collaboration with Roche for the treatment of chronic hepatitis B virus (HBV) infection. Dicerna is currently conducting a Phase 1 proof-of-concept trial of RG6346 in adult patients with non-cirrhotic chronic HBV infection. Current therapies for HBV, such as nucleos(t)ide analogs, can provide long-term viral suppression if taken continuously, but they rarely lead to long-term functional cures, as measured by the clearance of HBV surface antigen (HBsAg) and sustained HBV deoxyribonucleic acid (DNA) suppression in patient plasma or blood. By contrast, RG6346 is designed to employ RNAi to knock down selectively specific genes involved in the creation of HBV messenger RNA (mRNA) and the entry of the virus into liver cells. Preclinical data have demonstrated greater than 99.9% reduction in circulating HBsAg, as observed in mouse models of HBV infection. Unlike current therapies that typically provide long-term suppression of the virus, we believe RG6346 has the potential to provide a functional cure as part of a combination regimen for patients living with chronic HBV.
About the GalXC™ RNAi Technology Platform
Dicerna’s proprietary RNA interference (RNAi) technology platform, called GalXC™, aims to advance the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. GalXC-based compounds enable subcutaneous delivery of RNAi therapies that are designed to bind specifically to receptors on liver cells, leading to internalization and access to the RNAi machinery within the cells. The GalXC approach seeks to optimize the activity of the RNAi pathway so that it operates in the most specific and potent fashion.
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements we make regarding: Phase 1 proof-of-concept data for RG6346, an investigational GalXC™ RNAi treatment candidate for chronic hepatitis B virus (HBV) infection in development with Roche. The process by which investigational therapies, such as RG6346, could potentially lead to an approved product is long and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’s clinical research and other risks identified under the heading "Risk Factors" included in the Company’s most recent filings on Forms 10-K and 10-Q and in other future filings with the
1 One additional subject was enrolled in Group B (total n=9) to replace a subject determined to be ineligible after the study dose had been administered.
2 Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. The Lancet Gastroenterology and Hepatology. 2018;3(6):383-403.
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