Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Loomba Rohit,Morgan Erin,Watts Lynnetta,Xia Shuting,Hannan Lisa A,Geary Richard S,Baker Brenda F,Bhanot Sanjay The lancet. Gastroenterology & hepatology BACKGROUND:Diacylglycerol-O-acyltransferase 2 (DGAT2) is one of two enzyme isoforms that catalyse the final step in the synthesis of triglycerides. IONIS-DGAT2 is an antisense oligonucleotide inhibitor of DGAT2 that is under clinical investigation for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this trial was to examine the safety, tolerability, and efficacy of IONIS-DGAT2 versus placebo in reducing liver fat in patients with type 2 diabetes and NAFLD. METHODS:This double-blind, randomised, placebo-controlled, phase 2 study consisted of a 2-week screening period, a run-in period of up to 4 weeks, a 13-week treatment period of once-weekly dosing, and a 13-week post-treatment follow-up period. The study was done at 16 clinical research sites in Canada, Poland, and Hungary. Eligible participants were aged 18-75 years, had a body-mass index at screening between 27 kg/m and 39 kg/m, haemoglobin A (HbA) levels from 7·3% to 9·5%, and liver fat content 10% or greater before randomisation, and agreed to maintain a stable diet and exercise routine throughout the study. Enrolled participants were stratified on the basis of liver fat content during the run-in period (<20% or ≥20%) and then centrally randomised (2:1) to receive once weekly subcutaneous injection of 250 mg IONIS-DGAT2 or placebo for 13 weeks. Participants, investigators, funder personnel, and the clinical research organisation staff, including central readers of MRI scans, were all masked to treatment identity. The primary endpoints were the safety, tolerability, and pharmacodynamic effect of IONIS-DGAT2 on hepatic steatosis, according to absolute reduction from baseline in liver fat percentage as quantified by MRI-estimated proton density fat fraction and assessed in the per-protocol population. Pharmacodynamic performance was determined in the per-protocol population by the change in liver fat content from baseline to 2 weeks after the last dose. The per-protocol population included all randomised participants who received at least ten doses of study drug, with the first four doses administered in the first 5 weeks, did not miss more than three consecutive weekly doses, and who had no protocol deviations that might affect efficacy. All randomised participants who received at least one dose of study drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT03334214. FINDINGS:Between Nov 3, 2017, and Nov 28, 2018, we screened 173 people for eligibility. 44 were enrolled and randomly assigned to receive either IONIS-DGAT2 (29 participants) or placebo (15 participants). After 13 weeks of treatment, the mean absolute reduction from baseline was -5·2% (SD 5·4) in the IONIS-DGAT2 group compared with -0·6% (6·1) in the placebo group (treatment difference -4·2%, 95% CI -7·8 to -0·5, p=0·026). Reductions in liver fat were not accompanied by hyperlipidaemia, elevations in serum aminotransferases or plasma glucose, changes in bodyweight, or gastrointestinal side-effects compared with placebo. Six serious adverse events occurred in four patients treated with IONIS-DGAT2. No serious adverse events were reported in the placebo group. One of four patients reported three serious adverse events: acute exacerbation of chronic obstructive pulmonary disease, cardiac arrest, and ischaemic cerebral infarction, each considered severe and not related to study drug. Three of four patients reported one serious adverse event of increased blood triglycerides (severe, unrelated to study drug), deep-vein thrombosis (severe, unlikely to be related to study drug), and acute pancreatitis (mild, unrelated to study drug). INTERPRETATION:Our results suggest that DGAT2 antisense inhibition could be a safe and efficacious strategy for treatment of NAFLD and support further investigation in patients with biopsy-proven NASH. Based on the pharmacological target, the response to treatment observed in this study population could extend to the broader population of patients with NAFLD. FUNDING:Ionis Pharmaceuticals. 10.1016/S2468-1253(20)30186-2

RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection. Yuen Man-Fung,Schiefke Ingolf,Yoon Jung-Hwan,Ahn Sang Hoon,Heo Jeong,Kim Ju Hyun,Lik Yuen Chan Henry,Yoon Ki Tae,Klinker Hartwig,Manns Michael,Petersen Joerg,Schluep Thomas,Hamilton James,Given Bruce D,Ferrari Carlo,Lai Ching-Lung,Locarnini Stephen A,Gish Robert G Hepatology (Baltimore, Md.) BACKGROUND AND AIMS:ARC-520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral antigens and hepatitis B virus (HBV) DNA. APPROACH AND RESULTS:We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse-transcriptase inhibitor (NUC)-experienced patients with hepatitis B early antigen (HBeAg)-negative (E-neg) or HBeAg-positive (E-pos) disease. A total of 58 E-neg and 32 E-pos patients were enrolled and received four monthly doses of PBO (n = 20 E-neg, 11 E-pos), 1 mg/kg ARC-520 (n = 17 E-neg, 10 E-pos), or 2 mg/kg ARC-520 (n = 21 E-neg, 11 E-pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC-520 dose were compared to PBO. Both E-neg and E-pos high-dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E-neg and E-pos patients, respectively. The low-dose groups did not reach statistical significance in either study. E-pos patients showed a dose-dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low-dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed. CONCLUSIONS:ARC-520 was active in both E-neg and E-pos, NUC-experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin. 10.1002/hep.31008

Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Yuen Man-Fung,Heo Jeong,Jang Jeong-Won,Yoon Jung-Hwan,Kweon Young-Oh,Park Sung-Jae,Tami Yvonne,You Shihyun,Yates Phillip,Tao Yu,Cremer Jennifer,Campbell Fiona,Elston Robert,Theodore Dickens,Paff Melanie,Bennett C Frank,Kwoh T Jesse Nature medicine Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population. 10.1038/s41591-021-01513-4