GS-12-Ascending dose cohort study of inarigivir - A novel RIG I agonist in chronic HBV patients: Final results of the ACHIEVE trial

Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to “cure” HBV. Agreement among the conference participants was reached on some key points. “Functional” but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post‐treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg‐positive or negative chronic hepatitis, who are treatment‐naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV “functional cure”, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.

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“…(91) Ongoing clinical trials have shown a mild decrease in serum levels of HBV DNA, HBV RNA and HBsAg in response to SB 9200 therapy. (92)…”

Section: Stimulator Of Interferon Genes Agonistsmentioning

confidence: 99%

“…Inarigivir soproxil (Spring Bank) Phase II Dual mode of action: RIG-I Agonist and interference with the interaction of the viral polymerase and pgRNA. The ACHIEVE trial showed dose-dependent antiviral response on HBV DNA and HBV RNA (92)…”

Section: Aic649 (Aicuris)mentioning

confidence: 99%

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

et al. 2020

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“…As is the case of the above-mentioned viral markers, HBV RNA values are higher in naive HBeAg-positive than in HBeAg-negative CHB patients, 64,80,81 with the lowest levels reported in HBV inactive carriers. 73,[77][78][79] In a recent report, high HBV RNA levels were associated with a higher risk of developing HCC. 82 Some studies have shown a weak correla-tion between serum HBV RNA and the amount of intrahepatic cccDNA in all phases of HBV infection.…”

Section: Serum Hbv Rnamentioning

confidence: 98%

“…76 The relatively low sensitivity of current techniques prevents HBV RNA detection in 10 to 29% of naive HBeAgnegative patients. 73,[77][78][79] Hence, it is evident that more accurate, standardized assays for serum HBV RNA determination are needed to assess the usefulness of this marker in relation to current and future HBV treatment.…”

Section: Serum Hbv Rnamentioning

confidence: 99%

“…44 A phase 2 escalation study of inarigivir, an oral dinucleotide RIG-I agonist with a dual action (antiviral and immune-mediated), resulted in a mean HBV RNA decline of 1.14 logIU/mL in HBeAg-negative CHB patients treated with 200 mg per day of inarigivir monotherapy for 12 weeks. 79 In summary, measurement of HBV RNA could be useful to monitor the effectiveness of therapy beyond HBV DNA suppression, particularly in NA-treated patients, as theoretically, NAs do not act on cccDNA or inhibit transcription of pgRNA. HBV RNA can also help predict which patients will have an HBV relapse after treatment discontinuation, and it has the potential to evaluate the efficacy of new HBV drugs, including immunomodulators.…”

Section: Serum Hbv Rnamentioning

confidence: 99%

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Role of Biomarkers in Guiding Cure of Viral Hepatitis B

et al. 2019

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Chronic hepatitis B (CHB) virus infection is a global public health threat affecting approximately 257 million individuals worldwide. Hepatitis B surface antigen (HBsAg) loss has been the classic endpoint to define functional cure and decrease the large pool of individuals with CHB. Current treatments with nucleos(t)ide analogues persistently suppress hepatitis B virus (HBV) deoxyribonucleic acid in most CHB patients, but rarely achieve functional cure. New viral biomarkers, such as quantitative HBsAg, hepatitis B core-related antigen, and HBV ribonucleic acid, and combinations of these markers have the potential role of guiding HBV cure by enabling selection of the best candidates for therapy, identifying individuals with a higher likelihood of achieving HBsAg loss, and helping in the design of studies with new drugs. However, some of the assays used to analyze these markers require standardization and improvements in the level of detection. Analysis of host biomarkers to assess the host immune response to HBV is also important, as the natural course of CHB is determined by the interplay between viral replication and the immune response. These biomarkers are, however, in an early phase of development.

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