Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference

Abstract

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level < 100 IU/mL and HBV DNA < LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg positive or negative CHB, who are treatment-naive or virally suppressed on nucleos(t)ide analogs. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA < LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA < LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.

Figure 1:

HBV Life cycle and drug targets. 1) Viral entry inhibitors bind to the NTCP receptor to prevent de novo infection. 2) Inhibition of formation or degradation of cccDNA. 3) siRNA and ASO target and degrade viral transcripts leading to inhibition of viral protein synthesis. 4) CAMs inhibit the formation of the core protein and encapsidation of pre-genomic RNA. 5) NAs target the reverse transcriptase of the HBV polymerase and act as chain terminators of nascent DNA. 6) NAPs prevent secretion of HBsAg. NTCP, sodium taurocholate co-transporting polypeptide; cccDNA, covalently closed circular DNA; siRNA, small interfering RNA; ASO, antisense oligonucleotides; NA, nucleos(t)ide analogues; HBsAg, hepatitis B surface antigen

Figure 2:

Algorithm for investigation and management of ALT flares during conduct of trials of investigational agents

Figure 3:

HDV life cycle and drug targets. Bulevirtide (BLV) blocks de novo infection by binding to the NTCP receptor. Lonafarnib (LNF) impairs HDV assembly and secretion by inhibiting farnesyl transferase which is required for prenylation of L-HDAg. IFNα and IFNλ profoundly suppress HDV amplification during cell division by inducing IFN stimulated genes (ISGs). NAPs selectively block assembly and secretion of subviral HBsAg particles and/or HDV ribonucleoprotein assembly. HBV, hepatitis B virus; HDV, hepatitis D virus; IFN, interferon; L-HDAg, large hepatitis D antigen; NAP, nucleic acid polymer, NTCP, sodium taurocholate co-transporting polypeptide; S-HBsAg, small hepatitis B surface antigen.

Figure 4:

The patient focused approach in drug development and the clinical trial continuum 1. https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act. Last accessed October 28th, 2022. 2. https://www.fda.gov/about-fda/cdrh-patient-science-and-engagement-program/patient-preference-information-ppi-medical-device-decision-making. Last accessed Nov 23,2022.