LETTERS TO THE EDITORS
DOI: 10.1111/apt.15636
Letter: the perilous road to a functional cure for hepatitis B infection
EDITORS,We read with interest the recent review article by Smolders et al1focusing on the clinical pharmacology of current and investiga-tional hepatitis B virus (HBV) therapies that have reached at least phase 2 clinical trials. These drugs encompass various functional classes—including a HBV entry inhibitor (bulevirtide), capsid assem-bly modulators (JNJ-56136379 and ABI-H0731), a secretor inhibi-tor (REP-2139), an RNA interference drug (ARO-HBV or JNJ-3989) and an immunomodulator (inarigivir). Notably, all of these investi-gational compounds have been studied in combination with current therapies, ie, nucleos(t)ide analogues (NAs) and/or pegylated-in-terferon alfa (peg-IFN-α). The quest for novel drugs against HBV infection reflects important unmet needs in the field.2 For example, treatment with peg-IFN-α offers relatively low cure rates, and is ac-companied by serious side effects. Similarly, NAs can be very effec-tive at suppressing the virus, but rarely result in its full eradication from the liver.2The results of Smolders et al1 indicate that treatment with most of these investigational compounds resulted in HBV DNA and/or RNA decline/loss, to a similar or higher extent than that observed with NAs treatment. More remarkably, treatment with REP-2139, ARO-HBV, and inarigivir has been reported in some HBsAg loss/decline. The authors concluded that if further evidence will demon-strate that these three agents are able to increase the number of patients with a functional cure (i.e., HBsAg loss), this would be a sig-nificant improvement compared to current therapy. However, they also raise a word of caution by advocating more in-depth investiga-tions on pharmacokinetics and safety.
On December 26, 2019, there was bad news concerning inarigi-vir, one of the investigational compounds mentioned by Smolders et al1 in their excellent review. Dosing of inarigivir 400 mg in the CATALYST 2 trial—which examined the administration of this drug in NAs-suppressed chronic HBV patients—has been stopped be-cause of safety concerns.3 Specifically, three subjects participating in this study showed evidence of hepatocellular dysfunction and an elevation of alanine aminotransferase levels, potentially consistent with liver injury rather than immune flares.3 Similar bad news was reported on October 3, 2019, for AB-506—an oral capsid inhibi-tor being developed for chronic HBV infection—which was being evaluated among healthy volunteers in a 28-day phase 1a/1b trial.4During the study, two volunteers paradoxically had evidence of acute hepatitis and further clinical development of AB-506 was halted.4The failure of some novel therapies for HBV infection clearly indicates that the road to a functional cure for this condition is hard and perilous. However, with approximately 257 million people worldwide living with chronic HBV,1 these setbacks should not deter the confidence of investigators in pursuing the strategic goal of providing a functional cure for this major public health threat.作者: StephenW 时间: 2020-2-14 14:36