*3.3. JNJ-56136379*

JNJ-5613379 (JNJ-6379) is an oral drug, which has at least two mechanisms of action on HBV infection. First, it interferes with the HBV capsid assembly, and second, it prevents cccDNA formation during de novo infection. Recently, Vandenbossche et al. demonstrated a dose-proportional increase in plasma concentration and AUC of the drug administered to healthy subjects [32]. However, this is true for dosages up to 300 mg, while with a double dose of 600 mg, the clearance decreased, determining a less than dose-proportional increase in the drug. Moreover, the drug showed a very long half-life of 120–140 h. Significantly, the drug clearance also decreased with lower weight [32]. No clear information regarding the metabolism of this drug is currently available. However, since a renal excretion of 18% has been recently reported, a certain share of hepatic metabolism probably exists. How this might potentially result in a drug–drug interaction (DDI) is still unclear [33]. Importantly, no severe adverse reactions were reported in the first in vivo single and multiple dose trial in healthy volunteers, and there was no dose limiting toxicity [34]. Only one patient experienced an elevation of ALT and AST during the treatment, but it was not possible to link it with any certainty to therapy [35]. A phase 2, randomized, open label study is currently ongoing to evaluate efficacy, pharmacokinetics, safety and tolerability of response-guided treatment with this drug combined with NA and Pegylated Interferon Alpha-2 [36].

#### *3.4. ABI-H0731*

ABI-H0731 is an orally administered, HBV core protein inhibitor, which also blocks several other steps in the HBV life cycle, including the HBV DNA synthesis and cccDNA formation. For this very reason, core inhibitors might have a more profound inhibitory effect on overall HBV replication than nucleoside analogs alone [37,38]. In a recent randomized, placebo-controlled, first-in-human study by Man-Fung Yuen et al., ABI-H0731 pharmacokinetics were assessed in healthy volunteers and HBV chronic patients. Overall, the authors' aim was to identify a safe and effective dosing schedule for phase 2 clinical studies [39]. Interestingly, this study showed that ABI-H0731 has dose-proportional pharmacokinetics, since steady-state Cmax, Cmin, and AUC increased when a higher dose of the drug was administered. The drug was rapidly absorbed, with mean time to maximum plasma concentration (Tmax) values of 2 × 50–4 × 17 h, and inter-individuals' variability in pharmacokinetic parameters was low. Furthermore, a moderate-fat meal intake has a significant impact on absorption, causing an approximately 45% increase in AUC. These findings are supportive of once-daily dosing of this drug. Nevertheless, it is interesting to note that chronic HBV patients experienced a higher exposure to the same dosages of ABI-H0731 than healthy individuals, suggesting a currently unexplored hepatic metabolism of the drug and hanging question marks over cirrhotic patients on the

one hand, and potential drug–drug interactions on the other. Regarding the efficacy of ABI-H0731 in chronic HBV, when administered as monotherapy for 28 days (and 28 days of follow-up), the drug exhibited a dose-related antiviral activity, with mean maximal HBV DNA decline from baseline of 1 × 7 log10 IU/mL at 100 mg to 2 × 8 log10 IU/mL at 300 mg after 28 days, for both HBeAg positive and negative participants. To further confirm that a combination therapy is preferable, a more profound HBV DNA decline of treatment was seen when patients were treated with both an NA and ABI-H0731, compared with the placebo [40]. Therefore, the combination might not only maximize the antiviral potency but also avoid treatment-emergent resistance. Regarding the safety data, while a macular/maculopapular rash should be considered during the treatment, since some moderate cases occurred, the treatment was well tolerated overall [39].
