Discussion
CHB, HBV infection, liver decompensation, hepatomegaly, liver stiffness, hepatitis, steatosis, chronic disease
ADVERSE REACTIONS, VIRUS, LIVER DECOMPENSATION, LIVER CIRRHOSIS, ADVERSE REACTION, HEPATOCELLULAR CARCINOMA, LACTIC ACIDOSIS, HEPATITIS, STEATOSIS, CHB, CHRONIC DISEASE
In this phase 1b study, we examined the safety, tolerability, PK profiles, and preliminary clinical efficacy of Canocapavir, a novel CAM-E CpTA for the treatment of patients with CHB. Our results showed that Canocapavir was safe and well tolerated in patients with CHB, and serum HBV DNA and HBV pgRNA were profoundly reduced after a 28-day treatment of Canocapavir.Since CHB is a chronic disease and requires long-term treatment, safety is an important feature that a new drug must possess. In this study, an overall 50% incidence rate for adverse reactions was observed, which were not significantly correlated with the drug dosage. Most adverse reactions in this study were mild in severity, including elevation of ALT or AST. The data show that 12.5–37.5% of the patients who received Canocapavir had a grade I adverse reaction, while 50% of patients who received placebo had a grade I–II adverse reaction. These findings were similar with other CAM-E CpTAs, such as NVR 3–778 and ABI-H0731 [In our previous study [In contrast to this observation, we also noticed that in patient E4005, who received the placebo, the ALT level was 21.4U /L at baseline and increased gradually after day 31 (i.e., 3 days after the last dosing of the placebo), reaching to a maximum of 158.2 U/L on day 64. Similarly, in another patient (E4007) who also received the placebo, the ALT level was 65.8 U/L at baseline and increased gradually after day 15, reaching a maximum of 300.9 U/L on day 57 (Additional file Chan et al. have reported that in cases of liver cirrhosis, the optimal cutoff values for the liver stiffness measurement were 8.4 kPa (98% sensitivity), 9.0 kPa (maximum sum of sensitivity and specificity), 13.4 kPa (94% specificity), and 13.4 kPa (maximum diagnostic accuracy, 85%) [The occurrence frequency and rate of AEs, such as an increased ALT level, were similar among the different treatment groups. For example, the occurrence frequencies of an increased ALT level in the 50 mg, 100 mg, and 200 mg groups of Canocapavir and placebo were 2, 3, 3, and 3 cases, respectively (Table It has been reported that in the treatment with nucleos(t)ide analogues, a decrease of serum phosphorus levels and an increase of serum creatinine levels were observed; these can also happen in the presence of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Severe acute exacerbations of hepatitis have been found in HBV-infected patients who have discontinued anti-hepatitis B therapy with nucleos(t)ide analogues [The PK profiles of Canocapavir showed rapid absorption (TThe conversion of HBV RNA to DNA occurs within viral core particles in the cytoplasm through reverse transcription, which is the prerequisite for both generations of progeny virus particles and replenishment of the HBV cccDNA pool in the nucleus. It has been postulated that complete and sustained disruption of the processes mentioned above may help accelerate the exhaustion of the cccDNA pool, eventually leading to permanent sterilization of HBV infection [The changes in HBsAg, HBeAg, and HBcrAg levels have been studied for several CpTAs in phase I–II trials and generally are limited [One subject (E2003) was found to have a pre-existing substitution (P25S) in the HBc known to reduce the susceptibility of the virus to CpTAs [This study provides the first clinical evidence that substantial inhibition of viral production in patients with CHB can be achieved by Canocapavir treatment. In a previous report, long-term entecavir therapy was associated with a decreased incidence of liver decompensation and hepatocellular carcinoma [