4 weeks for "functional healing"! GSK anthososide oligonucleotide therapy hepatitis B IIa phase study achieved positive results.

On August 28, GSK announced the antisant oligonucleotide drug GSK'836 (GSK322883) at the 2020 International Hepatology Conference (Digital ILC 2020). 6) Positive results were obtained in a Phase IIa study of patients with chronic hepatitis B, and GSK'836 treatment for 4 weeks significantly reduced HBSAg levels and HBV DNA load compared to placebo.
The IIa phase study included 31 patients treated with nucleoside (NA) drugs or nucleoside analogophobic therapy who were stable and who did not receive nucleoside therapy, and assessed the efficacy of 4 weeks of subsuter injection GSK'836 treatment at two dose levels of 150 mg and 300 mg.
after the last dose of subsulpheric injection, all patients continued to receive standard nucleoside antiviral drugs (tynofovir or entecavir) for six months and assessed whether HBsAg levels could continue to decline.
end points of the study included safety and tolerance, and the main therapeutic endpoints included serum HBsAg levels at week 4 and changes in HBV virus DNA load over baseline.
other endpoints include some antiviral and pharmacological parameters.
300 mg dose group data showed that a decrease in HBsAg levels was observed in patients treated with nucleoside drugs (hepatitis B e antigen plus) and without nucleoside medication (hepatitis B e antigen plus and hepatitis B e antigen-) HBsAg levels decreased by more than 3 log10 IU/ml in 6 patients over 9 days, of which 4 patients had HBsAg levels below the detection limit of 0.05IU/ml (unsealable, defined as "functional cure").
Also observed that 2 "functionally cured" patients were unable to detect HBsAg for long periods of time, including 1 patient treated with nucleosides (from day 36 to 113) and one patient who was not treated with nucleosides (day 23 to 126).
4th week of the main efficacy endpoint data included: HBsAg levels decreased by 2.51 log10 IU/ml in patients treated with nucleosides (n=4), with 3 patients reducing HBsAg levels by more than 3 log10 IU/ml on the 29th day.
1 patient was not included in the data analysis set because the treatment was terminated on the 4th day, and the placebo-controlled patients (n=2) were reduced by 0.01 log10 IU/ml.
HBsAg levels decreased by 1.56 log10 IU/ml in patients who were not treated with nucleoside drugs (n=12), of which 3 patients had hBsAg levels reduced by more than 3 log10 IU/ml on the 29th day, and placebo-controlled patients (n=6) decreased by 0.00 log10 IU/ml.
HBV DNA load in patients who were not treated with nucleoside drugs (n-12) was reduced by 1.66 log10 IU/ml, of which 5 patients were reduced by more than 2 log10 IU/ml.
placebo-controlled patients (n-6) were reduced by 0.00 log10 IU/ml.
safety, 5 out of 17 patients observed mild to moderate injection site reactions, including erythema, pain, itching, swelling and/or bruising.
a sharp increase in ALT levels observed during HBsAg removal in patients, which may reflect the removal of infected liver cells, increased ALT levels asymptomatic, and self-remission.
is acceptable for safety and tolerance, and also supports longer treatment times.
GSK'836 was jointly discovered by GSK and Ionis Pharmaceuticals, GSK in August 2019 reached a number of anti-oligonucleotide anti-HBV projects licensing cooperation with Ionis, GSK'836 is one of the assets, GSK currently owns all of GSK'836 development, registration and commercial interests.
based on this data, GSK has decided to continue to advance phase IIb studies code-named B-Clear, B-Fine and B-Together in Europe, Africa, North America and Asia by the end of 2020.
B affects about 260 million people worldwide, with 900,000 deaths each year from liver failure and liver cancer caused by hepatitis B, one of the world's major public health burdens.
currently used to treat hepatitis B nucleosides and nucleoside analogophobic drugs can suppress the hepatitis B virus, but can not completely remove the virus from the body.
Mainly because the hepatitis B virus enters the host body and integrates its genome into the NDA in the nucleus of the host liver cell, forming co-priced closed ring DNA (cccDNA), which is then used to synthesize the proteins needed for mRNA and viral particles.
The current drug can only reduce HBsAg and viral DNA levels, it is difficult to completely remove cccDNA, and it is easy to bounce back after stopping the drug, so there is still an urgent need to develop new treatments that can be functionally cured (HBsAg levels cannot be detected) and completely cured (clear cccDNA) of hepatitis B.
GSK'836 is an anthopedic oligonucleotide that specifically identifies mRNAs used to express viral antigens (pathogenic proteins) in liver cells infected with HBV, inactivates viral mRNA by mobilizing the enzyme system of the liver itself, and inhibits levels of the viral protein HBsAg in order to achieve functional cures of hepatitis B.
antisant oligonucleotide drugs are still only used to block viral DNA replication at an earlier stage by acting on viral mRNA, and it is still difficult to completely remove cccDNA.
drugs with new mechanisms of action are still needed if the goal of "total cure" is to be achieved.
apoptosis inhibitor (IAP) inhibitor is a brand-new antiviral action agent, its target is not the HBV itself, but on the host cell, by inducing HBV infection of liver apoptosis, thus having the possibility of completely clearing cccDNA, is one of the potential cures for hepatitis B.
Aprassin Pharmaceuticals also presented clinical data on its IAP inhibitor APG-1387 at digital ILC 2020 on August 27.
Preclinical studies reported in this oral report showed that HBsAg, HBeAg and HBV DNA in the serum, as well as HBcAg and HBV replication intermediates in infected liver tissue, were completely removed from the serum at 4-20 weeks using APG-1387 in three different models of chronic hepatitis B mice compared to the control group, and that they do not bounce back after discontinuation of treatment.
in-depth study found that HBV removal may be related to the increase in frequency and function of HBV-specific CD4 plus and CD8 plus T cells in the liver, and that TNF alpha knock-out, CD4-plus, or CD8-plus T cell defects can completely block the removal effect of APG-1387 on HBV.
addition, gene avocation analysis of RNA-seq in liver tissue showed that APG-1387 injection induced an increase in intra-hepatic immunologic-related gene expression, and that these genes were similar to the differential gene expression spectrum in the liver of acute HBV-infected chimpanzee models.
above results show that APG-1387 can remove HBV infection in a variety of chronic mouse models through unique apoptosis induction and immunomodulation mechanisms.
application of IAP inhibitors is expected to become a new immunotherapy solution to promote functional cure of HBV.
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