Three hot anti-HBV candidates: GS-9620, NVR-1221, ARC-520

HBV and HCV are two major cause of liver disease. There is no vaccine for hepatitis C, but novel combination therapies containing NS3/4A protease inhibitors, NS5A inhibitors and NS5B polymerase inhibitors can cure up to 90% of patients. However, the treatment of chronic hepatitis B is not so smooth.

It is estimated that more than 350 million people are chronically infected with HBV. Vaccines for the prevention of hepatitis B have been routinely recommended for infants since 1991. However, for patients who have developed a chronic HBV infection, there is no medical cure.

Current treatment for chronic HBV infection is limited to nucleoside analogues (lamivudine, adefovir, tenofovir, telbivudine, entecavir) and interferon-α/PEG-interferon-α. Here is a mini-review covering three hot candidates for the treatment of HBV infections.

  1. GS-9620

GS-9620 is an oral Toll-like receptor-7 (TLR-7) agonist developed by Gilead Sciences (NASDAQ: GILD). Toll-like receptors control host immune response against pathogens through recognition of pathogen-associated molecular patterns. TLR-7 is a pathogen recognition receptor mainly expressed in lysosomal/endosomal compartments of plasmacytoid dendritic cells (pDCs) and B lymphocytes. Stimulation of TLR-7 induces interferon-α secretion by pDCs and activation of other lymphocytes.

In preclinical studies, researchers administered GS-9620 to chimpanzees 3 times each week for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg[1]. Both the virus levels and the number of HBV-infected liver cells were reduced. The mean maximum reduction of viral DNA was 2.2 logs, while reductions of >1 log persisted for months. Gilead has initiated a phase II clinical trial to evaluate the safety and efficacy of GS-9620.

  1. NVR-1221

NVR-1221 is a small molecule antiviral agent target the core/capsid protein of the hepatitis B virus. This molecule can bind to all oligomeric forms of HBV core such as the capsid protein dimer (the capsid building block) and the assembled capsid (a complex of 120 capsid protein dimers).

Novira Therapeutics, the developer, has successful completed a phase Ia clinical study in 40 healthy volunteers. The company intends to start a Phase Ib clinical trial to test NVR-1221 in 96 chronic HBV patients as mono-therapy and in combination with approved agents.

  1. ARC-520

ARC-520 is RNAi therapeutic candidate developed by Arrowhead Research (NASDAQ: ARWR).

Three hot anti-HBV candidates: GS-9620, NVR-1221, ARC-520

A drug delivery vehicle called Dynamic Polyconjugate was developed for the targeted delivery of cholesterol-conjugated siRNA to hepatocytes[2].

The positive preclinical data from a test with a chimpanzee was presented at the 2013 AASLD Annual Meeting. Intravenous administration of two doses (2 mg/kg, 3 mg/kg) of ARC-520 resulted in substantial and sustained reductions in HBV DNA, HBeAg, and HBsAg. HBV DNA levels dropped by 17-fold by day 4, exhibited a 36-fold decline following the second dose, and returned to baseline by day 43.

Recently, Arrowhead disclosed new data from the ongoing phase IIa study. For patients in cohort 1 (1 mg/kg), mean nadir HBsAg was -39% with a mean change on day 85 of -31%; for patients in cohort 2 (2 mg/kg), mean nadir HBsAg was – 51% (0.3 log) with a mean change on day 85 of -22%. The observed treatment effect at 2 mg/kg is much lower than investors’ expectation (about 1 log reduction in HBsAg). Arrowhead shares were down 50% on October 8. Data collection for HBsAg reduction in cohort 3 at 3 mg/kg is still ongoing.

Just like old drugs, both GS-9620 and ARC-520 can’t kill the virus completely. Even if 99% of virus is killed, the remaining 1% will grow strong again after withdrawal of the drug. Recurrence is only a matter of time.

[1] Gastroenterology. 2013, 144(7), 1508-1517.

[2] Mol Ther. 2013, 21(5), 973-985.


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