What is Hepatitis D?
The hepatitis D (delta) virus (HDV) is a virus which can only replicate in the liver of patients who already have HBV infection (please see here). This is because HDV does not contain the genes for producing a surface envelope protein and instead uses the surface antigen protein (HBsAg) produced either from cccDNA or integrated HBV DNA. The process of the final assembly and secretion of HDV is identical to that of subviral particles of HBV.
Current estimates are that HDV co-infection is present in 15-20 million people worldwide with HBV infection, but recent new surveillance efforts indicate that this number underestimates the true prevalence of co-infections. This infection represents an urgent unmet medical need as, the progression of liver dysfunction to fibrosis, cirrhosis and potentially hepatocellular carcinoma (liver cancer) is more rapid when HDV infection is present than with any other form of viral hepatitis. The rapid evolution of liver disease during HDV co-infection results in 80% of untreated patients developing cirrhosis within 10 years of becoming infected.
There is no approved therapy for HDV co-infection
Several different therapeutic approaches have been attempted to treat HDV co-infection, the most successful being interferon, which can control HDV infection during long term therapy (2 years) in up to 50% of patients. However, many of these patients relapse after interferon therapy is withdrawn. Other experimental therapies which block the entry of HDV into hepatocytes or which interfere with the maturation of the HDV ribonucleoprotein particle (HDAg) have met with limited success in controlling HDV directly and have little or no effect on HBsAg without which no significant immune control of HBV or HDV infection can be expected.
NAPs directly target both HBV and HDV infections
REP 2139 effectively blocks the assembly and release of HBV SVPs (see the section on HBV), which use the same host processes as HDV for secretion. Additionally, REP 2139 has a potent and direct antiviral effect against HDV replication which is distinct from its effects on SVP assembly and release. This direct effect against HDV replication appears to be mediated by the interaction of REP 2139 with the small and large forms of the hepatitis delta antigen, which self assemble during HDV replication by the interaction of exposed hydrophobic surfaces. These surfaces are efficiently targeted by REP 2139 (see section on NAPs) and likely result in inhibition of multiple steps in the HDV replication cycle. REP 2139 is unique in its ability to simultaneously target HBsAg replenishment and multiple steps in the HDV lifecycle.
REP 2139 has achieved a breakthrough result in HBV / HDV co-infection.
In Replicor’s first clinical study, a limited exposure to REP 2139 therapy (30 weeks) achieved potent and rapid declines > 5 log from baseline in all patients, which became undetectable in all but one patient. This potent HDV RNA response is unique amongst all agents currently in development for HDV infection. This direct effect against HDV was in addition to the reduction / clearance of HBsAg and immunological restoration with the addition of immunotherapy against the underlying HBV infection. Additionally, functional control of both HBV and HDV infection was maintained after all therapy was removed in 36% (HBsAg undetectable), 55% (HBV DNA undetectable) and 63% (HDV RNA undetectable) which has been stable for two years and accompanied by restoration of normal liver function. Longer exposures to REP 2139 in combination with immunotherapy is expected to significantly increase these response rates.