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http://www.arrowheadresearch.com/pdf/whitepaper-hbv-3-7-12.pdf
Hepatitis B Virus Program
Abstract
Hepatitis B is a viral hepatitis representing a major global health problem. According to the
World Health Organization (WHO), some 360 million people, or 5% of the world’s population, suffer from chronic hepatitis B and are therefore at risk of cirrhosis, decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma and death. Despite this threat to global health, the chronic hepatitis B patient population still has substantial unmet medical needs that must be addressed for effective treatment and control of the disease. Current treatment regimens, based on interferons and antivirals, are not reliably effective in eradicating infection in chronically infected patients; are often rendered ineffective by the emergence of resistant strains of the virus; and suffer from problematic dosing schedules and debilitating side effects that negatively impact patient compliance.
Arrowhead researchers have shown that small interfering RNA (siRNA) therapeutics have the capacity to knockdown production of all hepatitis B genes and thereby significantly decrease the number of infectious viral particles and viral antigens. This reduction in viral and antigen load is designed to permit the immune system to mount an effective response to chronic hepatitis B infection resulting in virological suppression, biochemical remission, histological improvement and prevention of complications.
Arrowhead Research Corporation has combined its advanced expertise in RNAi with its
proprietary Dynamic PolyConjugate™ (or DPC™) siRNA delivery technology to develop a novel therapy for the effective treatment of HBV in patients without the liabilities associated with current treatment options. Arrowhead’s DPC/siRNA candidates have generated strong data in a number of in vitro and in vivo preclinical studies including those involving transgenic and nontransgenic mouse models of hepatitis B disease.
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Arrowhead Hepatitis B Therapeutic
Arrowhead HBV Product Opportunity
The large target market population, the impending global health care crisis engendered by
hundreds of millions of patients progressing into end-stages of the disease, and the
inadequacies of current approaches to treatment make it critical that new strategies to treat
chronic hepatitis B be pursued. Of the many emerging novel antiviral treatment modalities
currently being considered for chronic hepatitis B, RNAi is one of the most promising.
HBV is susceptible to RNAi because it replicates via an RNA intermediate and, to date, a
number of studies have described an antiviral effect of RNAi against HBV in vitro and in vivo
(Stein LL, Loomba R. Drug targets in hepatitis B virus infection. Infect. Disord Drug Targets.
2009;9(2):105-116). Recently a Phase I safety study of NUC B1000, a plasmid DNA construct designed to produce four siRNA molecules, showed that the treatment was safe and well tolerated. NUC B100 was designed to specifically reduce the viral antigen load in addition to viral titer (Gish RG, Satishchandran C, Young M, Pachuk C. RNA interference and its potential applications to chronic HBV treatment: results of a Phase I safety and tolerability study. Antivir Ther. 2011;16(4):547-54).
Rationale
siRNA Design
An RNAi therapeutic has the unique ability to significantly reduce the amount of circulating viral antigens (Lau, Khokhar et al. 2000; Papatheodoridis, Dimou et al. 2002; Romano, McCallus et al. 2006). A reduction of viral antigens is considered crucial to effective therapy because it is the expression of viral proteins that is the primary cause of liver disease from HBV infection (Chisari and Ferrari 1995). An individual infected with HBV can produce in the liver and secrete into the blood as many as 1010 infectious HBsAg-containing viral DNA particles per milliliter of serum and a vast excess of HBsAg-containing particles that do not include the infectious DNA. Leaders in the field of HBV therapeutics hypothesize that the function of this large excess of particles that do not contain HBV DNA may be to absorb antibodies that would otherwise neutralize the virus, and that potent reduction of HBV antigens would allow the patient’s immune system to clear the infection (Ganem and Prince 2004). Even chronically infected patients produce antibodies to HBV proteins (Webster, Reignat et al. 2004). RNAi can be used to target multiple components of HBV production in addition to the pregenomic RNA that would be reverse transcribed to generate the viral DNA. All HBV genes are encoded within open reading frames that overlap. As a result, a single siRNA can target the mRNAs that produce HBsAg proteins, the viral polymerase, the core protein that forms the capsid, and the HBeAg. The most favorable outcome in chronic HBV infection is HBsAg seroconversion, whereby elimination of HBsAg by the immune system is accompanied by a robust antibody response to this antigen.
DPC™
DPC™ technology is Arrowhead’s proprietary polymer-based approach to the safe and
efficacious delivery of siRNA delivery. It is fundamentally different from current siRNA delivery systems that are based on liposomes or lipid nanoparticles. The platform provides for more efficient delivery of siRNA to tissues; is amenable to linkage to targeting ligands and enjoys a relatively straightforward, cost effective manufacturing scheme.
Arrowhead has developed a DPC™ formulation and, to date, has demonstrated its safety in
non-GLP single and multiple dose toxicology studies in animals. Also, it has utilized DPC™ to deliver siRNA therapeutics to hepatocytes in non-human primates with up to 99%
knockdown of the target gene.
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发表于 2012-3-7 21:09
