Loading ...
Sorry, an error occurred while loading the content.

Fwd: NATAP: HCV Drug ISIS 14803 Not Effective

Expand Messages
  • claudine intexas
    NATAP http://natap.org/ _______________________________________________ Antisense Drug ISIS 14803 Did Not Reduce HCV RNA A phase I trial of an antisense
    Message 1 of 1 , Nov 6, 2005
    • 0 Attachment
      NATAP http://natap.org/
      _______________________________________________
      Antisense Drug ISIS 14803 Did Not Reduce HCV RNA

      A phase I trial of an antisense inhibitor of Hepatitis c virus (ISIS 14803), administered to chronic Hepatitis C patients

      4-week, safety study was accompanied by concerning ALT flares in a subgroup of patients. Transient plasma HCV RNA reductions greater than fluctuations generally seen in untreated patients were observed in 3 of 28 ISIS 14803-treated patients

      Journal of Hepatology

      John G. McHutchisonab, Keyur Patelab, Paul Pockrosb, Lisa Nybergb, Stephen Piankob, Rosie Z. Yuc, F. Andrew Dorrc, T. Jesse Kwohc

      Received 11 April 2005; received in revised form 6 September 2005; accepted 12 September 2005 published online 25 October 2005.
      Uncorrected Proof

      ABSTRACT
      ISIS 14803 is a 20-unit antisense phosphorothioate oligodeoxynucleotide that binds to hepatitis C virus (HCV) RNA at the translation initiation region of the internal ribosome entry site (IRES) and inhibits protein expression in cell culture and mouse models. This Phase I, open-label, dose-escalation trial of ISIS 14803 was performed in chronic HCV patients.
      Methods

      At least 7 days after receiving an initial single dose, twenty-eight patients received 0.5-3mg/kg ISIS 14803 thrice weekly for 4 weeks by intravenous infusion or subcutaneous injection.
      Results

      In most patients, the 4-week treatment did not reduce plasma HCV RNA. However, 3 patients receiving ≥2mg/kg had transient HCV reductions of 1.2-1.7log10 that persisted ≤32 days. These reductions were accompanied by asymptomatic, self-resolving elevations in serum alanine transaminase (ALT) levels to >10× the upper limit of normal. Two other patients had ALT flares without plasma HCV reduction. No clinical signs, symptoms of hepatic dysfunction, or laboratory changes in albumin or prothrombin time accompanied ALT elevations.
      Conclusions

      ISIS 14803 treatment was associated with HCV reductions in only 3/28 patients. ALT flares in 5 patients also occurred. Further studies to evaluate ISIS 14803 treatment and the mechanisms of the ALT flares are now required.

      INTRODUCTION
      Approximately 170million people worldwide are infected with hepatitis C virus (HCV), and infection persists in approximately 75-85% of cases, making hepatitis C infection an important cause of chronic liver disease Lauer and Walker, (2001); NIH Consensus Development Conference Statement, (2002); Consensus, (2002); Alter et al., (1999); Lavanchy and McMahon, (2000). Liver cirrhosis and end-stage liver disease due to HCV is now the most common indication for liver transplantation in the United States. Moreover, the disease burden due to chronic infection is expected to increase over the next decade (Kim, (2002)). Treatment with peginterferon and ribavirin provides effective therapy in 50-60% of HCV patients Manns et al., (2001); Fried et al., (2002). However, this therapy is costly, prolonged, not suitable for many patients, and has significant side effects (NIH Consensus Development Conference Statement, (2002)). Thus, numerous efforts to develop new therapies are in progress
      (Pawlotsky et al., 2004).

      HCV genomic RNA is an attractive drug target because it is both the informational precursor for viral protein synthesis and an essential component of infectious virus (Penin et al., (2004)). Antisense therapeutics employ nucleic acids, usually oligonucleotides <25 nucleotides long, to disrupt protein translation through Watson-Crick base-pairing of the antisense agent to the target RNA (Crooke, (1999); Crooke, (2001); Gerwitz et al., (1998); Scherer and Rossi, (2003)). Phosphorothioate oligodeoxynucleotides promote target RNA degradation via cellular RNase H enzymes (Crooke, 1999; Crooke, 2001; Gerwitz et al., 1998; Scherer and Rossi, 2003). Generally, the mechanisms that degrade RNA are the most potent (Crooke, 1999; Crooke, 2001; Scherer and Rossi, 2003).

      Several groups have identified antisense oligonucleotides that inhibit HCV RNA and polyprotein synthesis in in vitro, cell culture, and mouse models (Mizutani et al., 1995; Seki and Honda, 1995; Vidalin et al., 1996; Wakita and Wands, 1994; Alt et al., 1995; Lima et al., 1997; Brown-Driver et al., 1999; Hanecak et al., 1996; Zhang et al., 1999). One of these oligonucleotides, ISIS 14803, is a phosphorothioate oligodeoxynucleotide that is complementary to the HCV translation initiation region within the internal ribosome entry site (IRES) (Hanecak et al., 1996; Zhang et al., 1999). ISIS 14803 can reduce HCV RNA in immortalized human hepatocytes expressing a portion of the HCV genome (Hanecak et al., 1996). In addition to having the phosphorothioate modification, ISIS 14803 also contains 5-methyl-cytosine, instead of cytosine, which reduces the pro-inflammatory nature of this type of oligonucleotide (Zhang et al., 1999; Krieg, 2002; Levin et al., 2001). Here, we describe the first
      clinical study of this HCV-specific antisense approach. The study was performed in patients with chronic hepatitis C infection who had previously not responded to therapy or were unsuitable candidates for standard therapies.

      Discussion
      This first clinical evaluation of an antisense inhibitor for HCV was primarily designed to evaluate the safety profile of ISIS 14803. The study design and dose selection were based on the high similarity of ISIS 14803 to other phosphorothioate oligonucleotides in preclinical toxicology and pharmacokinetic studies (Levin et al., 2001; Dorr et al., 2001).

      With the exception of serum transaminase elevations, primarily in ALT, the safety profile of ISIS 14803 was similar to other phosphorothioate oligodeoxynucleotides. The most frequent side effects were non-specific and included headache, fatigue, arthralgia, insomnia, and some gastrointestinal side effects. Aside from the transient aPTT prolongations following intravenous infusion, which are typical of this drug class, clinical laboratory abnormalities were observed only in the 5 ALT-flare patients. All patients receiving the drug subcutaneously experienced at least 1 local injection site reaction. These reactions were mainly mild or moderate erythema and induration at the injection site and did not affect dosing.

      In the 5 patients with ALT flares, ALT increased to 8.6-18.4×ULN. These ALT flares were asymptomatic, self-resolving, and not associated with changes in albumin or prothrombin time or hematology and urinalysis parameters. Similar ALT elevations were not seen in ISIS 14803 toxicology studies in mice and monkeys (unpublished results). ALT flares have also not been observed in clinical studies of other oligonucleotides of the same chemistry, and such studies encompass more than 2000 patients with a variety of inflammatory, virologic, and oncologic diseases (Gerwitz et al., 1998; Dorr et al., 2001; Geary et al., 2001; Yu et al., 2001; Bennett, 1999; Field, 1999). A single liver biopsy performed during an ALT flare in this study did not reveal histological evidence of hepatotoxicity. However, HCV-infected hepatocytes could have increased sensitivity to oligonucleotide. Another potential source for the ALT elevations is the nonspecific pro-inflammatory property of this chemical class.
      Phosphorothioate oligodeoxynucleotides have been shown, primarily in rodents, to stimulate expression of pro-inflammatory cytokines and proliferation of B-cells (Krieg, 2002; Levin et al., 2001). However, we did not observe increases in serum TNF-α, IL-4, or IFN-γ following ISIS 14803 dosing. Induction of autoimmune liver disease was also examined as a possible cause for the flares. Yet neither anti-nuclear nor smooth muscle antibodies were detected, and the histology of the single biopsy was not consistent with autoimmune hepatitis.

      In this study, we also found that 3 patients of 13 treated at the two highest dose levels had significant (>1.0log10) reductions in viral load. These reductions were temporary and tended to return to baseline over a variable time period following therapy. These reductions are intriguing because HCV levels are relatively stable over 3-month periods in untreated patients (Nguyen et al., 1996; Yoshimura et al., 1997). Yet the origin of these HCV reductions is unclear. Based on sequence analysis of virus specimens collected in this study, the IRES-quasispecies diversity in Patient 108 evolved during and following treatment, a change that has not been observed in interferon-treated patients (Soler et al., 2004). Thus, at least in Patient 108, the HCV changes may have been due to interactions between ISIS 14803 and HCV RNA. However, the post-treatment HCV reduction in Patient 208, and the occurrence of ALT flares with all 3 HCV reductions, suggests that other mechanisms may be involved.
      While the ALT flares in this study differ in several aspects from the immune clearance-mediated flares in antiviral therapy of chronic HBV, immune clearance may have a role in the ALT flares and HCV reductions seen with ISIS 14803 (Perrillo and Mason, 1994; Hoofnagle et al.; 1988, Liaw et al.; 1999). Studies examining the potential role of peripheral and intrahepatic lymphocytes in HCV-specific and non-specific immunological responses during ALT flare would be instructive.

      In conclusion, ISIS 14803 administration in this initial, Phase I, 4-week, safety study was accompanied by concerning ALT flares in a subgroup of patients. Transient plasma HCV RNA reductions greater than fluctuations generally seen in untreated patients were observed in 3 of 28 ISIS 14803-treated patients (Nguyen et al., 1996; Yoshimura et al., 1997). Further investigation into the relationship between the HCV reductions and ALT flares in ISIS 14803-treated patients, and into which effect is secondary to the other, is needed.
      _______________________________________________
      NATAP nataphcv mailing list -- nataphcv@...

      This is an annoucement-only mailing list. Do not reply.

      To unsubscribe: send a blank email to nataphcv-request@... with a subject of unsubscribe.


      For more information, see http://seven.pairlist.net/mailman/listinfo/nataphcv

      _______________________________________________


      ----------

      _______________________________________________
      NATAP nataphcv mailing list -- nataphcv@...

      This is an annoucement-only mailing list. Do not reply.

      To unsubscribe: send a blank email to nataphcv-request@... with a subject of unsubscribe.


      For more information, see http://seven.pairlist.net/mailman/listinfo/nataphcv

      _______________________________________________


      [Non-text portions of this message have been removed]
    Your message has been successfully submitted and would be delivered to recipients shortly.