Telaprevir (VX-950) a novel antiviral treatment for Hepatitis C virus patients

Introduction

The hepatitis C virus (HCV) epidemic continues to be a serious health threat, infecting over 170 million people worldwide (Lin et al. 2005). Moreover, three to four million people are newly infected each year (Ressink et al. 2006). The infection is often asymptomatic in its early stages, but the majority of HCV-infected individuals develop chronic hepatitis over time, which eventually advances to liver scarring (cirrhosis), and liver cancer (hepatocellular carcinoma) (Moriishi and Matsuura 2007). The epidemiology of the virus is not well understood. However, it is known that HCV is transmissible through sexual contact and blood-to-blood contact. In the United States, blood-to-blood transmission of HCV is greatest among injecting drug users (IDUs). Although the virus can be acquired through blood transfusions, and contact with other sources of infected blood product (Simmonds 2000).

Standard care for Hepatitis C patients: Interferon alfa-2b plus ribavirin

Since 1998, standard care for patients infected with hepatitis C has been weekly injections of interferon alfa-2b combined with daily oral administration of ribavirin (Keeffe 2006). Interferons function by disturbing viral replication through immune response stimulation. More specifically, they activate immune cells, such as natural killer cells and macrophages; they increase recognition of infection by up-regulating antigen presentation to T lymphocytes; and they increase the ability of uninfected host cells to resist new infections (Hunt 2009). The drug’s other component, ribavirin, is a prodrug which when metabolized resembles purine RNA nucleotides. In this form, it interferes with the RNA metabolism required for viral replication. The mechanism of interference is not well understood (Feld and Hoofnagle 2005). Side effects of the drug range from mild flulike symptoms to severe symptoms like hair loss, bloody stools, depression and suicidal tendencies (AHFS 2010). While the interferon/ribavirin combination drug sustained response rates are 54-56%, these results imply that 40-50% of patients do not have lasting improvements with treatment (Feld and Hoofnagle 2005). Pharmaceutical companies are developing alternative HCV treatments in attempt to improve care for infected individuals. One such candidate drug is Telaprevir (VX-950) co-developed by Vertex and Johnson & Johnson.

Telaprevir (VX-950), a novel antiviral treatment for Hepatitis C

Telaprevir (VX-950) clinical trials

Reviewed below are two of numerous clinical studies that aimed to evaluate some aspect, eg. antiviral activity, pharmacokinetics, and/or the safety, of telaprevir treatments in individuals infected with HCV.

Reesink et al.

Reesink et al. performed a phase I, placebo-controlled, double-blind study that evaluated the antiviral activity, pharmacokinetics, and safety of telaprevir (VX-950) alone. More specifically, the aim of the study was to evaluate the safety and tolerability of ascending multiple doses of VX-950 in patients with chronic hepatitis C. To be eligible patients: were male or female, between the ages of 18 and 65 years old, had body mass indexes (BMIs) between 18.5 and 29.0 kg/m2 (males) or 18.5 and 32.5 kg/m2 (females), had a HCV RNA level ≥1 X 105 IU/mL, had HCV genotype 1 (any subtype), and had an alanine aminotransferase (ALT) concentration ≤4 times the upper limit of normal.

Three panels of patients that met the aforementioned criteria were enrolled. Panels 1 and 3 comprised of 10 patients on VX-950 and 2 on placebo. Panel 2 comprised of 8 patients on VX-950 and 2 on placebo. Patients were randomly assigned to VX-950 or placebo, both were administered as an oral suspension. For 14 consecutive days, patients received either 450 mg (panel 1) or 750 mg (panel 2) VX-950 every 8 hours (q8h), 1250 mg (panel 3) VX-950 every 12 hours (q12h), or a matching placebo regimen (Reesink et al. 2006).

The antiviral activity of VX-950 was assessed by measuring plasma HCV RNA levels. The drug’s pharmacokinetics was assessed by measuring the concentration of VX-950 in the plasma. Patients were monitored for safety and tolerability at regular intervals from the start of dosing through the experiments competition. Safety assessments included physical examinations and vital signs, clinical laboratory tests, 12-lead digital electrocardiograms (ECG), and questioning about adverse side effects (Reesink et al. 2006).

Reesink et al. found rapid and substantial viral decline in patients treated with VX-950 for fourteen days: all patients treated with VX-950 had at least a 2-log10 decrease from baseline in HCV RNA. HCV RNA levels decreased steadily in the 450-g q8h and 1250-mg q12h groups until day seven. Between day 7 and 14, HCV RNA levels in these groups actually increased, demonstrating viral breakthrough. Reesink et al. hypothesized that this breakthrough was related to the selection of HCV variants with decreased sensitivity to VX-950.

The median HCV RNA value decreased through the entire dosing period in the 750-mg q8h group. Moreover, HCV RNA decreased below the limit of detection (10IU/mL) in 3 patients: 1 in the 450-mg q8h group and 2 in the 750-mg q8h group. Three additional patients had HCV RNA levels that were below the lower limit of quantification (30 IU/mL) at day 14 (Reesink et al. 2006).

Regarding the pharmacokinetics of the drug, VX-950 accumulated on multiple dosing with a median accumulation index of 1.8. The initial rapid decline in HCV RNA was related to maximal exposure to VX-950, and the second phase of viral decline was sustained by trough concentrations of the drug (Reesink et al. 2006). There were no severe or serious adverse side effects and no breaks in the dosing regime or discontinuations due to adverse events. The most frequent adverse events were headache, flatulence, diarrhea, frequent urination, dry mouth, fatigue, abdominal pain, nausea, back pain, dry skin, and common colds. No clinically significant laboratory results in hematology or clinical chemistry tests occurred in any of the patients. Furthermore, no patients had clinically significant changes in ECGs from the predosing baselines (Reesink et al. 2006).

Ultimately, VX-950 was effective in reducing viral load in a population in which 79% of patients had not responded to prior interferon based regimens (Reesink et al. 2006). Where interferon based treatments failed to achieve a lasting viral response, VX-950 was successful. Interestingly, clinicians and researchers have begun to study the effects of a combination treatment, part old interferon/ribavirin and part new VX-950. One such study was conducted by Forestier et al. who investigated the antiviral activity of telaprevir combined with peginterferon alpha-2a in patients with chronic hepatitis C. The experimental design and results are reviewed below.

Forestier et al.

Much of Forestier et al.’s study design and organization is the same as Reesink et al. The experiment’s participant criteria were entirely the same as Reesink et al., with the addition that only individuals who had not previously been treated for hepatitis C were eligible to participate. The study was placebo-controlled for telaprevir; peginterferon alfa-2a treatment was open-labeled. Twenty total patients were enrolled and randomized into three treatment panels: 4 patients received a placebo orally q8h for 14 days and peginterferon alfa-2a via subcutaneous injection once weekly for 2 weeks; 8 patients received telaprevir orally q8h for 14 days; and 8 patients received telaprevir orally q8h for 14 days and peginterferon alfa-2a once weekly for 2 weeks. The first telaprevir dose was a 1250-mg loading dose, and the following doses were 750-mg q8h. Subcutaneous injects of interferon alfa-2a were at a dose of 180µg on days 1 and 8 (Forestier et al. 2007).

Like Reesink et al., Forrestier et al. observed viral decline in two phases. Overall, patients treated with telaprevir and interferon alfa-2a had greater decreases in HCV RNA and more sustained declines in comparison to patients with telaprevir only treatments. The median change in HCV RNA from baseline to day 15 was -1.09 log10 in the placebo and peginterferon alfa-2a group and -3.99 log10 in the telaprevir group. The greatest decrease in HCV RNA was in the telaprevir and peginterferon alfa-2a combination group, from baseline to day 15 RNA was -5.49 log10 (Forestier et al. 2007).
The second phase of decline was more sustained in the telaprevir and peginterferon alfa-2a group than in the telaprevir alone group. In the telaprevir group, 4 patients had continued decline, 2 patients had viral plateau, and 2 had viral rebound whereas, all patients in the telaprevir and peginterferon alfa-2a group had continued decline during the entire drug dosing period. In the telaprevir group, 1 patient had undetectable HCV RNA levels at day 15. In comparison, 6 patients in the telaprevir and peginterferon alfa-2a group were below the lower limit of quantification in HCV RNA levels, and 4 patients had undetectable HCV RNA levels (Forestier et al. 2007).

Conclusions

Taken together, the findings of Reesink et al. and Forestier et al. confirm that telaprevir significantly decreases HCV replication, as measured by viral RNA. Furthermore, these trials confirm that a sustained viral response can be obtained using telaprevir where the standard interferon alfa-2b plus ribavirin treatment had previously failed. Forestier et al. adds to the discussion the notion of combing new and old antiviral treatments (telaprevir and interferon alfa-2a), and presents a convincing study that supports the administration of a combined treatment for maximal antiviral activity.

Implications on pharmaceutical industry and individuals infected with Hepatitis C

References

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Lin, Kai et al. 2006. VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potential antiviral activities in HCV replicon cells. Antimicrobial Agents and Chemotherapy. 50:1813-1822.

[www.hcvadvocate.org Keeffe, Emmet B. MD. 2006. Treatment of chronic hepatitis C impact on natural history. The HCV Advocate. January 2006.]

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National Center for Biotechnology Information, US National Library of Medicine. 2010. Ribavirin. (27 Oct. 2010).

Feld, Jordan J. and Jay H. Hoofnagle. 2005. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 436: 967-972.

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Forestier et al. 2007. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology. 46: 640-648.