Tyzeka (telbivudine)

Tyzeka is a synthetic thymidine nucleoside analogue with activity against hepatitis B virus (HBV) DNA polymerase. Tyzeka inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate. Incorporation of Tyzeka into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication.

Tyzeka is specifically indicated for the treatment of chronic hepatitis B in adult subjects with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Tyzeka is supplied as a white to slightly yellowish film-coated, ovaloid-shaped tablet for oral administration. The recommended initial dose of the drug is 600 mg once daily, taken orally with or without food.

FDA Approval
FDA approval of Tyzeka was based on the results of one clinical trial. This randomized, double-blind, multinational trial, dubbed 007 GLOBE, enrolled 1,367 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative subjects. The trial was designed to compare 600 mg of Tyzeka once daily to 100 mg of lamivudine once daily, for a treatment period of up to 104 weeks. The primary endpoint was a composite serologic endpoint requiring suppression of HBV DNA to < 5 log10 copies/mL in conjunction with either loss of serum HBeAg or ALT normalized. Secondary endpoints included histologic response, ALT normalization, and various measures of antiviral efficacy. In HBeAg-positive patients, 75% of the telbivudine subjects and 67% of the lamivudine subjects had a therapeutic response. In HBeAg-negative patients, 75% of the telbivudine subjects and 77 % of the lamivudine subjects had a therapeutic response. Secondary analysis indicated that treatment with Tyzeka reduced HBV DNA levels by 6.45 log10, versus 5.54 log10 for treatment with lamivudine (p<0.001) and led to improvements in ALT normalization (77% versus 75%), HBeAg Seroconversion (23% versus 22%) and HBeAg Loss (26% versus 23%).

Ongoing Study Commitments

• Idenix has agreed to complete and submit the final study report for Study NV-02B-007, the 104-Week, Phase 3 registrational trial comparing the efficacy and safety of telbivudine to lamivudine in subjects with HBeAg-positive and HBeAg-negative chronic hepatitis B and compensated liver disease.
  Protocol Submission: Study Ongoing
  Final Report Submission: July 2007
• Idenix has agreed to conduct and submit a final study report to evaluate the use of LdT in the treatment of chronic HBV infection in minority racial/ethnic groups that were under-represented in the pivotal clinical trials (Blacks/African Americans, Hispanics).
  Protocol Submission: June 2007
  Final Report Submission: June 2010
• Idenix has agreed to conduct and submit a final study report for an efficacy and safety study of telbivudine in subjects who are co-infected with HIV and HBV. This study should include analysis of virologic, biochemical, and serologic endpoints for both HIV and HBV. It should also include evaluation of safety, and evaluation of HBV and HIV resistance.
  Protocol Submission: June 2007
  Final Report Submission: June 2010
• Idenix has agreed to complete and submit the final study report for Study NV-02B-011, the double-blind trial comparing the efficacy and safety of telbivudine to lamivudine in subjects with chronic hepatitis B and decompensated liver disease.
  Protocol Submission: Study ongoing
  Final Report Submission: April 2010
• Idenix has agreed to complete and submit the final study report for Study NV-02B-018, the open-label trial comparing the efficacy and safety of telbivudine to adefovir dipivoxil in subjects with HBeAg-positive compensated chronic hepatitis B.
  Protocol Submission: Study ongoing
  Final Report Submission: June 2007
• Idenix has agreed to complete and submit the final study report for Study NV-02B-022, the open-label, non-comparative trial assessing the long-term antiviral efficacy and safety of telbivudine in subjects with HBeAg-positive and HBeAg-negative compensated and decompensated chronic hepatitis B that have been previously treated in Idenix-sponsored telbivudine studies.
  Protocol Submission: Study ongoing
  Final Report Submission: May 2012
• Idenix has agreed to conduct and submit a final study report for a study evaluating CYP induction potential for telbivudine using in vitro or in vivo studies.
  Protocol Submission: January 2007
  Final Report Submission: January 2008
• Idenix has agreed to conduct and submit a final study report(s) for in vitro studies to evaluate if telbivudine is a P-gp inhibitor.
  Protocol Submission: January 2007
  Final Report Submission: January 2008
• Idenix has agreed to conduct and submit a final study report for a study to determine the anti-HBV cell culture combination activity relationships of telbivudine with entecavir.
  Protocol Submission: December 2006
  Final Report Submission: April 2007
• Idenix has agreed to conduct and submit a final study report for a study to determine the anti-HBV combination activity relationships of telbivudine in cell culture with the HIV NRTIs abacavir, emtricitabine, lamivudine, tenofovir, zalcitibine, and zidovudine.
  Protocol Submission: February 2007
  Final Report Submission: November 2007
• Idenix has agreed to conduct and submit a final study report for a study to determine the susceptibility to telbivudine and adefovir of the HBV rtA181 variants, rtA181T and rtA181S.
  Protocol Submission: Study ongoing
  Final Report Submission: November 2007
• Idenix has agreed to conduct and submit a final study report for a study to determine the susceptibility in cell culture of HBV harboring the following mutations of highly conserved amino acid residues among HBV isolates: R22C, W58G, L69P, L82M, P99L, L180M, L209V, T240I, I254F, P261L, G295E, A307V, L331F, or A342T. These amino acid substitutions were found in the viruses of patients who experienced virologic failure (serum HBV DNA levels =1,000 copies/mL at Week 52) to telbivudine therapy.
  Protocol Submission: February 2007
  Final Report Submission: February 2008 and December 2009
• Idenix has agreed to conduct and submit a final study report for a study to determine the mitochondrial toxicity of telbivudine in growing muscle cells, cell lines and primary cells, and primary hepatocytes with appropriate controls to validate the results.
  Protocol Submission: March 2007
  Final Report Submission: March 2008
• Idenix has agreed to complete and submit a final study report for ongoing genotypic and phenotypic analyses of HBV DNA from patients who experience virologic failure to long term telbivudine therapy (serum HBV DNA levels =1,000 copies/mL) in ongoing clinical trials.
  Protocol Submission: Study ongoing
  Final Report Submission: July 2007, July 2008 and July 2009

Adverse events associated with the use of Tyzeka may include, but are not limited to, the following:

• respiratory tract infection
• fatigue
• malaise
• abdominal pain
• nasopharyngitis
• headache
• elevated blood CPK
• cough

In addition Tyzeka was shown to cause myopathy in conjunction with increases in creatine kinase (CK) values, several weeks to several months after starting therapy. Among patients with telbivudine-associated myopathy, there has not been a uniform pattern with regard to the degree or timing of CK elevations and predisposing factors are unknown. Patients should be advised to report promptly unexplained muscle aches, pain, tenderness or weakness. Treatment should be interrupted if myopathy is suspected, and discontinued if myopathy is diagnosed.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Tyzeka is the unmodified ß-L enantiomer of the naturally occurring nucleoside, thymidine.It inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of Tyzeka into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication. Tyzeka is an an inhibitor of both HBV first strand and second strand synthesis.

Jones R, Nelson M Novel anti-hepatitis B agents: A focus on telbivudine. International journal of clinical practice 2006 Oct;60(10):1295-9

Zhou XJ, Fielman BA, Lloyd DM, Chao GC, Brown NA Pharmacokinetics of telbivudine in healthy subjects and absence of drug interaction with lamivudine or adefovir dipivoxil. Antimicrobial agents and chemotherapy 2006 Jul;50(7):2309-15.

Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, Han S, Poynard T, Myers M, Chao G, Lloyd D, Brown NA; Telbivudine Phase II Investigator Group A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005 Aug;129(2):528-36.

Lai CL, Lim SG, Brown NA, Zhou XJ, Lloyd DM, Lee YM, Yuen MF, Chao GC, Myers MW A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology 2004 Sep;40(3):719-26.

For additional information regarding Tyzeka or hepatitis B virus, please visit the Tyzeka web page.