Replies to post #1387 on Idenix Pharmaceuticals (IDIX)

[gofishmarko]

VA monograph on Tyzeka , dated May 2007.

http://www.pbm.va.gov/monograph/Telbivudine.pdf

Worth a look , also. It has a chart near the end showing the VA costs for the various HBV drugs.

Summary conclusions :

"Conclusions

In the phase III trial, telbivudine was noninferior to lamivudine in achievement of Therapeutic and Histological Response in both HBeAg subpopulations. Telbivudine displayed more rapid and potent virologic activity than lamivudine. Lamivudine, at the time of study initiation, was the
appropriate comparative agent; however, it is no longer considered as a first-line agent due to high rates of resistance associated with long-term therapy. The safety profile of telbivudine was similar to lamivudine with the exception of elevations of CK. Genotypic resistance was seen with lamivudine and telbivudine at one year; resistances rates continued to increase at year two. Longer follow-up studies are needed to assess the durability of telbivudine beyond two years. Although not compared in head to head trials, resistance rates seen with telbivudine are likely
higher than with adefovir and entecavir. The VA cost of telbivudine is comparable to adefovir.

Recommendations

Although telbivudine displayed potent virologic activity, the data appear to suggest a higher incidence of resistance to telbivudine than other recommended first-line oral nucleos(t)ide options (i.e. adefovir, entecavir). Due to clinical failures associated with resistance, clinicians are
selecting first-line agents that minimize the development or selection of resistance. Thus, adefovir and entecavir are preferred oral agents for treatment of chronic hepatitis B in
nucleos(t)ide-naïve patients while telbivudine should be considered second-line oral therapy. However, telbivudine as with lamivudine may have a role in certain clinical scenarios such as short-term or combination therapy. Further studies are needed to define the role of telbivudine in combination with nucleotides or peginterferon for the treatment of chronic hepatitis B."

[bladerunner1717]

Thanks, gofish. That certainly doesn't sound too good. I'll wait to hear what Dew has to say, but it doesn't look too promising from what you've uncovered.


Bladerunner

[DewDiligence]

If those AASLD guideline are still in place after the two-year Tyzeka data released last fall, then NVS and IDIX better get to work changing them because they are clearly out of date.

I’ve posted at length about the randomized head-to-head data showing Tyzeka superiority to Hepsera (#msg-21365649), which is the leading HBV drug in terms of sales.

The two-year resistance profile of Tyzeka in patients where the drug works is excellent—see #msg-14377860:

>>
“For telbivudine-treated patients who achieved PCR negativity at week 24, the per-protocol rates of resistance at two years were 4 percent in HBeAg-positive patients and 2 percent in HBeAg-negative patients. Per GLOBE study protocol, resistance was defined as HBV DNA return to >5 log, or to within 1 log of baseline.”
<<

The higher resistance figures in the references you cited are ITT figures, which are irrelevant for the reason mentioned in #msg-14403420: in patients where Tyzeka never works in the first place, it’s immaterial whether it induces strains that are resistant to Tyzeka because these patients will be switched to another therapy. There is no preclinical or clinical evidence I’m aware of that a short regimen of Tyzeka induces resistance to Baraclude or Hepsera.

Regarding HBV/HIV co-infected patients, this is a clear differentiating factor for Tyzeka because it has zero efficacy against HIV in animal models and thus it can’t cause premature resistance to HAART cocktails as Lamivudine, Baraclude, Hepsera, and Viread can. (The interferon drugs have this benefit too, but they are rarely used in HBV due to their poor therapeutic index.)

Lamivudine and Viread are approved drugs for HIV, Hepsera is a close chemical cousin of Viread, and Baraclude recently received a warning for its activity against HIV (#msg-17360663). With a modicum of marketing, Tyzeka should clearly become the HBV drug of choice in HBV/HIV co-infected patients.

All told, it’s clear that the AASLD guidelines you referenced either are obsolete (i.e. a googling error) or they should be obsolete. I will find out which.

[DewDiligence]

If those AASLD guidelines are still in place after the two-year Tyzeka data released last fall, then NVS and IDIX better get to work changing them because they are clearly out of date.

I’ve posted at length about the randomized head-to-head data showing Tyzeka superiority to Hepsera (#msg-21365649), which is the leading HBV drug in terms of sales.

The two-year resistance profile of Tyzeka in patients where the drug works is excellent—see #msg-14377860:

>>
“For telbivudine-treated patients who achieved PCR negativity at week 24, the per-protocol rates of resistance at two years were 4 percent in HBeAg-positive patients and 2 percent in HBeAg-negative patients. Per GLOBE study protocol, resistance was defined as HBV DNA return to >5 log, or to within 1 log of baseline.”
<<

The higher resistance figures in the references you cited are ITT figures, which are irrelevant for the reason mentioned in #msg-14403420: the resistance that occurs is almost entirely within the subgroup of patients where Tyzeka never works in the first place. (These patients will of course be switched to another drug.) There is no preclinical or clinical evidence I’m aware of that a short regimen of Tyzeka induces resistance to Baraclude or Hepsera.

Regarding HBV/HIV co-infected patients, this is a clear differentiating factor for Tyzeka because it has zero efficacy against HIV in animal models and thus it can’t cause premature resistance to HAART cocktails as Lamivudine, Baraclude, Hepsera, and Viread can. (The interferon drugs have this benefit too, but they are rarely used in HBV due to their poor therapeutic index.)

Lamivudine and Viread are approved drugs for HIV, Hepsera is a close chemical cousin of Viread, and Baraclude recently received a warning for its activity against HIV (#msg-17360663). With a modicum of marketing, Tyzeka should clearly become the HBV drug of choice in HBV/HIV co-infected patients.

I suspect the AASLD guidelines tend to lag behind the state of the art and this is one reason Baraclude took so long to ramp up despite being clearly the best approved HBV drug during 2005 and 2006.

[DewDiligence]

Baraclude was not added to the AASLD treatment guidelines for HBV until Feb 2007, almost two years after its FDA approval in Mar 2005.

This blows your assertion that Tyzeka is deficient for not being on the AASLD guidelines right out of the water.