Replies to post #1381 on Idenix Pharmaceuticals (IDIX)

[gofishmarko]

I've been curious about the reasons for the slow uptake of Tyzeka , so I did a little web searching. I came across the recently updated (2007) AASLD Treatment Guidelines for HBV.

pdf at :

https://www.aasld.org/eweb/docs/chronichep_B.pdf

The bottom line is that Tyzeka is clearly relegated to the second tier of treatment options , for almost all patient cohorts. Adefovir , entecavir , and pegifn are listed as front-line , with various qualifications depending on whether patients are naive , lam-resistant , HIV-pos , etc.

Until IDIX can produce data that shows a good head-to-head comparison versus the currently-favored agents ( over several years , probably ) , it's hard for me to see how Tyzeka will ever capture a market share similar to those other drugs. I realize that the AASLD guidelines are not the last word , especially considering the global market , but they carry a lot of weight in the U.S. and probably the EU , as well.

Here's a couple of excerpts from the pdf ( See Table 11 for a summary of tx. recs ):

"Telbivudine is an L-nucleoside analogue with potent
antiviral activity against HBV. Clinical trials showed that
telbivudine is more potent than lamivudine in suppressing
HBV replication. However, telbivudine is associated
with a high rate of resistance and telbivudine-resistant
mutations are cross-resistant with lamivudine.
Therefore, telbivudine monotherapy has a limited role in
the treatment of hepatitis B."

"Patients who are not on HAART and are not
anticipated to require HAART in the near future
should be treated with an antiviral therapy that does
not target HIV, such as pegIFN-
, adefovir, or entecavir.
Caution should be exercised if entecavir is used
in this setting. Although telbivudine does not target
HIV, it should not be used in this circumstance."

"In choosing which antiviral agent to use as the firstline
therapy, consideration should be given to the
safety and efficacy of the treatment, risks of drug resistance,
costs of the treatment (medication, monitoring
tests, and clinic visits), as well as patient and provider
preferences, and for women—when and whether they plan to start a family. ...

...In view of the high rate of drug resistance during long-term treatment, lamivudine and telbivudine are not preferred except where only a short course of treatment is planned."

etc.

[DewDiligence]

Hepsera 2Q07 sales increased 32% year-over-year and surpassed a $300M run rate for the first time:

http://biz.yahoo.com/bw/070719/20070719005871.html?.v=1

>>
Hepsera sales were $75.2 million for the second quarter of 2007, a 32 percent increase from $56.8 million in the second quarter of 2006, driven primarily by sales volume growth in the United States and Europe.
<<

The HBV market is still in its infancy and is growing by leaps and bounds.

[DewDiligence]

Tyzeka Competition

[Added: general info on Viread, latest sales figures for Baraclude and Hepsera, historical sales data for Baraclude, new black-box warning for Baraclude in HIV co-infected patients, and importance of premenopausal women in the overall HBV market. The contents of this post will be updated from time to time as new information becomes available.]


Tyzeka competitors within the HBV arena fall into two main categories: nucleosides and nucleotides. Ultimately, the standard of care for treating HBV will likely turn out to be a combination of a nucleoside and a nucleotide, as discussed in #msg-21249681. However, until combination therapy takes root, any drug approved for HBV as a monotherapy ought to be considered a Tyzeka competitor. (I’m excluding the interferon drugs because they offer a poor efficacy-vs-tolerability tradeoff and are rarely used in HBV.)

The HBV drugs other than Tyzeka that are garnering non-trivial sales are Lamivudine (a.k.a. Epivir-HBV) from GSK, Hepsera from GILD, and Baraclude from BMY. In late 2008 or early 2009, Viread from GILD will almost certainly be approved for HBV and will supplant Hepsera for all practical purposes (#msg-20743204, #msg-21636346).

Let’s consider each of these drugs with a focus on the U.S. market. For the most part, the dynamics of the HBV market in western Europe are similar to those in the U.S., although the approval dates for the drugs are somewhat different.

The following graph shows the sales of Lamivudine (red), Hepsera (black), Baraclude (magenta), and the overall market (indigo) from early 2002 to late 2006. Tyzeka is not shown because the x-axis of the graph stops at the point when Tyzeka was approved.





The first observation from this graph is that the overall HBV market (indigo) is growing rapidly. On its most recent CC, GILD (the maker of Hepsera) stated that the total number of HBV patients treated in the U.S. grew by 50% (from 32,000 to 48,000) in the two-year period from early 2005 to early 2007.

Of the three drugs in the graph, only Lamivudine (red line on graph) is declining. The reason for the decline is that Lamivudine is an old drug (approved in 1998) that is procuring very few new patients; however, Lamivudine sales are declining slowly because patients who are already on Lamivudine treatment have no reason to switch drugs unless there is a viral breakthrough.

Lamivudine is not a competitor to be unduly concerned about because Tyzeka is clearly more efficacious. The evidence of this rests on the one-year data from the GLOBE study, which formed the basis of Tyzeka’s worldwide approvals and is specified in the FDA product label: (http://www.fda.gov/cder/foi/label/2006/022011lbl.pdf , p.12-15, especially Table 3 on p.15).

After two years of treatment, the superiority of Tyzeka to Lamivudine was even more pronounced than after one year. This can be seen in the data presented by NVS and IDIX at the 2006 AASLD conference (#msg-14377860).

--
The leading HBV drug in the market currently is Hepsera (black line on above graph), which is doing $300M in annualized worldwide sales (#msg-21401098). What has made Hepsera a successful drug commercially is that it was the second direct-antiviral agent approved for HBV (in 2002) and was thereby well positioned to procure patients who experienced a viral breakthrough on Lamivudine or never responded to Lamivudine. In other words, much of Hepsera’s business comes from second-line treatment.

Hepsera has a good resistance profile, but it is weak on efficacy, where it is absolutely no match for Tyzeka. This can be seen in dramatic fashion in the following two plots, which show head-to-head data of Tyzeka (Telbivudine) vs Hepsera (Adefovir) at 24 and 52 weeks, respectively:



At 24 weeks, the mean log reduction in viral load
was 6.30 for Tyzeka vs 4.97 for Hepsera. The
% of patients who were PCR-negative at 24 weeks
was 39% for Tyzeka vs 12% for Hepsera.




From week 24 to week 52, patients on Tyzeka
continued to outperform patients on Hepsera.
Moreover, patients who switched from Hepsera
to Tyzeka midway through the trial performed
better than those who stayed on Hepsera.

--
Baraclude was the third direct-antiviral agent approved for HBV (in 2005). After a very slow start ($20M in the first year), Baraclude is currently doing $236M in annualized worldwide sales (#msg-21567340).

Baraclude is a fine drug. Although there have been no head-to-head studies of Baraclude vs Tyzeka that have been completed yet, we know that Baraclude’s efficacy is comparable to Tyzeka’s on every metric (#msg-14404551, #msg-18389527).

There are, however, a few features of Tyzeka that give it an edge against Baraclude:

• Tyzeka sells at a 30% lower price (#msg-21652956).

• Tyzeka has no food interaction. Baraclude, on the other hand, must be taken two hours before or two hours after food intake.

• Tyzeka has no activity against HIV, which is advantageous in treating individuals who are co-infected with HBV and HIV because Tyzeka causes no resistance to HIV drugs. Baraclude does cause such resistance, and a black-box warning on this subject was recently added to the FDA Baraclude label (#msg-21652925).

• Tyzeka is safer during pregnancy and this is stated in the FDA labels for the two drugs. Since mother-to-child transmission is one of the main ways people end up with chronic HBV, it is especially important for women of childbearing age to be treated for HBV early enough to have a decent chance for seroconversion before becoming pregnant.

For the above reasons, I will be very surprised if Tyzeka does not eventually catch up to Baraclude in worldwide sales. However, it may take a while for this to happen because patients being treated for chronic HBV generally stay on their existing therapeutic regimen until they experience a viral breakthrough. This can be vividly seen in the slow sales ramp that Baraclude experienced during 2005, its first year on the market (#msg-21567340).

Dew