Replies to post #77073 on Biotech Values

[woofer]

iwfal, I couldn't go to sleep so I've been preparing a response to your post, which I'll hopefully have for you tomorrow.

In the meantime, I thought you might find this interesting- and a little bit humorous, keeping in mind that Vertex conducted this study too......

Principal results of the Phase Ib clinical trial are as follows:

· VX-950 was well-tolerated across all three dose groups with no serious adverse events reported, and no treatment discontinuations.

· Treatment with VX-950 also resulted in significant reductions in plasma HCV-RNA. Within three days of treatment, the median reduction in HCV-RNA was greater than 3 log10 in all three VX-950 dose groups.

· In the dose group receiving 750 mg of VX-950 every 8 hours, there was a further reduction in viral levels between days 3 and 14 of treatment, with mean and median HCV-RNA reductions of greater than 4 log10 at day 14.

· Trough plasma concentrations of VX-950 were highest in the 750 mg every 8 hour dose group. In the 450 mg q8h and 1250 mg q12h dose groups, maximal effects were seen between days 3 and 7 of treatment.

· Subsequently, there was an increase of approximately 1 log10 in median HCV-RNA between days 7 and 14 evident in both groups.
http://www.hivandhepatitis.com/hep_c/news/2005/aa/051105feat.html
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And something of historical significance if nothing else....

Whether hepatitis C virus will develop resistance to VX-950 or other protease inhibitors isn't known. Schiff notes that unlike HIV, the hepatitis virus doesn't hide inside cells where drugs can't reach it. So if the drug keeps viral levels low, there's a good chance the virus won't become resistant. It's even possible, Schiff says, that hepatitis C protease inhibitors will work all by themselves, without the need for combination therapy.
http://www.hepcassoc.org/news/article106.html

[ghmm]

HCV treatment/Rash:

My continued investment thesis in ITMN (on the HCV side) is not that I think Telaprevir isn't a potent drug, its more that if it has a competitor without a rash with comparable efficacy it'll be a no brainer choice for physicians/docs. I think it gets lost on some of these message boards that they are talking about drop outs because of rash and people are overlooking that a much larger number get rash (or just even having a higher risk going into therapy) but now patients stay on because of the efficacy. But if a therapy could offer both efficacy and no additional rash risk what would you choose?

Even if both Roche (with ITMN/VRUS) and Vertex come up with all oral therapies in the not-to-distant future for some patient populations the side-effect profile will be a factor in their success. Unless Vertex can produce substantially efficacy in shorter durations I think there is a lot of room for a competitor (Roche or otherwise). A competitor could tout even a 24 week (minimal side-effect) treatment duration that is all oral with better SVR than what Vertex may get in a shorter duration (that is more tolerable then currently being studied). Which would you choose if your a patient or a doc giving advise?

[woofer]

What do you think accounts for the fact that patients who took telaprevir for double the time- 24 weeks, had a smaller percentage of reported Grade 3 rash (4%) than those who were on telaprevir for only 12 weeks (6%)? The reason I point this out is because statistics can be misleading, especially with so few people involved.

Grade 3 rash was observed in 7 (6%), 5 (4%), 6 (5%) and 1 (1%) patients in T12/PR24, T24/PR48, T24/P24, and PR48, respectively.

[woofer]

iwfal, I thought this was an interesting set of statistics.....

Eleven (10%), 29 (25%), 10 (9%), and 5 (4%) patients discontinued due to AEs in T12/PR24, T24/PR48, T24/P24, and PR48, respectively.

......and since you brought them up and said,

Note the much greater incidence of rash in the telaprevir arms than in the no-telaprevir arm. Same with the discontinuation due to AEs.

......I thought I'd point out something else (other than what I'd already mentioned in another post about the rashes).

I find it curious that in the arm with no telaprevir, the drop out rate was only 4%....so I did a little additional research using the words interferon ribavirin drop out rate -telaprevir. I tried to avoid articles about trials where peg-interferon alfa-2b was used instead of peg-interferon alfa-2a to give you more benefit of the doubt, and here are the first articles I came upon. I'm at a loss to explain why all these drop out rates are higher.

But before you skim over them, I thought I'd give the only explanation I could think of......

Exclusion Criteria

Subject has any contraindications to Pegasys® or Copegus® therapy
Evidence of hepatic decompensation in cirrhotic subjects
History of organ transplant
History of, or any current medical condition which could impact the safety of the subject in participation in the study
http://clinicaltrials.gov/ct2/show/NCT00627926?show_locs=Y

Now the articles with much higher drop out rates (using a combination therapy of peg-interferon and ribavirin alone):

More than one-third of patients in both arms discontinued the study prematurely for any reason; Jacobson explained that this high drop-out rate is typical of trials under "real world" conditions. The frequency of serious adverse events was similar in both arms (11-12%).
http://www.bioplusrx.com/news/improved_response.aspx

This unusual drop-out rate of 28.42% was mainly caused by losing contact with patients (14.74%) and premature termination of therapy (13.68%).
http://www.ncbi.nlm.nih.gov/pubmed/17345816

Thirty patients completed treatment; patients were withdrawn due to transplantation (n = 2), severe anaemia (n = 1), dermatitis (n = 1) and non-response (n = 1) resulting in a drop-out rate of 14%.
http://cat.inist.fr/?aModele=afficheN&cpsidt=18695768

While patients in the double-dose arm required more dose reductions, the discontinuation rate was the same in both arms (about 35% overall; 12% due to adverse events).
http://www.aidsmap.com/en/news/088FBA45-76E1-4464-9B25-8303AB937B87.asp

Twenty patients (33.3%) discontinued treatment prematurely, but only in 10 (16.6%) was discontinuation due to adverse events.
http://www.liebertonline.com/doi/abs/10.1089/aid.2006.22.315?cookieSet=1&journalCode=aid

Twelve relapsers (group A: 5; group B: 4; group C: 3 = 15%) and 19 nonresponders (group A: 4, group B: 7 and group C: 8 = 25%) stopped therapy prematurely. 40% total.
http://www.medscape.com/viewarticle/460556_print

Side effects of treatment, however, are essentially universal. These led to modification of the dosage of interferon and/or ribavirin in 35-42% of patients treated with pegylated interferon in large, randomized clinical trials and discontinuation of therapy in 14-19% of these patients.(3,4) The most common side effects and their prevalence in these clinical trials are listed in Table 1.
http://www.hepatitis.va.gov/vahep?page=prtop04-cs-01

What happened to the 50% success rate that doctors keep talking about? 29% is much lower than that. And look the drop out rate. This is something that is seldom mentioned. 31% discontinue with current therapy because it is intolerable? Wow! So, only a 41% success rate after 31% drop out. Hmmm
http://www.hepatitis-central.com/mt/archives/2004/10/hepatitis_inter.html