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March 03, 2010 – Comments (5) | RELATED TICKERS: VRTX , ANDS.DL , ITMN

In the spirit of a recent excellent post on Anadys Pharamceuticals and their experimental hepatitis drug ANA598, I’ve decided to do a little more in depth analysis of the hepatitis C field and share it with my CAPS compatriots. I’m hoping to eventually find the time to describe the hepatitis C programs of about ten developmental biotechs as well as a few competing compounds from large cap companies. But first, a little background.

The hepatitis C virus (HCV) is an RNA virus of the family Flaviviridae. There are six well-established genotypes but only the first three are commonly identified in human infections. Genotype 1 (70% of patients) has a worse prognosis than genotypes 2 and 3, which are essentially equivalent. In the United States, HCV is typically contracted through sharing needles during IV drug use. Chronic infection occurs in 50-80% of infected individuals and will eventually result in cirrhosis and liver failure if untreated.

The hepatitis C virus wasn’t even identified until the mid 1980’s. Alpha interferons, natural inhibitors of viral replication, were approved as treatment of hepatitis C in the 1990’s. A well-established metric for the efficacy of treatment is a sustained virologic response (SVR), which means undetectable hepatitis C RNA six months after termination of treatment. With the original thrice weekly, 48 week course of alpha interferon injections, SVR’s were about 10% for genotype 1 and 30% for genotypes 2 and 3. The next advance came in 1998 with approval of oral ribavarin, a synthetic nucleoside that has minimal activity against hepatitis C alone but significantly augments the efficacy of alpha interferon. The mechanism of ribavarin activity is not well understood. Combination therapy with interferon and ribavirin increased the SVR to 30% for genotype 1 and 60% for genotype 2/3. Another major step forward occurred in 2001 with approval of Schering’s PEG-Intron, which had a substantially longer half-life than prior alpha interferons. This allowed both a reduced frequency of injection and improved efficacy. SVR’s for PEG-Intron combined with ribavirin are 40% for genotype 1 and 82% for genotype 2/3. A year later Roche added Pegasys, using the alpha-2b form rather than the alpha-2a interferon used in PEG-Intron but with similar efficacy.

The current standard of care for chronic hepatitis C infection is different for genotype 1 and genotype 2/3. Genotype 1 requires a 48 week course of treatment with a weekly injection of a PEGylated alpha interferon as well as daily oral ribavirin. For genotype 2/3, 24 weeks of treatment with the same regimen achieves optimal results. In addition, rapid responders (RVR) who are negative for hepatitis C RNA after 4 weeks may stop treatment earlier (24 weeks for genotype 1 and 16 weeks for genotype 2/3).

Developing therapies for hepatitis C include further modifications and upgrades of the existing interferon and nucleoside compounds, as well as completely new weapons such as HCV protease inhibitors (telaprevir, boceprevir, ITMN-191). The HCV NS3/NS4a serine protease catalyzes protein processing that is necessary for viral replication. Vertex’s telaprevir is the most advanced and so far the most successful of the  protease inhibitors, so I’ll kick off my hepatitis C series with some information about completed and upcoming trials of telaprevir. In the notes below, TVR is telaprevir and PR is standard of care PEG-IFN + ribavirin. In all the studies TVR is administered together with PR and the numbers indicate weeks of treatment. Therefore TVR12/PR48 indicates 12 weeks of TVR with PR followed by 36 weeks of PR alone.

COMPLETED TRIALS

PROVE 1 – final results were released in 4/08. Phase IIb study of treatment-naïve genotype 1(260 pts). Comparison of TVR12/PR12, TVR12/PR24, TVR12/PR48 with PR48 control. SVR was 35% for TVR12/PR12, 61% for TVR12/PR24 and 67% for TVR12/PR48 vs 41% for PR48. RVR was 79%. RVR’s did not benefit from treatment beyond 24 weeks. 18% discontinuation of TVR due to rash.

PROVE 2 – final results were released in 2008. Phase IIb study of treatment-naïve genotype 1 (323 pts). SVR was 69% for TV12/PR24, 60% for TV12/PR12, 30% for TV12/P12 (no ribavarin), and 46% for PR48.  13% discontinuation due to side effects with TVR vs 10% without.

PROVE 3 - final results were released in 4/09. Phase IIb study of treatment-failure genotype 1. SVR was 51% for TVR12/PR24 and 52% for TVR24/PR48 compared to 14% on PR48. Rash led to discontinuation of treatment in 5% of TVR pts and resolved afterward.

Study C208 – final results 10/09. Comparison of bid and tid dosing of TVR as well as combination with Pegasys or PEG-Intron in treatment-naïve genotype 1 (T12/PR24). RVR’s stopped treatment at 24 wks and non-RVR’s continued PR through week 48. Total follow up was through week 72. Twice daily or thrice daily dosing did not seem to make any difference. RVR was about 80% with Pegasys and 68% with PEG-Intron. SVR was about 82% for all groups.

TRIALS IN PROGRESS

Study 107 – phase II roll-over study of control pts from PROVE trials who did not achieve SVR. Initial protocol was for T12/PR24 which was then switched to T12/PR48 in null responders only. Initial plan to eliminate new null responders at 4 wks was also scrapped. In 10/09 interim analysis of 94/117 pts showed about 56% SVR in prior partial and null responders, 90% SVR in prior relapsers, 75% SVR in prior viral breakthroughs. 23/51 prior null responders were excluded from interim analysis due to their completion of trial prior to protocol amendments. Final results will be released later in 2010.

ADVANCE – phase III telaprevir in treatment-naïve genotype 1 (1050 pts). Three groups of 350 pts: TVR12/PR24, TVR8/PR24, PR48. TVR groups will continue PEG/RBV to week 48 unless they are rapid responders, in which case only follow-up. Follow up continues to week 72. TVR dosing was completed in 2/09 and initial data is expected in Q2 2010.

REALIZE – phase III telaprevir in treatment-failure genotype 1 (650 pts). TVR 12/PR48 with TVR beginning at either week 1 or week 5, as well as a PR48 control group. Initial data is expected in summer 2010.

ILLUMINATE – phase III telaprevir in treatment-naïve genotype 1 (500 pts). TVR12/PR48, with RVR split into two groups at week 24, one with no further treatment and one with PR to week 48. All pts followed through 72 wks. Telaprevir dosing was completed in 5/09 indicating that trial should be finished by 7/10.

Combination trial TVR/VX-222 – initiated 3/10. VX-222 is Vertex’s developmental HCV polymerase inhibitor, acquired by purchasing the private biotech outfit ViroChem last year. Four groups of treatment naïve genotype 1, total 100 pts. 12 weeks of TVR/VX-222 with or without PR, and 100mg or 400mg VX-222. RVR will discontinue at 12 weeks. Non-RVR will continue PR for 24 weeks if no prior PR and at 12 weeks if already receiving PR.  Interim data is expected in Q2 2010.

As we can see 2010 is shaping up to be the year that we will see if telaprevir is destined to be the next paradigm shift in the treatment of hepatitis C. To the best of my knowledge Vertex has not released any interim or RVR data from the phase III trials. However, the phase II trials indicate that telaprevir is highly active in HCV and if the phase III data is consistent Vertex’s share price will likely move north of 60. The concern of course is that Vertex already has a market cap over 8B despite an absence of marketed products and a history of dilutive financings. Compare this to Cephalon with a market cap of 5B and quarterly revenues over 500M and Genzyme with a market cap of 15B and quarterly revenues over 1B. Vertex has other promising products in the pipeline as well but any developments threatening the commercialization of telaprevir (such as that nasty rash) could drop the share price more than 50%. Very high stakes.

In my next post on HCV I’ll discuss the competing  HCV protease inhibitors in development, including Merck’s boceprevir and Intermune’s ITMN-191, and what threat if any they pose to future profits from telaprevir. I’ll try and get to polymerase inhibitors after that so I can discuss Anadys and ANA598, since Portefeuille’s post was what motivated me to review HCV more comprehensively.  I hope that Port and our other high-performing biotech hobbyists will help me correct any inaccuracies and add to our information database on HCV therapies so that we can become a resource for investors around the web.

5 Comments – Post Your Own

#1) On March 04, 2010 at 11:30 AM, Mrsvedit (< 20) wrote:

Thank you for taking on this project of educating about HCV. I run a grass roots nonprofit called Greenview Hepatitis C Fund, which raises awareness of HCV and raises funds for HCV research (mostly seed money at this point.) I have a blog on my website where I try to relay the most relevant and current HCV news. I will post an entry referring to your blog. Would you like to become a regular blogger on my blog as well? Keep up the good work. Debbie@hepcfund.org 

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#2) On March 04, 2010 at 6:14 PM, zzlangerhans (99.78) wrote:

I appreciate your interest. My post here is directed towards investment in biotechnology companies that are developing treatments for hepatitis C. I'm not a hepatitis specialist and have no credentials to dispense health-related information, even on a blog. You are more than welcome to link or refer to what I write here, as I am planning a fairly comprehensive series of posts on developing treatments for hepatitis C.  

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#3) On March 07, 2010 at 11:49 AM, uclayoda87 (29.14) wrote:

From an investment point of view are the number of patients requiring a new therapy for Hep C large enough for these companies to make profit?  Are they looking to expand the indications for these potential treatments to patients with other more common viral illnesses?  With small clinical trials, the safety issue is never really addressed, unless a high percentage of adverse outcomes become apparent quickly.  So even if efficacy is demonstrated and the treatment reaches the market, profits may be short-lived as was the case for Vioxx.

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#4) On March 12, 2010 at 10:32 PM, PI222 (< 20) wrote:

Boceprevir is currently scheduled to come out at the same time as telaprevir.  Both completed enrollment of phase III studies in Feb 2009 so those patients completed their therapies recently.  Also, before reviewing the polymerases you should review the next generation proteases.  All proteases are not equal.  Genentech and Merck's next gen proteases look amazing

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#5) On April 29, 2010 at 3:03 PM, JanisandFriends (< 20) wrote:

Thank you for this article, it educated many of our friends who are waiting to treat and retreat.

We had part one and part two on our blog for months. If you decide to update your article the link I left may be beneficial to you. As always anyone is welcomed to use any information from our blog and website. Our information comes from internet conferences/Liver meeting/Trial Results, Etc . At times even from people at our forum/message boards who are in such trials.

Wish I had the courage to add these drugs to my portfolio.

Thanks again

Tina @ J&F

Website http://janis7hepc.com/2010_internet_hcv_conference_rep.htm

Blog http://hepatitiscnewdrugs.blogspot.com/

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