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Hepatitis C for Fools II: The Other Protease Inhibitors

Recs

15

March 08, 2010 – Comments (18) | RELATED TICKERS: MRK , VRTX , ITMN

Last week, to the great ennui of the CAPS community, I began a new blog series to address the underlying science behind baby biotech. I kicked things off with the fascinating subject of hepatitis C and the protease inhibitor telaprevir, being developed by Vertex. To develop the subject of protease inhibitors further I'll discuss the laggards in the field, Merck’s boceprevir and Intermune’s ITMN-191.

As I described previously, the current standard of care in hepatitis C is PEGylated interferon alpha + ribavirin. This combination treatment yields SVR of 40% for genotype 1 and 82% for genotype 2/3. Phase II data indicates that adding telaprevir to the regimen increases SVR to as much as 70% for genotype 1, and phase III data will be released in a few months.

Merck inherited boceprevir via their merger with Schering-Plough which closed in 11/09. Since the Schering-Plough website is no more and Merck doesn't provide much in the way of clinical trial data on theirs, collecting data on boceprevir is quite work-intensive.

COMPLETED TRIALS

SPRINT-1 - final results 4/09. Phase II boceprevir in 595 treatment-naive genotype 1. Groups received 28 or 44 weeks of boceprevir after 4 weeks of PR (lead-in) or at the beginning of treatment, and a control group received 48 weeks of PR. SVR's were 75% for 44 weeks with lead-in, 56% for 28 weeks with lead-in, 67% for 44weeks without lead-in, 54% for 28 weeks without lead-in, and 38% for PR control. Another treatment arm with low dose ribavirin had poor results. In the lead-in groups, null responders after 4 weeks had a 55% SVR with 44 weeks boceprevir and a 25% SVR after 28 weeks boceprevir. Treatment discontinuation due to side effects was 9-19% in boceprevir arms vs 8% in PR arm.

TRIALS IN PROGRESS

SPRINT-2 - phase III boceprevir in 1099 treament-naive genotype 1. All three groups receive 48 weeks PR (PEG-Intron +ribavirin). One group also receives 28 weeks boceprevir and one group also receives 48 weeks boceprevir. Boceprevir is begun 4 weeks after initiation of PR. Boceprevir patients with RVR by week eight of treatment stop all treatment after 28 weeks. Enrollment completed 1/09. Study completion 6/10 per clinicaltrials.gov.

RESPOND-2 - phase III trial boceprevir in 404 treatment-failure genotype 1. All three groups receive 48 weeks PR. One group also receives 36 weeks boceprevir and one group receives 48 weeks boceprevir. Boceprevir patients with RVR by week eight of treatment stop all treatment after 28 weeks. Enrollment completed 11/08. Study completion 4/10 per clinicaltrials.gov.

While the conventional wisdom is that boceprevir is not as promising as telaprevir, the 75% best SVR for boceprevir compares favorably to the 67-69% SVR seen for telaprevir in the PROVE trials. However, telaprevir definitely has the advantage with respect to data in treatment-failure patients. Only limited data is available for boceprevir, from the null responders in the 4 week lead-in periods in SPRINT-1. But data from the PROVE-3 and ongoing Study 107 trials of telaprevir indicate it has substantial efficacy in patients who have already failed other regimens. Given the potential variability between phase II and phase III data however, boceprevir definitely has the potential to be a significant fly in Vertex's ointment come summer.

And now on to Intermune. The protease inhibitor ITMN-191 has been renamed RG7227 due to a partnership with Roche. The main twist here is that Intermune has been using ritonavir to boost RG7227 levels in trials. Ritonavir is an inhibitor of cytochrome P450-3A4, which degrades protease inhibitors such as the ones being developed for hepatitis C.  

COMPLETED TRIALS

Several short phase I trials

INFORM-1 - combination of RG7227 + Pharmasset's polymerase inhibitor RG7128. Highest RG7227 dose cohort had 63% undetectable viral RNA after 2 weeks in treatment-naive and 25% undetectable viral RNA in prior null responders.

TRIALS IN PROGRESS

Phase Ib multiple ascending dose study of RG7227 + ritonavir + PR for 15 days in treatment-naive patients. Initiated in 9/09. Two lowest dose cohorts have been reported, with RVR seen in more than 50%. Trial will continue with higher dose cohorts and likely expansion of treatment to 12 weeks.

Phase IIb study of RG7227 + PR (no ritonavir) for 12 weeks. Initiated in 9/09. Preliminary data is expected in late Q1 or early Q2.    

PLANNED TRIALS

Phase IIb of RG7227 + ritonavir + PR for 12 weeks. Expected to begin in Q3 2010.

INFORM-2: RG7227 + ritonavir + RG7128 for 12 weeks. Expected to begin in H2 2010.

Intermune's data is mostly viral kinetics rather than the SVR variety, as they seem to have elected to go with shorter studies to accelerate development. This makes comparisons with telaprevir and boceprevir rather difficult in these early stages. Given that they are far behind in the race, Intermune and Roche are intelligently breaking new ground by combining RG7227 with ritonavir and a polymerase inhibitor, as well as with the standard of care.

If I decide to continue on with this series the next installment will explore the Hepatitis C polymerase inhibitors, such as Pharmasset's RG7128 and Anadys' ANA598. 

18 Comments – Post Your Own

#1) On March 11, 2010 at 9:43 AM, TMFJake (73.62) wrote:

Keep them coming!  I'd also be interested in your thoughts on ITMN (market overreaction?) and the follow Klarman strategies associated with PDLI and FACT (time to get out now?).  Fool On!

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#2) On March 11, 2010 at 9:45 AM, TMFJake (73.62) wrote:

Obviously, your discussin ITMN above, but I'm interested in whether you think the market overreacted over the last few days to the FDA approval...

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#3) On March 11, 2010 at 9:48 AM, portefeuille (99.61) wrote:

FDA approval

not yet ...

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#4) On March 11, 2010 at 10:14 AM, TMFJake (73.62) wrote:

Right final vote May 4 on pirfenidone, with the advisory panel recommending to approve this week.  Question is whether the market is jumping the gun, and/or whether there's even more upside if the approval goes through on May 4.  

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#5) On March 11, 2010 at 10:22 AM, Bethamphetamine (< 20) wrote:

Well, there's at least one person here who is excited about your blog!  Thank you for this great information!

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#6) On March 11, 2010 at 10:26 AM, portefeuille (99.61) wrote:

at least one

then it is at least two.

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#7) On March 11, 2010 at 10:57 AM, zzlangerhans (99.78) wrote:

First of all I was way wrong on PDLI and FACT, one of my worst calls (that FACT was overpriced). So no further opinions from me on that whole situation. Pirfenidone is another sore spot, as I was very confident and very wrong in my opinion that the FDA position papers would be negative. What I do know is that the pirefnidone phase III was inconclusive on efficacy. The FDA I thought I knew does not support NDA applications that have questionable efficacy. Certain comments from the advisory panel are practically open admissions that pirfenidone received positive votes to provide "hope" for patients with an incurable disease. In other words, if it doesn't really work at least it's a placebo. If the FDA approves this first pass, I will consider this to be a major pendulum swing and I will have to adjust my trading strategies for a new, softer FDA.  

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#8) On March 11, 2010 at 12:49 PM, TMFJake (73.62) wrote:

Thanks ZZ, even your waving of the white flag is instructive...

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#9) On March 11, 2010 at 2:17 PM, AndrewGreenBull (99.19) wrote:

I accidently found that you are a biotech trader too! Thank you for sharing your info!

Normally I don’t make a comment because I don’t have time, but I do rec after I read the post to show my respect to other people’s work, even when I don’t agree with their opinions.

I will come to your blog more often to get tips of your picks if you don’t mind.

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#10) On March 11, 2010 at 4:54 PM, PDTBiotech (92.00) wrote:

Hey zz,

Great posts on the HCV stuff.  Interesting market, the estimated ramp rates analysts are using for sales models of VX-950 are about as high as I've ever seen.

As for your comments on the FDA, I agree, and I’m not liking where this situation is headed.  FDA requires two Phase III trials showing statistical significance of a clinical benefit to get approval.  There are very good reasons for this, including the fact that results often vary widely between centers.  As much as industry pundits like to thrash the FDA for “squashing innovation”, there are some drugs out there with very weak efficacy making a hell of a lot of money because they showed statistical significance in two Phase III trials and the FDA approved them, even if it took an insane amount of patients because the efficacy and/or the unmet need was very low (Plavix, Singulair, etc).  Did we really need the last three statins or TNFs?  Obviously not, but the FDA approved them too.

Then you have situations like pirfenidone right now, which reminds me of Provenge in 2007.  That was another case where the drug FAILED TO MEET ITS PRIMARY ENDPOINT and the market was still clamoring for it to get approved.  Like this situation, the committee voted that it was safe and efficacious, and the stock exploded.  Then the FDA gave DNDN an approvable letter and asked for more data.  Rather than noting that the FDA would’ve made themselves and the whole approval process irrelevant by approving a drug that hadn’t met any of its endpoints, burned investors accused them of killing people’s dads, hating innovation, etc.

I’ve seen arguments that in cases like IPF pooled data from two trials should be acceptable because there’s currently no standard of care.  Personally I disagree, but the real question is what the FDA will do.  Here are, to me, some things that might justify a speculative contrarian bet:

*CAPACITY I missed its primary endpoint by a ton, and it wasn't just the 72 wk, the 60wk was also not stat sig. 

*There was no SPA, so the FDA won't look like they're contradicting themselves if they don't approve.

*At the panel meeting the FDA's tone wasn't particularly welcoming, they described the pooled analysis as "exploratory" and noted that the 10% change in FVC as a threshold for clinical benefit is still debatable.

For the record, here are some July puts (PDUFA is early May): 30 (5.50); 25 (3.50); 20 (2.45); 15 (1.10); 10 (0.35).  They'll be interesting to watch/own as the poop nears the fan.

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#11) On March 11, 2010 at 8:44 PM, zzlangerhans (99.78) wrote:

I like the idea of Intermune puts. I regretted my decision not to pull the trigger on Medivation puts and the premium on those was a lot higher. I'd wait until the beginning of May to avoid a possible postponement of the PDUFA, which is a potential concern even though an advisory panel has already met. In late April I'll probably write an option post like I did on Medivation, except this time I'll buy 5 or 10 put contracts to make it interesting.  

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#12) On March 12, 2010 at 12:59 AM, Troy2008 (96.36) wrote:

Still waiting for you to short EXAS smart guy. Nice call on ITMN. LOL.

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#13) On March 12, 2010 at 1:13 PM, zzlangerhans (99.78) wrote:

I'll be there before long. Don't make me send sirwanksalot to kick your ass again.

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#14) On March 13, 2010 at 10:58 AM, PDTBiotech (92.00) wrote:

I feel your pain on the Medivation puts.  I've been pretty conservative about using options on bets I thought had a good risk-reward profile, and have missed out on a lot of profit overall because of it.  I don't have a very good feel for when FDA announces they're going to delay a meeting relative to when the meeting was first scheduled - is there any consistency there?  I'm hoping ITMN holds as much of this price as it can, and would like to jump into some puts some time in the second half of April.  DNDN originally went down to the high end of the previous year's price range when they got show down, so 15 or 20 seems likely to me for ITMN.  Any ideas on where it might settle?

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#15) On March 17, 2010 at 6:17 PM, zzlangerhans (99.78) wrote:

All depends on the nature of the hit. If the FDA states efficacy is unsatisfactory and requests a new study, I'd hazard below 20. I wouldn't muck with any puts with a strike less than 25 for sure.

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#16) On March 19, 2010 at 9:30 AM, dcsilver (63.91) wrote:

Hey ZZ - what are your thoughts on CBRX?  Any? Richard Perry just picked up 6,000,000 shares slightly above today's trading price.  CEO bought 100,000 shares also after the news of their recent sale of a key product.  Unfortunately, I don't know/understand what they're selling....

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#17) On April 19, 2010 at 6:50 PM, PDTBiotech (92.00) wrote:

I've been doing a little digging - FDA seems to be announcing delays later and later, several recent ones haven't been announced until the original PDUFA date.  Delay is usually 90 days.  That is not cool.

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#18) On May 22, 2010 at 6:00 AM, portefeuille (99.61) wrote:

If I decide to continue on with this series the next installment will explore the Hepatitis C polymerase inhibitors, such as Pharmasset's RG7128 and Anadys' ANA598.

Anadys Announces Completed 12-Week Results From Phase II Combination Study of ANA598 With Interferon and Ribavirin

The "too good" placebo response puzzle (see comments #6,7,10, 13 here) appears to have been resolved.

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IL28B Genotyping-Preliminary Assessment

Based on a preliminary assessment of IL28B genotyping from approximately sixty percent of the patients in the Phase II study, Anadys can now offer additional perspective on the response of the patients who received placebo plus standard of care (control arm) in the study.  Recent scientific studies have shown that individuals with the IL28B CC genotype, present in approximately 37% of Caucasian HCV patients and a lower percentage of patients in other ethnic groups, are substantially more responsive to SOC than patients with other IL28B genotypes.  In the SOC control arm of the ANA598 study, 56% of the patients who have been genotyped to date are of the CC genotype while in the ANA598-treated arms only 21% of the patients who have been genotyped to date are of the CC genotype.  Anadys believes that the high proportion of CC patients in the SOC control arm of the ANA598 Phase II study relative to the overall population likely contributed to a higher cEVR rate than has been seen historically.

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