Good news from Vertex

[Andiamo1]

From: thestreet.com
http://www.thestreet.com/_yahoo/newsanalysis/biotech/10409937.html?cm_ven=YAHOO&cm_cat=FREE&cm_ite=NA


The new telaprevir data that Vertex released Monday suggested that the drug may be effective in treating hepatitis C patients who have failed to respond to previous treatment.

These patients are considered the hardest to treat because they either don't respond to drugs like interferon and ribavirin, or their virus returns after treatment.

Vertex treated these so-called null responders and relapse patients with telaprevir plus interferon and ribavirin. Early results suggest that telaprevir was able to suppress the hepatitis C virus in these patients, although final data on cure rates is not yet available.

[willing]

mike: interesting find. Reminds me a bit of those stories of finding new drugs by searching exotic rain-forest plants:  a structure with such strong anti-viral effect "is derived from the HCV non-structural 5A membrane anchor domain. " seems like new molecular motifs, like new ideas, are hard to come by..


all: this thread, with all its good recent PI news wouldn't be complete without a mention of R1626, Repeating that same EASL search above on r1626 turns up encouraging news from Roche.

From:
HIGH END-OF-TREATMENT RESPONSE (84%) AFTER 4 WEEKS OF R1626, PEGINTERFERON ALFA-2A (40KD) AND RIBAVIRIN FOLLOWED BY A FURTHER 44 WEEKS OF PEGINTERFERON ALFA-2A AND RIBAVIRIN

Conclusion: RVR-2 and RVR-4 among patients receiving R1626, PEG-IFNa-2a and RBV positively correlated with end-of-treatment (week 48) response. Overall 84% of patients in the TRIPLE-1500 arm had undetectable HCV-RNA at week 48 compared with 65% for patients receiving PEG-IFNa-2a + RBV. R1626-associated hematological abnormalities were reversible.

and from
LOW LEVEL OF RESISTANCE, LOW VIRAL FITNESS AND ABSENCE OF RESISTANCE MUTATIONS IN BASELINE QUASISPECIES MAY CONTRIBUTE TO HIGH BARRIER TO R1626 RESISTANCE IN VIVO

"there was no evidence for resistance selection to R1626 after 2 weeks of monotherapy or 4 weeks of combination therapy. ..Conclusions: These results suggest that the high barrier to the development of resistance to R1626 in vivo may be related to low level of resistance, low replication capacity and lack of pre-existence in the viral quasispecies of R1626-resistance mutations."

[mikesimon]

I didn't know where else to put this article so here it is. I have no idea what to make of it but perhaps you will.

HCV Peptide C5A Has Potent Antiviral Activity Against HCV and HIV

"NEW YORK (Reuters Health) Apr 02 - A synthetic peptide derived from a hepatitis C virus (HCV) protein - dubbed “C5A”—has a unique virucidal mode of action with potent activity that renders HIV and HCV particles noninfectious, according to new research.
“C5A appears to represent the prototype of a new generation of antiviral agents that may have promise for the prevention and treatment of HIV,” Dr. Francis V. Chisari, at The Scripps Research Institute in La Jolla, California, and colleagues report in the PNAS Early Edition posted online April 1.
C5A is an alpha-helical peptide with both hydrophilic and lipophilic regions that is derived from the HCV non-structural 5A membrane anchor domain.
“We originally discovered C5A by screening a synthetic peptide library consisting of an overlapping series of (polymers) for antiviral activity against HCV,” Dr. Chisari told Reuters Health.
“I think the synthetic C5A peptide is virucidal for HCV and HIV by inserting its rigid corkscrew-type structure into the outer leaflet of the lipid bilayer of the envelopes of both viruses and, by torsional stress, essentially shredding them,” the scientist explained. “Without an intact envelope, both HCV and HIV are not infectious.”
They found that C5A prevents infection of macrophages, dendritic cells, and CD4+ T lymphocytes “by multiple HIV clade representatives and multidrug-resistant viruses.” In addition to its ability to block transmission of HIV by dendritic cells and transmigration across primary genital epithelial cells, C5A can also abrogate an ongoing T cell infection.
C5A is nontoxic in rodents at concentrations up to 200 times higher than the concentration required for antiviral activity in vitro.
“We are particularly intrigued by the opportunities created by C5A’s entirely unique mechanism of action,” Dr. Chisari said. “By destroying HCV and HIV particles outside the cell, C5A should prevent viral spread to uninfected cells.”
“Because C5A targets the viral lipid membrane, viruses can’t escape from its antiviral activity the way they do from all the other antiviral agents that are in use for HIV and under development for HCV,” he continued. “Therefore, C5A could be combined with any of the ‘conventional’ antivirals to prevent the spread of viruses that become resistant to those drugs.”
With its ability to destroy virus on contact, C5A may also be uniquely effective as a microbicide to prevent sexual transmission of HIV and HCV, he added.
“I have formed a company (Viriome, Inc) that has licensed C5A from the Scripps Research Institute,” Dr. Chisari said. “Viriome is carrying out the preclinical analysis of C5A, and is currently seeking a partner in the pharmaceutical industry to advance it to the clinic".
Proc Natl Acad Sci USA 2008
See: http://www.medscape.com/viewarticle/572427?sssdmh=dm1.343778&src=nldne

Mike

[3txsofar]

The abstract that has raised all of the interest is not related to Prove 3.  It is instead based on data from treating patients from Prove 1 and Prove 2 who did not SVR.  Because Vertex did the testing, they know exactly how each patrient responded and can reliably classify each as null, partial, etc. From the abstract - "Background: VX06-950-107 is an ongoing open-label study of TVR/P/R in genotype 1 HCV subjects who failed to achieve SVR in the control arms (P/R) of the TVR Phase 2 studies."

I believe that the company is holding on to any Prove 3 data until after they discuss it with the FDA.  And since they can pursue registration with the prove 3 data, that is a very wise idea, especially since the open-label data discussed in the EASL abstract is so powerful, it increases the liklihood of great Prove 3 data.

[FullOfHope77]

Good stuff! I've really done well with the stock even though I've waited for several months for this to happen but in 4-5 days I've really done well as I loaded up in the teens.

I feel certain that Miked is an example of what you will experience soon. You should be getting ready for 4 week testing I guess?

Thanks for sharing Eric! Always good stuff....

[geterdone]

Info, all good.

http://www.fool.com/investing/high-growth/2008/04/01/vertex-proves-it-almost.aspx

[willows]

Hmmm..rash or nausea?   I have to admit that some of the lab rats descriptions of the "rash from hell" has given me a few sleepless nights, but it is impossible to know which PI will help the most.  I am not biochemistry-smart enough to understand the exact mechinisms of each, so I trust in my doctor a lot.  Right now, I don't believe he has any favorites, he's just invested in Telaprevir's earlier time frame.  All of these numbers are subject to change at the drop of a hat...or a stock price..as it is.

You do biochemistry pretty darn good, thanks for the hard work.  Won't life be easier when all this is straightened out and we realize the full potential of the Hep C drug market?  I sound like a stock pusher, but it is really just a way to keep track of the new drugs.  All I know...and I haven't said this out loud for a long long time...I really hate this virus.

Willow

[willing]

Even with the benefit of some sleep and coffee I couldn't make sense of the above abstract and decided there is just not enough information given to fully decipher it. (eg at what week did the DSMB-ordered cutover take effect ? 24 "additional" weeks in addition to what?). Unfortunate, because this is currently the best available data, including svr outcome since it started back in '05,  on the benefits of re-tx with a PI for those for whom soc failed.

The clinicaltrials description
http://clinicaltrials.gov/show/NCT00160251
is no help.

Perhaps after the Milan meeting they'll put out a clearer version. Meanwhile however, there's value in the part of the abstract that starts with "Response to the addition of boceprevir". Because of the cutover, most of these guys got boceprevir later in tx. Not surprisingly, the benefit from adding the PI was a function of how strong their ifn response was : all those with a 2 log or better by 12 were und at eot vs 50% of those with 1 to 2 log vs 20% of those with lt 1 log. That's eot, and they don't give enough info to assess the relapse rate, but seems encouraging data for all non-responders who got EVR or close to it. Also, I found it significant that eot rates were "highest in control patients who had boceprevir added to their regimen". Ths is still just my pet theory, but I think it supports "extended-lead-in", eliminate much of the virus with soc before adding the PI.

From what's available now, the two ns3 PIs look very similar and there seems to be no advantage to waiting for BC over VX. Additional data will help, but at this point it seems to come down to whether you'd rather risk  rash or nausea. Hopefully, VX will release more of its prove3 data and get going with applications to make vx available for re-tx. Meanwhile, congratulations on keeping such a great attitude!

[willows]

Call me crazy, but I get all sort of goofy when I even DARE to think that another treatment might be considered in 4Q 08 and available to us sometime in 2009.  This virus has whacked my perspective....to tx in 2009 seems unbelieveable.  In a good, sci-fi sort of way.

I'll take any bit of good news I can and enjoy it to the max.  I'm here, hoping for early approval, right along with you.  Nice to think there is a chance for a bit of light at the end of this crazy tunnel.  Sometimes, it is just the smallest thing that makes the difference.  Good to hear from you again.

Willow

[Xhrles]

Hi Willow, Nice to see you all happy and hopeful again. Good news for all non responders and all heppers. Vertex said on their last call that they would decide on filing for Telaprevir non responder use sometime in 4Q 08 but maybe they can speed it up with strong data. Should make it available sometime in 09 but the FDA can approve whenever they are satisfied with safety and benefits. Lets hope for an early approval.

[willows]

Well, Schering could use some good news today, thats for sure, but my well respected doc is pretty gung ho on Telaprevir and I share his enthusiasm.  Our considerations are time related...I have waited almost five years now and like Eric, I am stage three, grade 1 and not sure I want to wait the extra year it will take for boceprevir.

In my case, the early bird gets my worm and hopefully, my virus.  It's early here on the west coast and I'm still pretty happy about the news yesterday.    The contrasting of Telaprevir and Boceprevir was fairly clear and to me, I have to hope for FDA approval for us non-responders rapidly.  If Vertex can gain approval, I have faith they will go the extra distance to make that happen, the revenue alone from the quarter million of us non responders would go a long ways towards speeding up the work on their next generation PI.  

As to the issue of a definition of a non-responder, I had a 2 log response at 12 weeks but never totally cleared the virus, which makes the idea of a 4 week indicator attractive to me, plus, and this makes me laugh, 12 has usually been my lucky number.  I'll take 12+12 anytime.

So much on the line, it is scary...but finally scary in a good way.  I have never minded getting excited about a fly in the ointment......beats the grinding reality of "no other treatment"......and to raise odds to about 65%.....just makes me want to rock and roll.

Ain't this interesting?  

willows

[willing]

MH's software choking on the html tag delimeters again - here it is with " lt " and " gt "

Background and Aims: Boceprevir is a mechanism-based inhibitor of the HCV-NS3 protease. We studied the efficacy and safety of boceprevir and Peginterferon-alfa-2b (PEG-IFN-alfa-2b) in 357 genotype-1  null  responders to peginterferon/ribavirin (P/R). Methods: All patients had documented  lt 2log10 decrease in HCV-RNA after 12wks of P/R therapy or failure to achieve an undetectable HCV-RNA if treated more than 12 weeks. All patients received PEG-IFN-alfa-2b (1.5 g/kg/wk) plus boceprevir 100/200/400 or 800 mg po TID, or B400/R; the control was P/R/B placebo with cross-over to active boceprevir (400/800) at TW17 for detectable HCV-RNA at TW12. Results: Safety analysis by independent Drug-Safety-Monitoring-Board (DSMB) determined that lower doses of boceprevir were less effective and resistance to boceprevir was increased in the absence of Ribavirin (R). Therefore DSMB recommended all patients who showed a viral response to boceprevir (HCV-RNA  lt 10.000IU) switch to P/R/B800 for an additional 24wks (n=143). Sustained virologic response (SVR) ranged from 2% (control) to 14% but no patients were treated initially, or for >24wks, with P/R/B800. Early response to therapy (HCV-RNA Undetectable  lt 5wks) and viral negativity for >36 wks were major factors determining SVR. End of therapy (EOT) response rates ranged from 6%-32%, being higher in the P/R/B400 and P/B800 groups and highest in control patients who had boceprevir added to their regimen [14/34 (32%)]. Response to the addition of boceprevir was evaluated in the control arm based on P/R response at TW12; all 4 patients with a >2 log10 decrease at TW12 had undetectable HCV-RNA on P/R/B, compared to 50% with a 1-2 log10 decrease, and 20% of those with  lt 1 log10 decrease. Boceprevir resistant variants were detected in the majority of subjects not achieving SVR. The safety of P/R/B800 was similar to that seen with P/R, except for incremental anemia (1-2 gm/dL) and nausea. No increase in skin disorders. Conclusions: Some  null  responders to P/R can achieve an SVR with P/R/B800 but response is dependent on residual interferon responsiveness. Treatment failures to P/R with  gt 2 log10 viral drop at TW12 may be good candidates for P/R/B800 therapy. Initial therapy with P/R, prior to the addition of boceprevir, provides additional benefit.

[willing]

yes, that w12 79% number is from the lead-in arm, 69% otherwise (vs 34% control).

Interesting point about the different rescue policy - this suggests the bc anemia discontinuations might be more severe than vx's - though in both cases the set of  anemia discontinuations seems very small (vx's 2% to bc 1%).

A looming question is how readily PI-based RVR stats in re-tx will translate to SVR - for non-responders rather than relapsers my hunch is not very closely. There actually already is some information about this in the schering study I referenced to willows above - but I'm too fuzzy-headed at the moment to make sense of it (crossovers in both the control and low bc groups? )  . Perhaps someone else can post a recap. Here's the full text

"Background and Aims: Boceprevir is a mechanism-based inhibitor of the HCV-NS3 protease. We studied the efficacy and safety of boceprevir and Peginterferon-alfa-2b (PEG-IFN-alfa-2b) in 357 genotype-1 �null� responders to peginterferon/ribavirin (P/R). Methods: All patients had documented <2log10 decrease in HCV-RNA after 12wks of P/R therapy or failure to achieve an undetectable HCV-RNA if treated more than 12 weeks. All patients received PEG-IFN-alfa-2b (1.5�g/kg/wk) plus boceprevir 100/200/400 or 800 mg po TID, or B400/R; the control was P/R/B placebo with cross-over to active boceprevir (400/800) at TW17 for detectable HCV-RNA at TW12. Results: Safety analysis by independent Drug-Safety-Monitoring-Board (DSMB) determined that lower doses of boceprevir were less effective and resistance to boceprevir was increased in the absence of Ribavirin (R). Therefore DSMB recommended all patients who showed a viral response to boceprevir (HCV-RNA 24wks, with P/R/B800. Early response to therapy (HCV-RNA Undetectable 36 wks were major factors determining SVR. End of therapy (EOT) response rates ranged from 6%-32%, being higher in the P/R/B400 and P/B800 groups and highest in control patients who had boceprevir added to their regimen [14/34 (32%)]. Response to the addition of boceprevir was evaluated in the control arm based on P/R response at TW12; all 4 patients with a >2 log10 decrease at TW12 had undetectable HCV-RNA on P/R/B, compared to 50% with a 1-2 log10 decrease, and 20% of those with 2 log10 viral drop at TW12 may be good candidates for P/R/B800 therapy. Initial therapy with P/R, prior to the addition of boceprevir, provides additional benefit."

[Andiamo1]

Does the comparison take the pre dosing of Boceprevir into consideration.  I believe they start Riba 4 weeks prior to the first dose of the PI.

The discontinuation results don't take into account that Vertex does not allow rescue drugs and Schering does.

I have no idea why the numbers only include 54 patients nor why there is a difference in distribution of patients that are difficult to cure.  There was nothing in the screening criteria that would have caused that.  I was enrolled in April and I was one of the first.  Some people failed the screening process or decided not to go ahead, so some additional people were added.  Not enough to justify the difference in numbers.

If we assume
      that the SOC statistics for SVR hold for the study patients in the prove trials.
      signicantly more patients from the treatment failure group achieved RVR
Then we can conclude that the naive patient body would also show the same incremental advantage over SOC since the 50% of the naive group that would fail SOC will be reduced by the same percentage is the prove 3 study of treatment failures.

Since we can't predict ahead of time who will fail, it pays to treat everyone with the PI.

[miked]

Like Andiomo1, I too was in the Prove 3 trial only 12 weeks triple tx followed by 12 weeks SOC.

Last week was my 24 week post tx PCR.

Today I learned that my blood chemistry came back with normal results across the board (ALT, SGT, Cholesterol, etc.).  The nurse commented on how good my labs were.

My PCR VL results are still out so I don't know yet if I continue to be UND...if so I'm considered cured.  If not I relapsed.

I'm obviously apprehensive.

Three years ago after 32 weeks of SOC tx , I experienced a viral breakthrough and was taken off tx.

Right now I'm a non-responder who will be extremely happy to hear that I'm UND after 24 weeks of stopping Prove 3.  By definition I would be considered cured.

I'll report back with my findings.

miked

[willing]

susieQ: the table in their abstract defines the various categories of previously-treated patients. It breaks down to 27 non-responders (in 3 sub groups per above above post) plus 1 breakthrough and 4 relapsers. BTW - I have no reason to believe this is hype - it just seems a very preliminary and selective release of information.

andiamo: it's worth comparing the vertex and schering submissions to the upcoming easl 5 each plus the above late-breaking poster (From
http://www.easl.ch/liver-meeting/program/search.asp
select "abstract body" and enter either boce/preva for search; for the poster you actually have to list them all and then search in that page).

The 12 week und rate for bc (sprint1 ) with the soc lead-in, at 79% ,seems very much in line with the corresponding vx (prove2) values of 73% and 79% for 24-week and 12-week dosing. However schering's data is based on a higher proportion of difficult to treat patients (16% black, 7% cirrhotic) to vx's (94% caucasian 7.5% F3). Discontinuation percentages also seem very close, both about 10%, but with rash as a factor only in vx. Also encouraging is that vx cut its relapse rate in half by going from 12 to 24 weeks - which is also the bc duration.  Overall, at 24 week duration, these two look very similar as one might expect given the similar mechanism.

As a study participant you may have more insight into this, but given that they announced full prove3 enrollment on June 12, with 360 patients plus 110 controls:
http://investors.vrtx.com/releasedetail.cfm?ReleaseID=248679
RVR data should have been available 4 weeks after start, say Oct. allowing July and August for enrolled patients to start. So now, in April, why are they only releasing data on 54, half of one arm?

willows: One of the easl schering studies also focused on the previously treated. It's small and a bit of a mess because they switched dosing half-way through but  on the plus side includes svr follow up  data. The conclusions suggest no silver bullet but  value in adding a  PI for re-tx, provided you show some level of ifn response.

"Boceprevir resistant variants were detected in the majority of subjects not achieving SVR. The safety of P/R/B800 was similar to that seen with P/R, except for incremental anemia (1-2 gm/dL) and nausea. No increase in skin disorders. Conclusions: Some null responders to P/R can achieve an SVR with P/R/B800 but response is dependent on residual interferon responsiveness. Treatment failures to P/R with >2 log10 viral drop at TW12 may be good candidates for P/R/B800 therapy. Initial therapy with P/R, prior to the addition of boceprevir, provides additional benefit."

[Andiamo1]

The fly in the ointment is that once the resistant variants are selected by tvr something has to kill them off - what? Maybe even sluggish ifn response is enough but this won't show up in the week 4 rvr data - have to wait for the svr stats, similarly for the 1 breakthrough and 4 relapsers.
------------------------------------------------------------------------------------------------------------------------------

One theory that is widely discussed is that the resistant variants are weakened virions and much more susceptible to SOC.

RVR means undetected by week 4, so what do you think is not included in the week 4 data.

By the way, I don't totally disagree with you; there is too much hype in all these releases.

[willing]

ok - maybe I'm  being grouchy, but there seems to be a bit of "irrational exuberance" here. The vertex 3/31 press release says nothing but points to the EASL abstracts. These are online already and the late-breaker poster by "Poordad, Shiffman.. etc" seems to be the relevant one (no direct URL is available,  you have to search the easl program for it)  Comparing it with the prove 3 study design filed with the fda:
http://clinicaltrials.gov/ct2/show/NCT00420784
indicates they are releasing week 4 data from comparing arm4 (12+12) with arm 1 (control). Some thoughts:

- the fda description calls for 110 in each arm, however the poster indicates "To date 54 subjects were enrolled". If they had full prove 3 enrollment by June 12, per their own release, why aren't they releasing data for all subjects?

- No mention of arm3 (24 tvr/p/r) why? again, if all 110 started by June this is known by now (perhaps "full enrollment" by last June did not mean everyone had started by then?).

- Among the 54, we have 27 non-responders (17 no 1log-by 1, 3 no 2-log-by-12 and 7 no und-by 24). By definition these are guys for whom IFN either had no effect or very slow effect. Are we surprised that an ns3 protease works in this group? This is a drug with a completely different and much more direct mechanism than ifn - there's every reason to expect it's equally effective in those who do and don't respond to  ifn. The fly in the ointment is that once the resistant variants are selected by tvr something has to kill them off - what? Maybe even sluggish ifn response is enough but this won't show up in the week 4 rvr data - have to wait for the svr stats, similarly for the 1 breakthrough and 4 relapsers.

- "To date 54 subjects were enrolled, 52 were dosed and 32 completed Week 4 assessment" - 20 patients over 24 weeks is a pretty significant loss. Where'd they go?

Personally, I'd love to see tvr approved as an adjunct for relapers (and remain skeptical of whether it'll help non-responders) - but can we really tell whether it's helping until more and more complete data coms in?

[moahunter]

yes, but if you were to die, that might be cheaper still for insurance (I remember reading once how smoking benefits societies because it kills people off before they get old, require pensions, and incur age related medical issues). In saying that, it is not so much a cost to the "insurance company" as to the "insured", I guess it just passes on, although if too much is approve, the insurance company premiums may become uncompetitive.

I can understand analysts discussing this, as the implications are enourmous in terms of market size. If the market is highly limited, that will also influence pricing, which may need to increase to generate a decent return on investment. Seems to me the true blockbuster would be to get a PI that will be accepted as SOC rather than for a smaller group, but that may be a harder sell.

[Andiamo1]

I don't know the answer to your question.  Some of the analysts are talking about that, but they love to hype things, so who knows.  I do think that for someone like myself  that has tried many times and failed and is rapidly progressing towards cirrhosis, insurance companies would rather pay for the drug than a liver transplant.  Altruism is wonderful isn't it?

Procrit is a drug approved for only chemo patients, but some insurance companies will include Riba.

[moahunter]

Do you think they can fast track for just one group? Once the drug is on the market, anyone doctor can use it for anyone (i.e. the genie is out of the bottle, if you will). In saying that, insurance companies typically will not fund a drug if it is classed as "experimental" or similar, so to this extent, I guess it could be approved just for non-responders. It is going to be interesting to see how the FDA handels these new drugs, and how long it will take, given all the concerns of late from approving drugs to fast.

[Andiamo1]

I am in the 48 week arm, so my numbers are not available yet.  I think early indications are that there is not going to be much difference between the two arms.  

My hope is that the FDA will now fast track the non-responder group.

Eric

[willows]

The numbers were absolutely delightful...something like 70% of previous non responders had null virus at 4 weeks compared to 10% of the control group.  As a non-responder who has been on HOLD by the doc waiting for Telaprevir, I'm pretty dam happy today.

As for the stock...it has traded about 13 million shares already compared to an average of 2 mil a day and is up about $5.00.  The movement of the stock has always been secondary for me, but today...I have the best of both worlds...good news on both fronts.  

By the way, are your numbers included in the abstract?  Are you one of the wonderful folks who worked hard at the trials and may have helped me take one more baby step towards SVR?  Either way, thanks for the post....today is a good day.

Willow

[Andiamo1]

The stock is roaring today: up 25% so far.