Vertex down 15%

[Upbeat]

Oh my

Just noticed that Vertex stock is down over 5 bucks a share. Over 15%.  I wonder who knows what. I don't own the stock but I hope its not a bad omen for the meeting.

                                                                                                                                        Ron

[Willy50]

I've seen that resistant mutations may also be a problem for Boceprevir too but that's not much of a stretch.  That Darn Virus (that sounds like it could be a fun movie title) seems to mutate around everything.  

I based my theory that they may be too similar to be synergistic based on they are both PI's and share other similarities. They may be like Peg-Intron and Pegasys; similar but not quite the same.  This is one area that I'll just say no clue.  (They both end with "previr" too.  : ))

On the other hand..... There is at least one presentation at the AASLD (but you probably already knew that) which could shed some light on the topic.  I'd guess both companies know or have theories.

On the back side of the other hand...... if Vertex knows something that could help their "comrade in arms"....SGP, I wonder if they would post a paper on it.  They may already figure they've done some heavy lifting for their competitor.  It kind of reminds me of drafting in a bike race.  If Schering watches Vertex they can save themselves some money and learn from the mistakes or discoveries illuminated by the Vertex trials.  I mean, I wonder if the Vertex no-ribiviren arm had been more successful would have SGP had a variation on the same theme?

Getting back to the crazy issue....maybe this is the wrong thread for it but what happens if the Vertex prior treatment failure trial (also known as Prove 3) comes close to the results of Prove 1 and 2?  I don't understand (yet) why the naives seemed to do so well in the Boceprevir trial and the treatment failures trial seem to have a poor response rate.  So far the Vertex Prove 3 participants seem to be attaining an RVR and maintaining that status till treatment end.  I wonder where the failures in the Boceprevir trial occur?

Oh yeah....tying that thought to the title of the thread....... what would success with Prove 3 spell for the stock price?  Likewise....do we look to the poor results of the Boceprevir harder to treat group as what we can expect of Telaprevir Prove 3 results?  (I suppose that may deserve a different thread and may soon be answered by the Prove 3 results as they roll in.  They are sure looking good so far.)

Willy

[jmjm530]

This thead certainly has its share of willpower.

[willing]

>They may be too similar to have a synergistic effect if combined (or staggered in treatment)

I'm curious whether you've seen anything indicating this is the case. Escape mutations for  950  seem pretty well characterized "Mutations have been identified in the NS3 protease gene at positions 36, 54, 155 and 156 conferring resistance to TVR in vitro and in vivo" from aasld'07 abs 50.  but I haven't seen anything comparable for 503034. If different  mutations at different amino acids are involved, I would think the virus would have to develop both to obtain a viable NS3 protein. Given that its search  is basically limited by the error rate of the viral polymerase and the amount of replication, I'd expect these to be additive.

(also there's some promising information on r1626 mutations in abs 1298)

[Willy50]

several points;
1)  It's really to soon to be able to make real comparisons between the two compounds.  Schering-Plough has released very little information and based on the seeking alpha article they may continue to release very little.  
The early Phase 2 trial comparisons are different design so as to make comparisons to the two compounds difficult.
The current trial designs are also different so as to make comparisons difficult.  How did they compute the numbers offered?  Was it based on the initial first doing of SOC or the first initial dosing of Boceprevir?  One would assume that it was from the first dose of any drug.  From the design data offered it's also hard to grasp exactly how the participants tapered into treatment.  The data seems to be a teaser or even a spoiler dropped right before EASL.

Whereas the trial design make it hard to compare these drugs we almost can't escape the end point data.  As surely as there was a start date there will be an end of trial response rate and SVR12 and SVR 24  data.  I believe that some people are just ending the Boceprevir Triple dosing stage now and may continue for another 24 weeks of SOC.  If so....the SVR data is a ways off

2) In spite of the news bombshell that was dropped there is so far very little information that is offered or will be offered.  There seems to be conflicting information out there about both compounds.
Vertex is allowing that while the rash issue affected larger numbers of people who treated they seem to be downgrading the seriousness of it that leads to discontinuation.
We will see response rates, discontinuation rates and SVR rates discussed at the AASLD as well as data and theory on mutations and perhaps even discussion which may foreshadow Phase 3 trial design.  

So far as Boceprevir we are fortunate to have another lead compound advance. Like Vertex, this one may not be perfect either but the are showing comparable 12 week response rates.

They also seem to have issues with resistant varients.

They also have issues with troublesome side effects and have drop outs in the most responsive arms in the teens in spite of the fact that the participants were allowed rescue drugs.  Thankfully there does not seem to be a rash issue.

It remains to be seen which compound is better.  The trial designs may continue to stymie efforts to compare the two drugs.  

The bottom line is that suddenly and thankfully we have 2 potentially great new drugs that seem to be advancing successfully thru trials.  They may be too similar to have a synergystic effect if combined (or staggered in treatment) but there could even be that potential down the road.  At the minimum we have 2 likely contenders for FDA approval (cross your fingers).

MREmeet suggested that all companies following in the wake of these developments also benefit from the scientific advances that are made during these trials.  (It may be a reason that SGP passed on a no-ribiviren arm)  Vertex's successes will also benefit the Schering research and vica versa.  The gap is being closed every week on finding a better cure.  It's pretty exciting and encouraging news.

best,
Willy

[willows]

I read another take on Scherings approach to dosing with boceprevir today.  Since Schering has MAJOR money tied up in Peg-Intron, if they dose up front with 12 to 24 weeks of their own SOC, they are still guaranteed the revenue stream from those meds.  My info came from an e-mail from my doc and his take was.....They may be stressing the reduction of viral mutations to PI's by pre dosing, but they are also setting up the perfect conditions for mutations against IFN.   And exposing all of us to a longer duration of SOC.  Having a few lingering issues myself from IFN that have not resolved after two years, well, I understand Doc's trepidation.  

I may be shot as the messenger bringing only the negative news, but if you read the conference call of Schering today, they were asked SPECIFICALLY twice about EVR and RVR and dodged the question both times.  This is a company that specifically avoided including African-Americans in their first trials until they got spanked.  Then they expanded and included those folks, but not until they were forced too.  I will be labeled as sooo pro Vertex that it has clouded my judgement, but I'm not really caring too much about that.  

After reading and researching for three days now, i do not believe we are getting the portions of the information we need to make a good decision about boceprevir and the patient in me wishes that our second generation PI was coming from a company with a better track record than Schering with it's Peg Intron bias.  But, like the rest of us, I will take my PI's and my tx and, with the help of the gods, my SVR from where ever I can get it.

So I'm a bit negative....I read something today I really loved...."There's a small chance I may be going to hell."  I like it, makes it easier to post and advocate information and an attitude that I know may be unpopular here.  My bias is showing, but I also hope my reading and research and due diligence is coming thru here too.  Drop SCH503034 into google and read some of the information out there.  Interesting.

[mremeet]

"It begs a trial both ways to see which way the virrii die off faster but it makes some sense."

Looks like they've already trialed both groups (i.e. 24 and 28 wk) side by side. And this guy's enthusiam and somewhat measured-coy talk suggests he already thinks this strategy has merit to it. And he already has a buttload of data in his grubby little hands right now too, so that makes his comments especially interesting. As to which way the "virii die off faster", I'm sure the initial viral decline is much faster with triple therapy administered concurrently when compared to SOC only and then the PI introduced a month later (for obvious reasons). The real questions are, how completely does this strategy expunge the remaining virus? Does it really help to prevent the rise of PI resistant variants? Will it be able to shorten treatment times beyond even what triple therapy suggests so far? Will it lower overall side effect profiles (including the relief provided by a possibly shortened treatment time) and thereby enhance adherance rates? And of course, will it improve overall net SVR rates?

"IF this is an effective method what will happen when Vertex does this?"

If it works for boceprevir, I see no reason whatsoever why it wouldn't work for telaprevir either. PI's have similar modes of efficacy and to my knowledge the general mechanism under which PI resistant mutants are evolved are the same with most or all protease inhibitors (certainly their monotherapy results share very similar rebound profiles).


"I'd guess that Vertex was aware of this idea and so who is right?"

I wouldn't be certain they were aware of it at the beginning of their phase IIb testing (although I'm sure they do now). Vertex is a little ahead of SP, and it's also probable that Schering learned of how resistant strains were being produced in some of the Vertex trial participants and therefore formulated this strategy as a possible way to nip it in the bud. Either way, it'll be damned interesting to hear more on this. This could be a simple tweak in treatment that may offer big benefits, especially for those who need those benefits most.

[Willy50]

"(1)You had [hit] the prime immune system and we think that priming helps decrease the viral load, and that we think is important. Also (2) based on our learnings because we would like to be able think this would result in a fewer mutations in that particular population, which is an important clinical parameter.

It's an interesting idea.  It begs a trial both ways to see which way the virrii die off faster but it makes some sense.

If the earlier efficacy tests on Boceprevir showed that it was less effective maybe the structure of the trial provided the great results.  IF this is an effective method what will happen when Vertex does this?  Does anyone recall that Alinia also did the same thing?  I'd guess that Vertex was aware of this idea and so who is right?

Anyway..... 2 very interesting concepts.  We've discussed predosing before here with ribiviren so the idea isn't new but it's interesting to see the application with PI's.

The second part....with the mutant variants also makes some sense but we'll see how it shakes out.  If this method is a more effective means of providing efficacy or reducing the resistant varients perhaps it might also be tried in the Phase 3 Vertex trials.

Thanks for posting the link Jasper.  The link had several other references in it.  One lead me to think that they weren't going to discuss the results much at the AASLD maybe not till year end or early 2008.

Willy

[geterdone]

I was also re-reading the abstracts of the prove I and II of vertex and there is no mention of them pre dosing with PR before introducing the Telaprevir into the mix at week 4 but then again the whole report is not out yet. Now, if SP introduces this in there up coming Phase III trials it will be interesting to see the results but I don’t think we’ll see this until 08 or 09. Sorry for not being long in the word department to explain fully but I’m still treating, LOL!

jasper

[mremeet]

Thanks for geterndun on posting that excellent link geterdon. That's really interesting to read about their unique dosing strategy, I was sort of wondering why they had that quasi-odd 28 week group in the mix. I can see now what they were thinking and it sounds like an excellent idea. Preload the IFN and riba without dosing the protease inhibitor for a month. This gets the patient fully juiced and equilibriated on SOC, IFN and riba are stabilized at optimum levels first. The viral load in all likelihood will decline significantly (probably a log or 2 or more), and when the PI is finally introduced 4 weeks later, it'll be a case of instant synergy between all three drugs. An antiviral shock and awe if there ever was one. And that pharmaceutical trifecta hits just when the virus needs it least. Its breeding population is strongly eroded by then (maybe being less than a 100th of the starting VL), so its much less likely to come up with PI resistant mutants and it'll have a lot less time to do so. I imagine the lights would go out for the virus very quickly at that point. It's like spraying the virus with gasoline while hitting it with a million baseball bats. Only after the spraying is finished, a match is introduced - meanwhile the baseball batting continues. I like it, I can see the wisdom here and it sounds good.

Normally when the IFN and riba and a PI are introduced the PI does most of the eradication in the first few days/weeks. Only later do the other drugs really start to build up and activate the body's referred immune responses. But that takes time, and in that time the virus is more likely to be able to come up with PI resistant mutants. This might especially be the case for people with high VL's or relatively sluggish responses to SOC drugs. But this SOC preloading strategy largely circumvents that problem. Not sure this strategy is really necessary for those with a low starting VL (as evidenced by pln going UND on VX+SOC in 4 days flat) and generally success was observed in nearly all of us with the concurrent start of SOC+VX. But still this staged/delayed introduction of the PI sounds very good. Normally we think the faster the initial viral decline the better, but this unique tack has me re-thinking that. Also, I'd imagine this strategy may end up more reliably shortening the course of treatment as well. If this strategy does work for the reasons speculated, it may truly truncate the treatment to something less than what appears to be the new emerging PI+SOC standard of 24 weeks for geno 1 (without going into individualized treatment assessments for the moment). Anyway, thanks again for the link geter, cool schtuff.

[geterdone]

http://seekingalpha.com/article/50797-schering-plough-q3-2007-earnings-call-transcript

Schering-Plough  Boceprevir

Tom Koestler
Yeah, John, as far as you know, we have this naive patient trial which is ongoing. We are looking at 24, 28, and 48, weeks of dosing. So, the Phase II trial that we have reported on, reported on 12 weeks of exposure to the program. Now we have a fast track status with FDA and as you can imagine we have got everything. We do just about right with FDA in terms of plans for going forward. But right now I think it's fair to assume that we are feeling pretty confident about the design of our run-in phase, which is the utilized interferon plus [Ribavirin] for four weeks, before dosing with a protease inhibitor. There is couple of reasons for that. First reason is that it takes four weeks to get the study state with these molecules, which is important.

You had [hit] the prime immune system and we think that priming helps decrease the viral load, and that we think is important. Also based on our learnings because we would like to be able think this would result in a fewer mutations in that particular population, which is an important clinical parameter.
John Boris - Bear Stearns
When will you start Phase III, Tom?

Tom Koestler
Okay. So…
Fred Hassan
Right now, we are not going to comment on that at this point in time. As I said, we are still on Phase II and when we are prepared to initiate Phase III we will let you know. Thank you,

[Willy50]

You are right and thanks.  I "misspoke".  I think the data should have all been expressed as EVR and NOT RVR.  One reason that the stock dropped was that in one Boceprevir study the 12 week results were 79% EVR.  I believe that the Prove 1's best arm result was 70% EVR and in the Prove 2 it was 79%.

In other words they seem to have comparable EVR results.  

In Prove 1 the triple therapy arm achieved a 79% RVR but by week 12 it had eroded to 70%.  I'm not sure if that would be due to breakthrus or discontinuations.  It wouldn't surprise me if the basic pattern were similar for Boceprevir but it may not be.

Thanks for the post. I was wrong using RVR where EVR should have been used.  This is one area where the two trials can be compared.  The SVR rate will be one of real tests.  The dropout rate, the side effects, and the treatable symptoms will also be factors in the marketability of both compounds.

Presumably we'll have much more data at the AASLD.

best,
Willy

[Proactive]

I really can't speak for others, but my opinion of statements pulled out of ones arse "And the reason they didn't reveal RVR data must be it is really ugly." they really aren't worth the paper it takes to clean up the mess....

[abby105]

there are lots of misunderstanding here. Schering didn't provide RVR data, which means patients achieved undetectable in 4 weeks and kept it till 12 weeks. That's a huge difference between EVR, which means achieved undetectable within 12 weeks. 50-60% EVR can actually achieve SVR, but 90% RVR can achieve SVR. Undetectable means <10IU/ml. Schering has more cash than Vertex, so budget shouldn't be the reason they choose looser standard. And the reason they didn't reveal RVR data must be it is really ugly.

[susan400]

That doesn't matter to me that they use Peg-Intron because I actually had a better response rate with  Peg-Intron than I ever did with the Pegasys-even though the sides were a little bit harder between the 2, given a choice, I'll take the rougher sides of Peg-Intron for the better response rate (in my body).  Granted, on paper and in other people's experience-the Pegasys might have more documents supporting Pegasys - I have no idea....I'm sure that there's some piece of paper somewhere saying the Pegasys works better---I haven't even bothered to look into it, I just know that in my body Peg-Intron had a better viral load response than the Pegasys.    Susan

[JOHNWS]

Great information and thanks to everyone that inputed. I agree with Susan who cares about stock price as long as these compounds work and cures all of us of this evil disease. I know it is hard to compare the two, the reason I was asking was obviously Vertex has released alot more information than SCH has. Does anyone know the difference between a serine protease inhibitor which is the SCH drug and the Vertex drug which is a different protease inhibitor. I asked the research nurse why peg intron and not pegasys she said SCH does not allow pegasys in its trial because it is made by a rival company.

[nygirl7]

The more trials the merrier is my opinion.  Welcome to John and his new information right?  It's all neither here nor there as long as they are working on finding cures for heppers. The rest, all moot and FUN to discuss and compare!

[Willy50]

They are both  protease-inhibitors, they work on the same concept.
They are both in Phase 2 trials
The response rate is not only similar, but identical ( 79% RVR'ed in both trials; I'm using Prove 2)
We have members from both trials, I think comparison is natural.
John had a theoretical treatment question and MREmeet tried to respond while couching it in that it was  from general data.  By the time there is "fact" Johns treatment will have long ended.

I just tried to buffer the information.  We don't really know.  I agree that it's too soon to draw conclusions but perhaps not to make comparisons.  I pointed out yesterday in several posts that the trials were different and so we couldn't/shouldn't really compare them and I also did so somewhat in my last post.

best,
Willy

[nygirl7]

Amen sister a voice of reason!  As long as they are investigating other drugs in addition to Vx which just might not pan out - things are good.  It is NOT a one size fits all world - unfortunately there might be several options required for different folks.

[susan400]

It doesn't really matter to me at all what happens with the stock with either one of these drugs, as I'm not invested in either of them.  What does matter to me is that there are new drugs being developed that may be a potential treatment for me down the road, that may actually work and that may actually not give me the huge rash that the VX did and that also (as a bonus), may allow rescue drugs.  I don't even care if they pay for the rescue drugs-as long as they will allow me to take them if I need them.   Susan

[Proactive]

How on earth can anyone make a comparison between Telaprevir and Boceprevir? One simply doesn't have the data, seems like a waste of time to even attempt it.

[Willy50]

By the way......the data we have on Telaprevir suggests that what MREmeet is saying has some basis.  I'd say it's right on except that it hasn't been officially validated as of yet but that it may be reinforced further at the AASLD.  We are probably more likely to shoot from the hip about our takes on these things.  Scientists may not officially confirm such things for years.  I still feel that it's sound advice or a reasonable "take" on your status given the amount of information floating around

My assumption is that we may see a relationship between the current lead PI's (Telaprevir and Boceprevir) that may mimic the relationship between Peg-Intron and Pegasys; not identical but very similar.  Extending that relationship further we may even see them design trials so that the results are not easily compared.  If the differences are obvious that might be one thing but if they are closely similar in performance neither one may wish to be decisively proven to be inferior to the other.  Both know that there's plenty of business out there for them without having proof that they are #1 or #2.  For this reason we may actually not see clear comparisons.  (Has anyone wondered what the outcomes would have been in the Boceprevir trial with Pegasys?-that trial may be a ways off. : ))

If the two compounds are similar and you can compare the results of the Prove trials to the Boceprevir trials you may indeed be "out of the woods".  

On the other hand.....the early trials of Boceprevir showed less viral efficacy than Vertex's compound.  IF it were so..... you may need a longer triple therapy treat time or followup with SOC to better assure oneself of an SVR.  The data to support a conclusion really is barely out there yet for Vertex.  I'd be even more cautious about reaching one about Boceprevir treatments.  It might be better to be safe (in overtreating a little) than sorry.

best,
Willy

[mikesimon]

Jim meant that - in the future I will try and stick to "topics"  at hand and not "tropics" at hand. I personally would prefer the tropics but that's just me. Mike

[jmjm530]

Mre: And as far as paranoia and seeing "things where they aren't"
------------------
Yes, indeed, I could have worded that a lot better, and have often wished for an "edit" function here. I do apologize because it came out wrong. Just trying to make John more comfortable, not you uncomfortable and your points about not knowing who people are here are well taken.

And as far as "following someone around"  or characterizing what people say -- frankly, I took offense when you did just that the other day when you said to me

"...Not trying to put you in the hot seat, but frankly I do think you sometimes intimate an overly blase "ohh it's not so serious" vibe when discussing a possible plan of action when it comes to people with advanced fibrosis (i.e F3)..."

That doesn't mean it's right for me to do the same or similar. In the future I will try and stick to tropics at hand, and not the person behind the topic, and I truly hope you do the same.


-- Jim

[mremeet]

Yep, considering your fabulous early viral clearance, based on what we now know about telaprevir's ability to deliver SVR's with as little as 4 weeks of treatment, I'd guess it's more than likely you've been SVR for months now.