News on the Tarvacin Trials

[Florida wife]

In September I posted that my husband would start the Tarvacin trials this month. Actually, he was supposed to receive his med administration this past Monday. We went to his evaluation visit on 10/31. Unfortunately, some prior blood work indicated an elevated AFP (alpha feto protein), and he had a CT scan. The scan indicated a significant number of enlarged lymph nodes along his gastric vein. Under the Peregrin guidelines, he was disqualified until we could identify the problem. The concern was that he may have lymphoma. Thankfully a biospsy for cancer was negative and my husband has been placed back on the trial list for December.

Has anyone heard from anyone else in the Tarvacin trials? Positive results??

[couldn't think of a nickname]

Yes, Albuferon looks like it will eventually replace interferon, if thinks keep going as they have. That does tend to get overshadowed, but it might be better tolerated too, so that is no less important, especially if future therapy still includes a form of interferon.

[keepsmiling]

i tend to agree with you.  if goal is to get the best drugs out as soon as possible, then i will assume that the FDA is agreeing with their approach and has blessed it accordingly.  big waste of money and rather stupid if vertex was told no and they did it anyway.  i should mention that they did talk about alferon, mmpd, and nm283 as well during the call.  i am more excited about the PIs but didn't mean to leave out the others.

[couldn't think of a nickname]

Thanks for the info, and for the call number, I will listen to it, no doubt.
Now, it seems like there is much debate over timeline, and how long it would take to cure, which is of great interest to all of us. As far as I know (and I don't know how far this is, but it is what is out in the public domain), 1 month tox studies are complete, and they are in the process of completing 3 month tox studies. They might not have longer term studies, we will see if they are needed. They have pointed out that SGP has done them, and had no issues, speaking in general to this type of approach (By the way, they call SGP's PI very good, they take the high road).

I guess there are different schools of thought on this, and maybe these docs don't agree, or have different data to back up their opinion that shorter trials won't work.
VRTX is using the rules that are in force today, to make assumptions about their therapy. It has been shown you need to treat for 3, maybe 4 times the amount of time it takes to go undetectable. Those who are undet. at 4 weeks, treat 12, those at 8 treat 24, those at 12, treat 48, etc.
My question is, if that is so at 8 and 4 weeks, why wouldn't that work for maybe 2 weeks? These same docs IMO would have said that shorter treatments were not possible a few years ago.

Point no. 2 is that we shouldn't assume anything, pro or con, regarding what the FDA wants. They won't say what they have talked to them about, only that they have had ongoing, frequent discussions with them. I would certainly hope, and find it harder to believe, that they would put this timeline out for public use unless they had some feedback from the FDA.

Guess what? this is all speculation right now anyway. If they show SVR, especially high SVR, with a 3 month combo, why would the FDA make them do it for a year? FDA evaluates things on their own merits, not because it takes something else 4 times as long. Also, there you might find an outcry for delaying a needed med to market.
It might turn out that everyone is wrong, or maybe either one is right. Makes for great debate, but there won't be an answer until the data is done.

All of the above, except for the treatment durations, represent my opinion only.

As far as riba goes, I don't see a place for it. Illogcial if 950 alone gets half undetectable in 2 weeks, while being dosed much less efficiently than going forward (2-3 times more active in blood with food). Didn't even need interferon for that.
Again, IMHO, but the fastest path to reg. is interferon and 950.

[keepsmiling]

listened to the discussion with dr.schiffman this morning.  he provided top-line assessment of the conference.  worth listening to  if you have time (888-286-8010, passcode is 14849219).  you have 2 weeks from today to listen.
key comments:  clearly 950 is the most potent.  thinks IFN will always be part of therapy, and due to role of RBV in preventing relapse, likely that it will be needed to achieve shorter duration of therapy.  regarding resistance issues, may be exaggerated as everyone is comparing PI usage in HIV patients (where IFN is not typically used) to our setting where it is... resistance showed up in BID model of 950, however dosing moving forward will be TID for the time being, so not that relevant.  he didn't buy into the regulatory path of 950.  believes that shorter trials (1 and 3 months) are being done because they don't have tox data to support longer trials like schering does, and perhaps they have a supply issue (remember that discussion?).  regardless, even if they use one and three month phase II studies, with no control arm as it sounds right now, he thinks they will have to do 48 week duration trial (phase III) to get approval.  might be able to leverage outcomes of phase II data if REALLY overwhelming, but he wouldn't bet on that.  as for pill burden, TID is going to be the way it is for now.  a caller implied that schering was going to have to do higher dose studies and that raises the question of why they used the dose that they did (tox problems or packaging issues with higher dose?)  1.5 - 2L drop compared to 950 drop of 3L along with 40% of pts who became undetectable vs no one on schering's drug at the doses they chose would appear to put 950 ahead of the game, but still very risky approach.
sorry so long.  thought i would write while it was still in my head.

[couldn't think of a nickname]

great job on the fundraising. I can be wrong, but it seems at this stage of development, I knew more about 950 than the CF compound.
I think when that compound gets in the clinic, we might hear a little more, but as with everything else, it comes down to the data.

p.s. it just occurred to me that they are probably closed-lipped because of the possible legal ramifications for all involved-not only for trial outcomes, but leaking word can affect the investment aspect, and could lead to trouble. This was a reason given by VRTX for announcing 950 data last May. They didn't want word to leak out, get distorted, etc. They wanted to control the news flow, and I think that is the right thing to do. It is too hard to undo a rumor.

[miked]

Thanks for your input about the CF compound.  We've raised over $500K for the Cystic Fibrosis Foundation and have good contacts but they are closed lipped about what's going on with Vertex...probably because it's so early.

[couldn't think of a nickname]

at this point, I do not know much more than what they said in their last earnings report, as it seems like there hasn't been as much said about this one. I have known for a while that the CF foundation was funding them for that, so maybe contacting them (or VRTX for that matter) might help. Since this is a preclinical compound, I wouldn't expect them to say much as it has miles ahead of it. I have heard them casually mention this over the last couple of years though. For a frame of reference, 950 has been in development for 11 years, and it took 10 years to get into the clinic. Hopefully the CF compound will be in the clinic next year.
I can give you an example on a different topic, and that is MS. The week after VRTX announced the data, BIIB (Biogen Idec) announced that they found the key enzyme responsible for destroying the myelin sheathing around the nerve that is the source of MS, and incredibly, found a way to reverse it. This was in a lab, not even in animals yet, and has huge hurdles ahead of it, but many feel it was an important finding. I called BIIB to gather info, as that could someday be a big deal. They really couldn't say much since it was early. That news probably got missed because VRTX was getting a lot of attention at that time, but it, too, was important. BIIB has had issues with their current MS drug, meanwhile, you don't hear reports on that positive news. Early stage stuff is so hard find.
I hope that they have something for both diseases. I will give them credit for this: They do seem to go after some of the tougher illnesses.

Keep: Thanks for your report from the conference. I, too, have always wondered if their expected treatment was too short, but they have had logical explanations for it. I can see the merits of their arguements, but only time will tell. It is a fair question, but when it comes from a competitor, it does put it in a different light.
As far as registration path, they have said they have been having discussions with the FDA for a while now. I don't think they would be stupid enough to not do what the FDA would want. Talk about a negative stock reaction and lawsuit to boot if that did happen, I don't think they would risk that.
It is funny how the hurdles change, although they are all important. At first, phase 1 was seen as a big hurdle as BILN didn't get past that one. Now, it is on to the next hurdle, which is whether initial results can be built upon. If it is, and I think/hope it will, I will predict the next hurdle. That will be "what about geno 2 and 3, and what about a 6 month followup instead of 3?"

This is like an olympic hurdling event. Even though you clear one, there's another, but eventually, someone will reach the finish line.

For someone who said he wasn't going to post anymore, I sure became quite verbose.

[keepsmiling]

regarding your question about CF, from Vertex's press release last month,  "Vertex has identified a series of compounds that could act as “potentiators” –– compounds that directly increase the gating ability of the defective ion channel –– and “correctors” –– compounds that enhance the number of Cystic Fibrosis Transmembrane Regulator (CFTR) channels at the cell surface. Vertex expects to advance a compound for CF into clinical development in 2006".  to my knowledge, 950 is not being developed for CF.

[keepsmiling]

thought you might find it interesting that dr. sulkowski (on the panel for the SCH presentation at the meeting last night) completely dissed vx950's regulatory path.  objectivity at its finest.  he mentioned that their plan to do 1 and 3 month trials for phase II is unlikely to be successful given standard path of 24-48 weeks.  one other person DID make the point that the plan of having no control arm (if that is what they do) is not an issue really because the data w/IFN and RBV is known anyway.  i did ask about pill burden -  answer was that due to the motivation of patients, they don't see it as an issue, and that the size is "quite reasonable".  back later.

[miked]

Thanks again for all of your data about VX-950.

I have another Vertex question for you...what do you know about Vertex's compound for Cystic Fibrosis(CF)?  My son has CF.  The Cystic Fibrosis Foundation(CFF) is funding Vertex for R&D because of their expertise with small molecule drug development; they claim to have a drug in trials in the 2006 timeframe.  

I haven't missed the irony that the same company may save both of our lives.

Mike.

[keepsmiling]

also - thank you also for listing the abstracts in one of your previous notes...

[couldn't think of a nickname]

I get the impression that they are doing 1 riba arm based on recommendations from the medical community. I really hope they don't need it, and I think they don't expect it to be part of the future of treatment including their drug.
On the CC there were many questions about the viral variants, and it did seem at times that those asking needed to be reminded it was in dose groups that will not likely be used in future trials. It goes back to the popular thought, that if you knock it out fast enough, it isn't an issue.

[jmjm530]

They are definitely covering their bases, including with the medical community, which makes sense since they are a public company.

It was interesting to note the very low standard needed for what I believed was FDA approval --  which is for Vertex to work as well non-pegalayted interferon.

So, on one hand, they are forging ahead with almost mystical (but realistic) expectations of a 1-3 Hep C knock-out punch with almost no side effects (WOW) but at the same time they're not ruling out using Vertex in some lesser,  companion capacity should the trial data come out differently. That's partly why they keep hedging their expectations. But with SVR data coming out early next year, the wait for results really isn't that long.

-- Jim

[jmjm530]

First sentence, third paragraph should have read:

"...of a 1-3 *month* Hep C knock-out punch..."

[rudy222]

The Idenix  NM283 Phase IIb trial is exclusively for Genotype 1 non-responders.  

rudy

[GoofyDad]

Another thing I think I heard in the variant discussion was that they attributed the build-up of variants as simply some variants stacking up because they weren't being killed off as quickly. This was found in the sub-optimally dosed 'Plateau' group and was attibuted to lower vx-950 sensitivety in certain variant strains. I don't think I heard them say tx was spawns any increases in variant production or viral mutation - but I should listen again - next time while I'm awake.

[keepsmiling]

i wish they would have said a bit more about the pill burden in the vertex Q/A... i found two pictures of the pill.  one looks like the size of a tylenol, and the other looks quite a bit larger - like a rounded TMP/Sulfa tablet which are BIG.  taking 15 or so of those a day along with everything else would not be fun.

[GoofyDad]

Something that I thought was obvious in its absence in the analysts questions was what could happen to derail the drug? What are the unknowns that have yet to be cleared? Obviously it could be no-SVR or viral rebound, health issues such as heart or kidney probs, or the growth of big purple elephants on patients foreheads. Some of these are more likely outcomes than others. Which of these are things VX is concerned about and why?

[keepsmiling]

if i were guessing, it sounds like a 150mg pill.  makes for easier dose titration.  unlikely that it is 750mg.  i have heard 9-18 pills per day in the study.  if in the  750mg tid arm, looking at 5 pills tid.  i am at the conference and maybe someone will shed some light..... vx seems more willing to share than others.

[couldn't think of a nickname]

I am not too sure about that, I would like them to address it. I do know it has a 75% drug load which is very high, which should mean smaller/fewer pills to get dosage. Looking at the tylenol 500 mg gel caps, they are about the size that the pill looked on the slides. It is quite possible that the pills are 375 mgs.

I would rather not speculate but wait for hard facts on this. Also, it would be in their best interest to do it in as few pills as possible. The therapy cost as they say has been established, and to fit into to similar pricing, fewer pills should equal larger margin.

[GoofyDad]

Sandi - Thanks again for your thoughts. One more thing to consider is that there are proabable differences between the mechanisms that cause breakthroughs and those that cause relapses in short term tx'ers. I'm not sure it's applicable to apply the theory behind quasispecies-mutation tiggered breakthroughs to relaspses in short term tx'ers. Just my opinion, of course. Hope your having a good weekend.  


Mind saying how you changed the protocol after your breakthrough? I'm sure you posted it before, but I miss things and get befuddled.
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CTOAN - Thanks for your insights.

[jmjm530]

Important to reinterate that the variant virus only showed up in the monotherapy sub-optimal dosing group, and therefore not believed to be a factor moving forward, as higher doses were tolerated almost as well as the placebo group with very minor sides. A new formulation is also in the works using an oral tablet to be taken with food to increase Vertex absorbtion.  Also, later in the conference call, it was suggested that in the combo therapy trials (Vertex and Peg) variants would be a non-issue becase of the action of the Peg.

It appears that the SVR data we're all looking for will be available early next year, probably on a 12-week tx course using the optimal dose of Vertex and Peg.

Later, will follow Vertex monotherapy data. Later still, the possiblity of triple therapy using ribavirin, but I'm guessing they only have this on the back burner in case they don't get the SVR numbers they're looking for with either dual or monotherapy.

Lastly, talk of a protease "cocktail" using other protease inhibitors, still unexplored and therefore unnamed. Very exciting stuff going on. A lot of people are keeping their fingers crossed.

-- Jim

-- Jim

[GoofyDad]

Setting aside the pill size,  listening to the webcast last night I wondered about compliance on 3x/day with food regime. Getting decent food down at 8 hour intervals is going to challenge some folks. That's a meal at 10PM, 6AM, and 2PM - or 8-4-12 - (hmmm that's Dr Pepper time). I mean, it's a small price to pay for SVR, but still, I would expect to see a lot of late dosing with that regime.

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Another thought on the viral variant issue we discused earlier - I think I heard them say this variant spawning activity is normal in replicating viruses, and not unique to HCV or treatment.

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CTOAN - I think you maybe covered this before - but let's say FDA approval were to come tomorrow. The stock should shoot up, I would think. What risks are removed by FDA approval that creates the boost in stock price - or it simply a matter of shortened time to a meaningful revenue stream?

[couldn't think of a nickname]

There is an article that is extremely bullish on VRTX because of 950 in today's Barrons, page 37.
That aside, as far as sides go, I think this has seen more detailed analysis than many other drug candidates so far, for such an early stage. Here is why I think that:
1. toxicology studies on multiple animal species before testing in humans, at various doses, and lengths of time. 3 month tox study is being done as we speak. Others do tox studies too, so they are not the only ones.

2. 2 different cardiac studies done on all patients in the original trial, no one in the trials had any changes at all, and they were detailed studies. This was apparently done because of BILN 2061, and remember, that lead scientist is now employed by VRTX.

3. Viral variant studies so far are unprecedented as far as study goes. They stated that to their knowledge, no one has studied this issue like they have. As a side note, the drug did diminish the effectiveness of the variants which as has been noted, only occurred in the suboptimal dose groups. The best dose group did not have an issue with this. They also found that 1 variant did not result in viral rebound or replication.

4. VRTX has stated in the past that Phase I is the toughest stage to pass with anti-virals in most cases. Look at VPHM. Some speculate the stock crashed because there will soon be a generic to their successful antibiotic. I think it coincided with phase I data that was not that impressive. Polymerase inhibitors are not as potent as protease inhibitors.

The risks are, SVR of course, and longer duration side effect profiles.

I think the SVR will come because if it can drive it down to nothing so fast, there isn't much reason to think it can't do SVR like the current therapy does, and current therapy is much slower working. I think that a much larger percentage of people will be SVR than current therapy, but now, studies have to show this.

As far as the side effect profile, fortunately, this drug should not be taken long at all, which helps. But, so far, we have seen only 2 weeks worth of side effect profiles. To play devil's advocate with myself here, current treatments have their sides show up by that point and time anyway, and in some cases, get worse. It is encouraging that the most common side was headache, and I think it was the same incidence rate as placebo. I think fever should be common in ANYONE taking medicine for this, at it would show our immune systems to be actively eliminating the virus, and I would expect that in the first few days. I have not seen this mentioned though.

I never liked taking any medication my whole life, because I felt it wasn't natural to my body. I have only taken them when I needed it, and sometimes, I should have taken antibiotics, decongestants, etc. sooner. When one has a headache, it isn't due to a lack of aspirin in one's system. It seems like there is always a trade off for the medicines we take, the key is to make it a small one.

They have said, and I agree, that phase II would be the phase that can reduce much of risk in the drug (and company), and we will start to see some early phase II data I believe, in the second quarter of next year.