Bad news re Vertex's Telaprevir (and all the PIs)

[mike716]

[A friend just sent me this rather discouraging news article from yesterday, on Telaprevir. I think it's still up in the air whether the PIs will be approved, because of this issue with it.

Vertex's Experimental Telaprevir Resisted by Some Strains of Hepatitis C
By Rob Waters - May 05, 2010

Vertex Pharmaceuticals Inc.’s experimental hepatitis C treatment knocks out so much of the rapidly mutating virus it lets drug-resistant strains grow instead, requiring multidrug cocktails to defeat it, a study said.

In patients infected by a common strain of the hepatitis C virus, as many as 20 percent of viral particles became resistant to Vertex’s telaprevir within two days of taking it, according to researchers at Los Alamos National Laboratory in New Mexico. They used patient data from clinical trials of the drug to create a mathematical model based on the number of virus mutations found during treatment.

Doctors and drugmakers are searching for new hepatitis C treatments because the standard two-drug therapy works in only half of patients and causes side effects that are hard for many to tolerate. The study published today suggests those current medicines still will be needed given the degree of resistance to telaprevir.

“That’s the most rapid drug resistance for any agent that’s ever been observed,” said Alan Perelson, a Los Alamos scientist and the senior author of the study published today in the journal Science Translational Medicine.

About 170 million people, 3 percent of the world population, are infected with hepatitis C, according to the World Health Organization. The liver disease, spread by contact with infected blood, develops slowly, scarring livers over years or decades and may lead to liver cancer and require a transplant.

Two-Drug Combination

Many people don’t know they’re infected and aren’t getting treatment. Among those who are, most take a two-drug combination of the generic antiviral pill ribavirin and alpha interferon, sold under the brand name Pegasys by Swiss drugmaker Roche Holding AG and as Pegintron by Whitehouse Station, New Jersey- based Merck & Co.

The two drugs fortify the immune system, helping it clear the virus from the patient’s blood, and generate about $2 billion a year in sales. They also can cause protracted flu-like symptoms and trigger anemia.

Telaprevir, from Cambridge, Massachusetts-based Vertex and its partner, Johnson & Johnson of New Brunswick, New Jersey, is racing against another experimental drug, boceprevir from Merck, to become the first new hepatitis C treatment approved in a decade. Both are so-called protease inhibitors, similar to drugs used against the AIDS virus HIV, that block an enzyme that viruses use to copy themselves.

1 Trillion Particles

Hepatitis C copies itself so quickly that the typical patient makes about 1 trillion viral particles a day, Perelson said. With each new copy, there’s a chance of a genetic mutation and some of these mutations make the virus resistant to drugs.

“You’re making so much virus that it is literally a certainty” that every letter of genetic code will be changed at least once in the course of a day, Perelson said.

When patients take telaprevir, it kills off the normal, unmutated viral particles. The few mutants that are resistant grow in number and become increasingly hard to kill, Perelson said in a telephone interview.

The findings are consistent with what Vertex has learned from its clinical trials, said Robert Kauffman, the company’s chief medical officer.

Cocktail Solution

“For all direct-acting antivirals against hepatitis C, resistance is likely to develop fairly quickly,” Kauffman said in a telephone interview yesterday. “The solution to that problem is a cocktail.”

Vertex fell 92 cents, or 2.4 percent, to $37.55 at 4 p.m. in Nasdaq Stock Market composite trading. The shares have fallen 12.4 percent this year.

For now, any drug combination, or cocktail, will need to include interferon and ribavirin and the side effects they cause, Perelson said. If the Vertex or Merck drugs are approved next year and become part of a patient’s cocktail, as company executives predict, it may reduce treatment time to six months from a year.

Treatment that avoids the current regimen may still be some years away, Kauffman said. Vertex this month began a trial of telaprevir with an experimental drug called VX-222, a different type of antiviral, to see if the two drugs can defeat the virus.

To contact the reporter on this story: Rob Waters in San Francisco at ***@****.

[mike716]

Since in my last blood test my hep enzymes were down to normal range, I'm in a denial phase at the moment. It's sorta like the manic phase of a manic-depressive complex: I can feel the return of fear and loathing  as I get into position for the the second round of the biopsy-or-not-to-biopsy derby approaching.

M.

[mike716]

What telaprevir trial were you in?

[gypsyjoey]

In the spirit of Keep it Simple Stupid (K.I.S.S.)

I treated twice previously with Interferon & Riba without success.

I treated for 7-months with Telapravir added to those drugs and am still clear 10-months post treatment.

That is all I have to know.

Joey

[merryBe]

Do not let yourself be tainted with a barren skepticism. (Pasteur)

There's a lot of reason to suspect that down the road therapies will be far more effective and less toxic. Every week I see some news on what sugars, and fats and proteins all do to this virus...and which herbs interrupt transcription or some other phase of viral replication. That's the good news.

The other issue is that at your stage you really don't have that much time. The same thing Trish and I are facing is where you also are at. For my money the attempt to halt things would be to embrace the triple therapy horns and all...if not to go the preventative route full bore.
Personally I'm planning on doing both.  The real issue here is time....
beyond that, preventative add up, but could buy one time to wait...maybe, but I think they need to be taken seriously and at correct dosages to really do that.

Check your messages.

[mike716]

Thanks for the comic relief, Rocker. I needed it .

Mike

[Rockerforlife]

Mike,take er easy man,I understand what your saying aboiut the mutation problem,but before this even does happen,this planet is going to hell anyway

[merryBe]

I think the bru-ha-ha over super strains is greatly exaggerated.

It's true, it is possible, of that we can be sure.

However it's also true that species have enormous adaptive potential and highly complex immune systems.

When you stop to think about it, mass extinctions are almost exclusively the result of the catestrophic events of the planet, floods, asteroids, etc.. The adapative nature of out immune systems and those of the smallest one cells creatures, allows us to write new code to our DNA as fast as any retrovirus can rewrite it's own.

I know it sounds absurd, but really, it's as if you have two software programmers sitting side by side...one writes a fatal bug, the other one writes the fix for it. As long as the QA guy does his job (code is viable) the patch will work.
When you get down to the molecular level that's what has always taken place, cells adapt, evolve if you will, by seeing where a weakness lies and rewriting a line of code.

It's rather impossible for us to comprehend the complexity of all this, as each little strand of DNA contains 3 billion lines of code....our cells all have it, and the virus does as well. Bottom line is the human being has been effectively fighting unseen enemies of immense complexity for a very long time, and we will continue to do so.

I think the benefit of wiping out viruses far outweighs the risks. Many of the deadliest diseases on the planet arrise from them.
Just as we once began the attack on the bacterium of the planet, and have wiped out many microbes that used to kill millions, it's high time we attacked the viral world, and we may find this world holds the keys to why cancers form as well. Causes of cancers are still poorly understood, but many are now known to have have a viral or parasitic component.

If we were to stick to the gloom and disaster theologies of what might go wrong we would still be dealing with polio, small pox, leprosy and a whole host of other scourges we no longer have to face.
I think Pasteur was on the right track, and a return to fear will never produce better long term outcomes.

[Trish77]

You're not being baited in the slightest.  You're simply being disagreed with.  Is THAT so hard to understand?  Anyone who doesn't agree with you is a conformist sheep?  Geez, Mike.  Your logic simply doesn't stack up and I don't see the same level of risk as you do any more than I see the worldwide conspiracy against heppers that you do.  It has nothing to do with conforming or non-conforming.  Impossible really to discuss this coherently when you're going to treat those who disagree with you as ignoramuses for doing so. So..yeah...that might as well be the last thing said on it.

[mike716]

I'm getting kinda tired of all this baiting, but I'll make a last attempt at stating my case. Sure, if SOC+PI is the only thing available, of course I'm gonna do it. What choice have I got? But my points are that there should be somethhing better available and that it shouldn't be something that's gonna maybe cause a worse epidemic down the line. Is that so hard to understand? It's no contradiction, as far as I can see.

But I guess anything I (or anyone else?) says that doesn't toe the conformist line is a no-no, huh?

Okay, I'll just shut up and do as I'm told (not).

Mike

[spectda]

20 percent is the amount of people that don't respond to the treatment supposedly, From what I understand only a portion of those people create dominant mutations that don't eventually die off. I may have misunderstood of course.

[Trish77]

Previously:  "The only question is about the consequences of large numbers of infectees taking this combination, in particular if 20% of them still do not eliminate the virus and henceforth can spread a drug-resistant virus, perhaps a virus with higher transmission and virulence (I say "perhaps" only). "

Currently:  "My point was not about individual decisions to treat, not even my own, but about the direction of research and funding. "

Well you've gone from "the only question" to a whole other point now to research and funding. You're kind of all over the place as long as you have something to rant about it seems. It was your "only question" that I was responding to.  You can't be all that concerned if you're willing to take a PI and contribute to this potential spread of a drug-resistant virus.

I'm not trying to pick on you, Mike, really I'm not.  You're just so inconsistent.  Railing away at Big Pharma and the nasty conspiracy one minute and then getting checked out for participation in a drug trial the next.  Talking about our moral obligations towards the greater global Hep C community in not contributing to a potential PI-resistant strain of Hep C and then declaring you'll probably take a PI.   Like a case of do what I say but not what I do.  

[mike716]

My point was not about individual decisions to treat, not even my own, but about the direction of research and funding.

[Trish77]

We'll have to agree to disagree, Mike.  I think the risk of creating an undefeatable resistant mutant strain of HCV that takes over the world is quite low.  If you really thought this was an issue, you wouldn't be doing the PI's and yet you plan to and you consider yourself in a high-risk category with regards to probability of success.  So you of all people, if you choose and suggest we should be looking at this from a moral perspective, would be a perfect candidate for not doing a PI in the scenario you paint.  As it is, I wouldn't let any of this discourage anyone from doing a PI.  I would simply put the factors in place that would contribute to the best possible chances for success - those things that help maintain adherence to therapy for the duration and deal with any factors that might reduce effectiveness of the drugs while on treatment - which isn't a whole lot different than the prep for SOC alone.  Add a PI to the mix and chances for success increase considerably.  

[HectorSF]

Referring to the original article by Rob Waters, is a health reporter for Bloomberg News.

I think that other posters have shown that most if not all of the information in the article has been know for many years regarding drug resistance and PIs. This was something that was learned my years ago when treatments for HIV were being developed. The idea of the drug "cocktail" which is what I think the author was trying to infer (VX-222) is an important concept and is why treatment with Telaprevir is combined with peg-interferon and ribaviron at the present time. In the future PIs should as Telaprevir will be combined with other antivirals as HIV medicine is. The peg-interferon and ribaviron parts of the HCV cocktail are used to eliminate the viral mutants that remain after Telaprevir eliminates the main HCV virus which is the most robust "fittest" of all the viruses and is the majority of the virus population. The main HCV virus or "wild virus" as it is called is what returns if UND is not achieved or the rebounds during treatment or there is a relapse after treatment. No SVR.

Main points about HCV viral mutants and variations:

Definitions:
“Wild type” is the dominate virus
“Mutants” mutations of the parent “wild type” virus

* (First and foremost) Mutants are there all the time in every person with chronic HCV. HCV mutates more rapidly then HIV. HCV has a high rate of replication with approximately one trillion particles produced each day in an infected individual. Due to lack of proofreading by the HCV RNA polymerase, HCV also has an exceptionally high mutation rate, a factor that may help it elude the host's immune response.
* Mutants were first uncovered by Vertex using their “Population sequencing” model – hundred of PCR tests per time point yielding the entire sample of virus population.
*       Vertex showed that the use of Telaprevir knocks down the main HCV virus “wild virus” 3-5 logs, this allowed the viewing of the mutants. The mutations are the majority of the virus that remain if a patient viral load plateaus or rebounds. I.E. Treatment does not eliminate the virus.
* RVR is a predictor of SRV because if the main or “wild virus” is driving down to zero quickly (within 4 weeks), no “parents” (wild viruses) exits to create the mutants.
* Peg-interferon and ribavirin role in the cocktail is to eliminate the remaining mutants.

I believe this clinical and modeling data is important in the understanding the HCV virus and as such and will help to lead to future improvements in treatments for all HCV sufferers. Antivirals are the biggest step in improvement of % of SVR since the peg-interferon/ribavirin combo.

Bottom Line:
59 Percent of Patients Overall Achieved SVR with Telaprevir-Based Regimens in Study 107 after not achieving SVR with at Least One Prior Course of Treatment for Hepatitis C Virus Infection.
56% of prior treatment null responder patients achieved SVR with a 48-week telaprevir-based regimen
97% of prior treatment relapsers
55% of prior treatment partial responders achieved SVR with 24-week or 48-week telaprevir-based regimens

Cheers!
HectorSF

[nygirl7]

Hansmiami this is a serious trial you should look into as it's gotten well past its test stages.................it's working wonders for people who failed other attempts.

[WriteItDown]

I think that anyone who has treated for HCV certainly knows enough so as not to run the risk of infecting others.  Remember, this is a blood-borne disease that is not so easily transmitted. Of course, there will always be mistakes, but my feeling is that the risk of spreading viral mutations is quite low.

[mike716]

All current epidemic viruses are mutations that have increased in virulence (ability to cause mortality in the infected body) as their difficulty in transmission has been lessened by transfusion, intravenous blood factor use, and intravenous drug use.

Microbes are evolving all the time, as are all forms of life. Their speed of mutation depends in great part on environmental pressures. In a stable host environment, microbes co-exist in and with the host species. There exists what's called endemic immunity. Few die from the microbe. But when the host environment changes, the microbe adapts. If transmission is made easier for the microbe, it can increase its virulence without lessening its frequency in the host population. If it is attacked - by another microbe (inter-parisitic competition), by pharmaceuticals that affect its genetics, etc. - it evolves to evade the threat.

There is no "stable" microbial genome without a "stable" host environment. Attacking a microbe's genetics is a destabilization of the microbe-host relationship. The microbe will evolve.

Epidemiology must concern itself with the dynamic situation. If it does not, it plays into the strategy of the microbe.

Mike

[Trish77]

"To my mind, SOC+PI is a stop-gap until something different and better is found. But that is not the way this is being handled by the authorities."

I think it is being handled as simply the next best thing to SOC and not the next and last best thing.  They continue to trial drugs that may even replace SOC and Vertex is already trialling a companion drug with Telaprevir.  So I don't really see any evidence of anyone being complacent about this current crop of Phase III / Phase IV PI's as being as good as it gets.  I think the quest will continue to come up with something that gives near 100% cure rates and reduces treatment time along with the quest for something that gets rid of the nasty interferon.

I think the chance of spreading a mutant HCV is very minimal, far less than the risk of producing a superbug from antibiotics which are far more prevalent and the illnesses they're used for far more prevalent as well.

[mike716]

Please, let's try to get one thing straight: There's no question here about whether SOC+PI works. It works. The only question is about the consequences of large numbers of infectees taking this combination, in particular if 20% of them still do not eliminate the virus and henceforth can spread a drug-resistant virus, perhaps a virus with higher transmission and virulence (I say "perhaps" only).

What this thread is about is moral responsability. Perhaps the threat of producing resistant strains that can cause a renewed epidemic is too small to weight the scales. But the question is real. It's a question of primary importance today. Put in other terms, it's this: Do I do what is best for me, even at an unacceptable cost to the human species? Or do I sacrifice my individual well-being, happiness, health, even life, in order to preserve the human species? This question, the "business" of health care is ignoring.

Don't forget, I don't say SOC+PI is implicated in this way. I don't have enough facts. No one does, yet. That's the problem with making genetic attacks on viruses. We don't know for sure what the consequences are.

This is a question that every MD must ask before prescribing antibiotics for a bacterial infection, and it's a valid question as regards SOC+PIs. It is a question that big pharma and its government henchmen never consider, or discard as not being their concern. But in a sense it is the only important question today. Not whether to take SOC+PIs, but whether to accept responsability for others.

I, for one, will probably end up taking SOC+PI if my condition worsens and there is no other approved medication. But I don't believe that it is a solution to the problem, and I think it has been blown way out of proportion for purely financial gain, with little consideration of the long-term consequences.

To my mind, SOC+PI is a stop-gap until something different and better is found. But that is not the way this is being handled by the authorities.

Mike

[Diane12855]

I thought the whole reason for the Ribaviron is to stop the virus from replicating. If it is doing its job, then the chance of mutations goes WAY down... right? I know I'm a newbe and haven't read all of the articles everybody else has read... but I have read all the documentation that comes with my meds. Since this part wasn't taken into account in the article, it kind of looks to me like they were WANTING to be able to say it doesn't work.

[TeeTom]

All I can say is I have hepc type 1a the worst one. I have been in a roche trial with the PI that they are testing. At the begining my viral load was over 5mil, at week 10 I was delcared UND and been there for 6 weeks now.

My point is, There are other drugs besides Tela that have also had good results

Teetom

[Rockerforlife]

The goods news far out weighs the bad news,80% cured rates for Bocep is nothing to snezze at,.

[WriteItDown]

Something that improves the body's immune response -- that's interferon. I think one key point you have to keep in mind here is that it's extremely hard to find cures for complex viral diseases like HCV. So, while it is a problem that the protease inhibitors create resistant strains, the benefits of these drugs (high cure rate) outweighs the risk.

[mike716]

Hi, Brent? How's it going?

You wrote:

} Can we really compare transmission of these mutant strains with
} transmission of bacterial infections? I am thinking that the transmission
} vectors here are going to put a damper on this spread.

I think the same biological "rules" apply to both. The danger is that both the transmissibility and virulence of the microbe will increase. It has been shown that this does occur when demographics (population concentration, and therefore increased transmission) favors the virus, as seems to have occurred with HIV. Pressuring the microbe with drugs may also have this effect, as the microbe develops better transmission and higher virulence in order to survive and offset the attack on it. The main danger is to the continued effectiveness of the specific drugs being used as therapy, but there may also be a residual effect on future infectees. This is the history of resistant TB, and perhaps also of the recent flu epidemics.

As you say, it may not occur. But the approach being taken to HCV - attacking it genetically - is the one most likely to have undesirable consecuences. A vaccine or other method of increasing the body's immune response, or meds that stop the fibrosis of hepatic tissue, would be safer.

} I understand that the FDA has no objection to the humanitarian use of Telap and Bocep for genotype 1 SOC
} failures, but that Vertex and Schering have not applied for the approval.

Not sure what you mean by this. Why would the PIs need special approval for second-time Tx?

Mike

Mike