Aa
PSI-7977 + BMS-790052 trial , or, Boce + SOC tx?
looking for suggestions/recommendations:
1st time treating, have prescription in hand for boceprevir and pegasys and ribavirin.
but was contacted same day about possibility of trial with psi-7977 and bms-7900052.
the trial would be without interferon and ribavirn, and if I fail to respond, they promise to add interferon and ribavirn to make a 4drug combo.
is it worth the gamble, or should I play it safe and take the script?
fyi, I am 36, healthy otherwise, 1b, ct, 5mil vl.stage 2, grade 2 bx.
just curious what others here would do? thanks very much.
1st time treating, have prescription in hand for boceprevir and pegasys and ribavirin.
but was contacted same day about possibility of trial with psi-7977 and bms-7900052.
the trial would be without interferon and ribavirn, and if I fail to respond, they promise to add interferon and ribavirn to make a 4drug combo.
is it worth the gamble, or should I play it safe and take the script?
fyi, I am 36, healthy otherwise, 1b, ct, 5mil vl.stage 2, grade 2 bx.
just curious what others here would do? thanks very much.
Thanks - link works. Great analogy...although the Death Star seemed more formidable and look what happened there, eh?
" However it gets the basic point across that a mutation of the green alanine at position 156 is not only going to disrupt tela binding but also that of any similar small molecule such as boce or TMC435. "
I completely understand that - though the picture helps considerably. A DAA that targets in the same way as Telaprevir is not going to be effective when mutations have become resistant to the way Telaprevir operates. The question goes further beyond that. Are Telaprevir mutations resistant to all DAA's? The answer to that is a general "no" but it takes some work to determine which ones and which combinations are most effective...and then the question goes further beyond that to what ARE the risks of DAA's and pairing of DAA's? And I'd add another question yet...is this resistance permanent? Does not seem to be in the case of Telaprevir, it seems 2 - 3 years with exceptions. And so on. Much to know. Thanks for this.
" However it gets the basic point across that a mutation of the green alanine at position 156 is not only going to disrupt tela binding but also that of any similar small molecule such as boce or TMC435. "
I completely understand that - though the picture helps considerably. A DAA that targets in the same way as Telaprevir is not going to be effective when mutations have become resistant to the way Telaprevir operates. The question goes further beyond that. Are Telaprevir mutations resistant to all DAA's? The answer to that is a general "no" but it takes some work to determine which ones and which combinations are most effective...and then the question goes further beyond that to what ARE the risks of DAA's and pairing of DAA's? And I'd add another question yet...is this resistance permanent? Does not seem to be in the case of Telaprevir, it seems 2 - 3 years with exceptions. And so on. Much to know. Thanks for this.
sorry Trish, posted a bad link. try:
http://www.medhelp.org/user_photos/show/142031
all NS3/4A PIs target the same satellite dish but with differently shaped ammunition. The picture doesn't really capture the difference in scale between the small-molecule inhibitor and the large macro-molecule that is the viral protein (it's more like Luke Skywalker flying up to the Death Star). However it gets the basic point across that a mutation of the green alanine at position 156 is not only going to disrupt tela binding but also that of any similar small molecule such as boce or TMC435.
thanks for the wishes! Still seems too soon to think about closing in, but holding steady.
http://www.medhelp.org/user_photos/show/142031
all NS3/4A PIs target the same satellite dish but with differently shaped ammunition. The picture doesn't really capture the difference in scale between the small-molecule inhibitor and the large macro-molecule that is the viral protein (it's more like Luke Skywalker flying up to the Death Star). However it gets the basic point across that a mutation of the green alanine at position 156 is not only going to disrupt tela binding but also that of any similar small molecule such as boce or TMC435.
thanks for the wishes! Still seems too soon to think about closing in, but holding steady.
Thx willing ...your input is always appreciated.. hope you are doing well down the stretch
Will
Will
Thanks for the pointer to the picture. I can't access it from here but will try alternately. I'm sure it will be informative and I thank you.
"However those changes will have no bearing on drugs that target different viral proteins, such as NS5B"
This is the aspect I was commenting to, whether resistance to one DAA confers resistance to all - or not, or resistance to one protease or polymerase confers resistance to all - or not, from my limited understanding of it to date. Thanks for your comments also.
Hope you are maintaining well enough...and closing in.
Trish
"However those changes will have no bearing on drugs that target different viral proteins, such as NS5B"
This is the aspect I was commenting to, whether resistance to one DAA confers resistance to all - or not, or resistance to one protease or polymerase confers resistance to all - or not, from my limited understanding of it to date. Thanks for your comments also.
Hope you are maintaining well enough...and closing in.
Trish
dointime: "This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy " agreed that this looks like a big breakthrough. To get approval they must have some pretty good data.
PI monotherapy is currently viewed very suspiciously. In the VIC package insert, proscription against monotherapy is the first item under Prescribing Information. In fact I recall Pawlotsky questioning the ethics of even PI + low/no rbv trials like the one you were in.
It would be interesting to know the mechanism of PSI-7977 - does it target a highly conserved part of the viral genome? Even Houdini-like HCV virions can't wriggle out of all traps.
The 'high barrier to resistance' claim has been made by many drugs, but a monotherapy rx is a way stronger statement. As far as I know the Rong/Perleson analysis is not specific to tela but applies to all drugs from which the virus can easily evade (currently including all NS3 PIs).
Will,Trish: as far as I know dointime's "satellite dish" analogy is on point, see eg the picture at
http://assets10.medhelp.org/user_photos/142031_tn?1278429732
changes in the viral sequence like A156T that result in "bumps" in the dish at the green, orange, magenta or yellow positions, are enough to stop the tela from binding to the dish but still allow the NS3/4A protein to do its job. However those changes will have no bearing on drugs that target different viral proteins, such as NS5B
PI monotherapy is currently viewed very suspiciously. In the VIC package insert, proscription against monotherapy is the first item under Prescribing Information. In fact I recall Pawlotsky questioning the ethics of even PI + low/no rbv trials like the one you were in.
It would be interesting to know the mechanism of PSI-7977 - does it target a highly conserved part of the viral genome? Even Houdini-like HCV virions can't wriggle out of all traps.
The 'high barrier to resistance' claim has been made by many drugs, but a monotherapy rx is a way stronger statement. As far as I know the Rong/Perleson analysis is not specific to tela but applies to all drugs from which the virus can easily evade (currently including all NS3 PIs).
Will,Trish: as far as I know dointime's "satellite dish" analogy is on point, see eg the picture at
http://assets10.medhelp.org/user_photos/142031_tn?1278429732
changes in the viral sequence like A156T that result in "bumps" in the dish at the green, orange, magenta or yellow positions, are enough to stop the tela from binding to the dish but still allow the NS3/4A protein to do its job. However those changes will have no bearing on drugs that target different viral proteins, such as NS5B
I apologize for interrupting your thread.....whichever way you decide ..wish you the best..
Will
dointime...thx again ..I very much appreciate your time and input..
Best to you....
Will
No problem, Will. Always nice when someone shows appreciation for the time and effort given, even though you didn't find it helpful.
Perhaps someone else will have something to offer you and, as dointime noted, if you come across something yourself that sheds further light on this, I'm sure it would add value if you posted it.
Trish
Perhaps someone else will have something to offer you and, as dointime noted, if you come across something yourself that sheds further light on this, I'm sure it would add value if you posted it.
Trish
I think that the science of cross resistance is pretty well understood now by the scientists working at the coal face, so to speak . As Trish says, there is a wealth of experience coming out of the work on HIV.
Having said that, I believe that there is much that we, the public, are not told about. That goes especially for drugs which are still in testing. Drug companies get their information about resistant mutations by studying them during the trials, not by preventing them!
In light of this I think it is never a bad thing to maintain a healthy scepticism. Thanks for highlighting this question. I'd be interested to know if you come across any more info on it.
dointime
Having said that, I believe that there is much that we, the public, are not told about. That goes especially for drugs which are still in testing. Drug companies get their information about resistant mutations by studying them during the trials, not by preventing them!
In light of this I think it is never a bad thing to maintain a healthy scepticism. Thanks for highlighting this question. I'd be interested to know if you come across any more info on it.
dointime
" HAART Retroviral treatment for HIV "
Correction...I believe that should read HAART treatment for HIV...being Highly Active Anti-Retroviral Treatment". Hope I have that right this time. Didn't sound right and had to look it up....not familiar enough with HIV/AIDS terminologies.
Ref. http://www.avert.org/treatment.htm
Correction...I believe that should read HAART treatment for HIV...being Highly Active Anti-Retroviral Treatment". Hope I have that right this time. Didn't sound right and had to look it up....not familiar enough with HIV/AIDS terminologies.
Ref. http://www.avert.org/treatment.htm
Perhaps you can post the studies you haven't read yet - that might be helpful to keep from posting things you've read already. :-P
"however I guess what I was wondering about .. and have never seen any thing that said specifically if you had a failed tx with an NS5A there would be no cross res to a NS3 and/ or a Poly."
While I think you're looking for a carte blanche statement that covers all DAA's, there are a number of studies about specific DAA's that declare they produce resistance mutations that are only resistant to the component that was targetted, while remaining vulnerable to DAA's that target alternate components.
Here's another study (that perhaps you've already read) that talks about a polymerase that targets NS5B. It mentions within the study that it's mutations are still susceptible to DAA's that target NS3, NS4B and NS5A.
http://www.natap.org/2011/EASL/EASL_73.htm
In this instance, NS5A and NS5B being both polymerase, it seems to indicate that attention needs to be paid to what mechanism the previous DAA attacked and would potentially develop resistance to when choosing a DAA for next therapy. If the DAA targets NS5B polymerase, as it does in this instance, the resistance mutation is to NS5B. However, a DAA that targets NS5A polymerase is still effective. If that is indeed the case, then it's insufficient to say that resistance to one polymerase means resistance to all polymerase. It depends which specific component of the virus that DAA was targeting.
That seems to be borne out over other studies that specifically look at resistance mutations resulting from a particular DAA and the fact that the mutations are to the particular cell component that the DAA is targeting, leaving the other components vulnerable to the specific and different targets of other DAA's.
The whole concept of quadruple therapy in targeting with *two* DAA's that target different molecules of the HCV virus is that while one develops mutations of the molecule each DAA targets, the other one mops up those mutations as it's targeting differently - resulting in the pairing of a DAA that targets the NS3 protease and a DAA that targets NS5A polymerase for example. That whole concept is based on the idea that resistance will occur only to a DAA that is targeting that particular component of the viron. HAART Retroviral treatment for HIV works on the same principle - it uses a combination of drugs that target different components of the HIV virus and mops up mutations. With HCV treatment starting to use the same approach, we'll have the same risks in that, over time, resistance to multiple DAA targets could result in and produce strains of HCV that are resistant to multiple DAA's.
In all your reading, have you come across a DAA targeting a specific component, NS3 for example, that shows resistance mutations to differing components such as NS4B, NS5A and NS5B? I have not as yet. You did mention you'd read articles that showed this as inconclusive? I'd be interested in reading any related articles you might find useful to post.
Trish
"however I guess what I was wondering about .. and have never seen any thing that said specifically if you had a failed tx with an NS5A there would be no cross res to a NS3 and/ or a Poly."
While I think you're looking for a carte blanche statement that covers all DAA's, there are a number of studies about specific DAA's that declare they produce resistance mutations that are only resistant to the component that was targetted, while remaining vulnerable to DAA's that target alternate components.
Here's another study (that perhaps you've already read) that talks about a polymerase that targets NS5B. It mentions within the study that it's mutations are still susceptible to DAA's that target NS3, NS4B and NS5A.
http://www.natap.org/2011/EASL/EASL_73.htm
In this instance, NS5A and NS5B being both polymerase, it seems to indicate that attention needs to be paid to what mechanism the previous DAA attacked and would potentially develop resistance to when choosing a DAA for next therapy. If the DAA targets NS5B polymerase, as it does in this instance, the resistance mutation is to NS5B. However, a DAA that targets NS5A polymerase is still effective. If that is indeed the case, then it's insufficient to say that resistance to one polymerase means resistance to all polymerase. It depends which specific component of the virus that DAA was targeting.
That seems to be borne out over other studies that specifically look at resistance mutations resulting from a particular DAA and the fact that the mutations are to the particular cell component that the DAA is targeting, leaving the other components vulnerable to the specific and different targets of other DAA's.
The whole concept of quadruple therapy in targeting with *two* DAA's that target different molecules of the HCV virus is that while one develops mutations of the molecule each DAA targets, the other one mops up those mutations as it's targeting differently - resulting in the pairing of a DAA that targets the NS3 protease and a DAA that targets NS5A polymerase for example. That whole concept is based on the idea that resistance will occur only to a DAA that is targeting that particular component of the viron. HAART Retroviral treatment for HIV works on the same principle - it uses a combination of drugs that target different components of the HIV virus and mops up mutations. With HCV treatment starting to use the same approach, we'll have the same risks in that, over time, resistance to multiple DAA targets could result in and produce strains of HCV that are resistant to multiple DAA's.
In all your reading, have you come across a DAA targeting a specific component, NS3 for example, that shows resistance mutations to differing components such as NS4B, NS5A and NS5B? I have not as yet. You did mention you'd read articles that showed this as inconclusive? I'd be interested in reading any related articles you might find useful to post.
Trish
Thx for that.....I had read most of the articles including the 2 Trish had posted...however I guess what I was wondering about .. and have never seen any thing that said specifically if you had a failed tx with an NS5A there would be no cross res to a NS3 and/ or a Poly.
Here's a very unscientific description. Sorry I don't have a reference except to look up the story of telaprevir, how it was designed and why.
My understanding comes from how telaprevir was designed and engineered. The virus receptor is shaped like a shallow concave satellite dish at the part where the telaprevir latches on to it, the ns3 protease. Once telaprevir has stuck on it, the virus can't latch on to anything else and is disabled.
But being very tricky, the virus can mutate so that this concave dish becomes even more shallow. Then the telaprevir cannot latch on and the virus escapes. That is how resistant mutations are is successful.
So if you use a DAA which targets another part of the virus, not this concave dish part, then it does not matter what shape the virus takes for the dish because that is not where it will be attacked. The ns5A for example attacks at ns5a. I haven't got round to studying what happens in that case.
So I hope this makes some sense and you can see the rational behind it that there is not going to be cross resistance between DAAs which have different targets.
dointime
My understanding comes from how telaprevir was designed and engineered. The virus receptor is shaped like a shallow concave satellite dish at the part where the telaprevir latches on to it, the ns3 protease. Once telaprevir has stuck on it, the virus can't latch on to anything else and is disabled.
But being very tricky, the virus can mutate so that this concave dish becomes even more shallow. Then the telaprevir cannot latch on and the virus escapes. That is how resistant mutations are is successful.
So if you use a DAA which targets another part of the virus, not this concave dish part, then it does not matter what shape the virus takes for the dish because that is not where it will be attacked. The ns5A for example attacks at ns5a. I haven't got round to studying what happens in that case.
So I hope this makes some sense and you can see the rational behind it that there is not going to be cross resistance between DAAs which have different targets.
dointime
I'm pretty sure this topic is covered in a very comprehensive article I read on this subject however I'm not sure where I've stored it! In the meantime, a study on a DAA that targets NS3, indicating that it was still susceptible to other DAA's that target different components of the virus.
http://www.natap.org/2011/EASL/EASL_55.htm
If you look in Table 3 near the bottom, the only cross-resistance occurred in other DAA's targeting NS3.
" GS-9451 NS3 resistance mutations are fully susceptible to other HCV inhibitor classes, including tegobuvir, GS-9669, and GS-6620 targeting NS5B; GS-5885 targeting NS5A; and interferon-α, and ribavirin"
Same thing only additional comments on it:
http://www1.easl.eu/easl2011/program/Posters/Abstract1126.htm
Summary: NS3 mutations resistant to GS-9451 were selected in patients treated with 200 mg or 400 mg GS-9451 by day 4, indicating pre-existing resistance mutations and potent inhibition of wild-type HCV by GS-9451. Lack of cross-resistance of GS-9451 resistance mutants to tegobuvir, GS-6620, GS-5885, IFN-α, and ribavirin, supports the use of these drugs in combination with GS-9451.
http://www.natap.org/2011/EASL/EASL_55.htm
If you look in Table 3 near the bottom, the only cross-resistance occurred in other DAA's targeting NS3.
" GS-9451 NS3 resistance mutations are fully susceptible to other HCV inhibitor classes, including tegobuvir, GS-9669, and GS-6620 targeting NS5B; GS-5885 targeting NS5A; and interferon-α, and ribavirin"
Same thing only additional comments on it:
http://www1.easl.eu/easl2011/program/Posters/Abstract1126.htm
Summary: NS3 mutations resistant to GS-9451 were selected in patients treated with 200 mg or 400 mg GS-9451 by day 4, indicating pre-existing resistance mutations and potent inhibition of wild-type HCV by GS-9451. Lack of cross-resistance of GS-9451 resistance mutants to tegobuvir, GS-6620, GS-5885, IFN-α, and ribavirin, supports the use of these drugs in combination with GS-9451.
I thank you for your input. I think I will go with the boc/peg/riba and keep my fingers crossed. If I am unlucky enough to be in the 25% who don't respond, then maybe by that time these trials who are not accepting naives now will expand the trials to nonresponders. I just wonder if this trial will turn out to be the silver bullet. Who knows, just wishful thinking. Perhaps It comes down to the evil you know vs the evil you don't. But as long as my stage 2 does't progress abnormally fast, the future of HcV tx seems bright.
If I were you based on my somewhat extensive experience with hcv drug trials, I would go with the current approved SOC (riba, inf, and teleprevir or boc). It's about 65% or more successful. You don't know what the side- or long-term effects of experimental drugs are and you're not in bad shape at the moment. Also keep in mind that once you decide on something it can limit you from the future trials you can participate in. Many trials require you to be "naive" to certain drugs, i.e., never be treated with them before. Not like the old days where they would let you try the latest thing for a trial. Thank the trial-lawyers for that.
To: Trish & dointime
I'm no expert either however that is my understanding of it as well. Resistance to one PI is not resistance to all PI's, only those that target the same mechanism of the virus. Any potential resistance to the NS5A PI's, would not preclude someone from treating with Boce/Vitrelis or Tela/Incivek that are NS3 targetters.
----------------------------------------------------------------------------------------------------------------------------
Well I guess that makes at least 3 of us.. as I have read many articles on potential cross resistance between NS3"s , Poly"s and NS5A"s going either way . and unless I am missing something or just not understanding some of the science-speak(which is very likely) I only see that definitively..they just don"t know yet.
If someone could point me to an article I very well may not have read I would much appreciate it.
Thx
Will
"Both boc and tela are ns3 protease inhibitors. The drugs in question here are a polymerase inhibitor and an NS5A inhibitor, meaning that they target different parts of the virus.
I'm no expert but my understanding is that if you have resistance to an ns3 protease inhibitor then you might have cross resistance to all of the ns3 protease inhibitors. However that should not matter if you are using a different class of DAA. "
I'm no expert either however that is my understanding of it as well. Resistance to one PI is not resistance to all PI's, only those that target the same mechanism of the virus. Any potential resistance to the NS5A PI's, would not preclude someone from treating with Boce/Vitrelis or Tela/Incivek that are NS3 targetters.
Trish
I'm no expert but my understanding is that if you have resistance to an ns3 protease inhibitor then you might have cross resistance to all of the ns3 protease inhibitors. However that should not matter if you are using a different class of DAA. "
I'm no expert either however that is my understanding of it as well. Resistance to one PI is not resistance to all PI's, only those that target the same mechanism of the virus. Any potential resistance to the NS5A PI's, would not preclude someone from treating with Boce/Vitrelis or Tela/Incivek that are NS3 targetters.
Trish
Hi willing,
That study by Rong and Perelson used data from a telaprevir trial and seems to be based on an underlying assumption that the virus is mutagenic enough to get round any single DAA.
Pharmasset, however, seem to be betting the farm that the virus can't mutate it's way round PSI-7977 and remain viable, and that this drug will take the place of interferon to mop up the mutations that arise from other drugs in the combo. They have taken the dramatic step of doing a monotherapy trial. If they are right then this is a game-changer for all future tx. I am trying to resist getting excited about it and urging caution until we see the results of larger trials. This would not be the first false dawn.
dointime
http://www.hivandhepatitis.com/hep_c/news/2011/0614_2011_b.html
"June 8, 2011 -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) "
That study by Rong and Perelson used data from a telaprevir trial and seems to be based on an underlying assumption that the virus is mutagenic enough to get round any single DAA.
Pharmasset, however, seem to be betting the farm that the virus can't mutate it's way round PSI-7977 and remain viable, and that this drug will take the place of interferon to mop up the mutations that arise from other drugs in the combo. They have taken the dramatic step of doing a monotherapy trial. If they are right then this is a game-changer for all future tx. I am trying to resist getting excited about it and urging caution until we see the results of larger trials. This would not be the first false dawn.
dointime
http://www.hivandhepatitis.com/hep_c/news/2011/0614_2011_b.html
"June 8, 2011 -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) "
Both boc and tela are ns3 protease inhibitors. The drugs in question here are a polymerase inhibitor and an NS5A inhibitor, meaning that they target different parts of the virus.
I'm no expert but my understanding is that if you have resistance to an ns3 protease inhibitor then you might have cross resistance to all of the ns3 protease inhibitors. However that should not matter if you are using a different class of DAA.
dointime
I'm no expert but my understanding is that if you have resistance to an ns3 protease inhibitor then you might have cross resistance to all of the ns3 protease inhibitors. However that should not matter if you are using a different class of DAA.
dointime
A little something to add to the previous comments...sometimes the Clinical Trial "fine print" seems to mean one thing, but gets used differently - caution!! I was in a clinical trial and very disappointed in their "escape clause".
One thing to keep in mind about the newly approved triple tx is that RVR (very early response) has been demonstrated to be highly correlated to SVR which gives you the opportunity to stop the tx quite early if your response is not promising; i.e. before a lot of the more difficult sx set in or PI-related mutations. This would allow you to conserve your health and well-being if you have to wait for something new. The trade-off is that Trials frequently want subjects that are treatment naive, but on the other hand - what are the odds you'd end up with placebo? It's a lot to consider. Get all the info you can - and then trust your gut! Good luck!
L
One thing to keep in mind about the newly approved triple tx is that RVR (very early response) has been demonstrated to be highly correlated to SVR which gives you the opportunity to stop the tx quite early if your response is not promising; i.e. before a lot of the more difficult sx set in or PI-related mutations. This would allow you to conserve your health and well-being if you have to wait for something new. The trade-off is that Trials frequently want subjects that are treatment naive, but on the other hand - what are the odds you'd end up with placebo? It's a lot to consider. Get all the info you can - and then trust your gut! Good luck!
L
I under stand your comment on the resistance issues ,however given he does not succeed on thr approved triple( ie. non.null breakthrough ,relapse .what have you... does he still not have resistance issues . From what I read to automatically to be able to go to a quad therapy (when approved).it is still an unknown about cross resistance
Thx.
Will
Thx.
Will
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