apologies if this gets posted twice - (first attempt got dropped)
I'm suprised they're considering null responders and would be curious to hear any details you have on this. My read of that recent editorial on vx escape mutations in "Gastroenterology" from last July
was that there were possible ethical issues with enrolling non-responders in vx trials as it would effectively amount to vx monotherapy, known to not be worthwhile. By treating with vx and selecting for vx-resistant strains in a failed vx/soc combo, non-responders may preclude effective use of vx in a later combo with say r1626.
"Another study to be published in the May issue of Gastroenterology19 provides a detailed molecular analysis of HCV resistance to telaprevir over 2 weeks of administration of different treatment schedules used in the clinical trial reported by Reesink et al.7 The authors carefully describe the dynamics of HCV quasispecies populations during therapy. They show that relapse related to selection of resistant variants mainly occurred in patients with lower exposure to the drug. Telaprevir had to be administered every 8 hours precisely, at a dose of 750 mg, to induce a sustained biphasic decline in viral replication. A higher dose administered every 12 hours, or a lower dose administered every 8 hours, was associated with frequent relapses or with a lack of second-phase viral decline. Both these phenomena could be due to selection of telaprevir-resistant variants. The principal mutations were V36M/A, T54A, R155K/T and A156S/T/V, and some patients harbored double-mutant populations. Interestingly, however, the most resistant virus (A156V/T) was also the least fit in vivo. The other variants that were intrinsically less resistant to telaprevir had better replication fitness and predominated in the patients in whom high-level replication resumed upon telaprevir administration. After treatment cessation, resistant variants were slowly replaced by the wild-type, sensitive virus.19 Resistance selection with STAT-C is not surprising: HCV bears all the characteristics required for the generation of mutant viruses, including rapid viral kinetics, large population sizes, and a quasispecies distribution of viral populations.20 In addition, antiviral drugs are, by definition, drugs that select for resistance.21 The most surprising finding in the study by Sarrazin et al.19 is the frequency and timing of the emergence of resistance: indeed, it occurred during the first week of administration in 21 of 28 treated patients. These results, together with the recent observations that valopicitabine can select for the RdRp S282T substitution after several weeks of administration, and that HCV 796 selects for the RdRp C316Y substitution in the vast majority of treated patients after only 3 days of administration (Villano S, et al, presented at the 1st International Workshop on Hepatitis C Resistance and New Compounds, Boston, Massachusetts, October 25–26, 2006), suggest that resistant variants are preexisting, fit, and ready to be selected by any specific HCV inhibitor. These findings disqualify HCV inhibitor monotherapy and raise major ethical issues as to whether naive or nonresponder patients should now be included in trials of STAT-C monotherapy, as there is a risk that they will be disqualified from future trials and therapies with drug combinations."
admittedly, that last sentence only discusses vx monotherapy, but for a non-responder the crucial effect of adding ifn cannot be counted on.
thanks - I guess this will become clearer over time. My expectation is that the manufacturers would favor enrolling naive over relapsers over non-responders, but we'll see.
Re that article, a brief summary of the abstract is that they looked at what sort of mutations conferred resistance to a similar class of drugs (all targeted at the ns3 protease) using a new way of estimating the overall advantage the virus receives by developing a given mutation. The xNNNy labeling of mutations means that at position NNN in the protein, amino acid x is mutated to a y. Looks like R155K (arginine to lysine at position 155) is the one that gives the virus the best, multi-drug, advantage. This was all done in a synthetic cell system, but as noted by Pawlotsky above, data confirms that it doesn't take the virus long to figure out which way to go in real patients. I haven't read the article yet, but it's interesting bocepravir wasn't included. These guys all worked at Abbott, maybe Roche wouldn't give them any?
RE: the study you linked to.
Vertex has a second generation PI in phase 1 trials and you can bet they designed it from the data they collected in the phase 2 trials of Telaprevir. It is only a matter of time before we have a cure that only involves taking a few pills.
I don't disagree overall.. but there's alot of potholes in the road ahead, and it may be several pills along with at least a few months of ifn..
- the large number of escape mutant leaks in *all* the current ns3 protease drugs (telaprevir, itm-191,boceprevir) are unlikely to be plugged any time soon.
- ns3-pi/soc combo by 2010 will be a big improvement which should push the success rate up significantly (10-15%?) but won't do much for non-responders and is unlikely to make big enough of a jump to sway relapsers reluctant to make another bad bet on soc (like me)
- until hcv-796 dropped off the map, schering was touting the polymerase/protease synergy, since it owned both. Now only roche is in that position and itm-191 is still in phase1. Unfortunately for patients, unless the same company owns both combo tests will be delayed. For example, with 1626 still in phase II, vx+1626 or boceprevir+1626 combo data may not be available until 2012
- resistance-wise r1626 seems to hold the lead. However, not all resistants are equally fit (the abstract desrt linked noted a 20 fold loss of processivity for one of the common mutations at ns3 position 155) and unfit mutations may, or may not, be easier to kill off. Here's a recent review that looks at some of the mix-and-match questions ahead:
I envy your position of being able to wait...for myself...the increase of even 15% makes the second round of SOC totally attractive at my own stage three. Living life in my skin...with my liver...has given me a very simplistic approach to Telaprevir and the success seen so far. It is simply a matter of weighing the difference between doing nothing for at least 5 more years versus the chance that Telaprevir will give me more resistant strains of the virus. I lose liver cells every day in either case and in the case of doing nothing, I really hate the zero odds. More than I hate the idea of IFN again.
I have a pretty good doc at the University of Washington and he says Telaprevir will up my odds of SVR this second time to about 30%....compared to the zero odds of doing nothing....kind of a no brainer. The work being done on drug combinations and ferreting out the resistant soldiers will go on for about 10 more years, following the arc of research and development in HIV drugs.
And I am so grateful that treatment is moving ahead so quickly. But in your article quoted, I did not see anything that would stop me from trying a triple combo. Indeed, it is my fervent hope that Vertex will DO as they stated in one of their last conference calls and request approval for non-responders on phase II data. Someone, somewhere must see the benefit of approval of that sort, rather than suffer thru a slew of "compassionate use" petitions. Because as I have degraded one full stage in 5 years...I am and will continue to push those petitions, before five more years is up.
So future looking research is groovy and getting groovier and more complicated by the minute.......but I've got my fingers crossed for Vertex and a simple little plan to help those of us already damaged by IFN. Wildly hoping it just may work...and nobody's died from it yet. Which CANNOT be said of liver destruction.
I just listened to a web cast at the Vertex web site from Mar 19 and it sounds like they see a HUGE market in the already treated population. They should be getting there data from the prove 3 testing in early April and plan on using that data to fast track it to the FDA. It sounds like triple thearpy will be around for awhile. They also talked about someday haveing an all oral drug treatment. Anyone can listen to it just register for free, its about 27 mins long
I have not listened to the Vertex web cast yet but I will.
Several on this site said that they were hoping for an early approval for previous treatment failures.
Since I did not clear with SOC (almost a 2 log drop at 12 weeks but back up to just a 1 log drop at 24 weeks). I was wondering if anyone knows anything about other previous drugs that have been approved more quickly than normal.
Using things that I learned from this site (ie predose riba, take it with fat, increased peg at the start, maybe even alinia as a quadruple therapy) I would probably give it a shot if it comes out early.
Since I needed neupogen to get me to 24 weeks with SOC, I dont see where being part of a trial would help me at all.
wow - 1 stage in 5 years is certainly cause to re-evaluate. I suspect all who have failed tx have their own sense of when it's time to stop waiting-and-watching and act on what's available NOW, though the uncertainty in evaluating developing fibrosis doesn't help make that decision.
The first interim results from prove 3 should be available soon and in fact from the study design it looked like only one arm, arm2 with 110 patients, will require 48 weeks of tx. They announced full PROVE3 enrollment on June 13 so there should be 12-week post eot data for the other three arms. It looks like if the data is favorable Vertex may be using it as possible grounds for requesting treatment-approval for tx-experienced before receiving approval for tx naive:
As a stage 3, one strategy to consider might be to wait until these results come out and, if they're at all favorable, talk to your dr about starting a 48 week soc-tx and betting on being able to add vx-950 at the end, if fda-approved in the interim. As far as I know, and this is speculation on my part, if you're a relapser who got to EVR rather a non-responder there is no reason to believe vx will be of lesser value at the end than at the beginning of tx (and it would make your petitions to the fda that much more compelling!).
Personally, I'm only delaying because I think I still can, and that would change pretty quickly in the face of quickening fibrosis progression.
I am in the 48 week prove 3 arm and just finished up the treatment two weeks ago. I am one of the earliest to start, but everyone else should be within 6 weeks of me.
I think the prevalent theory is that Telaprevir should be taken at the start of therapy not the end. It leaves some mutations that must be killed by SOC following the Telaprevir.
I don't quite understand why the clinical trial registry for prove3
gives may '09 as the prove 3 completion date. Working backwards, that would put the last eot at dec. 08 and from your comment and their June press-release announcing completion of prove3 enrollment it seems all the 48-week prove3'rs should have finished tx sooner than that...Anyway at least final data for the other three arms should be available. Did they schedule any vl tests between eot and 6-months post?
Agreed that the prevailing approach with all the new pis is to dose them up front, other than boceprevir which seems to have delayed a bit. However I wonder to what extent this reflects the structure of the drug trials and a bias towards tx naive patients. For the tx naive you clearly want to eliminate virus up front leaving soc as little as possible thus making success more likely and possibly being able to shorten tx.
In relapsers however, soc, notwithstanding early success, has proven itself incapable of eliminating residual virus. In this group assisting ifn with new meds may be more important in the end game. As I mentioned, this is just speculation on my part, but I'd be curious to hear of any research on the topic.
There are VLs done at EOT + 2, + 4, +12, +24, +48.
I don't have the forms in front of me, so I am positive about the first 3 and not sure about the last two. It might be +26 and +52.