Aa
2 Studies and a comment
Hello,
there are two new publications about Telaprevir from the Zeuzem-group (Germany) and a very good comment.
Regards, drofi
http://tinyurl.com/ysmpg2
New therapies for hepatitis C: VX-950 (telaprevir)
Hepatology Sept 2007
Apurva A. Modi, M.D., Jay H. Hoofnagle, M.D. * Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
No challenge in clinical hepatology is as great today as the management of patients with chronic hepatitis C who have failed to respond to an adequate course of antiviral therapy. At present, the optimal regimen is a combination of peginterferon and ribavirin.[1] When given for 24 or 48 weeks, this combination results in a sustained eradication of hepatitis C virus (HCV) and a long-term remission of the disease in at least 75% of patients with genotype 2 or 3 HCV infection and in 40%-50% of those with genotype 1.[2][3] Although impressive, these sustained virological response (SVR) rates leave as many as half of patients without benefit and with no means of ameliorating the subsequent course of the disease. Despite the importance of chronic hepatitis C (the leading cause of end-stage liver disease and need for liver transplantation in the Western world) and the intensity of the research on this viral infection, there have been no further improvements in response rates to therapy in many years. When will this change?
In this issue of HEPATOLOGY, two original articles provide exciting new results on a novel orally available antiviral agent that has potent effects against HCV in vitro and in vivo.[4][5] VX-950, now known as telaprevir, is a peptide-mimetic drug that was developed with structure-based drug design.[6] Telaprevir is a specific, reversible inhibitor of the HCV genotype 1 serine protease encoded by the nonstructural 3 and 4A region of the viral genome. This protease is essential for HCV replication,[7] and its inhibition in cell culture systems results in marked suppression of viral replication.[6][7] In humans, telaprevir is orally available and causes a rapid and marked decrease in serum HCV RNA levels.[8] In phase Ia studies using various doses and schedules, a dose of 750 mg of telaprevir given every 8 hours resulted in rapid 3-5 log10 decreases in serum HCV RNA levels in virtually all patients. Stopping therapy at 2 weeks led to a rapid return of HCV RNA to the pretreatment levels. These results suggest that longer term therapy might lead to the eradication of the virus in a high proportion of patients.
there are two new publications about Telaprevir from the Zeuzem-group (Germany) and a very good comment.
Regards, drofi
http://tinyurl.com/ysmpg2
New therapies for hepatitis C: VX-950 (telaprevir)
Hepatology Sept 2007
Apurva A. Modi, M.D., Jay H. Hoofnagle, M.D. * Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
No challenge in clinical hepatology is as great today as the management of patients with chronic hepatitis C who have failed to respond to an adequate course of antiviral therapy. At present, the optimal regimen is a combination of peginterferon and ribavirin.[1] When given for 24 or 48 weeks, this combination results in a sustained eradication of hepatitis C virus (HCV) and a long-term remission of the disease in at least 75% of patients with genotype 2 or 3 HCV infection and in 40%-50% of those with genotype 1.[2][3] Although impressive, these sustained virological response (SVR) rates leave as many as half of patients without benefit and with no means of ameliorating the subsequent course of the disease. Despite the importance of chronic hepatitis C (the leading cause of end-stage liver disease and need for liver transplantation in the Western world) and the intensity of the research on this viral infection, there have been no further improvements in response rates to therapy in many years. When will this change?
In this issue of HEPATOLOGY, two original articles provide exciting new results on a novel orally available antiviral agent that has potent effects against HCV in vitro and in vivo.[4][5] VX-950, now known as telaprevir, is a peptide-mimetic drug that was developed with structure-based drug design.[6] Telaprevir is a specific, reversible inhibitor of the HCV genotype 1 serine protease encoded by the nonstructural 3 and 4A region of the viral genome. This protease is essential for HCV replication,[7] and its inhibition in cell culture systems results in marked suppression of viral replication.[6][7] In humans, telaprevir is orally available and causes a rapid and marked decrease in serum HCV RNA levels.[8] In phase Ia studies using various doses and schedules, a dose of 750 mg of telaprevir given every 8 hours resulted in rapid 3-5 log10 decreases in serum HCV RNA levels in virtually all patients. Stopping therapy at 2 weeks led to a rapid return of HCV RNA to the pretreatment levels. These results suggest that longer term therapy might lead to the eradication of the virus in a high proportion of patients.
In t 14 days, the median decrease in HCV RNA was 5.5 log10 with telaprevir and peginterferon, 4.0 log10 with telaprevir alone, and only 1.1 log10 with peginterferon. These results suggest that peginterferon and telaprevir are synergistic (or at least additive) in their antiviral activity against HCV, and this finding is supported by cell culture results.
Does additive mean that the two drugs act independently of one another ( as in 5.5 log10 roughly equals 4.0 log10 + 1.1log10 ??
Does additive mean that the two drugs act independently of one another ( as in 5.5 log10 roughly equals 4.0 log10 + 1.1log10 ??
Whole heartily agree, glad to see your on std tx. if that is what your on, interferon and riba. I waited 2 + years on a hope and decided the best course of action was to just do it hope for the best. I will know one thing at the end of 48 weeks of std combo and that is, I made it! or I didn’t, but it will be 48 weeks well spent rather than waiting on a hope or the hype of a new drug that may or may not pan out and if it does it is not a guarantee that the insurance companies will embrace it right off the bat so good luck in your tx’ing!
jasper
jasper
As a 1A who failed to respond to mono-therapy for acute stage Hep C, I am dubious on the studies saying the efficiency of it. I am on combonation therapy now for full 48 weeks, and would have preferred to do that from the outset. I think people are better off doing the full thing, rather than potentially wasting 3 months of Tx in the hope of less side effects (which is what happened to me).
Yes, I understand. These are complex issues with many shades of grey and sometimes we have to pick here and there to get closer to the illusion of truth.
agreed on all counts - hence the caution that very little, if anything, in the ongoing discussions here about drug choices, duration, etc. apply to her case. Here's a relevant quote from that recent Scott/Gretchen JAMA review on current treatment for acute:
"In a series of well-defined studies, Kamal and colleagues65- 67 performed frequent ultrasensitive NATs (reverse transcription– PCR and TMA) to define the effect of various therapeutic regimens on the HCV persistence or clearance during acute infection. The molecular tests werecritical for defining treatment responses.Several controversial issues were resolved, including (1) optimal time after infection to initiate therapy (8-12 weeks); (2) optimal treatment duration (24 weeks); and (3) the important point that ribavirin is apparently not required for optimal responses during
acute infection, thus reducing the risk of major adverse effects (anemia). "
refs 65-67 are : (I think only 65.66 are on point)
65. Kamal SM, Moustafa KN, Chen J, et al. Duration
of peginterferon therapy in acute hepatitis C: a randomized
trial. Hepatology. 2006;43:923-931.
66. Kamal SM, Ismail A, Graham CS, et al. Pegylated
interferon alpha therapy in acute hepatitis C: relation
to hepatitis C virus-specific T cell response kinetics.
Hepatology. 2004;39:1721-1731.
67. Mangia A, Santoro R, Minerva N, et al. Peginterferon
alfa-2b and ribavirin for 12 vs 24 weeks in HCV
genotype 2 or 3. N Engl J Med. 2005;352:2609-2617.
"In a series of well-defined studies, Kamal and colleagues65- 67 performed frequent ultrasensitive NATs (reverse transcription– PCR and TMA) to define the effect of various therapeutic regimens on the HCV persistence or clearance during acute infection. The molecular tests werecritical for defining treatment responses.Several controversial issues were resolved, including (1) optimal time after infection to initiate therapy (8-12 weeks); (2) optimal treatment duration (24 weeks); and (3) the important point that ribavirin is apparently not required for optimal responses during
acute infection, thus reducing the risk of major adverse effects (anemia). "
refs 65-67 are : (I think only 65.66 are on point)
65. Kamal SM, Moustafa KN, Chen J, et al. Duration
of peginterferon therapy in acute hepatitis C: a randomized
trial. Hepatology. 2006;43:923-931.
66. Kamal SM, Ismail A, Graham CS, et al. Pegylated
interferon alpha therapy in acute hepatitis C: relation
to hepatitis C virus-specific T cell response kinetics.
Hepatology. 2004;39:1721-1731.
67. Mangia A, Santoro R, Minerva N, et al. Peginterferon
alfa-2b and ribavirin for 12 vs 24 weeks in HCV
genotype 2 or 3. N Engl J Med. 2005;352:2609-2617.
Jim, as mentioned before, our opinions are closer than the wording sometimes suggests. I completely agree!
OK. I peeked, but maybe you can translate. If what the graph is saying is that the older you are the worse your chances of SVR, how does that fit with the study that shows SVR rates identical, except for stage 4's? One possiblity is that the older population has more stage 4's. Anolther is that less compliance during treatment for older folks. Really don't know. But while seemingly dramatic, between let's say age 20 verus age 70, a couple of years here or there shouldn't make much difference. And in many cases, that's all that is being suggested. Watch and wait, doesn't necessarily mean wait forever.
Be well,
-- Jim
Be well,
-- Jim
Yes, there are other factors to consider besides stage, but I was addressing stage here because that is what 'Ala' appeared to be referring to. I later found out she is "acute' which is a different story. I do agree about the other factors you list although ironically those infected at a younger age appear to have a better chance of SVR. I would also think that since infected at a younger age, they therefore have had the virus longer. Do the two cancel each other out? Never quite figured that one out :) Lastly, I really think we now have to start factoring in the very real potential of future drug treatments into this equation. For discussions sake -- only -- assuming treating earlier servers up better SVR rates. But that's comparing SOC to SOC. On the other hand, treating now could mean treating with less effective drugs which could wipe out those the treating early benefits in spades. It's a tough and very individual decision. Individually we come out where we come out. As you know, I decided to wait until I had significant liver damage -- and that was before the newer drugs came out. I'll check out the graph later.
-- Jim
-- Jim
Hi Jim, you wrote: "A recent study suggests that the cure rate is identical for all stages of Hep C, except stage 4 which is cirrhosis."
We had the discussion before, and I still have the opinion it is less simple:
There are many factors responsible for the prognosis, from age, time of being infected, grade, VL, genotype, bodyweight, ironload, ethnic group, and so on and on.
As suggested in another thread: Time to start treating is an important factor too!
See the following graph: http://tinyurl.com/28nnkz (german fulltext)
On the left: chance in % to eliminate the virus. The german word Alter = age.
We had the discussion before, and I still have the opinion it is less simple:
There are many factors responsible for the prognosis, from age, time of being infected, grade, VL, genotype, bodyweight, ironload, ethnic group, and so on and on.
As suggested in another thread: Time to start treating is an important factor too!
See the following graph: http://tinyurl.com/28nnkz (german fulltext)
On the left: chance in % to eliminate the virus. The german word Alter = age.
I just read "Ala's" post in another thread and she does appear to be in the acute stage which would mean that her chances of getting rid of the virus are better if she treats now. I do question, however, why she's treating 48 weeks? My understanding is that treatment protocols for acute geno 1's is closer to 24 weeks with very good results. Even read they had good results without ribavirin. "Ala", hopefully you're seeing a hepatologist (liver specialist) as opposed to a gastroenterologist. I say this because acutes present different issues than those chronically infected and probably only a liver specialist (heptologist) will be up on the differences. As to your rise in liver enzymes per the other thread, given that you're acute, those numbers seem pretty normal. Also, keep in mind that those enzmes do not move in a linear fashion. In other words ALT 200 is not twice as bad as ALT 100, just somewhat higher.
-- Jim
-- Jim
I wasn't aware that "Ala" was acute. It appeared she was using the word "acute", not in the sense of "acute HCV" (within six months of initial infection) but in terms of length of infection, "....the more acute you were...". Of course, if "Ala" truly is acute (was infected within six months) then that's a different story and acute protocols apply which are different from the protocols most of us follow -- both in regards to the treatment decision as well as to length of treatment, and possibly even drugs and doses, depending on what study you read.
-- Jim
-- Jim
Upbeat, when you posted last week of why the drop in stock price this may have had something to do with it. The market knows well in advance and reacts just the same.
jasper
BOSTON -- Another nugget of positive clinical data came out last week from Vertex Pharmaceuticals and its experimental hepatitis C drug, but it has been a bit overshadowed by some downward volatility in the company's stock.
At a meeting of infectious-disease researchers in Chicago, investigators reported that some patients who prematurely discontinued treatment with Vertex's drug telaprevir were still able to clear the hepatitis C virus completely from their system.
"This speaks to the potency of telaprevir," says Cowen biotech analyst Rachel McMinn, who covers Vertex. "These patients received a short course of therapy with telaprevir [less than the 12 weeks they were supposed to receive] , but they still were able to achieve a sustained virologic response." McMinn has an outperform rating on Vertex, and Cowen doesn't do banking for the company.
While bullish on Vertex and telaprevir, McMinn was also responsible (albeit inadvertently) for raising some worries about the drug that caused the stock to take a midweek swoon.
In a short note to clients last Wednesday, McMinn lowered her prediction for the percentage of patients in the ongoing telaprevir U.S. phase II study who would achieve a sustained virologic response, or SVR. (In layman's terms, these patients are cured of hepatitis C.)
McMinn lowered her projected SVR range to 59% to 61% from her previous estimate of 61% to 65%. The actual data on telaprevir and its SVR rate will be made public in early November at a liver disease meeting being held in Boston.
Vertex shares were trading around $40 Wednesday when McMinn's note hit trading desks. The stock quickly fell about 7% to an intraday low of $37.33. The stock has only partially recovered, closing Friday at $38.24.
In a postnote interview late last week, McMinn said that she adjusted her estimate based on the data presented at this week's infectious disease meeting, but that she didn't intend to send a negative signal.
"Our earlier projections [for a telaprevir cure rate] were a little too high, but there was nothing negative fundamentally to take away from the data presented," she said.
To put these numbers in perspective, a hepatitis C cure rate of 59% to 61% for telaprevir would represent a significant improvement over the current standard of care, which only succeeds in eliminating the hepatitis C virus from about 40% of U.S. patients.
Telaprevir is a pill designed to attack hepatitis C by inhibiting the protease enzyme, one of the key enzymes the virus uses to copy itself. This "direct antiviral" approach differs from current hepatitis C drugs, which boost the immune system's ability to tamp down and eliminate the virus.
The current standard of care for hepatitis C patients is a weekly injection of long-acting alpha interferon combined with daily oral doses of a generic drug, ribavirin. A normal treatment course for Type 1 hepatitis C (the most prevalent form) takes 48 weeks to complete, and many patients find the side effects, such as flulike symptoms, anemia and depression, difficult to tolerate.
Telaprevir is being combined with interferon and ribavirin to create a more potent and less time-consuming hepatitis C treatment regimen. Three large phase II studies are underway, investigating various treatment schedules. The most promising combination so far treats hepatitis C patients for 12 weeks with the triple combination (telaprevir, interferon and ribavirin), followed by 12 weeks of interferon and ribavirin on their own.
That's 24 weeks of total treatment -- half the current standard of care.
At the infectious disease meeting held last week, investigators from the U.S.-based phase II telaprevir study, known as Prove 1, reported new details on a group of 27 patients enrolled in two arms of the study. These patients didn't receive the full 12 weeks of telaprevir for various reasons.
However, investigators were able to follow up on 19 of these 27 patients to determine whether even a shortened course of telaprevir would be effective enough to result in a cure. Of these 19 patients, 7 of them, or 37%, achieved an SVR, or cure. The other 12 patients relapsed.
It was entirely possible to assume that these hepatitis C patients who weren't able to complete their treatment would have relapsed or otherwise not have been able clear the virus from their system. Instead, at least some of them were cured, which suggests that telaprevir is a very potent drug, McMinn says.
Although data collected and presented on telaprevir have been promising so far, it's the results not yet made public that will inform the ultimate verdict on the drug. The most important telaprevir data to date will be presented Nov. 2-6 at the annual meeting of the American Association for the Study of Liver Disease.
Vertex shares have been on a monster run since late June, when shares had dipped to around $26. This week's volatility may be a precursor of more to come, as some investors choose to take profits instead of risking gains before new data are released in November.
jasper
BOSTON -- Another nugget of positive clinical data came out last week from Vertex Pharmaceuticals and its experimental hepatitis C drug, but it has been a bit overshadowed by some downward volatility in the company's stock.
At a meeting of infectious-disease researchers in Chicago, investigators reported that some patients who prematurely discontinued treatment with Vertex's drug telaprevir were still able to clear the hepatitis C virus completely from their system.
"This speaks to the potency of telaprevir," says Cowen biotech analyst Rachel McMinn, who covers Vertex. "These patients received a short course of therapy with telaprevir [less than the 12 weeks they were supposed to receive] , but they still were able to achieve a sustained virologic response." McMinn has an outperform rating on Vertex, and Cowen doesn't do banking for the company.
While bullish on Vertex and telaprevir, McMinn was also responsible (albeit inadvertently) for raising some worries about the drug that caused the stock to take a midweek swoon.
In a short note to clients last Wednesday, McMinn lowered her prediction for the percentage of patients in the ongoing telaprevir U.S. phase II study who would achieve a sustained virologic response, or SVR. (In layman's terms, these patients are cured of hepatitis C.)
McMinn lowered her projected SVR range to 59% to 61% from her previous estimate of 61% to 65%. The actual data on telaprevir and its SVR rate will be made public in early November at a liver disease meeting being held in Boston.
Vertex shares were trading around $40 Wednesday when McMinn's note hit trading desks. The stock quickly fell about 7% to an intraday low of $37.33. The stock has only partially recovered, closing Friday at $38.24.
In a postnote interview late last week, McMinn said that she adjusted her estimate based on the data presented at this week's infectious disease meeting, but that she didn't intend to send a negative signal.
"Our earlier projections [for a telaprevir cure rate] were a little too high, but there was nothing negative fundamentally to take away from the data presented," she said.
To put these numbers in perspective, a hepatitis C cure rate of 59% to 61% for telaprevir would represent a significant improvement over the current standard of care, which only succeeds in eliminating the hepatitis C virus from about 40% of U.S. patients.
Telaprevir is a pill designed to attack hepatitis C by inhibiting the protease enzyme, one of the key enzymes the virus uses to copy itself. This "direct antiviral" approach differs from current hepatitis C drugs, which boost the immune system's ability to tamp down and eliminate the virus.
The current standard of care for hepatitis C patients is a weekly injection of long-acting alpha interferon combined with daily oral doses of a generic drug, ribavirin. A normal treatment course for Type 1 hepatitis C (the most prevalent form) takes 48 weeks to complete, and many patients find the side effects, such as flulike symptoms, anemia and depression, difficult to tolerate.
Telaprevir is being combined with interferon and ribavirin to create a more potent and less time-consuming hepatitis C treatment regimen. Three large phase II studies are underway, investigating various treatment schedules. The most promising combination so far treats hepatitis C patients for 12 weeks with the triple combination (telaprevir, interferon and ribavirin), followed by 12 weeks of interferon and ribavirin on their own.
That's 24 weeks of total treatment -- half the current standard of care.
At the infectious disease meeting held last week, investigators from the U.S.-based phase II telaprevir study, known as Prove 1, reported new details on a group of 27 patients enrolled in two arms of the study. These patients didn't receive the full 12 weeks of telaprevir for various reasons.
However, investigators were able to follow up on 19 of these 27 patients to determine whether even a shortened course of telaprevir would be effective enough to result in a cure. Of these 19 patients, 7 of them, or 37%, achieved an SVR, or cure. The other 12 patients relapsed.
It was entirely possible to assume that these hepatitis C patients who weren't able to complete their treatment would have relapsed or otherwise not have been able clear the virus from their system. Instead, at least some of them were cured, which suggests that telaprevir is a very potent drug, McMinn says.
Although data collected and presented on telaprevir have been promising so far, it's the results not yet made public that will inform the ultimate verdict on the drug. The most important telaprevir data to date will be presented Nov. 2-6 at the annual meeting of the American Association for the Study of Liver Disease.
Vertex shares have been on a monster run since late June, when shares had dipped to around $26. This week's volatility may be a precursor of more to come, as some investors choose to take profits instead of risking gains before new data are released in November.
sorry if I'm repeating information you're already well aware of, but remember that effectively all of the discussion you'll find on this forum is not relevant to your acute (ie at onset) infection. For acute you don't want to wait for anything - untreated your chances of resolving the infection are on the order of 20%; with appropriate dosage/duration of ifn they're substantially better.
The following recent review of hcv treatment
http://tinyurl.com/yp2jwf
includes a section with uptodate references on treating acute infection.
The following recent review of hcv treatment
http://tinyurl.com/yp2jwf
includes a section with uptodate references on treating acute infection.
the German doctors might not be starting a phase three trial for teleprevir for 2 or 3 years but Vertex says they are starting phase 3 by the end of 07 or early 08. They should be announcing it in November. They are aiming for approval in 09. the sooner the better and once it gets approved then doctors can treat and customize as needed. Good luck to all that get in the trial.
Very few people have a symptomatic acute stage and therefore most of us treat in the chronic stage which is sometime after being infected for six months. A recent study suggests that the cure rate is identical for all stages of Hep C, except stage 4 which is cirrhosis. So going back to your thoughts, the virus "takes root" after around six months from date of infection. After that, it isn't going to take any more root. Liver damage, however, may progress as time goes by, but it's a very slow moving process.
-- Jim
-- Jim
I thought that more acute you were and the less entrenched the virus, the better chance for clearance? Wouldn't that argue for more aggressive treatment early on in an attempt to clear it before the virus really takes root in your system?
ala: I'm asking is why wouldn't you at least go 48 months on the current combo therapy?
--------------------------------------
Because, if you feel you have time to wait -- for example no significant liver damage -- then waiting for a treatment that promises double the cure rate in half the time is a reasonable choice when your weigh risks verus rewards. Just like not treating hep c has certain risks, the treatment drugs themselves also do. It's a matter of weighing relative risks and rewards of treating or waiting. With promising drugs like Teleprevir in the trial pipeline, it makes sense to factor it into that equation.
-- Jim
--------------------------------------
Because, if you feel you have time to wait -- for example no significant liver damage -- then waiting for a treatment that promises double the cure rate in half the time is a reasonable choice when your weigh risks verus rewards. Just like not treating hep c has certain risks, the treatment drugs themselves also do. It's a matter of weighing relative risks and rewards of treating or waiting. With promising drugs like Teleprevir in the trial pipeline, it makes sense to factor it into that equation.
-- Jim
I am somewhat confused. As someone recently diagnosed I am unclear on what is meant by the waiting for additional drugs? Wouldn't you go full bore with what is available now and then if that does not, for some reason, clear you after 48 months try the other medications should they be available by then? I mean, I guess what I'm asking is why wouldn't you at least go 48 months on the current combo therapy? Is this a stupid question?
much further than 2010 for vx does seem pessimistic unless the large-scale phase III turns up some skeletons in the closet, but considering that the basic structural research was pretty-much wrapped up by '04
http://tinyurl.com/yuqsho
that's still a long stretch from lab to drug-store - and that delay doesn't seem likely to change much regardless of what develops in the labs. Our best bet for more time may not be a biotech silver bullet but some more mundane inhibitor of fibrosis progression. Still if r1626's phase II doesn't fly well, it may be time to rethink things...
http://tinyurl.com/yuqsho
that's still a long stretch from lab to drug-store - and that delay doesn't seem likely to change much regardless of what develops in the labs. Our best bet for more time may not be a biotech silver bullet but some more mundane inhibitor of fibrosis progression. Still if r1626's phase II doesn't fly well, it may be time to rethink things...
I agree that 2 active agents will be what it takes to really make a dent in the population of failed tx'ers (metaphorically speaking ofcourse :))
I wonder about the timing too. VX950 is widely expected to be available circa 2010 - but doing VX+SOC is no picnic. When I speculate further than that I just get into the realms of my hopes and dreams, not anything based on today's reality. I hope that the lateral thinking of some genius will come up with some treatment which is more humane. Who cares about taking the pills for 48 weeks of more if they are safe and the sides are minimal. Well, that's what I hope. Isn't this supposed to be the dawn of the biotech and nanotechnology age when new development suddenly skyrockets faster than anybody living today can imagine?
dointime
I wonder about the timing too. VX950 is widely expected to be available circa 2010 - but doing VX+SOC is no picnic. When I speculate further than that I just get into the realms of my hopes and dreams, not anything based on today's reality. I hope that the lateral thinking of some genius will come up with some treatment which is more humane. Who cares about taking the pills for 48 weeks of more if they are safe and the sides are minimal. Well, that's what I hope. Isn't this supposed to be the dawn of the biotech and nanotechnology age when new development suddenly skyrockets faster than anybody living today can imagine?
dointime
thanks for the update. I'd be curious to hear how many others are betting on combining vx-950 with a polymerase inhibitor or other hcv-targeted therapy. The numbers on additivity of vx + soc vl reduction are decent and, by all expectations should be quite a bit higher for vx + an hcv-targeted drug that goes after something other than the ns3 protease.
I keep reading "forward looking statements" about how well this combo/cocktail approach is expected to work, but, meanwhile, am a bit disturbed that (a) drug candidates keep dropping like flies and (b) not a single combo clinical study has started yet ( I did see an in-vitro paper a while back) so my current estimate is 6- 7 years for something like R1626 +vx950. Anyone else have guesses on this?
I keep reading "forward looking statements" about how well this combo/cocktail approach is expected to work, but, meanwhile, am a bit disturbed that (a) drug candidates keep dropping like flies and (b) not a single combo clinical study has started yet ( I did see an in-vitro paper a while back) so my current estimate is 6- 7 years for something like R1626 +vx950. Anyone else have guesses on this?
Excellent post, Thanks!
Yup! Sure glad I did not wait for the new drug Telaprevir to come out, now possibly three years away, if then. Even then the interferon and ribavirin are the basic building blocks of any new future hcv agents. At 4.7m and gaining 300k dragons per year and left waiting for the new drugs to come out and being at stage 2 grade 2, I would be in a lot more trouble then than I am now if I had waited. Glad I started when I did even with all the nasty sx involved from both the Interferon and Ribavirin.
yes, yes jim I know it's only one studyand there will be others.
jasper
Yup! Sure glad I did not wait for the new drug Telaprevir to come out, now possibly three years away, if then. Even then the interferon and ribavirin are the basic building blocks of any new future hcv agents. At 4.7m and gaining 300k dragons per year and left waiting for the new drugs to come out and being at stage 2 grade 2, I would be in a lot more trouble then than I am now if I had waited. Glad I started when I did even with all the nasty sx involved from both the Interferon and Ribavirin.
yes, yes jim I know it's only one studyand there will be others.
jasper
In the meantime, a phase II trial of telaprevir in chronic hepatitis C, genotype 1, has been initiated, and early but still incomplete results were presented as a late-breaking abstract at the annual meeting of the European Association for the Study of the Liver.[11] In this second trial, telaprevir was given for 12 weeks in combination with peginterferon and ribavirin and compared with therapy with peginterferon and ribavirin alone. Patients who received triple therapy for 12 weeks stopped telaprevir and were then randomized to (1) stop all therapy at 12 weeks, (2) continue peginterferon and ribavirin for another 12 weeks (total duration = 24 weeks), or (3) continue peginterferon and ribavirin for another 36 weeks (total duration = 48 weeks). The 3 telaprevir-combination arms were compared to the standard of care: a 48-week course of peginterferon and ribavirin alone. Preliminary results indicated that 70% of the patients given triple therapy had no detectable HCV RNA (<10 IU/mL) at 12 weeks versus only 39% of the patients given the conventional combination therapy. When all therapy was stopped at 12 weeks in 1 arm of the study, relapses occurred, but there was inadequate follow-up to provide a reliable rate of SVR. The remaining categories of telaprevir-treated patients are still receiving peginterferon and ribavirin or are in active follow-up. These findings suggest that a 12-week course of triple therapy may not be adequate.
We now await studies in which triple therapy is given for a full 24 or 48 weeks, but until then, issues of safety and the success of abbreviated therapy will need to be addressed. Early results of the preliminary trials of telaprevir indicate a possible problem of tolerability. In the 2-week phase Ib trial, 25% of the patients developed a mild or moderate rash, but none required early discontinuation of treatment.[4] In the 12-week phase II trial, a higher proportion of patients receiving telaprevir developed a rash that led to early discontinuation for some.[11] The cause of the rash has not been elucidated.
Thus, telaprevir is a promising agent but still must pass the critical tests of ultimate efficacy and safety. If all goes well, phase III trials should begin within the next 1-2 years, and this means that new therapies for hepatitis C are at least 3 years away (2010 or beyond) from general availability. What else is available or might become available sooner?
Other approaches to the therapy of chronic hepatitis C include modifications of the dose and duration of combination therapy. The use of modified or improved interferons (such as consensus interferon, albumin-labeled interferon,[12] or omega interferon[13]) may be helpful, but they are unlikely to improve SVR rates to a great extent. Modified or improved forms of ribavirin include a prodrug, viramidine, which is now known as taribavirin.[14] Taribavirin has promise as a better tolerated form of ribavirin, but recent results indicate that it is less effective in increasing SVR rates.[15] Higher doses of ribavirin (1400-2400 rather than 800-1200 mg daily) have been studied in small clinical trials and appear to yield higher rates of SVR, but at the expense of much more toxicity (anemia requiring growth factor support and blood transfusions).[16]
Perhaps more promising are the many other small-molecule inhibitors of HCV that are currently in human trials, which include polymerase inhibitors (NM283, HCV-796 [RECENTLY DISCONTINUED STUDY DUE TO TOXICITY], and R1626) and protease inhibitors (BILN-2061, SCH503034, and SL196).[17-19] BILN-2061 was the first HCV-specific protease inhibitor to be assessed in humans, and preliminary studies showed great promise with marked activity against HCV genotype 1.[19] Unfortunately, toxicities were identified in laboratory animals receiving BILN-2061, and further development was abandoned. Another promising agent is NM283 (RECENTLY DISCONTINUED DUE TO TOXICITY), now known as valopicitabine, which is a cytidine analogue and RNA chain terminator.[20] Preliminary studies showed that valopicitabine had variable activity against HCV, but a high rate of gastrointestinal intolerance was found at the most potent doses. Unfortunately, in phase II studies of valopicitabine in combination with peginterferon, this regimen was less effective than the standard combination therapy and was ineffective in peginterferon/ribavirin nonresponders.[21][22] Finally, there are multiple innovative and molecular approaches to therapy, including the use of alpha-glucosidase inhibitors, modified cyclophilins, viral entry inhibitors, antisense molecules, ribozymes, and small interfering RNAs.[17] These approaches need major refinements and further assessments for safety before efficacy trials can be initiated.
The vicissitudes of the development of new agents for the therapy of hepatitis C are distressing but typical for new drug development. For every 10 new therapeutic agents that enter human trials, only 1 or 2 are likely to survive the careful scrutiny for efficacy and lack of toxicity. The 2 publications on telaprevir provide hope for the future. For the next 3-5 years, however, the combination of peginterferon and ribavirin is likely to remain the recommended regimen for the treatment of hepatitis C, and future optimal therapies of hepatitis C may employ 3 or 4 agents together rather than a simple regimen of 1 or 2.
References
We now await studies in which triple therapy is given for a full 24 or 48 weeks, but until then, issues of safety and the success of abbreviated therapy will need to be addressed. Early results of the preliminary trials of telaprevir indicate a possible problem of tolerability. In the 2-week phase Ib trial, 25% of the patients developed a mild or moderate rash, but none required early discontinuation of treatment.[4] In the 12-week phase II trial, a higher proportion of patients receiving telaprevir developed a rash that led to early discontinuation for some.[11] The cause of the rash has not been elucidated.
Thus, telaprevir is a promising agent but still must pass the critical tests of ultimate efficacy and safety. If all goes well, phase III trials should begin within the next 1-2 years, and this means that new therapies for hepatitis C are at least 3 years away (2010 or beyond) from general availability. What else is available or might become available sooner?
Other approaches to the therapy of chronic hepatitis C include modifications of the dose and duration of combination therapy. The use of modified or improved interferons (such as consensus interferon, albumin-labeled interferon,[12] or omega interferon[13]) may be helpful, but they are unlikely to improve SVR rates to a great extent. Modified or improved forms of ribavirin include a prodrug, viramidine, which is now known as taribavirin.[14] Taribavirin has promise as a better tolerated form of ribavirin, but recent results indicate that it is less effective in increasing SVR rates.[15] Higher doses of ribavirin (1400-2400 rather than 800-1200 mg daily) have been studied in small clinical trials and appear to yield higher rates of SVR, but at the expense of much more toxicity (anemia requiring growth factor support and blood transfusions).[16]
Perhaps more promising are the many other small-molecule inhibitors of HCV that are currently in human trials, which include polymerase inhibitors (NM283, HCV-796 [RECENTLY DISCONTINUED STUDY DUE TO TOXICITY], and R1626) and protease inhibitors (BILN-2061, SCH503034, and SL196).[17-19] BILN-2061 was the first HCV-specific protease inhibitor to be assessed in humans, and preliminary studies showed great promise with marked activity against HCV genotype 1.[19] Unfortunately, toxicities were identified in laboratory animals receiving BILN-2061, and further development was abandoned. Another promising agent is NM283 (RECENTLY DISCONTINUED DUE TO TOXICITY), now known as valopicitabine, which is a cytidine analogue and RNA chain terminator.[20] Preliminary studies showed that valopicitabine had variable activity against HCV, but a high rate of gastrointestinal intolerance was found at the most potent doses. Unfortunately, in phase II studies of valopicitabine in combination with peginterferon, this regimen was less effective than the standard combination therapy and was ineffective in peginterferon/ribavirin nonresponders.[21][22] Finally, there are multiple innovative and molecular approaches to therapy, including the use of alpha-glucosidase inhibitors, modified cyclophilins, viral entry inhibitors, antisense molecules, ribozymes, and small interfering RNAs.[17] These approaches need major refinements and further assessments for safety before efficacy trials can be initiated.
The vicissitudes of the development of new agents for the therapy of hepatitis C are distressing but typical for new drug development. For every 10 new therapeutic agents that enter human trials, only 1 or 2 are likely to survive the careful scrutiny for efficacy and lack of toxicity. The 2 publications on telaprevir provide hope for the future. For the next 3-5 years, however, the combination of peginterferon and ribavirin is likely to remain the recommended regimen for the treatment of hepatitis C, and future optimal therapies of hepatitis C may employ 3 or 4 agents together rather than a simple regimen of 1 or 2.
References
However, even before the application of VX-950 to humans, the specter of antiviral drug resistance was raised. In replicon cell culture systems, the application of VX-950 was found to select for HCV variants with drug resistance.[9] Similar kinetics for the development of antiviral resistance were found for other inhibitors of the nonstructural 3 protease, although these variants had different specific mutations and mechanisms of resistance. These findings indicated that the long-term use of HCV protease inhibitors would probably require a combination therapy with other protease inhibitors, HCV polymerase inhibitors, or perhaps peginterferon with or without ribavirin. It was the last combination that was eventually pursued.
In this issue of HEPATOLOGY, Forestier and her coinvestigators[4] from Saarland University Hospital, the University of Amsterdam, and Vertex Pharmaceutics describe the preliminary clinical results of a small phase Ib trial of telaprevir.[4] The report provides information on HCV RNA and alanine aminotransferase levels in 8 patients who received telaprevir alone, 8 who received telaprevir with peginterferon, and 4 who served as controls and received peginterferon alone for 2 weeks. Telaprevir was then stopped, but the patients were offered a continuation of treatment with a combination of peginterferon and ribavirin until 48 weeks and thus were provided the standard of care for chronic hepatitis C, genotype 1. Telaprevir led to a rapid decline in HCV RNA levels within 1-4 days. The combination of peginterferon with telaprevir resulted in a similar early decline in viral levels, but importantly, the combination therapy was associated with an additional, continuing decline after the first 4 days of treatment. At 14 days, the median decrease in HCV RNA was 5.5 log10 with telaprevir and peginterferon, 4.0 log10 with telaprevir alone, and only 1.1 log10 with peginterferon. These results suggest that peginterferon and telaprevir are synergistic (or at least additive) in their antiviral activity against HCV, and this finding is supported by cell culture results.[10]
The basis for the synergy between peginterferon and telaprevir is suggested by the second article in this issue on telaprevir by Kieffer and coworkers[5] from Vertex Pharmaceuticals and the Johann Wolfgang von Goethe University Hospital at Frankfurt, who investigated variations in the nonstructural 3 and 4A sequence of HCV from patients in this same phase Ib trial. HCV sequence variants with lower sensitivity to telaprevir arose in a high proportion of patients within 10-14 days of the initiation of therapy. However, the telaprevir-resistant variants of HCV appeared to be sensitive to interferon, and the subsequent treatment with peginterferon and ribavirin was associated with further decreases in HCV RNA and a lack of further detection of the viral variants. Thus, the apparent synergy of peginterferon and telaprevir may be due to the sensitivity of the low levels of telaprevir-resistant viral variants to interferon. Consequently, a short course of telaprevir followed by peginterferon and ribavirin may be highly effective, the protease inhibitor lowering HCV RNA to levels that are readily susceptible to peginterferon.
Although this is a promising approach, only limited information has been provided on its success. Forestier et al.[4] report 12-week follow-up results and Kieffer et al.[5] report 24-week follow-up results for the subsequent course of the 15 telaprevir-treated patients who were then treated with peginterferon and ribavirin. HCV RNA was undetectable (<10 IU/mL) in all patients at 12 weeks and in all but 1 at 24 weeks. No information is given on the results at 48 week or on the SVR results at 72 weeks, which, in view of the time of initiation of the study, should now be available.
In this issue of HEPATOLOGY, Forestier and her coinvestigators[4] from Saarland University Hospital, the University of Amsterdam, and Vertex Pharmaceutics describe the preliminary clinical results of a small phase Ib trial of telaprevir.[4] The report provides information on HCV RNA and alanine aminotransferase levels in 8 patients who received telaprevir alone, 8 who received telaprevir with peginterferon, and 4 who served as controls and received peginterferon alone for 2 weeks. Telaprevir was then stopped, but the patients were offered a continuation of treatment with a combination of peginterferon and ribavirin until 48 weeks and thus were provided the standard of care for chronic hepatitis C, genotype 1. Telaprevir led to a rapid decline in HCV RNA levels within 1-4 days. The combination of peginterferon with telaprevir resulted in a similar early decline in viral levels, but importantly, the combination therapy was associated with an additional, continuing decline after the first 4 days of treatment. At 14 days, the median decrease in HCV RNA was 5.5 log10 with telaprevir and peginterferon, 4.0 log10 with telaprevir alone, and only 1.1 log10 with peginterferon. These results suggest that peginterferon and telaprevir are synergistic (or at least additive) in their antiviral activity against HCV, and this finding is supported by cell culture results.[10]
The basis for the synergy between peginterferon and telaprevir is suggested by the second article in this issue on telaprevir by Kieffer and coworkers[5] from Vertex Pharmaceuticals and the Johann Wolfgang von Goethe University Hospital at Frankfurt, who investigated variations in the nonstructural 3 and 4A sequence of HCV from patients in this same phase Ib trial. HCV sequence variants with lower sensitivity to telaprevir arose in a high proportion of patients within 10-14 days of the initiation of therapy. However, the telaprevir-resistant variants of HCV appeared to be sensitive to interferon, and the subsequent treatment with peginterferon and ribavirin was associated with further decreases in HCV RNA and a lack of further detection of the viral variants. Thus, the apparent synergy of peginterferon and telaprevir may be due to the sensitivity of the low levels of telaprevir-resistant viral variants to interferon. Consequently, a short course of telaprevir followed by peginterferon and ribavirin may be highly effective, the protease inhibitor lowering HCV RNA to levels that are readily susceptible to peginterferon.
Although this is a promising approach, only limited information has been provided on its success. Forestier et al.[4] report 12-week follow-up results and Kieffer et al.[5] report 24-week follow-up results for the subsequent course of the 15 telaprevir-treated patients who were then treated with peginterferon and ribavirin. HCV RNA was undetectable (<10 IU/mL) in all patients at 12 weeks and in all but 1 at 24 weeks. No information is given on the results at 48 week or on the SVR results at 72 weeks, which, in view of the time of initiation of the study, should now be available.
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