Worth Reading June 3 2011
FDA May 23, 2011 Teleconference Briefing on Direct Acting Antivirals, Victrelis (boceprevir) and Incivek (telaprevir) transcript
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On May 23, 2011, FDA held a telephone briefing to discuss two Direct Acting Antivirals (DAAs) with health care providers and patient advocates having an interest in treatment for hepatitis C. The call was intended to provide an overview of the safety and efficacy data and complexity of dosing regimens, and respond to questions about the use of these recently approved protease inhibitors, indicated as part of combination drug therapy, for the treatment of hepatitis C.
The call was initiated in response to comments at the April 27 and 28, 2011 FDA Antiviral Drugs Advisory Committee meeting to consider data related to marketing applications for Victrelis (boceprevir) and Incivek (telaprevir), suggesting that additional information would be helpful in understanding the use of these drugs in clinical care.
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A record of the teleconference (approximately 50 minutes) is being made available in either of two formats:
Written Transcript
Download Audio Recording Podcast (22 MB)
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FDA May 23, 2011 Teleconference Briefing on Direct Acting Antivirals, Victrelis (boceprevir) and Incivek (telaprevir)
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Moderator: Richard Klein
May 23, 2011
3:30 pm EDT
Richard Klein: Good afternoon everyone. This is Richard Klein from the FDA’s Office of Special Health Issues, and I’d like to thank you for joining us this afternoon.
The purpose of today’s call is to update you about two direct acting anti-viral drugs to treat hepatitis C discussed at a meeting of the FDA Antiviral Advisory Committee on April 27 and 28.
At that meeting stakeholders made it evident that they would benefit from added guidance from FDA about complex treatment regimens described during the committee discussions and about possible adverse events associated with the antiviral treatment of hepatitis C. Today’s briefing is a response to those comments. Before we get started, I would like to briefly review how we will proceed.
With me in the room are Dr. Debra Birnkrant, Director of the FDA’s Division of Antiviral Products and Dr. Jeffrey Murray, Deputy Director of the Division and they will provide an overview of the data supporting the safety and effectiveness of these drugs to treat hepatitis C.
Immediately following the discussion, we will open the lines for your questions. Your phones will be on mute during the presentation. Prior to the start of the question-and-answer session, the operator will provide instructions on how to ask questions of FDA’s experts. Please be aware that the teleconference is being recorded for playback, so please state your name prior to joining the conversation. If you are asking a question, please be sure to speak clearly and directly into your telephone.
Before we begin the overview I have the extreme pleasure of introducing Dr. Margaret Hamburg, Commissioner of the Food and Drug Administration. Dr. Hamburg.
Dr. Margaret Hamburg: Thank you, Richard. I’m very pleased that I have the opportunity to join you and a very talented team of medical reviewers from FDA’s Division of Antiviral Drugs today to discuss the FDA’s recent approval of Victrelis, also known as Boceprevir and Incivek or Telaprevir; two direct acting antiviral drugs that represent a new direction in the treatment of hepatitis C and a significant improvement over the current standard of care.
These are two new innovative products that are worthy of notice and will make a difference literally saving lives. It’s also worth noting that today’s approval of Incivek represents the 15th new drug approved in just the first five months of this year.
I want to take this moment to congratulate Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research; Dr. John Jenkins, Director of the Office of New Drugs in The Center for Drugs Evaluation and Research, and their staff for all the work in reaching decisions in a timely manner, ensuring patient access to safe and effective new treatments.
A few short weeks ago FDA’s Antiviral Drugs Advisory Committee, one of several committees comprised of medical experts and community advocates, met to discuss both of these drugs. I want to thank that committee for the recommendations which unanimously voted to recommend approval of both drugs as well as to thank and congratulate the companies responsible for developing Incivek and Victrelis and the FDA staff for their diligence in completing these applications expeditiously ensuring that patients have access to highly effective new drugs as quickly as possible.
Today truly represents a great day for the more than 3 million American men and women currently living with chronic hepatitis C and the millions more living with this often difficult to treat disease worldwide.
Viral hepatitis continues to a leading infectious cause of death in the United States and many people don’t even realize they’re infected.
I want to commend many of the patient groups and healthcare organizations participating on today’s call who’s done an exceptional job raising awareness and encouraging millions of individuals at risk to go get tested.
Recently, the US Department of Health and Human Services - HHS - announced an action plan which most of you are probably familiar with by now titled Combating the Silent Epidemic, US Department Health and Human Services action plan for the prevention, care, and treatment of viral hepatitis.
The report outlines the comprehensive action plan to raise awareness about viral hepatitis, creates more opportunities to train health professionals to diagnose, treat, and vaccinate for hepatitis A and B and ultimately save lives and it builds upon the new Health Insurance Reform law to improve patient access to comprehensive viral hepatitis-related prevention and treatment services through expanded coverage.
The approval of these two new drugs will no doubt factor into this plan moving forward and their availability today is a testament to the hard work and dedication of academic researchers, diligent companies willing to invest in areas where existing therapies have failed or only provided temporary relief for patients, and an FDA staff willing to go the extra mile to ensure that patients have access to safe and effective new drugs.
As someone who has spent most of my career working on infectious disease issues and with first-hand experience treating and combating deadly infections, the significance of these approvals is not lost on me.
Before I turn it over to Dr. Debra Birnkrant whose division was not only responsible to the approval of these two drugs, but the approval this past Friday also of Edurant or Rilpivirine; another new treatment option for patients whose not received treatment for HIV infections.
I want to thank all of you on the phone for taking the time to join us in this call. Your continued support and engagement with FDA is essential to our mission. We are a regulatory agency that takes very seriously the science-based, data driven decisions that we make for and on behalf of the American people and beyond. All aspects of our mission are crucial to the health of individuals and the public health. I know that the work of organizations like all of yours is crucial too.
So with that, I’ll now turn the call over to Dr. Debra Birnkrant. Thank you very much.
Dr. Debra Birnkrant: Thank you, Dr. Hamburg. Good afternoon. I’d like to thank Dr. Hamburg for her opening comments that set the stage for the stakeholders meeting where Dr. Jeffrey Murray, Deputy Director of the Division of Antiviral Products and I will be sharing some of the details about the approvals of two new direct acting antivirals, Telaprevir and Boceprevir for use in combination with pegylated interferon and Rilpivirine for the treatment of genotype 1 chronic hepatitis C in adult patients.
As I wrote my memorandum in support of the approval of these DAAs, this time reminds me of the mid-1990s when we approved various antiretrovirals for the HIV infected population and the impact those approvals have had on patients’ lives. We expect to see a similar impact with the use of these new therapies in patients with chronic hepatitis C. It is truly an exciting time.
With that, I’d like to start with additional background and some concepts because we will be using these terms during our presentation. I also recommend that you review the approved prescribing information because we will not be able to go into detail in every aspect of these drugs.
To begin with as was mentioned chronic hepatitis C is both a global and domestic problem with 170 million estimated to be infected worldwide and approximately 3 million infected in the United States.
Of the 5.6 million veterans in veteran's healthcare in 2008, 2.6 had a diagnosis of chronic hepatitis C. Although the incidents of infection in the United States is decreasing, chronic hepatitis C related complications are increasing such as psorosis and hepatocellular carcinoma.
With the aging of the infected population more liver-related complications are expected in the next 10 to 20 years without the use of potent antiviral therapies. I’d also like to mention and underline that chronic hepatitis C is already the most common reason for liver transplantation.
Beginning with some definitions that are crucial to understanding how to properly use these products. The naïve population is a population described as a population who is receiving no prior therapy for hepatitis C including interferon or pegylated interferon monotherapy.
The no responder population is one that has had less than a (two log) reduction in HCV RNA at week 12 of a pegylated interferon Ribavirin regimen. A partial responder has had greater than or equal to a (two log) reduction in HCV RNA at week 12, but has not achieved HCV RNA undetectable at the end of treatment. And a responder relapser is one that has had HCV RNA undetectable at the end of treatment with a pegylated interferon based regimen, but HCV RNA detectable within 24 weeks of treatment follow up. This group is most closely related to the naïve population with regards to interferon responsiveness.
Additional definitions that are important. A rapid virologic response or RVR is one that is an undetectable HCV RNA at week 4 and an extended RVR or ERVR is an undetectable HCV RNA at weeks 4 and 12. Whether a sustained virologic response or SVR 24, we view this as a validated endpoint specified as absence of detectable HCV RNA in serum six months after completion of therapy. It’s the best indicator of successful therapy of chronic hepatitis C achieving an SVR is associated with fewer liver-related complications, less progression to hepatic carcinoma and both fewer liver-related deaths and improvement in all cause mortality.
The standard of care currently prior to these two approvals was use of pegylated interferon with Ribavirin. The treatment duration was for 48 weeks genotype 1 and 24 weeks genotypes 2 and 3. Response rate averaged approxmately 50% with a range of as well as 20%, it was high as 80% and this depends upon multiple factors such as HCV genotype, IL28B status, race, viral load, etcetera.
It’s most important to note that there are significant toxicities already seen with the standard of care. However, the benefit outweighed the risks for those products namely pegylated interferon and Ribavirin.
Before I turn this over to Dr. Jeff Murray who will describe the approval package related to Boceprevir, I wanted to mention response guided therapy, which is a treatment algorithm individually treatment based on virologic response. There are goals RGP or response guidance therapy and they are to shorten therapy if possible and those who exhibit favorable early viral kinetics and to identify subjects who are unlikely to have a response to lessen side effects, the emergence of resistance, and to decrease costs. And with that, I’d like to turn this over to Dr. Jeff Murray.
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Boceprevir
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Dr. Jeffrey Murray: Thanks, Dr. Birnkrant. I’ll now give an overview of some of the highlights in the Victrelis (Boceprevir) label. I’ll refer to the name of the drug as Victrelis from here on out This was approved on May 13, a week ago Friday for 200 mg. capsules and Victrelis is a hepatitis C protease inhibitor. I want to say that these protease inhibitors for hepatitis C are distinct from HIV protease inhibitors. There’s no cross activity or cross resistance expected.
The indication for Boceprevir Victrelis is for the treatment of chronic hepatitis C genotype 1 infection in combination with pegylated interferon and Ribavirin which are referred to as PR in adult patients with compensated liver disease, but including psorosis for those who are previously untreated or have failed previous PR therapy. So as I said, Victrelis must not be used as monotherapy. The efficacy of Victrelis has not been studied in patients who had previously received Victrelis or another protease inhibitor.
Victrelis in combination with PR has not been studied in patients documented to be historical non-responders as Dr. Birnkrant defined as less than a two log decline in HCV RNA by treatment week 12. But the clinical studies of Victrelis did include patients who were poorly interferon responsive. Subjects with less than a half a log decline in viral load at treatment week 4 during the lead in period of these protocols which I’ll describe with PR alone are predicted to be no responders and these patients appear to have a substantial treatment benefit with Victrelis.
An important usage comment is that poorly interferon responsive patients who were treated with Victrelis in combination with PR have a lower likelihood of achieving an SVR compared to those who are more interferon responsive and also with a lower SVR rate comes a higher rate of detection of resistance associated substitutions upon treatment failure.
The dose of Victrelis is 800 mg. administered three times a day every seven to nine hours with food. In this case a meal or a light snack and to emphasize it, Victrelis must be administered in combination with PR always.
Before I talk a little bit about the dosage and administration which is complex and doesn’t really lend itself well to a telephone venue, I did want to briefly review the clinical studies of Victrelis so the efficacy and safety of Victrelis as a treatment for chronic hepatitis C was assessed in approximately 1500 adult subjects in the phase 3 trials and the phase 3 trials were previously untreated (sprint) 2 or previously treated respond to.
And both of the trials - phase 3 trials - had similar designs. They both had three arms so they had a four-week lead in and the three arms in both studies included the control arm of PR alone which included a total of 48 weeks total duration of therapy. And then there was a triple therapy of arm after the lead in with PR plus Victrelis and then there was a response guided therapy arm.
In the naïve patients the response guided therapy arm, there was a chance of stopping all treatment at 28 weeks if patients had an undetectable viral load by week 8 and maintained that and in the treatment experience study respond to there was chance in the response guided therapy arm of stopping therapy at week 36 or after 32 weeks of the triple therapy.
As I said these are complex studies. You should refer to the label. We expect that these drugs will be used by hepatologists and other experts in the field. But in both studies there was a substantial and statistically significant result for adding Victrelis to peg-interferon and Ribavirin therapy.
In the naïve population, it was 63% to 60% for the Victrelis arms containing arms compared to 38% SVR and for the peg-Ribavirin arm.
And in respond two likewise there was a substantial and significant results with 59% to 66% achieving SVR in the Victrelis contained arms and 23% in the control the PR alone arm.
We did note that there was some numerical differences between response guided therapy and a full 44 weeks of triple therapy. We believe that to a large part some of these differences were in the psoriatic patients, so thus when we devise the dosage in administration’s schedule there were some certain modifications to the doses that were actually studied in the clinical studies to allow more patients to get targeted response guided therapy.
So if you go to the label, you will find that the dosage administration for Victrelis is divided into kind of two segments. One is for patients without psorosis and the other recommendations are for those with psorosis. So for patients without psorosis who were previously untreated or previous partial responders or relapsers to peg Ribavirin, there’s a table and the duration of treatment of all of these components is decided based on HCV RNA viral load assessments at treatment weeks 8, 12, and 24 and one will have to look closely at that table to look at the exact duration of treatment that is right for your particular patient or for how they’re responding.
For patients who are considered historical non-responders - those who had less than a two log decline in week 12 - they should receive 44 weeks of triple therapy after a four-week lead in. Likewise for patients with psorosis, a full 44 weeks of Victrelis in combination with PR after a four-week lead in is recommended.
There are futility analyses as there are futility time points as well at week 12 and 24. If viral load exceeds certain levels at that time all therapy should be stopped.
A little bit about the safety aspects and drug interactions. As far as contraindications because Victrelis must be used peginterferon and Ribavirin, the contraindications and mornings to interferon and Ribavirin therapy applies so Victrelis cannot be used in women who are pregnant or wanting to become pregnant and also in men whose female partners are pregnant.
And there’s also some co-administrations for drugs which are likely to be dependent on similar pathways of metabolism as Victrelis. Should refer to the label for that.
Besides pregnancy warnings to major warnings pertaining to Victrelis are that it can exacerbate a larger frequency of anemia and neutropenia already seen with peginterferon and Ribavirin and in fact the number of transfusions and dosage estimates with Ribavirin were higher when Victrelis was added to a PR regimen. Besides anemia and neutropenia other clinical side effects would be fatigue, nausea, headache, and an unpleasant taste of the drug.
And with that, I think those are the key highlights of the Victrelis label. I would say that as far as use in other special populations besides psorasis it’s currently not recommended for decompensated psorosis as PR therapy is also contraindicated in that population at this point.
Safety and efficacy has not been established in co-infection with HIV or hepatitis B or in pediatric patients at this time, but studies are ongoing. Dr. Birnkrant.
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Telaprevir
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Dr. Debra Birnkrant: Okay. I’ll now describe - I’ll start with the indication of the usage wording for Telaprevir and Incivek.
Incivek is a hepatitis C virus (NS348) protease inhibitor indicated in combination with peginterfereon, alpha riboviran for the treatment of genotype 1 chronic hepatitis C in adult patients of compensated liver disease including psorosis who are treatment naïve or have been previously treated with interferon based treatment including prior no responders, partial responders, and relapsers. Again, Incivek must not be used as monotherapy and must only be used in combination with pegylated interferon and Ribavirin.
There were three main phase 3 trials to support the approval of Telaprevir in addition to early clinical trials. The three pivotal trials were Study 108 which is also called the Advanced Trial conducted in treatment naïve subjects. Study 111 was a supportive trial in the naïve population. This was also called the (Elumina) Trial and Study 216 was a pivotal trial in treatment experienced subjects also referred to as the Realize Trial.
I’ll describe some of the trial strategies that were used in the various clinical trials.
In Study 108 in naïve, there was a treatment duration of 8 weeks versus a treatment duration of 12-week comparative control, and the design was such that to see if there was a shorter treatment duration might improve tolerability. That is, was 8 weeks as good as 12 weeks of Telaprevir in combination with pegylated interferon and Ribavirin.
Study 111 was designed to determine if there would be increased efficacy associated with longer duration of therapy for subjects who achieved an early virologic response.
And in treatment experience Study 216 was designed to assess delayed versus immediate start of therapy with triple combination.
Now I’ll refer to the approved prescribing information to describe the Telaprevir dosing recommendations and this is split out in a table between treatment naïve and prior relapse patients compared to prior partial and no responder patients.
For treatment naïve and prior relapse patients, two tablets of Telaprevir at a dose of 375 mg. every seven to nine hours with food should be taken and these are the conditions under which this should be taken and the duration of treatment.
Although HCV RNA is undetectable at weeks 4 and 12, then triple therapy with Incivek pegylated interferon alpha and Ribavirin should be dosed for the first 12 weeks.
If there is undetectable HCV RNA at 4 and 12 weeks, then a total duration of treatment is 24 weeks with an additional 12 weeks of dual treatment with pegylated interferon and Ribavirin.
If HCV RNA is detectable at weeks 4 and 12 during the first 12 weeks, again it’s triple therapy with Incivek, peginterferon alpha and Ribavirin, and then an additional 36 weeks for a total of 48 weeks of treatment duration. The additional 36 weeks is with dual therapy with pegylated interferon alpha and Ribavirin.
For prior partial and no responder patients, two tablets 375 mg. every seven to nine hours with food should be used in the following way: for all patients that fall under the prior partial and no responder categories, they should receive triple therapy for the first 12 weeks with Incivek, pegylated interferon alpha and Ribavirin then dual therapy with pegylated interferon alpha and Ribavirin for an additional 36 weeks for a total treatment duration of 48 weeks.
The laboratory data that’s used to support whether or not to continue treatment is based on an approved asset with a lower limit of quantitation of 25 international units per ML and a lower limit of detection of 10 international units per ML.
There are futility rules such that patients should not continue dosing if it doesn’t appear as though they’re responding early on. The reason for futility rules is to ensure that there’s a limitation to the development of resistance. And I refer those on the call to the prescribing information.
Turning to Study 108 in naïve all focus on the treatment duration of 12 weeks compared to control have pegylated interferon Ribavirin for 48 weeks. Overall the FDA rates were 79% for the Telaprevir combination group compared to 46% for the control group.
An early virologic response that is ERBR was seen in 78% of the T12 pegylated interferon Ribavirin compared to only 8% in controls.
The SVR in the ERVR subjects was 92% for Telaprevir for 12 weeks and combination of pegylated interferon and Ribavirin.
Relapse rates were quite low in those subjects receiving combination therapy with Telaprevir at a rate of 4%.
Turning now to the treatment experience trial Study 216 and prior interferon failures, the FDA rate in prior relapsers was 86% in the triple combination arm of Telaprevir dose for 12 weeks with pegylated interferon and Ribavirin compared to a rate of 22% in control.
For prior partial responders, it was 59% in the Telaprevir combination in group compared to 15% in the pegylated interferon Ribavirin control group and for prior no responders the response rate for SVR was 32% compared to 5% in control.
Looking at historically difficult to treat subgroups, Telaprevir also significantly improved outcomes for blacks, Latinos, and patients with psorosis. In the naïve study there were only 26 subjects that were black or African-Americans approximately 9% of the study population. The overall SVR rate among black African-American subjects was 62%. Of those who achieved an early virologic response or an ERVR 89% achieved an SVR.
In the experience Study 216, the overall SVR rate in this group was 63%. Again keep in mind that the numbers were small.
In Latino-Hispanics, they comprised 10% of the Telaprevir peginterferon group. They ERVR rates approximately 5% lower by comparable SVR rates to Caucasians and the overall SVR rate was 79% for Telaprevir containing regimen compared to 31% for controls.
Psorotic patients also have limited representation in the clinical trial database. Approximately 8% of the naïve subjects had psorosis. The overall SVR rate in this population was 61% in those who received a Telaprevir containing regimen. There was a suggestion of 48 weeks being better than 24 weeks with regard to SVR.
In the experience population approximately 25% had psorosis and the overall SVR rate was approximately 47% in those receiving a Telaprevir combination regimen compared to 13% in control.
I’ll now turn to a safety review. Approximately 3800 healthy and infected subjects were exposed to at least one dose of Telaprevir. In the phase 3 trial 1700 were exposed to Telaprevir.
I’ll focus on a few key areas namely rash, anemia, anorectal disorders, and general adverse events. You need to keep in mind that rash and anemia are both seen with pegylated interferon and Ribavirin therapy.
Rash and pruritus were identified in phase 2 trials and a monitoring and management plan was instituted for instituted for the phase 3 trials. There was also a dermatology expert panel that reviewed cases retrospectively.
Clinically and histologically the rash seen with Telaprevir is comparable to that seen with pegylated interferon and Ribavirin. It is described as an exematous maculopapular and papular lichenoid rash. The rash did not appear to be a drug-induced hypersensitivity type of rash. Less than 1% of subjects experienced a suspected severe rash such as Stevens Johnson and not all occurred during Telaprevir dosing period. The mechanism of rash was investigated, but remains unknown and there were no deaths related to rash.
I’ll now turn to anemia. The most problematic side effect of Ribavirin therapy is reversible hemolytic anemia. Telaprevir adds to the frequency and severity of this toxicity. Anemia was seen in non-clinical studies so we knew we had to monitor for it in the clinical trials. It’s highlighted in the warnings and precaution section of the label with recommendations of how to deal with anemia such as measuring hemoglobin baseline and every four weeks, utilizing Ribavirin dose reduction to manage anemia, and it’s important to note that Incivek should not be dose reduced, and if discontinued then should not be restarted.
Regarding anorectal disorders approximately 20% of subjects receiving Telaprevir had an anorectal disorder compared to 5% on control. The most commonly reported disorders in this category were hemorrhoids, anorectal discomfort, and anal pruritus. The time to onset is approximately ten days. Less than 1% were serious. Most were managed with topical agents. Again for this adverse event, the mechanism is unknown and in some mostly remains bothersome and rarely treatment limiting.
Adverse reactions seen in greater than or equal to more than 5% higher frequency in Telaprevir subjects compared to control were as follows: rash, fatigue, pruritis, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal discomfort, and (unintelligible) or interference with taste.
As I said conclude with summary efficacy comments. The addition of Telaprevir to pegylated interferon Ribavirin containing regimen significantly increased SVR rates compared to pegylated interferon Ribavirin alone across a broad range of populations and demographic subgroups. Highest SVR rates demonstrate that the overall duration of therapy can indeed be shortened without jeopardizing efficacy in naives and prior relapse groups.
Extending pegylated interferon and Ribavirin to 48 weeks in addition to 12 weeks of Telaprevir provides additional benefit for naïve subjects who did not achieve an early rapid virological response and in those who are previous interferon failures.
Regarding safety, rash, pruritus and anemia are the key to Telaprevir related toxicities and it is felt they can be monitored and managed appropriately. Anorectal disorders occur frequency, but appear only bothersome yet still manageable and there were no significant infections seen due to low white cells and no abnormal bleeding was seen due to low platelets. Thank you very much.
Richard Klein: Thank you, Dr. Birnkrant and Dr. Murray. And with that Angie, I wonder if we can open the question and answer portion of the call. And while we’re waiting to do that, I just had one quick question. You mentioned dosing with a meal and I’m wondering if the amount of food and the type of food has an impact on absorption when taking the drugs?
Dr. Debra Birnkrant: Well with regard to Telaprevir food absolutely has an effect on absorption and plasma concentration, so it is recommended that subjects or patients take Telaprevir three times a day every seven to nine hours with food that is low fat. It could be a meal, it could be a snack, but it should not be low fat. So examples of foods that can be used while taking Telaprevir include bagels with cream cheese, avocados, nuts, granola, et cetera.
Richard Klein: Thank you. And (Angie), do we have questions queued up?
Coordinator: At this time if you’d like to ask a question, please press star 1 on your touch tone phone and record your first and last name so that you may be announced. In order to withdraw your question, you will press star 2.
Once again if you’d like to ask a question, please press star 1 on your touch tone phone and record your first and last name so that you may be announced.
One moment please for our first question. Our first question comes from (Joel Levin). Your line is open.
(Joel Levin): Two questions. You didn’t mention the food for Boceprevir. What’s recommended for Boceprevir?
((Crosstalk))
Dr. Jeffrey Murray: …also with a meal, it could be a snack, but the high fat requirement is not needed. But it should be a meal or a snack.
(Joel Levin): Okay. So my real question is this maybe I’m missing something or maybe there’s something - it just seems strange to me - so with Victrelis Boceprevir if a patient is greater than 100 with viral load at week 12, they’re to stop Boceprevir. I think they’re supposed to stop the whole regimen. But with Telaprevir, it’s greater than 1000 at week 12 so why is there that difference?
Dr. Jeffrey Murray: Well, I think that the futility rules were based on looking at the data from the clinical trials and so Dr. Birnkrant can comment on the futility roles for Telaprevir. But in looking at these futility roles and how many patients by stopping early we would have missed SVRs in this database, we don’t think that you’re giving up any SVR or using the futility role of greater than 100 at week 12 and undetectable at 24. So it really depends on the data set.
Dr. Debra Birnkrant: For Telaprevir patients with an inadequate viral response are unlikely to achieve an SVR and the concern is that they may develop treatment emergent resistance of substitutions. The discontinuation of therapy is recommended in all patients with HCV RNA levels of greater than or equal to 1000 international units per ML at treatment week 4 or 12 or confirmed detectable HCV RNA levels at treatment week 24. And this is outlined in the package insert.
(Joel Levin): So the way you’re protecting people on Boceprevir is if they’re over 100 at week 12 - well if they’re over 100 at week 12 they’re supposed to stop the whole regimen, right?
Dr. Jeffrey Murray: That’s correct.
(Joel Levin): Okay. All right, so it’s basically based on the study data and trying not to lose people who still could get an SVR, right?
Dr. Debra Birnkrant: That’s absolutely correct because Telaprevir there’s still some patients between HCV RNA level of 100 to 1000 who still had an SVR.
(Joel Levin): Right, okay.
Dr. Debra Birnkrant: Okay.
(Joel Levin): Thank you.
Dr. Jeffrey Murray: Next question, please.
Coordinator: The next question comes from (Lauren Sant).
(Lauren Sant): Hi. This (Lauren Sant) (unintelligible) Ambassador's Program. You had mentioned that dosing is at seven to nine hours. Are there instructions for what happens if someone misses a dose and what they should do?
Dr. Debra Birnkrant: In the medication guide that a company’s package insert there are instructions about how to deal with missing one dose. If more than one dose is missed, however, that’s a much more difficult situation and you should probably talk to your physician about how to resume therapy.
(Lauren Sant): Okay. But it’s clearly stated in the package if they miss one by a couple of hours what they should do?
Dr. Debra Birnkrant: Absolutely.
(Lauren Sant): Great. Thank you.
Dr. Jeffrey Murray: Thank you, Lauren. Can we go on to the next question, please?
Coordinator: Next question comes from David Ross.
David Ross: Hi. This is David Ross, US Department of Veteran Affairs. First congratulations to you and the review team. I know this was a tremendous amount of work and this is a day all of us have been waiting for. Do you know when the summary basis of approval - I’m not talking about the full action package - but the summary for approval for Boceprevir and Telaprevir is going to go up on the web?
Dr. Debra Birnkrant: I don’t have an exact timeframe, but I’m told given the high priority or the high visibility of these drugs that it should be expedited. I can tell you now that both labels are up and both approval letters are online.
David Ross: Okay. Thanks...
((Crosstalk))
David Ross: I know one of the things we’re looking at is, you know, there’s obviously hugely complex decisions to be made in terms of the review of this, in particularly with regard to individuals who have treatment experience for no responders and we’re just looking at the two different drugs and the different study designs and it’s - you guys have living with the data for months. So having those up would be hugely helpful to people.
A second question this is obviously an area for emerging science. I have IL28B statuses looked at retrospectively and it’s really, really helpful to have that information on the label, and again we really appreciate that, but do you anticipate that there’s going to any follow on data that’s perspectively collected that may give guidance to providers as well as patients about how to incorporate that into clinical decision making?
Dr. Jeffrey Murray: Well one of the - as stated in the approval letter for Victrelis - one of the post-marketing commitments that Merck has agreed to do is that another study looking at the effect of IL28B and also looking at potentially shorter durations of therapy of Victrelis and/or PR. So we’ll hopefully be getting a protocol for that relatively soon. So that would be one of the post-marketing commitments.
David Ross: Okay. And then last question and again this is definitely an area of emerging science. There’s been data reported that (Easel) and (liver) meetings for the last couple of years in terms of an effective Vitamin B and Vitamin B regulated (unintelligible) products on SVR rates. There was a small interesting study from Israel randomized control trial last year at (Easel) showing a substantial effect from an (ex) US population. Is this anything - and I don’t know if this was considered during the review - but is this anything that again there might be follow on data to look at either in - I understand there may be things you can’t speak about, but I just - if it was considered in the review that would be great. But I just wanted to ask about that because Vitamin D level certainly they have instead that may affect SVR rates made a fool out of providers who are just kind of biting the bullet and giving Vitamin D.
Dr. Jeffrey Murray: Right. I don’t think we have any further information on that. I don’t think you’ll find it in the summary reviews. I don’t think that Vitamin D levels were specifically measured in relation to treatment outcomes and there’s no currently pending studies in the form of post-marketing commitments on that although I’m sure there might be a lot of investigator interest in that area with these new DAAs.
David Ross: Absolutely. Again thanks for all your hard work on this.
Dr. Jeffrey Murray: Thank you. Angie, can we take the next question please?
Coordinator: Yes, sir. Our next question comes from (Miles Heflin). Your line is open.
(Miles Helfin): Hi. Thanks. It’s (Miles Helfin) from thebody.com. Given that there appear to be relatively few significant differences in terms of efficacy or safety between Telaprevir and Boceprevir how would you guys advice a clinician who’s going to be choose between these two drugs?
Dr. Debra Birnkrant: Well the only way we would be answer that would be if they comparative in a head-to-head trial which they were not. So you’ll have to consult future treatment guidelines with regard to advice on that question.
(Miles Helfin): But I mean going forward in the future what’s a clinician or a patient to do when they’re trying to choose, “Well, all right. Which one of these drugs do I go with and incorporating that into a regimen?”
Dr. Debra Birnkrant: I think they should read the prescribing information quite thoroughly. When the Division Director and the other memos are up online, you should read those as well and perhaps await recommendations from professional organizations.
(Miles Helfin): Thanks.
Coordinator: Our next question will come from (Courtney McQueen). Your line is open.
(Courtney McQueen): Hi. This is (Courtney McQueen) from the Aids Begin. Thank you very much. I had two questions. First during the Advisory Committee Meeting there was discussion of triple therapy being the new standard of treatment for hepatitis C would you comment on that? Do you think triple therapy is now the new standard?
Dr. Debra Birnkrant: The Advisory Committee when posed that question clearly stated that there was a new standard of care now with the approval of these two new DAAs. So it appears as though there is a new standard of care and again we’ll have to await professional organizations treatment guideline recommendations to see what these professional societies are recommending.
(Courtney McQueen): Thank you. And my second question relates to people who are HIV HCV co-infected. The current approval is not for people who are co-infected. Do you have any idea about timelines for when such an approval might be considered?
Dr. Debra Birnkrant: For Telaprevir as part of the one post-marketing commitments, we asked (Verteck) to conduct a trial to evaluate treatment responses and safety among treatment naïve and experienced HIV HCV co-infected subjects and the time table is as follows: the final protocol submission should be January 2012, the trial is estimated that it should be completed June 2014 with a final report submitted 2014 as well in December. There’s a pilot study in progress as well.
(Courtney McQueen): Thank you very much.
Coordinator: Our next question will come from (Garrett Benson). Your line’s open.
(Garrett Benson): Yes. My understanding is that the treatment is for genotype 1s only, but when and if will genotypes 2 get an opportunity to - if they relapsed after their treatment - would they ever get an opportunity for the DAs?
Dr. Debra Birnkrant: For Telaprevir pilot studies were conducted in other genotypes and it didn’t appear as though it had adequate activity in genotypes other than 1, genotype 1A and 1B.
(Garrett Benson): Okay. Thank you.
Richard Klein: I’d like to thank Drs. Hamburg, Birnkrant, and Murray for their presentations and all the attendees for their participation.
I hope the exchange was informative and useful to you. If you do have questions after today’s call or comments about the briefing, you can direct them to me at richard.klein@fda.hhs.gov and I’ll be sure to direct questions to the appropriate FDA staffer for a response.
I hope you will share the information from today’s briefing with this colleagues and this concludes today’s stakeholder briefing on Boceprevir and Telaprevir and thank you very much for your participation. Have a good afternoon.
END
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm256753.htm
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On May 23, 2011, FDA held a telephone briefing to discuss two Direct Acting Antivirals (DAAs) with health care providers and patient advocates having an interest in treatment for hepatitis C. The call was intended to provide an overview of the safety and efficacy data and complexity of dosing regimens, and respond to questions about the use of these recently approved protease inhibitors, indicated as part of combination drug therapy, for the treatment of hepatitis C.
The call was initiated in response to comments at the April 27 and 28, 2011 FDA Antiviral Drugs Advisory Committee meeting to consider data related to marketing applications for Victrelis (boceprevir) and Incivek (telaprevir), suggesting that additional information would be helpful in understanding the use of these drugs in clinical care.
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A record of the teleconference (approximately 50 minutes) is being made available in either of two formats:
Written Transcript
Download Audio Recording Podcast (22 MB)
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FDA May 23, 2011 Teleconference Briefing on Direct Acting Antivirals, Victrelis (boceprevir) and Incivek (telaprevir)
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Moderator: Richard Klein
May 23, 2011
3:30 pm EDT
Richard Klein: Good afternoon everyone. This is Richard Klein from the FDA’s Office of Special Health Issues, and I’d like to thank you for joining us this afternoon.
The purpose of today’s call is to update you about two direct acting anti-viral drugs to treat hepatitis C discussed at a meeting of the FDA Antiviral Advisory Committee on April 27 and 28.
At that meeting stakeholders made it evident that they would benefit from added guidance from FDA about complex treatment regimens described during the committee discussions and about possible adverse events associated with the antiviral treatment of hepatitis C. Today’s briefing is a response to those comments. Before we get started, I would like to briefly review how we will proceed.
With me in the room are Dr. Debra Birnkrant, Director of the FDA’s Division of Antiviral Products and Dr. Jeffrey Murray, Deputy Director of the Division and they will provide an overview of the data supporting the safety and effectiveness of these drugs to treat hepatitis C.
Immediately following the discussion, we will open the lines for your questions. Your phones will be on mute during the presentation. Prior to the start of the question-and-answer session, the operator will provide instructions on how to ask questions of FDA’s experts. Please be aware that the teleconference is being recorded for playback, so please state your name prior to joining the conversation. If you are asking a question, please be sure to speak clearly and directly into your telephone.
Before we begin the overview I have the extreme pleasure of introducing Dr. Margaret Hamburg, Commissioner of the Food and Drug Administration. Dr. Hamburg.
Dr. Margaret Hamburg: Thank you, Richard. I’m very pleased that I have the opportunity to join you and a very talented team of medical reviewers from FDA’s Division of Antiviral Drugs today to discuss the FDA’s recent approval of Victrelis, also known as Boceprevir and Incivek or Telaprevir; two direct acting antiviral drugs that represent a new direction in the treatment of hepatitis C and a significant improvement over the current standard of care.
These are two new innovative products that are worthy of notice and will make a difference literally saving lives. It’s also worth noting that today’s approval of Incivek represents the 15th new drug approved in just the first five months of this year.
I want to take this moment to congratulate Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research; Dr. John Jenkins, Director of the Office of New Drugs in The Center for Drugs Evaluation and Research, and their staff for all the work in reaching decisions in a timely manner, ensuring patient access to safe and effective new treatments.
A few short weeks ago FDA’s Antiviral Drugs Advisory Committee, one of several committees comprised of medical experts and community advocates, met to discuss both of these drugs. I want to thank that committee for the recommendations which unanimously voted to recommend approval of both drugs as well as to thank and congratulate the companies responsible for developing Incivek and Victrelis and the FDA staff for their diligence in completing these applications expeditiously ensuring that patients have access to highly effective new drugs as quickly as possible.
Today truly represents a great day for the more than 3 million American men and women currently living with chronic hepatitis C and the millions more living with this often difficult to treat disease worldwide.
Viral hepatitis continues to a leading infectious cause of death in the United States and many people don’t even realize they’re infected.
I want to commend many of the patient groups and healthcare organizations participating on today’s call who’s done an exceptional job raising awareness and encouraging millions of individuals at risk to go get tested.
Recently, the US Department of Health and Human Services - HHS - announced an action plan which most of you are probably familiar with by now titled Combating the Silent Epidemic, US Department Health and Human Services action plan for the prevention, care, and treatment of viral hepatitis.
The report outlines the comprehensive action plan to raise awareness about viral hepatitis, creates more opportunities to train health professionals to diagnose, treat, and vaccinate for hepatitis A and B and ultimately save lives and it builds upon the new Health Insurance Reform law to improve patient access to comprehensive viral hepatitis-related prevention and treatment services through expanded coverage.
The approval of these two new drugs will no doubt factor into this plan moving forward and their availability today is a testament to the hard work and dedication of academic researchers, diligent companies willing to invest in areas where existing therapies have failed or only provided temporary relief for patients, and an FDA staff willing to go the extra mile to ensure that patients have access to safe and effective new drugs.
As someone who has spent most of my career working on infectious disease issues and with first-hand experience treating and combating deadly infections, the significance of these approvals is not lost on me.
Before I turn it over to Dr. Debra Birnkrant whose division was not only responsible to the approval of these two drugs, but the approval this past Friday also of Edurant or Rilpivirine; another new treatment option for patients whose not received treatment for HIV infections.
I want to thank all of you on the phone for taking the time to join us in this call. Your continued support and engagement with FDA is essential to our mission. We are a regulatory agency that takes very seriously the science-based, data driven decisions that we make for and on behalf of the American people and beyond. All aspects of our mission are crucial to the health of individuals and the public health. I know that the work of organizations like all of yours is crucial too.
So with that, I’ll now turn the call over to Dr. Debra Birnkrant. Thank you very much.
Dr. Debra Birnkrant: Thank you, Dr. Hamburg. Good afternoon. I’d like to thank Dr. Hamburg for her opening comments that set the stage for the stakeholders meeting where Dr. Jeffrey Murray, Deputy Director of the Division of Antiviral Products and I will be sharing some of the details about the approvals of two new direct acting antivirals, Telaprevir and Boceprevir for use in combination with pegylated interferon and Rilpivirine for the treatment of genotype 1 chronic hepatitis C in adult patients.
As I wrote my memorandum in support of the approval of these DAAs, this time reminds me of the mid-1990s when we approved various antiretrovirals for the HIV infected population and the impact those approvals have had on patients’ lives. We expect to see a similar impact with the use of these new therapies in patients with chronic hepatitis C. It is truly an exciting time.
With that, I’d like to start with additional background and some concepts because we will be using these terms during our presentation. I also recommend that you review the approved prescribing information because we will not be able to go into detail in every aspect of these drugs.
To begin with as was mentioned chronic hepatitis C is both a global and domestic problem with 170 million estimated to be infected worldwide and approximately 3 million infected in the United States.
Of the 5.6 million veterans in veteran's healthcare in 2008, 2.6 had a diagnosis of chronic hepatitis C. Although the incidents of infection in the United States is decreasing, chronic hepatitis C related complications are increasing such as psorosis and hepatocellular carcinoma.
With the aging of the infected population more liver-related complications are expected in the next 10 to 20 years without the use of potent antiviral therapies. I’d also like to mention and underline that chronic hepatitis C is already the most common reason for liver transplantation.
Beginning with some definitions that are crucial to understanding how to properly use these products. The naïve population is a population described as a population who is receiving no prior therapy for hepatitis C including interferon or pegylated interferon monotherapy.
The no responder population is one that has had less than a (two log) reduction in HCV RNA at week 12 of a pegylated interferon Ribavirin regimen. A partial responder has had greater than or equal to a (two log) reduction in HCV RNA at week 12, but has not achieved HCV RNA undetectable at the end of treatment. And a responder relapser is one that has had HCV RNA undetectable at the end of treatment with a pegylated interferon based regimen, but HCV RNA detectable within 24 weeks of treatment follow up. This group is most closely related to the naïve population with regards to interferon responsiveness.
Additional definitions that are important. A rapid virologic response or RVR is one that is an undetectable HCV RNA at week 4 and an extended RVR or ERVR is an undetectable HCV RNA at weeks 4 and 12. Whether a sustained virologic response or SVR 24, we view this as a validated endpoint specified as absence of detectable HCV RNA in serum six months after completion of therapy. It’s the best indicator of successful therapy of chronic hepatitis C achieving an SVR is associated with fewer liver-related complications, less progression to hepatic carcinoma and both fewer liver-related deaths and improvement in all cause mortality.
The standard of care currently prior to these two approvals was use of pegylated interferon with Ribavirin. The treatment duration was for 48 weeks genotype 1 and 24 weeks genotypes 2 and 3. Response rate averaged approxmately 50% with a range of as well as 20%, it was high as 80% and this depends upon multiple factors such as HCV genotype, IL28B status, race, viral load, etcetera.
It’s most important to note that there are significant toxicities already seen with the standard of care. However, the benefit outweighed the risks for those products namely pegylated interferon and Ribavirin.
Before I turn this over to Dr. Jeff Murray who will describe the approval package related to Boceprevir, I wanted to mention response guided therapy, which is a treatment algorithm individually treatment based on virologic response. There are goals RGP or response guidance therapy and they are to shorten therapy if possible and those who exhibit favorable early viral kinetics and to identify subjects who are unlikely to have a response to lessen side effects, the emergence of resistance, and to decrease costs. And with that, I’d like to turn this over to Dr. Jeff Murray.
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Boceprevir
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Dr. Jeffrey Murray: Thanks, Dr. Birnkrant. I’ll now give an overview of some of the highlights in the Victrelis (Boceprevir) label. I’ll refer to the name of the drug as Victrelis from here on out This was approved on May 13, a week ago Friday for 200 mg. capsules and Victrelis is a hepatitis C protease inhibitor. I want to say that these protease inhibitors for hepatitis C are distinct from HIV protease inhibitors. There’s no cross activity or cross resistance expected.
The indication for Boceprevir Victrelis is for the treatment of chronic hepatitis C genotype 1 infection in combination with pegylated interferon and Ribavirin which are referred to as PR in adult patients with compensated liver disease, but including psorosis for those who are previously untreated or have failed previous PR therapy. So as I said, Victrelis must not be used as monotherapy. The efficacy of Victrelis has not been studied in patients who had previously received Victrelis or another protease inhibitor.
Victrelis in combination with PR has not been studied in patients documented to be historical non-responders as Dr. Birnkrant defined as less than a two log decline in HCV RNA by treatment week 12. But the clinical studies of Victrelis did include patients who were poorly interferon responsive. Subjects with less than a half a log decline in viral load at treatment week 4 during the lead in period of these protocols which I’ll describe with PR alone are predicted to be no responders and these patients appear to have a substantial treatment benefit with Victrelis.
An important usage comment is that poorly interferon responsive patients who were treated with Victrelis in combination with PR have a lower likelihood of achieving an SVR compared to those who are more interferon responsive and also with a lower SVR rate comes a higher rate of detection of resistance associated substitutions upon treatment failure.
The dose of Victrelis is 800 mg. administered three times a day every seven to nine hours with food. In this case a meal or a light snack and to emphasize it, Victrelis must be administered in combination with PR always.
Before I talk a little bit about the dosage and administration which is complex and doesn’t really lend itself well to a telephone venue, I did want to briefly review the clinical studies of Victrelis so the efficacy and safety of Victrelis as a treatment for chronic hepatitis C was assessed in approximately 1500 adult subjects in the phase 3 trials and the phase 3 trials were previously untreated (sprint) 2 or previously treated respond to.
And both of the trials - phase 3 trials - had similar designs. They both had three arms so they had a four-week lead in and the three arms in both studies included the control arm of PR alone which included a total of 48 weeks total duration of therapy. And then there was a triple therapy of arm after the lead in with PR plus Victrelis and then there was a response guided therapy arm.
In the naïve patients the response guided therapy arm, there was a chance of stopping all treatment at 28 weeks if patients had an undetectable viral load by week 8 and maintained that and in the treatment experience study respond to there was chance in the response guided therapy arm of stopping therapy at week 36 or after 32 weeks of the triple therapy.
As I said these are complex studies. You should refer to the label. We expect that these drugs will be used by hepatologists and other experts in the field. But in both studies there was a substantial and statistically significant result for adding Victrelis to peg-interferon and Ribavirin therapy.
In the naïve population, it was 63% to 60% for the Victrelis arms containing arms compared to 38% SVR and for the peg-Ribavirin arm.
And in respond two likewise there was a substantial and significant results with 59% to 66% achieving SVR in the Victrelis contained arms and 23% in the control the PR alone arm.
We did note that there was some numerical differences between response guided therapy and a full 44 weeks of triple therapy. We believe that to a large part some of these differences were in the psoriatic patients, so thus when we devise the dosage in administration’s schedule there were some certain modifications to the doses that were actually studied in the clinical studies to allow more patients to get targeted response guided therapy.
So if you go to the label, you will find that the dosage administration for Victrelis is divided into kind of two segments. One is for patients without psorosis and the other recommendations are for those with psorosis. So for patients without psorosis who were previously untreated or previous partial responders or relapsers to peg Ribavirin, there’s a table and the duration of treatment of all of these components is decided based on HCV RNA viral load assessments at treatment weeks 8, 12, and 24 and one will have to look closely at that table to look at the exact duration of treatment that is right for your particular patient or for how they’re responding.
For patients who are considered historical non-responders - those who had less than a two log decline in week 12 - they should receive 44 weeks of triple therapy after a four-week lead in. Likewise for patients with psorosis, a full 44 weeks of Victrelis in combination with PR after a four-week lead in is recommended.
There are futility analyses as there are futility time points as well at week 12 and 24. If viral load exceeds certain levels at that time all therapy should be stopped.
A little bit about the safety aspects and drug interactions. As far as contraindications because Victrelis must be used peginterferon and Ribavirin, the contraindications and mornings to interferon and Ribavirin therapy applies so Victrelis cannot be used in women who are pregnant or wanting to become pregnant and also in men whose female partners are pregnant.
And there’s also some co-administrations for drugs which are likely to be dependent on similar pathways of metabolism as Victrelis. Should refer to the label for that.
Besides pregnancy warnings to major warnings pertaining to Victrelis are that it can exacerbate a larger frequency of anemia and neutropenia already seen with peginterferon and Ribavirin and in fact the number of transfusions and dosage estimates with Ribavirin were higher when Victrelis was added to a PR regimen. Besides anemia and neutropenia other clinical side effects would be fatigue, nausea, headache, and an unpleasant taste of the drug.
And with that, I think those are the key highlights of the Victrelis label. I would say that as far as use in other special populations besides psorasis it’s currently not recommended for decompensated psorosis as PR therapy is also contraindicated in that population at this point.
Safety and efficacy has not been established in co-infection with HIV or hepatitis B or in pediatric patients at this time, but studies are ongoing. Dr. Birnkrant.
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Telaprevir
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Dr. Debra Birnkrant: Okay. I’ll now describe - I’ll start with the indication of the usage wording for Telaprevir and Incivek.
Incivek is a hepatitis C virus (NS348) protease inhibitor indicated in combination with peginterfereon, alpha riboviran for the treatment of genotype 1 chronic hepatitis C in adult patients of compensated liver disease including psorosis who are treatment naïve or have been previously treated with interferon based treatment including prior no responders, partial responders, and relapsers. Again, Incivek must not be used as monotherapy and must only be used in combination with pegylated interferon and Ribavirin.
There were three main phase 3 trials to support the approval of Telaprevir in addition to early clinical trials. The three pivotal trials were Study 108 which is also called the Advanced Trial conducted in treatment naïve subjects. Study 111 was a supportive trial in the naïve population. This was also called the (Elumina) Trial and Study 216 was a pivotal trial in treatment experienced subjects also referred to as the Realize Trial.
I’ll describe some of the trial strategies that were used in the various clinical trials.
In Study 108 in naïve, there was a treatment duration of 8 weeks versus a treatment duration of 12-week comparative control, and the design was such that to see if there was a shorter treatment duration might improve tolerability. That is, was 8 weeks as good as 12 weeks of Telaprevir in combination with pegylated interferon and Ribavirin.
Study 111 was designed to determine if there would be increased efficacy associated with longer duration of therapy for subjects who achieved an early virologic response.
And in treatment experience Study 216 was designed to assess delayed versus immediate start of therapy with triple combination.
Now I’ll refer to the approved prescribing information to describe the Telaprevir dosing recommendations and this is split out in a table between treatment naïve and prior relapse patients compared to prior partial and no responder patients.
For treatment naïve and prior relapse patients, two tablets of Telaprevir at a dose of 375 mg. every seven to nine hours with food should be taken and these are the conditions under which this should be taken and the duration of treatment.
Although HCV RNA is undetectable at weeks 4 and 12, then triple therapy with Incivek pegylated interferon alpha and Ribavirin should be dosed for the first 12 weeks.
If there is undetectable HCV RNA at 4 and 12 weeks, then a total duration of treatment is 24 weeks with an additional 12 weeks of dual treatment with pegylated interferon and Ribavirin.
If HCV RNA is detectable at weeks 4 and 12 during the first 12 weeks, again it’s triple therapy with Incivek, peginterferon alpha and Ribavirin, and then an additional 36 weeks for a total of 48 weeks of treatment duration. The additional 36 weeks is with dual therapy with pegylated interferon alpha and Ribavirin.
For prior partial and no responder patients, two tablets 375 mg. every seven to nine hours with food should be used in the following way: for all patients that fall under the prior partial and no responder categories, they should receive triple therapy for the first 12 weeks with Incivek, pegylated interferon alpha and Ribavirin then dual therapy with pegylated interferon alpha and Ribavirin for an additional 36 weeks for a total treatment duration of 48 weeks.
The laboratory data that’s used to support whether or not to continue treatment is based on an approved asset with a lower limit of quantitation of 25 international units per ML and a lower limit of detection of 10 international units per ML.
There are futility rules such that patients should not continue dosing if it doesn’t appear as though they’re responding early on. The reason for futility rules is to ensure that there’s a limitation to the development of resistance. And I refer those on the call to the prescribing information.
Turning to Study 108 in naïve all focus on the treatment duration of 12 weeks compared to control have pegylated interferon Ribavirin for 48 weeks. Overall the FDA rates were 79% for the Telaprevir combination group compared to 46% for the control group.
An early virologic response that is ERBR was seen in 78% of the T12 pegylated interferon Ribavirin compared to only 8% in controls.
The SVR in the ERVR subjects was 92% for Telaprevir for 12 weeks and combination of pegylated interferon and Ribavirin.
Relapse rates were quite low in those subjects receiving combination therapy with Telaprevir at a rate of 4%.
Turning now to the treatment experience trial Study 216 and prior interferon failures, the FDA rate in prior relapsers was 86% in the triple combination arm of Telaprevir dose for 12 weeks with pegylated interferon and Ribavirin compared to a rate of 22% in control.
For prior partial responders, it was 59% in the Telaprevir combination in group compared to 15% in the pegylated interferon Ribavirin control group and for prior no responders the response rate for SVR was 32% compared to 5% in control.
Looking at historically difficult to treat subgroups, Telaprevir also significantly improved outcomes for blacks, Latinos, and patients with psorosis. In the naïve study there were only 26 subjects that were black or African-Americans approximately 9% of the study population. The overall SVR rate among black African-American subjects was 62%. Of those who achieved an early virologic response or an ERVR 89% achieved an SVR.
In the experience Study 216, the overall SVR rate in this group was 63%. Again keep in mind that the numbers were small.
In Latino-Hispanics, they comprised 10% of the Telaprevir peginterferon group. They ERVR rates approximately 5% lower by comparable SVR rates to Caucasians and the overall SVR rate was 79% for Telaprevir containing regimen compared to 31% for controls.
Psorotic patients also have limited representation in the clinical trial database. Approximately 8% of the naïve subjects had psorosis. The overall SVR rate in this population was 61% in those who received a Telaprevir containing regimen. There was a suggestion of 48 weeks being better than 24 weeks with regard to SVR.
In the experience population approximately 25% had psorosis and the overall SVR rate was approximately 47% in those receiving a Telaprevir combination regimen compared to 13% in control.
I’ll now turn to a safety review. Approximately 3800 healthy and infected subjects were exposed to at least one dose of Telaprevir. In the phase 3 trial 1700 were exposed to Telaprevir.
I’ll focus on a few key areas namely rash, anemia, anorectal disorders, and general adverse events. You need to keep in mind that rash and anemia are both seen with pegylated interferon and Ribavirin therapy.
Rash and pruritus were identified in phase 2 trials and a monitoring and management plan was instituted for instituted for the phase 3 trials. There was also a dermatology expert panel that reviewed cases retrospectively.
Clinically and histologically the rash seen with Telaprevir is comparable to that seen with pegylated interferon and Ribavirin. It is described as an exematous maculopapular and papular lichenoid rash. The rash did not appear to be a drug-induced hypersensitivity type of rash. Less than 1% of subjects experienced a suspected severe rash such as Stevens Johnson and not all occurred during Telaprevir dosing period. The mechanism of rash was investigated, but remains unknown and there were no deaths related to rash.
I’ll now turn to anemia. The most problematic side effect of Ribavirin therapy is reversible hemolytic anemia. Telaprevir adds to the frequency and severity of this toxicity. Anemia was seen in non-clinical studies so we knew we had to monitor for it in the clinical trials. It’s highlighted in the warnings and precaution section of the label with recommendations of how to deal with anemia such as measuring hemoglobin baseline and every four weeks, utilizing Ribavirin dose reduction to manage anemia, and it’s important to note that Incivek should not be dose reduced, and if discontinued then should not be restarted.
Regarding anorectal disorders approximately 20% of subjects receiving Telaprevir had an anorectal disorder compared to 5% on control. The most commonly reported disorders in this category were hemorrhoids, anorectal discomfort, and anal pruritus. The time to onset is approximately ten days. Less than 1% were serious. Most were managed with topical agents. Again for this adverse event, the mechanism is unknown and in some mostly remains bothersome and rarely treatment limiting.
Adverse reactions seen in greater than or equal to more than 5% higher frequency in Telaprevir subjects compared to control were as follows: rash, fatigue, pruritis, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal discomfort, and (unintelligible) or interference with taste.
As I said conclude with summary efficacy comments. The addition of Telaprevir to pegylated interferon Ribavirin containing regimen significantly increased SVR rates compared to pegylated interferon Ribavirin alone across a broad range of populations and demographic subgroups. Highest SVR rates demonstrate that the overall duration of therapy can indeed be shortened without jeopardizing efficacy in naives and prior relapse groups.
Extending pegylated interferon and Ribavirin to 48 weeks in addition to 12 weeks of Telaprevir provides additional benefit for naïve subjects who did not achieve an early rapid virological response and in those who are previous interferon failures.
Regarding safety, rash, pruritus and anemia are the key to Telaprevir related toxicities and it is felt they can be monitored and managed appropriately. Anorectal disorders occur frequency, but appear only bothersome yet still manageable and there were no significant infections seen due to low white cells and no abnormal bleeding was seen due to low platelets. Thank you very much.
Richard Klein: Thank you, Dr. Birnkrant and Dr. Murray. And with that Angie, I wonder if we can open the question and answer portion of the call. And while we’re waiting to do that, I just had one quick question. You mentioned dosing with a meal and I’m wondering if the amount of food and the type of food has an impact on absorption when taking the drugs?
Dr. Debra Birnkrant: Well with regard to Telaprevir food absolutely has an effect on absorption and plasma concentration, so it is recommended that subjects or patients take Telaprevir three times a day every seven to nine hours with food that is low fat. It could be a meal, it could be a snack, but it should not be low fat. So examples of foods that can be used while taking Telaprevir include bagels with cream cheese, avocados, nuts, granola, et cetera.
Richard Klein: Thank you. And (Angie), do we have questions queued up?
Coordinator: At this time if you’d like to ask a question, please press star 1 on your touch tone phone and record your first and last name so that you may be announced. In order to withdraw your question, you will press star 2.
Once again if you’d like to ask a question, please press star 1 on your touch tone phone and record your first and last name so that you may be announced.
One moment please for our first question. Our first question comes from (Joel Levin). Your line is open.
(Joel Levin): Two questions. You didn’t mention the food for Boceprevir. What’s recommended for Boceprevir?
((Crosstalk))
Dr. Jeffrey Murray: …also with a meal, it could be a snack, but the high fat requirement is not needed. But it should be a meal or a snack.
(Joel Levin): Okay. So my real question is this maybe I’m missing something or maybe there’s something - it just seems strange to me - so with Victrelis Boceprevir if a patient is greater than 100 with viral load at week 12, they’re to stop Boceprevir. I think they’re supposed to stop the whole regimen. But with Telaprevir, it’s greater than 1000 at week 12 so why is there that difference?
Dr. Jeffrey Murray: Well, I think that the futility rules were based on looking at the data from the clinical trials and so Dr. Birnkrant can comment on the futility roles for Telaprevir. But in looking at these futility roles and how many patients by stopping early we would have missed SVRs in this database, we don’t think that you’re giving up any SVR or using the futility role of greater than 100 at week 12 and undetectable at 24. So it really depends on the data set.
Dr. Debra Birnkrant: For Telaprevir patients with an inadequate viral response are unlikely to achieve an SVR and the concern is that they may develop treatment emergent resistance of substitutions. The discontinuation of therapy is recommended in all patients with HCV RNA levels of greater than or equal to 1000 international units per ML at treatment week 4 or 12 or confirmed detectable HCV RNA levels at treatment week 24. And this is outlined in the package insert.
(Joel Levin): So the way you’re protecting people on Boceprevir is if they’re over 100 at week 12 - well if they’re over 100 at week 12 they’re supposed to stop the whole regimen, right?
Dr. Jeffrey Murray: That’s correct.
(Joel Levin): Okay. All right, so it’s basically based on the study data and trying not to lose people who still could get an SVR, right?
Dr. Debra Birnkrant: That’s absolutely correct because Telaprevir there’s still some patients between HCV RNA level of 100 to 1000 who still had an SVR.
(Joel Levin): Right, okay.
Dr. Debra Birnkrant: Okay.
(Joel Levin): Thank you.
Dr. Jeffrey Murray: Next question, please.
Coordinator: The next question comes from (Lauren Sant).
(Lauren Sant): Hi. This (Lauren Sant) (unintelligible) Ambassador's Program. You had mentioned that dosing is at seven to nine hours. Are there instructions for what happens if someone misses a dose and what they should do?
Dr. Debra Birnkrant: In the medication guide that a company’s package insert there are instructions about how to deal with missing one dose. If more than one dose is missed, however, that’s a much more difficult situation and you should probably talk to your physician about how to resume therapy.
(Lauren Sant): Okay. But it’s clearly stated in the package if they miss one by a couple of hours what they should do?
Dr. Debra Birnkrant: Absolutely.
(Lauren Sant): Great. Thank you.
Dr. Jeffrey Murray: Thank you, Lauren. Can we go on to the next question, please?
Coordinator: Next question comes from David Ross.
David Ross: Hi. This is David Ross, US Department of Veteran Affairs. First congratulations to you and the review team. I know this was a tremendous amount of work and this is a day all of us have been waiting for. Do you know when the summary basis of approval - I’m not talking about the full action package - but the summary for approval for Boceprevir and Telaprevir is going to go up on the web?
Dr. Debra Birnkrant: I don’t have an exact timeframe, but I’m told given the high priority or the high visibility of these drugs that it should be expedited. I can tell you now that both labels are up and both approval letters are online.
David Ross: Okay. Thanks...
((Crosstalk))
David Ross: I know one of the things we’re looking at is, you know, there’s obviously hugely complex decisions to be made in terms of the review of this, in particularly with regard to individuals who have treatment experience for no responders and we’re just looking at the two different drugs and the different study designs and it’s - you guys have living with the data for months. So having those up would be hugely helpful to people.
A second question this is obviously an area for emerging science. I have IL28B statuses looked at retrospectively and it’s really, really helpful to have that information on the label, and again we really appreciate that, but do you anticipate that there’s going to any follow on data that’s perspectively collected that may give guidance to providers as well as patients about how to incorporate that into clinical decision making?
Dr. Jeffrey Murray: Well one of the - as stated in the approval letter for Victrelis - one of the post-marketing commitments that Merck has agreed to do is that another study looking at the effect of IL28B and also looking at potentially shorter durations of therapy of Victrelis and/or PR. So we’ll hopefully be getting a protocol for that relatively soon. So that would be one of the post-marketing commitments.
David Ross: Okay. And then last question and again this is definitely an area of emerging science. There’s been data reported that (Easel) and (liver) meetings for the last couple of years in terms of an effective Vitamin B and Vitamin B regulated (unintelligible) products on SVR rates. There was a small interesting study from Israel randomized control trial last year at (Easel) showing a substantial effect from an (ex) US population. Is this anything - and I don’t know if this was considered during the review - but is this anything that again there might be follow on data to look at either in - I understand there may be things you can’t speak about, but I just - if it was considered in the review that would be great. But I just wanted to ask about that because Vitamin D level certainly they have instead that may affect SVR rates made a fool out of providers who are just kind of biting the bullet and giving Vitamin D.
Dr. Jeffrey Murray: Right. I don’t think we have any further information on that. I don’t think you’ll find it in the summary reviews. I don’t think that Vitamin D levels were specifically measured in relation to treatment outcomes and there’s no currently pending studies in the form of post-marketing commitments on that although I’m sure there might be a lot of investigator interest in that area with these new DAAs.
David Ross: Absolutely. Again thanks for all your hard work on this.
Dr. Jeffrey Murray: Thank you. Angie, can we take the next question please?
Coordinator: Yes, sir. Our next question comes from (Miles Heflin). Your line is open.
(Miles Helfin): Hi. Thanks. It’s (Miles Helfin) from thebody.com. Given that there appear to be relatively few significant differences in terms of efficacy or safety between Telaprevir and Boceprevir how would you guys advice a clinician who’s going to be choose between these two drugs?
Dr. Debra Birnkrant: Well the only way we would be answer that would be if they comparative in a head-to-head trial which they were not. So you’ll have to consult future treatment guidelines with regard to advice on that question.
(Miles Helfin): But I mean going forward in the future what’s a clinician or a patient to do when they’re trying to choose, “Well, all right. Which one of these drugs do I go with and incorporating that into a regimen?”
Dr. Debra Birnkrant: I think they should read the prescribing information quite thoroughly. When the Division Director and the other memos are up online, you should read those as well and perhaps await recommendations from professional organizations.
(Miles Helfin): Thanks.
Coordinator: Our next question will come from (Courtney McQueen). Your line is open.
(Courtney McQueen): Hi. This is (Courtney McQueen) from the Aids Begin. Thank you very much. I had two questions. First during the Advisory Committee Meeting there was discussion of triple therapy being the new standard of treatment for hepatitis C would you comment on that? Do you think triple therapy is now the new standard?
Dr. Debra Birnkrant: The Advisory Committee when posed that question clearly stated that there was a new standard of care now with the approval of these two new DAAs. So it appears as though there is a new standard of care and again we’ll have to await professional organizations treatment guideline recommendations to see what these professional societies are recommending.
(Courtney McQueen): Thank you. And my second question relates to people who are HIV HCV co-infected. The current approval is not for people who are co-infected. Do you have any idea about timelines for when such an approval might be considered?
Dr. Debra Birnkrant: For Telaprevir as part of the one post-marketing commitments, we asked (Verteck) to conduct a trial to evaluate treatment responses and safety among treatment naïve and experienced HIV HCV co-infected subjects and the time table is as follows: the final protocol submission should be January 2012, the trial is estimated that it should be completed June 2014 with a final report submitted 2014 as well in December. There’s a pilot study in progress as well.
(Courtney McQueen): Thank you very much.
Coordinator: Our next question will come from (Garrett Benson). Your line’s open.
(Garrett Benson): Yes. My understanding is that the treatment is for genotype 1s only, but when and if will genotypes 2 get an opportunity to - if they relapsed after their treatment - would they ever get an opportunity for the DAs?
Dr. Debra Birnkrant: For Telaprevir pilot studies were conducted in other genotypes and it didn’t appear as though it had adequate activity in genotypes other than 1, genotype 1A and 1B.
(Garrett Benson): Okay. Thank you.
Richard Klein: I’d like to thank Drs. Hamburg, Birnkrant, and Murray for their presentations and all the attendees for their participation.
I hope the exchange was informative and useful to you. If you do have questions after today’s call or comments about the briefing, you can direct them to me at richard.klein@fda.hhs.gov and I’ll be sure to direct questions to the appropriate FDA staffer for a response.
I hope you will share the information from today’s briefing with this colleagues and this concludes today’s stakeholder briefing on Boceprevir and Telaprevir and thank you very much for your participation. Have a good afternoon.
END
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm256753.htm
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Telaprevir/Incivek Prescribing Information
Medication Guide
.
VICTRELIS™- Boceprevir: Prescribing Information and Medication Guide
.
Patient Assistance Program
.
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Programs
,,
Blog Notes;
,
Hello Folks,
Before shutting down the blog for the night I wanted to reiterate that Incivek, better known as telaprevir will be available for free to anyone who does not have insurance and if their annual household income is 100,000 or less. If you do have insurance regardless of your total household income Vertex will cover your co-pay or co-insurance costs up to twenty percent of the total cost of treating with incivek
From Vertex;
For eligible patients, the program includes the following:
Here is the information on Boceprevir
If you have been prescribed a Merck medicine, you may be eligible for the program if all 3 of the following conditions apply:
Find out more information by calling the phone numbers provided.
The Patient Assistance links will remain on the sidebar of this blog
.
Sending out hope to all of you tonight.
.
Tina
.
Medication Guide
.
VICTRELIS™- Boceprevir: Prescribing Information and Medication Guide
.
Patient Assistance Program
.
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Programs
,,
Blog Notes;
,
Hello Folks,
Before shutting down the blog for the night I wanted to reiterate that Incivek, better known as telaprevir will be available for free to anyone who does not have insurance and if their annual household income is 100,000 or less. If you do have insurance regardless of your total household income Vertex will cover your co-pay or co-insurance costs up to twenty percent of the total cost of treating with incivek
From Vertex;
For eligible patients, the program includes the following:
- Insurance Benefits Research and Support: Vertex case managers research patients’ insurance benefits for INCIVEK combination treatment, assists people with insurance appeals and helps guide them to other forms of financial support, including Vertex’s free medicine and co-pay program;
- Free Medicine Program: Vertex gives INCIVEK for free to people who do not have insurance and have an annual household income of $100,000 or less; and
- Co-Pay Support: Vertex covers co-pay or co-insurance costs up to 20% of the total cost of INCIVEK for people who have private insurance plans that cover INCIVEK, regardless of their household income.
Here is the information on Boceprevir
If you have been prescribed a Merck medicine, you may be eligible for the program if all 3 of the following conditions apply:
- You are a US resident and have a prescription for a Merck medicine from a doctor licensed in the United States.*
AND - You do not have insurance or other coverage for your prescription medicine.
Some examples of other insurance coverage include private insurance, HMOs, Medicaid, Medicare, state pharmacy assistance programs, veterans assistance, or any other social service agency support.
AND - You cannot afford to pay for your medicine.
You may qualify for the program if you have a household income of $43,560 or less for individuals, $58,840 or less for couples, or $89,400 or less for a family of 4.**
*You do not have to be a US citizen. Legal residents of the United States are also eligible.
** For income limits in Alaska, Hawaii, Puerto Rico, US Virgin Islands, and Guam, please call 1-800-727-5400.
http://www.merck.com/merckhelps/patientassistance/qualify.htmlFind out more information by calling the phone numbers provided.
The Patient Assistance links will remain on the sidebar of this blog
.
Sending out hope to all of you tonight.
.
Tina
.
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