Abbott Laboratories' Management Presents HCV Program Update (Transcript)

 |  About: Abbott Laboratories (ABT)
by: SA Transcripts


Good day, ladies and gentlemen, and welcome to the Abbott HCV Program Update. My name is Caris, and I will be your coordinator for today. [Operator Instructions] As a reminder, this call is being recorded for replay purposes.

And I would now like to the hand the call over to your host for today, Mr. John Thomas, Vice President, Investor Relations and Public Affairs, Abbott. Please proceed, sir.

John B. Thomas

Thanks, Caris. Good afternoon, and thank you for joining us for this brief update on our advancing interferon-free Hepatitis C program. Joining me on today's call is Dr. Kris Kowdley, Director of the Liver Center of Excellence and the Digestive Disease Institute at the Virginia Mason Medical Center and Clinical Professor of Medicine at the University of Washington in Seattle. Dr. Kowdley is the first author of the data presented today. Also on the call today is Dr. Scott Brun, Head of Clinical Development for Abbott, and will be for AbbVie. Dr. Kowdley will walk us through the Phase IIb Aviator data presented today at AASLD, and Dr. Brun will provide an update on our HCV program and Phase III studies. Following their comments, we'll take your questions. Given the participants of today's call, we'd like to keep questions clinical in nature and specific to our HCV program. If you have other questions, you can follow up with us as usual. Corresponding slides for this call are available on Abbott's website and can be downloaded at

Before we get started, some statements may be forward-looking for purposes of the Private Securities Litigation Reform Act of 1995, including the planned separation of the research-based pharmaceutical company from a diversified medical products company and the expected financial results of the 2 companies after the separation. Abbott and AbbVie caution that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements, and there is no assurance as to the timing of the planned separation or whether it will be completed. Economic, competitive, governmental, technological and other factors that may affect Abbott and AbbVie's operations are discussed in Item 1A Risk Factors to our annual report on Securities and Exchange Commission Form 10-K for the year ended December 31, 2011, and then in the interim reports filed on Form 10-Q for subsequent quarterly periods. Except as required by law, Abbott and AbbVie undertake no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments.

And with that, I'll now turn the call over to Dr. Kowdley. Dr. Kowdley?

Kris Kowdley

Thank you very much. On behalf of the co-investigators, it is my pleasure to present the results of Aviator, the M11-652 trial. This study is a 12-week, interferon-free treatment regimen using ABT-450 ritonavir, ABT-267, ABT-333 and ribavirin, and achieved SVR12 rates observed data of 99% in treatment-naïve patients and 93% in prior null responders with hepatitis C genotype 1 infection.

The next 2 slides show the pertinent disclosures for the co-investigators and co-authors. ABT-450, identified as a lead compound by Abbott and Enanta, is a potent HCV NS3/4A protease inhibitor that is co-administered with ritonavir and dosed once daily. ABT-267 is an NS5A inhibitor that is dosed once daily, and ABT-333 is a non-nucleoside polymerase inhibitor dosed twice daily.

ABT-450 ritonavir containing interferon-free combinations have previously achieved SVR rates of higher than 90% in genotype 1 infected patients in exploratory studies. Goal of this study was to identify optimal interferon-free, direct-acting antiviral combinations in patients with hepatitis C genotype 1 infection or either previously treatment-naïve or null responders to prior therapy with interferon and ribavirin. This study includes direct-acting antiviral combination treatment durations up to 24 weeks. Only the 8- and 12-week treatment results will be presented now.

This slide shows the study design. Above the bar is the population of patients that was treatment-naïve and at the bottom of the slide are the population of patients who are null responders. The regimen and duration is shown on each of the bars. And as you can see, a number of different approaches were considered in the study design, including ribavirin-sparing regimens and regimens that used 2 instead of 3 direct-acting antiviral agents. On the right side of the slide are shown the doses of ABT-450 used. And I want to point out that 150 will be the dose going forward, and a standard dose of ritonavir was used in all study groups. Ribavirin at weight-based 1,000 to 1,200 milligrams daily was used in this study.

The primary and secondary study efficacy endpoints are the SVR24 rates. The data presented here are the SVR12 rates, and the SVR24 rates will be presented subsequently at a future meeting. The key eligibility criteria for the study were fairly standard for studies of this type: age 18 to 70; chronic HCV genotype 1; absence of cirrhosis based on biopsy, FibroScan or FibroSure test results. Treatment-naïve patients, previously had not received any antiviral therapy for hepatitis C, null responders, had received at least 12 weeks of pegylated interferon and ribavirin and failed to achieve at least a 2-log reduction in HCV RNA. HIV or hepatitis B co-infection were excluded.

This slide shows the baseline characteristics of the patients in the various treatment regimens in this study. As you can see, going across from left to right, with the exception of one of the groups, the population was over half male and predominantly white race. The mean age in most of the groups was over 50, but barely so. And 2 of the groups, the mean age was barely under 50. IL28B CC genotype was available in all subjects. And as you would expect, the treatment-naive patients showed approximately 27% to 34% IL28 CC genotype versus the treatment null responders at a much lower frequency, 2.2% to 4.4%, as would be expected in patients who previously had failed therapy. Mean HCV RNA level was fairly common across all groups at 6.5 logs, and a majority of the patients in this study actually had the more difficult to treat genotype 1a infection, which range from 59% to 70.7% in the different treatment groups.

This slide shows the primary results of the study based on intention-to-treat analysis for the 8- and 12-week arms. The first point worth mentioning is that across all the groups, very high rates of SVR12 were observed, ranging from 85.4% up to 97.5% in the various treatment-naïve groups and up to 93.3% in the null responder groups. The optimal regimen that contained 3 direct-acting antivirals and ribavirin resulted in 97.5% SVR12 in treatment-naïve patients and 93.3% in the null responder group.

More data about the response rates and some of the individual features are shown on this slide. As you can see, breakthroughs were rare. And only 3 patients had virological breakthrough in the null responder group treated with 450 ritonavir, 267, 333 and ribavirin as shown on the last slide -- last column. Relapses were primarily observed only in patients who received 8 weeks of therapy as shown on the third line. However, in patients that received the optimal regimen of 3 direct-acting antivirals and ribavirin, only one patient in the treatment-naïve group relapsed and no patient in the null responder group relapsed. When we look at the optimal treatment regimen, we saw that intent-to-treat results showed 97.5% SVR12 in the 3 DAA and ribavirin group and observed data results of 98.7%. The comparable results in the null responders, a much more difficult to treat group historically, was almost as good at 93.3% for both ITT and observed data results.

This slide shows the breakdown of results for patients with HCV subtype 1A versus 1b. It is generally believed that 1b patients are easier to treat. And it was very interesting to note that in almost every category of treatment assignment, approximately 100% of patients or 100% of patients achieved SVR12. And in fact, in only one of the groups of genotype 1b was observed data SVR12 not 100%, and in this case, it was 96%. These data suggest that for patients with genotype 1b, regimens that might avoid ribavirin or might use fewer DAAs could be considered in future trials. Furthermore, when we look at the optimal treatment regimen of ABT-450 ritonavir, 267, 333 and ribavirin, we saw excellent results of SVR12. Even in the more difficult to treat genotype 1a patients and even in the null responders with genotype 1a, 89% of patients achieved an SVR12, which is encouraging as a clinician and researcher and provides hope.

We examined the results for SVR12 by IL28 genotype. And the short answer is that IL28B CC versus non-CC does not appear to influence very much the results of treatment in this particular study. As you can see, there are very high rates of SVR12, and there do not appear to be any significant differences between CC versus non-CC patients.

Resistance analysis has been conducted and is ongoing in the 8- and 12-week treatment arms. In the 8-week arm, so far, no treatment emergent resistance-associated variants have been seen in relapse samples from 6 of 9 patients. And in the 12-week treatment arms, the majority of breakthrough and relapse samples have showed emergence of variants known to be selected by ABT-450, 267 or 333. Although this is in a very small number of cases, ongoing studies plan to examine the resistance profile in more detail and will be presented subsequently.

I'd now like to turn to adverse events and laboratory abnormalities and address safety issues. No study drug-related serious adverse events were noted. One serious adverse event, namely arthralgia, possibly related to study medication, was noted in a 24-week treatment arm patient. However, only 2 of 448 patients have discontinued treatment due to AEs attributed to study drug by the investigator. These 2 are characterized by cholestatic hepatitis in a patient with gallstones and a second patient with a range of different symptoms. Both events resolved, and both patients achieved sustained biological response.

Moderate-to-severe adverse events, possibly or probably related to study drug, with a greater-than-5% incidence in any arm, are shown on this slide. Fatigue, headache, insomnia and nausea were the most common adverse events described and were infrequently noted, with the exception of one group, where it was noted in approximately 8%. In the majority of the groups, it was 5% or less.

Grade 3 to 4 laboratory abnormalities occurring in more than one patient in the 8- and 12-week arms are shown here. The only laboratory abnormality that occurred with any frequency was an elevation in total bilirubin, which was noted in 6.7% of the treatment-naïve patients and 12.2% of the null responders. The elevation in total bilirubin in the vast majority of cases was less than 3 grams per -- milligrams per deciliter in total, was predominantly indirect and resolves spontaneously without any adjustment, discontinuation or interruption of therapy.

A few patients were noted to have an elevation of serum ALT, as noted on the second line. In most of these cases, these ALT elevations spontaneously resolved by 2 to 3 weeks, and in no case, was the elevation in ALT associated with an increase in serum bilirubin. The other adverse laboratory abnormalities noted on this slide are listed. And as you can see, they occurred quite infrequently, and in no case, was study drug interrupted or discontinued [ph] because of these laboratory abnormalities.

We noted with interest that the ribavirin-free arms had no significant decrease in serum hemoglobin compared to the ribavirin-containing arms, where the mean change in hemoglobin was approximately a 2-gram reduction as shown on this slide. We noted significantly smaller mean hemoglobin decrease at week 12, lower incidence of hemoglobin decrease to less than 10 grams per deciliter and a trend towards fewer events of anemia, insomnia, nausea and cough in the ribavirin-free arms. These data support particularly in easier-to-treat populations and as part of our ongoing study designs, consideration of ribavirin-free regimens in the treatment development.

In conclusion, the 12-week, 3 direct-acting antiviral and ribavirin regimen showed the greatest efficacy for both treatment-naïve and null-responder populations. In the genotype 1a-infected treatment-naive patients and infected null responders, which are traditionally more difficult to treat, SVR12 ITT rates of 96% and 89%, respectively, were described, which are encouraging. High SVR12 rates were seen across all IL28B genotypes. We noted with interest that in the 124 genotype 1b-infected treatment-naive or null-responder patients in any of the 12-week treatment arms, there were no virological failures. The combination of ABT-450 ritonavir, 267 and 333, therefore, will be studied both with and without ribavirin in planned Phase III trials. And a co-formulated tablet, containing ABT-450 ritonavir and 267, will be used in Phase III trials going forward.

I would like to knowledge that safety was studied extensively, and these combinations appear to be well tolerated through 8 to 12 weeks of treatment, the most common adverse events for fatigue, headache, insomnia and nausea. As expected, we did note transient asymptomatic elevation of indirect bilirubin, which seemed to resolve spontaneously and was consistent with the previously known effect of ABT-450 ritonavir on the bilirubin transporter, OATP1B1. And it appeared that fewer than 1% of patients discontinued due to adverse events.

I would like to acknowledge the co-investigators coordinators and patients, who participated in this study. Thank you for your attention.

Scott C. Brun

Thank you, Dr. Kowdley, for both this presentation, as well as the excellent job you did at the late breakout session of the AASLD meeting. And thank you, everyone, for joining us today. I think you can see from the data that Dr. Kowdley just outlined, we're very pleased with the efficacy demonstrated in the Phase IIb Aviator study. These are very strong results, and they demonstrate that our interferon-free regimen offers the potential for a compelling and clinically relevant improvement over current treatments for patients with genotype 1 infection. What I'd like to do over the next few minutes is to provide some additional context on the data to date and walk through the details of our recently initiated global Phase III registrational program, which will be conducted in genotype 1 patients.

From the slide, as a remainder, our HCV program contains compounds that span 3 mechanisms of action, including our boosted protease inhibitor, ABT-450; our NS5A inhibitor, ABT-267; and our non-nucleoside polymerase inhibitor, ABT-333. As we previously have stated, our goal remains to bring to market a potent, well-tolerated and easy-to-administer treatment that delivers very high cure rates without requiring the use of interferon and across the most represented of patient populations globally, including very importantly, those who are traditionally the hardest to treat. The data that have been presented to date confirm that we're very well on target to achieve that particular goal.

Now the Phase IIb Aviator study represents the most comprehensive set of interferon-free, DAA combination treatment data in genotype 1 patients that has been available to date. The study was designed to examine a variety of regimens across different patient populations in order to answer multiple questions and to support the selection of optimal interferon-free regimens for Phase III confirmatory studies. The results from the Aviator trial, build upon earlier findings from our Phase II pilot and co-pilot studies, with Aviator demonstrating very strong efficacy across all treatment arms in both genotype 1 naïve, and of particular importance, pegylated interferon-experienced patients. Now from a safety perspective, all regimens were well tolerated with very few patients in the study discontinuing treatment due to adverse events.

Now with these strong results in hand and following discussions with regulatory authorities around the world, we've recently initiated our comprehensive genotype 1 registrational program with the start of our very first Phase III study. And we're well on track to begin all of the remaining registrational trials in the coming weeks. Our global program will include study of naïve and experienced patients with HCV genotype 1 infection, as well as certain special populations, including patients with cirrhosis. We're going to evaluate our 3 direct-acting antivirals, both with and without ribavirin, for 12 weeks. Our Phase III triple DAA regimen consequently includes very notably a successfully co-formulated, 2-tablet regimen of our protease inhibitor, ABT-450, with low-dose ritonavir; and our NS5A inhibitor, ABT-267. So again, all 3 active ingredients in the same co-formulation administered once daily. Patients will also receive our polymerase inhibitor, ABT-333, given as one tablet twice daily. And once again, I'd like to emphasize that we will be evaluating regimens both with and without ribavirin. Now this Phase III program is broad. It's comprehensive. It is going to include more than 2,000 patients and span 29 countries around the globe.

To walk you the specifics on this slide of our genotype 1 registrational program, there will be 6 studies included. As noted on the slide, the first 2 studies, named SAPPHIRE-I and II 2, are both placebo-controlled trials evaluating our triple DAA regimen plus ribavirin in genotype 1a and 1b treatment-naïve as well as treatment-experienced patients. In the next group of trials, we have 3: SAPPHIRE-III, SAPPHIRE IV, and PEARL-II 2. And these will explore ribavirin-free treatment across a variety of populations. Each of these 5 studies, I want to stress, is 12 weeks in duration.

Finally, in the TURQUOISE-II study, we'll evaluate our 3 DAA combination with ribavirin in compensated cirrhotic patients, including both naïve and experienced genotype 1a and 1b patients. And this study will include not only 12 but also a 24-week duration of therapy. Additionally, while not part of the initial registration package, we are also planning a Phase III study called TURQUOISE-I, which will be conducted in HIV and HCV co-infected patients. Similar to TURQUOISE-II, this regimen will include the 12- and 24-week courses of therapy and will include our triple DAA regimen with ribavirin. Now just as a reminder, genotype 1 is the most prevalent HCV genotype in key developed markets, and it represents more than 70% of patients in the U.S., as well as more than 60% of patients in Western Europe. The timing of our registrational study supports commercialization in the early 2015 time frame, which puts us in a very strong competitive position. It's our stated goal and intent to be the first to launch an interferon-free regimen for genotype 1 patients through the conduct of this registrational program.

Now our Phase III combination offers a much simpler treatment for patients versus today's standard of care. Our regimen is compact, including a total of 4 pills, plus or minus ribavirin, for only 12 weeks' duration. Now in contrast, the current standard of care requires up to 48 weeks of treatment, including weekly interferon injections, a direct-acting antiviral administered 3x a day with food, plus ribavirin administered twice daily. And as you're likely aware, treatment with interferon is difficult for many to tolerate. Side effects can range from fatigue and sleep disturbances to depression, anxiety, irritability, as well as personality changes.

As Dr. Kowdley outlined, all regimens in the Aviator study were well tolerated with an overall rate of drug-related discontinuations of less than 1%. Across our entire development program, discontinuations for any reason have been very low. Additionally, we have not seen gastrointestinal or lipid side effects of the type that have been observed with the use of ritonavir in the HIV setting. Low-dosed ritonavir pharmacokinetic enhancement allows for higher drug levels, and we believe this approach helps us to achieve the high cure rates that we've observed with this regimen to date. And remember, unlike HIV treatment, which is chronic, this is a 12-week short course of therapy.

Additionally, we have an extensive drug-drug interaction program that will provide guidance on how to use our regimen and relevant concomitant medications, including treatments used in population such as of those with HIV co-infection and in the post-transplant setting. As I mentioned, we plan to conduct a Phase III study in HIV-HCV co-infected patients, and we expect to start that trial next year.

Now I'd like to move on to briefly mention our other ongoing trials, as well as our next-generation Hepatitis C Program, which will be moving into the clinic very soon -- very shortly. As Dr. Kowdley outlined, in Aviator, we saw very high rates of cure in genotype 1b patients. Now to be specific, we saw no virologic failures in any of the 12-week treatment arms with this population, including the ribavirin-free arm.So we recognize that some patient populations may respond very well to even more simplified regimens without compromising the strong efficacy evident in the Aviator trial. Now as such, we're actively evaluating a 2 DAA once-daily, ribavirin-free regimen of our co-formulated protease and NS5A inhibitors in genotype 1b patients in an ongoing Phase II trial.

I really also want to mention that we have an active clinical program in Japan, where we're currently in Phase II development. Our study in Japan includes patients with genotype 1b, as well as genotype 2 infection, which are the most common forms of hepatitis C in Japanese patients. We're evaluating 12- and 24-week interferon, as well as ribavirin-free treatment regimens that contain boosted ABT-450 and ABT-267 administered once daily. And importantly, we're looking to expand as interferon, ribavirin-free, once-daily treatment into other countries across Asia where we see similar viral epidemiology.

Then there's our Navigator study, which evaluates our boosted ABT-450 and ABT-267 regimen, with and without ribavirin, in genotypes 2 and 3. It's ongoing, and we expect results in 2013.

Now finally, I'd like to mention that we also have a very compelling, next-generation program under way, something we haven't spoken about much in the past. But we have compounds entering human trials in the coming weeks. On pre-clinical studies, these promising assets have shown broad genotypic activity, including activity against isolates that have resistance to first-generation DAAs. Our next-generation assets also support once-daily dosing without ritonavir, as well as the ability to co-formulate. Probably you can see from all of these programs, we're very committed to this therapeutic category. And we're going to continue to work to evolve the treatment paradigm over the years to come.

So to sum up, Aviator represents the largest and most comprehensive interferon-free data set presented to date with SVR12 data. The results separate our regimen from competitive approaches in a number of genotype 1 populations, including importantly, the most difficult-to-treat, prior-interferon, null-responder patients. Now as you know, the HCV landscape has changed significantly over the past year. And it certainly continues to evolve. Based on what we've seen with competitor programs, we continue to have a high level of confidence that we have the potential to achieve a strong leadership position in this very, very promising therapeutic space.

So with that, I'd like to go ahead and turn it back to John Thomas, who will open the call up for questions you might have.

John B. Thomas

Thanks, Scott. In addition to Dr. Kowdley and Dr. Brun, we also have with us Dr. Barry Bernstein on the line to help answer questions. Dr. Bernstein is the Head of Infectious Disease Development and the Project Director for Abbott's HCV development program. So Caris, with that, we will now open up the call for questions.

Question-and-Answer Session


[Operator Instructions] And your first question comes from the line of Mike Weinstein with JPMorgan.

Michael N. Weinstein - JP Morgan Chase & Co, Research Division

And so, I guess, my first question is the product map question. And if I look at 333, which is right now BID, what is the roadmap for getting that to QD dosing? If you could shed some light on that, that would be helpful.

Scott C. Brun

Yes. It's Scott Brun. I'll go ahead and take that. So a couple of things. First of all, as I said in certain populations, particularly those with 1b infection, we think there's a potential to eliminate 333, which essentially leaves us with a 2-pill, once-a-day regimen of the protease and the NS5A inhibitor. In parallel, we're also looking at ways to work with formulations to make ABT-333 a once-daily drug. And we'll be doing that in parallel with the current Phase III program, as well as the next-generation program where, again, we've got PI NS5A with very promising resistance and PK characteristics, where we think we can get to a once-daily -- fully once-daily regimen.

Michael N. Weinstein - JP Morgan Chase & Co, Research Division

And the co-formulation work that -- Scott, I know you have talked about this. This has been going on for a while. But what additional PK testing do you need to do relative to combining 450, 267 and ritonavir?

Scott C. Brun

Well, that is done. The 450, ritonavir and 267, we have a successful co-formulation. And that, I should make very clear, that co-formulation of the PI NS5A and the ritonavir boost is being dosed in the Phase III study. So any of the additional work is looking at making ABT-333 a once-daily component.

Michael N. Weinstein - JP Morgan Chase & Co, Research Division

Okay, perfect. And doctor, let me ask you one question. I'll let others jump in. So doctor, the Wall Street is looking at the data that's come out in the last couple of days. And one of the conclusions relative to the AbbVie program is that it looks likely that, in order to get the highest SVR rates, that you need to have ribavirin in the mix. Can you give us your thoughts on -- as you look forward to the Phase III study, what you think you'll see in the arms that have both -- that are both with and without ribavirin?

Scott C. Brun

I think that we need to get a better idea about which patients might potentially be eligible for ribavirin-sparing regimens. So I think it's clear from the data that I presented in the 652 trial, that inclusion of ribavirin in the most-difficult-to-treat patients is beneficial. One can speculate that, as we start to really develop a more individualized patient profile for therapy, namely include factors such as viral load, include factors such as prior therapy, include factors such as genotype 1a versus 1b, there may be a growing proportion of patients that might be eligible for ribavirin-free regimens. So I would say I remain encouraged, enthusiastic. But I would say that it's probably a bit over-enthusiastic to think that ribavirin may completely be eliminated for all patients. But even at a short time ago, we didn't think it was possible that ribavirin would be excluded. And so the fact that we're seeing the results that I've shown you, I think can keep us quite optimistic that for at least many of the patients that we see, this could be a consideration. I might add to that, the beauty of the Phase III program is in genotype 1b naïve and experienced, we're looking at ribavirin-free regimens and certainly in genotype 1a naïve. So we'll be able to characterize those response rates, provide those data and then clinicians can make their own choice with how they want to proceed with the inclusion of ribavirin in the regimen.


And your next question comes from the line of David Lewis, Morgan Stanley.

Steve Beuchaw - Morgan Stanley, Research Division

It's Steve Beuchaw here for David. Dr. Kowdley, I wonder if you could speak to the importance of the treatment of -- treatment duration. Clearly, the 12-week data we've got here gets to something more convenient, potentially safer than the 24-week treatments. But as the bar gets higher, and you think about the potential for shorter treatment, maybe it's 4 weeks or 8 weeks, how significant is treatment duration as a consideration for you, as we're starting to think about improving on an already very high bar?

Kris Kowdley

Yes, excellent question. And I think as a clinician and a doctor, I can tell you that there are stepwise incremental adjustments and considerations that patients have to make in their life, whether it has to do with family, whether it has to do with job, whether it has to do with other things that get in the way. And I think there's a very, very big difference to me as a physician telling a patient to take a year of therapy or 6 months of therapy. But I think when you're talking about 12 weeks, it becomes very attractive. And whether it would be that much more desirable for an individual patient to then want 8 weeks of therapy or 4 weeks of therapy, I think it seems as a practicing clinician, to me, less important. The hurdles are not so great. Patients can often plan their lives around the 3-month window, whereas the 6-month window takes into account things like travel, job, children, schooling, et cetera. Another consideration, which may be a factor, and now I'm sort of thinking a little bit outside the box, is that as we start treating patients in other settings and maybe in other countries or institutionalized settings, there may be some considerations where a period -- a finite short period of therapy while the patient is being closely monitored might be attractive. But I would say that, in my opinion, in my practice, most patients are very happy to be told that a 3-month commitment is what we're asking for them. Obviously, less would be better, but I don't think it's that important compared to the longer durations we've been dealing with.

Steve Beuchaw - Morgan Stanley, Research Division

That's really helpful. And then just one for Scott. I wonder, Scott, if you could spend more time on the next-gen program. Not so much the details of the compounds, but what is it that you're looking to accomplish? What are the key objectives for the platform and how it might compare to what we've seen coming out of Aviator?

Scott C. Brun

Yes, sure. Thanks, Steve. So essentially, what we're looking for is to get to a once-a-day, co-formulated regimen that would not require the use of ritonavir boosting, that would not require the use of ribavirin, that would provide the kind of high cure rates and tolerability across a range of genotypes similar to what we saw with genotype 1 in Aviator. So I think we can see, when you look at non-genotype 1, the work that's been done in interferon-free so far, certainly, we're seeing the use of ribavirin. I think there's starting to be some questions now based on the most recent data what the SVR rates may ultimately look like in genotype 2, 3 with interferon-free regimens. So we'd really like to come up with that complete one-size-fits-all. And we've concentrated on optimizing resistance and pharmacokinetic characteristics based on all the lessons that we've been learning with these interferon-free regimens over the last several months to the past year.


And your next question comes from the line of Glenn Novarro with RBC Capital Markets.

Glenn J. Novarro - RBC Capital Markets, LLC, Research Division

Two questions for Dr. Kowdley. First, in your practice, if Abbott comes to the market with its current regimen and Gilead is going to come to the market with a 1- to 2-pill regimen, how does Abbott fit in to your practice? I would imagine the Gilead program will be the program of choice among most practices. Then I have a follow-up.

Kris Kowdley

Well, I'm not sure that I would be in a position to guess what most practices might do. I think at this point, as a physician and an investigator, we're excited that there seem to be a variety of different regimens that seem effective and offer cures for our patients. But as far as speculating as to what might happen in the marketplace, I would defer that to people that are experts in that area.

Glenn J. Novarro - RBC Capital Markets, LLC, Research Division

I think I was asking your specific practice.

Kris Kowdley

Yes. Well, I think in our practice, we would be -- we will probably be using all regimens that are approved by the FDA and be making decisions based on efficacy data and patient populations. And I think at this point, since Phase III trials are in progress or still being planned, it's a little bit hard for me personally to make that leap and guess what the future might hold in my practice.

Glenn J. Novarro - RBC Capital Markets, LLC, Research Division

Okay. And then just with respect to ritonavir, it seems like the committee does have issues with ritonavir owing to its drug-to-drug interaction issues. What's your view on ritonavir? Will this be a limiting factor to adoption of the Abbott program?

Kris Kowdley

Well, I think that, clearly, there will need to be education of physicians and providers to understand the properties of ritonavir. But I think that we have a couple of advantages with regard to incorporating ritonavir-based regimens, either as part of the Abbott combination therapeutic strategy or other companies or other development programs that use ritonavir. And namely, the first of that ritonavir, to me, as a clinician, has been around for a long time. And there are many treaters, particularly in the HIV community, that are comfortable using ritonavir. And I think the second point is that in the treatment of hepatitis C, we've learned so much in the last couple of years with the advent of boceprevir and telaprevir in understanding effects of drug-drug interactions, understanding the need for dose adjustments. So I think it's going to be a very different landscape than when protease inhibitors or direct-acting antivirals were first introduced in that therapeutic area. I think it will be different for those reasons.

Scott C. Brun

Glenn, it's Scott Brun. I'd like to weigh in, given the fact, as you know, we've got our legacy HIV program, which I've been involved with. So certainly, I've worked with ritonavir for a very long time. I mean the dose that we're using, 100 milligrams once daily, is an extremely common use in HIV-infected patients who are receiving lifelong chronic therapy with very complicated polypharmacy. And certainly, with the boosted protease inhibitors, clinicians have been able to manage that quite well. Within Aviator, as Dr. Kowdley has laid out, I mean we have not seen discontinuations for ritonavir-type side effects nor discontinuations for issues related to drug interactions. And so we feel that based on the drug interaction studies that we're doing right now, we are coming up with a comprehensive program, so that we're are going to be able to fully educate clinicians for what they need to do during that short 12-week patient -- 12-week treatment period, if there's any types of modifications that need to be done. So certainly, we feel that the ritonavir is playing a very important part in providing these very high cure rates across broad patient populations, both naïve and null responders. And we think if that's what it takes to achieve those cure rates, we'll certainly be able to provide guidance. So that should not be a significant issue for clinicians.


And your next question comes from the line of Larry Biegelsen.

Lawrence Biegelsen - Wells Fargo Securities, LLC, Research Division

One for Dr. Kowdley and one for Scott.

[Technical Difficulty]

Dr. Kowdley, I think you said in the presentation that adherence, that really didn't cause any issues. But as you go into larger studies in even more centers, how can you ensure compliance with the multi-pill regimen such that you don't run into breakthroughs?

Kris Kowdley

Well, we are looking into all of the factors that might potentially have contributed to the very small number of patients that broke through or relapsed in the 3 DAA and ribavirin regimens. The numbers are very, very small. And it's a large overall cohort. So just considering all the various possibilities with such a large number of patients, the very low rate of relapses or breakthroughs would suggest that issues of adherence or compliance might not pose a problem. But as you've already heard some comments that were raised, I think that the ways to improve adherence will obviously be enhanced by reducing the pill burden. The Phase III trials, as were pointed out by the Abbott colleagues, will include a co-formulated tablet with the NS5A and the protease ritonavir administered once daily. So that will be a very important step forward. And I think that all of the pharmaceutical companies and therapeutic experts in this area are really keen on trying to achieve the least number of medications used. And furthermore, the avoidance of ribavirin might also provide another big boost by preventing anemia and reducing some of those side effects. So I think all of the steps that are being taken and the planning forward should hopefully improve adherence and compliance.

Lawrence Biegelsen - Wells Fargo Securities, LLC, Research Division

And Scott, that was very helpful -- Dr. Kowdley. Scott, I'd like to get your reaction to the data we saw today with Gilead 7977 and Bristol's daclatasvir. The question we're getting, and it'd be useful to hear your perspective, is if Gilead can replicate these results with 5885, where would Abbott's regimen fit in?

Scott C. Brun

Yes. No, absolutely. So certainly, very interesting and encouraging data I think throughout the afternoon today. So one of the questions that I think comes up has to do with, as you go into broader patient populations, as you scale up to large Phase III trials, what can you potentially expect here? I mean, to begin with, there's a whole question about daclatasvir and 5885. How interchangeable are they? I think we're going to need to see that. Another question that certainly comes up is -- again, as you go beyond treatment-naïve patients into -- or even within treatment-naïve patients into harder-to-treat populations, how are things going to fare? And that could very well differ from regimens. I mean, in HIV, we've seen cases where in the easier-to-treat first-line, therapy patients, everything looks pretty much the same. But then as you begin to move away from there, the regimens really begin to differentiate themselves. And so what we feel with our regimen -- again, we have 450 patients that Dr. Kowdley presented on. And across all of the regimens by the stringent intent to treat, no regimen to worse than 85%. So that tells me you can go down to 8 weeks, you can drop ribavirin and you see minimal loss in SVR12 compared to the core 3 DAA ribavirin regimen that we're taking forward. And so consequently, I feel very confident that as we go into Phase III, particularly with the 93% rate in null, that to your prior question about adherence and compliance, that even if patients were to miss some pills, miss some ribavirin, that our rates are going to remain pretty robust. And I think we need to see that from other regimens. Again, there's been more data coming out on the 7977 ribavirin regimens that as you begin to go to 8 weeks, as you begin to go in the more fibrotic patients, cut back on the ribavirin dose, that those high SVR rates may begin to erode. And so consequently, I guess, I think one of the strengths of our program is the fact that we've done a very comprehensive evaluation of a number of variables. And that as we scale up, we think that even as you get into these more-difficult-to-treat populations, that our Phase III results should remain robust. But that certainly -- again, I think the bottom line is the race is still on. I think we are in a very good position to be first to market with an interferon-free regimen for genotype 1. Our Phase III is going to be enrolling -- it is enrolling. And I think we need to go from there and see how things continue to evolve.


And your last question comes from line of Tim Anderson with Sanford Bernstein.

Tim Anderson - Sanford C. Bernstein & Co., LLC., Research Division

I have 3 questions. When you say co-formulated, can you verify that you mean a single pill or 3 medicines or could that be 2 pills packaged together? And then the control arms for the TURQUOISE and SAPPHIRE trials, is that active control, placebo control or no control? And then the 3 patients who had breakthrough, how are they salvaged?

Scott C. Brun

Sure. So the first question, again, to be very clear, you've got the 450 HCV protease inhibitor; the ritonavir, number 2; the 267 NS5A, number 3, all co-formulated together. And that's 2 pills once a day. And then the ABT-333 is separate but that in places where we're able to do it, like the U.S., will be co-packaged. So it'll be a one-prescription regimen: 3 pills in the morning, one at night for the ribavirin-free particular version. With regard to question 2, the control arms, 2 of the SAPPHIRES are going to have placebo-controlled arms. The ribavirin-free studies will have ribavirin-containing reference arms. And so we're not going to be having any interferon containing arms to act as control arms. And then with regard to the 3 patients for breakthrough, we don't yet have salvage information on those particular patients. As a matter of fact, I'm not sure what the therapeutic decision has been made with regard to their disposition. But certainly, as we collect those data, they'll be presented in the future.

I think that ends our question-and-answer period. But we've covered a lot of ground tonight. And before I turn it back to John, I'd like to go ahead and sum up. I think it's very important to stress that our Aviator study is really -- it's the most comprehensive, interferon-free combination trial to date. And again, we're talking about 450 patients with SVR12 data. I think very importantly, when you look at the 3 DAA regimens, with and without ribavirin, that were taken forward into Phase III, these Phase II data suggest that we've got a very high potential for SVR rates well above 90%, not only in treatment-naïve but, again, in the null-responder patients, where the 93% rate that we've seen in Aviator is, I have to say, unparalleled. Certainly, those of you who sat through some of the presentations yesterday afternoon could see just how hard these null-responder patients are to treat and how many of these DAA approaches reached nowhere near the types of responses that we're seeing here. Now I think very importantly, when you look at this trial in aggregate, and there's lot of data here to tell us a lot of things, we're seeing remarkable consistency and robustness across all of the arms. And again, I go back to the 8-week in the ribavirin-free arms, everything performed at 85% or above. And so if a patient were to be less than optimally adherent on either of the ribavirin or on the duration of therapy, it looks like we're going to lose little SVR. So in summation, how do I look at this? I think that as we expand in the broader patient populations that may have greater adherence challenges or other demographics that make them harder to treat, we have a safety net or a cushion of sorts. Because with this very potent and well-tolerated regimen, we would expect that our Phase III SVR rate should be very consistent with our Phase IIb observation. And while we have some very interesting point estimates on some other regimens in treatment-naïve patients, I don't feel that at least in my mind, that we have similar assurance that the scale up to Phase III will necessarily be as consistent as the Phase IIb results that we've seen.

So look, we are moving full speed ahead. We've initiated Phase III with confidence. We're going in big, over 2,000 patients, 29 countries. Our regimens are selected. We don't have any need for any interim analysis or pause during the program. We're in Japan, the second-largest global market. We're looking at a -- as we said, the 2-drug, once-daily riba-free regimen that we're looking to expand into genotype 1b, and let's not forget the Phase I next-generation program, is going to be beginning very imminently.

So that being said, I know it's getting late for many of us, I want to thank you for your time and attention to the program. I hope you're getting a sense of how excited we're feeling about this program. And that being said, why don't I go ahead and how about turn it back over to John Thomas to wrap this up?

John B. Thomas

Okay, Scott, thanks a lot. And thank you, Scott, for taking the time. And thank you, Dr. Kowdley, as well as Dr. Bernstein. Thanks, everybody, for joining us. If you have any other questions, please give us a call. This concludes the call for today. A replay will be available on Abbott's Investor Relation website at beginning later this evening. Thank you, all, for joining us, and have a good evening.


Now ladies and gentlemen, that does conclude today's conference. Thank you for your participation. You may now disconnect. Have a wonderful day.

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