Achillion Pharmaceuticals' CEO Hosts Sovaprevir Clinical Program Update Conference (Transcript)

Achillion Pharmaceuticals, Inc. (NASDAQ:ACHN)

Sovaprevir Clinical Program Update Conference

July 01, 2013 4:15 pm ET

Executives

Glenn Schulman - Director of Investor Relations

Milind S. Deshpande - Chief Executive Officer, President and Director

David Apelian - Executive Vice President & Chief Medical Officer

Analysts

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

Alethia Young - Deutsche Bank AG, Research Division

Rachel L. McMinn - BofA Merrill Lynch, Research Division

Matthew Harrison - UBS Investment Bank, Research Division

Brian P. Skorney - Robert W. Baird & Co. Incorporated, Research Division

Y. Katherine Xu - William Blair & Company L.L.C., Research Division

Philip Nadeau - Cowen and Company, LLC, Research Division

Howard Liang - Leerink Swann LLC, Research Division

Christian Richard - Merlin Nexus

Jason Kolbert - Maxim Group LLC, Research Division

Operator

Good day, ladies and gentlemen, and thank you for standing by, and welcome to the Achillion update conference call. [Operator Instructions] As a reminder, today's conference may be recorded.

It's now my pleasure to turn the floor over to Dr. Glenn Schuman, Senior Director of Investor Relations. Please go ahead.

Glenn Schulman

Thank you, Jerry [ph] and good afternoon, everyone. Thanks for joining us today as we provide an update on recent developments in the sovaprevir clinical program. Hopefully, everyone received a copy of this afternoon's press release providing the most recent update on the sovaprevir clinical program in announcing the clinical hold recently placed on that drug program. If you have not received this news release or would like to be added to our distribution list, please feel free to call or email me in the office at (203) 752-5510 after the call. This news release is also available from our website at www.achillion.com.

Joining me this afternoon on the call from Achillion are Dr. Milind Deshpande, our President and Chief Executive Officer; Dr. David Apelian, Executive Vice President and Chief Medical Officer; Gautam Shah, Executive Vice President and Chief Compliance Officer; Mary Kay Fenton, Senior Vice President and Chief Financial Officer; and Joe Truitt, Senior Vice President of Business Development and Chief Commercial Officer.

Before we begin, I'd like to caution that comments made during this conference call by management will contain forward-looking statements that involve risks and uncertainties regarding the operations and future results of Achillion. I encourage you to review the company's past and future filings with the Securities and Exchange Commission, including, without limitation, the companies Forms 10-K and 10-Q, which identify specific factors that may cause actual results or events to materially differ from those described in the forward-looking statements. Furthermore, the content of this conference call contains time sensitive information that is accurate only as of the date of the live broadcast today, July 1, 2013. Achillion undertakes no obligation to revise or update any statements reflective of events or circumstances after the date of this conference call.

I -- so, going to turn it over now to Dr. Deshpande. He's got some brief remarks and then we're going to open up for Q&A. [Operator Instructions] So with that, Milind?

Milind S. Deshpande

Thanks, Glenn, and thank you joining us this afternoon. Today, Achillion announced that on Friday, June 28, the FDA made a written request for additional information regarding sovaprevir, Achillion protease inhibitor being investigated for the treatment of chronic HCV. The request was prompted by elevations in liver enzymes that we noted and reported to the FDA when sovaprevir was dosed in combination with ritonavir-boosted atazanavir, a commonly prescribed HIV treatment.

We believe that the interactions are for ritonavir-boosted atazanavir with sovaprevir and their competing metabolic pathways made for elevations in ALT that was not anticipated. To provide clarity, I will take a few moments to walk you through exactly what was noted in our trials and the actions that we have taken in response. I will start out by summarizing the clinical study that we undertook to study the drug-drug interactions between sovaprevir and ritonavir-boosted atazanavir. Those study had 3 parts. Subjects were dosed with atazanavir boosted with ritonavir alone in period 1, those alone with sovaprevir in period 2 and a combination of sovaprevir and atazanavir ritonavir in period 3. Dosing was for 14 days in each period, with a washout of at least 5 days between periods.

There were no ALT elevations in period 1 and 2 when sovaprevir and ritonavir-boosted atazanavir were dosed independently. In period 3, when we dose sovaprevir and atazanavir boosted with ritonavir, we observed elevations in ALT. There were 2 subjects that had grade 4 elevations and 3 subjects that had grade 3 elevations out of a total of 31 healthy volunteers that were dosed in this study. Most subjects met the criteria for an SAE. And post-treatment ALT levels are either returning to baseline or are trending towards baseline.

Once the interaction was noted, we immediately summarized the findings from the drug-drug interaction study for the agencies and following initial discussions with the FDA, we submitted an extensive data package, which included the safety from the drug-drug interaction study, the preliminary PK data from the same drug-drug interaction study and we also submitted safety analysis from our ongoing -007 trial, which is a 12-week combination trial of ACH-3102 plus sovaprevir in presence of ribavirin. I'll take a couple of minutes to summarize the observations that we had from the drug-drug interaction study as well as from the interim analysis of -007 trial.

From the drug-drug interaction study, the PK data showed that the atazanavir levels was increased approximately up to 250%. Exposures of sovaprevir was increased by about 44 fold, as compared to sovaprevir alone arm. And relative to the doses that are currently being evaluated in Phase II, combination study, the exposures in the DDI were about 300 fold higher than that the 200 milligram dose that is currently being evaluated and the exposures in the DDI study were about 50 fold higher than the 400-milligram dose that is being studied in the -007 trial. Safety analysis from the -007 trial where we have data up to 6 weeks clearly showed that there are no safety issues in that trial. We did not see any graded elevations with ALT nor any other safety findings from that trial.

Aside from these studies that I just mentioned, the drug-drug interaction study that I mentioned, we have completed 7 other drug-drug interaction studies, which includes DDI studies with methadone, Midazolam, oral contraceptives, digoxin, atorvastatin, as well as ACH-3102. In all these studies, we have not seen any interactions with sovaprevir and there were no safety issues in these studies that was conducted.

After submitting the preliminary data to the agency, we maintained an open dialogue with the FDA with a clear understanding of the data and report that we need to submit in order to resolve this matter. It is important to note that dosing in patients already enrolled in the -007 trial combining sovaprevir with ACH-3102 is not affected. As I mentioned a moment ago, there has been no safety issues in the ongoing trial. It is also important to note that the FDA has allowed us to complete enrollment in this trial despite the findings in the drug-drug interaction study.

We remain confident that we will be able to address the FDA concerns surrounding this DDI in a timely manner. The FDA has requested study reports and an integrated safety analysis from ongoing and completed clinical trials with sovaprevir. We believe that we will be able to provide this information to them in a timely fashion and continue our development program as planned.

As regards to our previously announced milestones which are RVR in third quarter followed by SVR4 in fourth quarter from a combination trial of sovaprevir, ACH-3102. Those milestones remain unaffected. Overall, the development plans to complete Phase IIb studies by mid-next year and to start the registrational trials by the end of 2014 also remain unchanged.

So aside from the issue that we have seen in terms of increased sovaprevir exposures in the DDI trial, there have been no other issues in terms of safety with sovaprevir or any other trials that we are conducting. I would also like to reiterate the rest of Achillion's strong HCV portfolio regarding our strong HCV portfolio. Our development of ACH-3422, a uridine nucleotide prodrug remains on track for an R&D submission in first quarter of 2014. Furthermore, ACH-2684, our second potent NS3 protease inhibitor for treatment of HCV, remains in active development and is a Phase II-ready asset.

Overall, we are very confident in our compounds and their development path towards markets, including sovaprevir, which we believe continues to be a safe well-tolerated and potent agent for treatment of HCV. We believe that we have clarity regarding what FDA would like to see with respect to this DDI issue and we expect to deliver those things in a timely fashion. Our timeline remains unchanged for our combination trial of -007, and we also believe that the long-term clinical development path for our [relief] [ph] combinations remains intact and that we will be able to initiate registrational studies with sovaprevir and 3102 as planned during the second half of 2014.

Thanks again for your attention. And I will turn it back to the operator, who will open it up for your questions. Thank you.

Question-and-Answer Session

Operator

[Operator Instructions] And it looks like our first question will come from the line of Brian Abrahams with Wells Fargo Securities.

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

I think one of the advantages that you've talked about over the years for sovaprevir has been relatively low potential for drug-drug interactions, just given its metabolism. So I'm curious if you have any insights why you're seeing what you're seeing metabolically in this study, if this might -- this path might involve other agents and what this might mean when you think about the long-term competitive positioning of your combo? And then maybe just as a corollary to that, if you can talk about your level of confidence given some of the patient-to-patient variability we've seen in exposure in prior sovaprevir studies that, that 400 milligram dose is not going to touch at that -- at the top end, that 50-fold elevation in exposure you got in this study?

Milind S. Deshpande

Thanks for the question, Brian. I'll start out with the overall profile of sovaprevir as it relates to our drug-drug interaction. So as I mentioned in the call, we have done many drug-drug interaction studies with sovaprevir, which includes CYP3A4 substrates inducers of P450 isozyme, PGP inhibitors compounds that are substrates for OATP transporters such as atorvastatin and in all these studies, we did not detect any significant drug-drug interactions or any other issues. So I think overall, the profile for sovaprevir, as it relates to drug-drug interactions, is fairly robust. In this particular study, I think what we might be seeing is a combination of a CYP3A4 inhibitor, as well as compounds that may affect the other alternative elimination mechanisms for sovaprevir, such as inhibition of MrP2 and DCRP. So it's a little more complex picture with having a CYP3A4 inhibitor, as well as a compound like atazanavir that may affect elimination mechanism. So this might be a fairly rare situation and I think -- and I say that based on the data that we have from other clinical trials that we have done for DDI with sovaprevir. So I think overall, the profile of sovaprevir in terms of having minimal drug-drug interactions is probably still fairly good. We will complete the analysis from this particular trial, but preliminary assessment looks like it is a combination of 2 or 3 multiple mechanisms affecting the metabolic pathway of sovaprevir. Also keep in mind that we did see increases in the concentrations of atazanavir as well in this study. So that's also -- that also could be a [confounding] [ph] factor in this particular study. Overall, in terms of the competitive positioning of sovaprevir, I think based on the other DDIs that you have the seen, as I said earlier, I think it's still pretty robust. In terms of the safety margin, as compared to the 400-milligram dose, as I've said, what you saw in this study, we still have more than 54 margin as compared to the 400-milligram dose and a 354 margin as compared to the 200-milligram dose. So the base margins are also fairly robust. So David, do you want to comment on Brian's question?

David Apelian

Sure. I think that a critical piece of this story, Brian, is that the preliminary PK data doesn't show marginal increases of sovaprevir and the DDI setting with atazanavir. We're seeing a pretty profound difference in exposure here. So it gives me confidence that at the doses we're using and, for example, -007 the 204-milligram PIC dose, I'm confident we're not going to seek certain -- even remotely close to that type of exposure.

Operator

Our next question will come from Alethia Young with Deutsche Bank.

Alethia Young - Deutsche Bank AG, Research Division

I guess I just want to be reminded of what kind of safety database you have with sovaprevir, and this will be the DDI work you've done. And then additionally, just how do you give the FDA comfort around your ongoing trial? And is there anything you can do to help them kind of be comfortable that this trial doesn't have the same amount of risk?

Milind S. Deshpande

So Alethia, I will take the first 2 questions, address the safety database that we have for sovaprevir and also a brief summary of the DDI studies that we've done with sovaprevir and hand it over to David in terms of how did we assure the FDA that we will not have issues, particular issues, in our ongoing trial. So as I mentioned on the call, we have done multiple drug-drug interaction studies with sovaprevir and just [today that it is] [ph], again, the drugs that we have tested are methadone, Midazolam, atorvastatin, digoxin, oral contraceptives and obviously, ACH-3102. These are studies that have been completed and we have not seen any effect of these drugs on the pharmacokinetics of sovaprevir and there were no safety issues that had been -- that arose in these clinical trials. In terms of the overall safety database that we have for sovaprevir, I believe that we have dosed sovaprevir now in over 400 subjects and healthy volunteers. And the longest treatment period that we have dosed with sovaprevir was for 12 weeks using the 200, 400 and 800-milligram doses. And the 200- and 400-milligram doses were safe and well tolerated. That data was reviewed by the FDA. And the FDA has agreed that moving forward with the 200- and 400-milligram doses is safe and that should provide efficacious exposures as well. So that's in the safety database that we have for sovaprevir as well as the DDI studies that we have done to date. And I'll hand it over to David, to answer the question on how this will reflect on the ongoing studies.

David Apelian

Sure. Thanks, Milind. I think part of the FDA's recommendations to us speak for themselves and that they've allowed us to continue dosing in the -007 trial, as well as continue to enroll additional patients into segment 1 of that trial. So I think that conveys their sense of confidence in the safety profile in the -007 combination trial in terms of the DDI-specific findings, not reflecting any new or unexpected safety implications for -007 using 200- and 400-milligram doses as we've designed that trial. And I think the best way to continue to move the program forward is to be proactive with the agency, be very forthcoming with the safety updates for that trial and to continue the really positive and proactive dialogue we have with them. I think that's a key feature of how we move that program going forward.

Operator

Our next question will come from Rachel McMinn with Bank of America Merrill Lynch.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

I guess, Milind, I'm going to ask you to go back, because I felt like you sort of threw a lot of numbers out there and I honestly, like, I just -- I'm not even sure I understand what doses were tested and where the exposures went. So I guess my first question is like can you talk about what doses were actually tested in the DDI study and then what exposures happened over what period of time? Because these were out like 300x, 50x, I just -- I want to understand the doses. So can we start there?

Milind S. Deshpande

Yes, sure. So let me start with the doses of sovaprevir and the doses of atazanavir, ritonavir that were used in the DDI study. In the drug-drug interaction study, we used a 300-milligram tablet formulation of sovaprevir and the exposures that we attained with the 300-milligram tablet are about 15% higher than the 400-milligram dose that we are using in the current clinical trial, which is -007.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

Okay, and then so you gave that for -- was it a single dose or it was multiple doses over a couple of days?

Milind S. Deshpande

Yes, so the sovaprevir was administered for 14 days. So that study had 3 arms. So the first arm was dosing of atazanavir boosted with ritonavir for 14 days. That was period 1. The second period was sovaprevir alone for 14 days. And the third period was sovaprevir in combination with atazanavir boosted with ritonavir for 14 days.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

And when did you actually see the ALT increases?

Milind S. Deshpande

The -- I'll hand it over to David so that he can give you more color on that.

David Apelian

Sure, we first picked up the grade 3 increases on Day 13 of a 14-day combination arm of the trial and we noted that there were several other patients that had lower grade as well and decided to stop dosing in those patients before they proceeded to Day 14. And at that time, we implemented pretty rigorous follow-ups for those patients to track their ALTs daily and to make sure that these participants, who were healthy volunteers, our first interest was to make sure that they were being monitored very closely for their safety and to track any changes that would require more aggressive management. And I think the good news is that these patients all trended back even to normal or back below grade 2 ALTs and did not show any signs of decompensation, either clinically or based on other LFT measurements, which is coagulation factors. So seeing that cluster of cases in aggregate, we believe warranted conservative action on our part and we initiated a dialogue with the FDA at that point.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

And so, but then, so do you have data to understand when you started to see the blood increases? Or you had said like the 300 milligram dose translated into a 300-fold increase in 5 milligram exposure. Did I have that right?

David Apelian

So, as the sequence of events was that when we initially saw these cluster of cases, as you can imagine, we didn't have PK data yet. We surveyed our other clinical programs and didn't see any effects like this or aggregate effects like this in our other studies and we exited that at the PK testing immediately suspecting that, that was the likely cause. And what Milind mentioned to you were the preliminary PK data from the study that showed up to 350-fold increases compared to the 200-milligram exposure, PIC exposure, and up to 50-fold increases compared to the 400-milligram exposures. So the PK testing is still ongoing. We, yet, don't have the final PK data. And when we initiated the dialogue with the agency, one for the first things they asked us for was to send them whatever PK data we have, which we obviously complied with and it's based on those preliminary data that we are seeing these profound multiple differences in exposure than what would have been anticipated.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

And then just to clarify, the increase in exposures that you saw were in patients with the ALT elevations? So that's like -- is that fair?

David Apelian

We expedited those cases, as you might imagine, to be tested first. And as the testing continues, we're still seeing multiples that are in that range or very high multiple range, but we're seeing that those first patients have the highest multiple exposures. The numbers that I mentioned to you are the highest. So up to 350 and up to 50 was the highest exposure. But we're seeing that number track in the very high multiple range and we don't have the final data yet, so I can't give you the final answer on the total data set.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

And then just last -- sorry, last question for me. I know I severely violated your rule, but, just, I don't understand what clinical hold means. I mean, typically when we're saying there's clinical hold, we think a program is, like, no longer allowed to dose or enroll additional patients. So here, it's like the FDA's placed you on clinical hold but, but what -- I guess what does that mean in the context of your drug?

David Apelian

I think this largely stems from some of the administrative consideration of how the FDA views things in terms of INDs and not necessarily in terms of the practical implications of what the recommendation is. So, for example, -007 is been conducted under the 3102 IND as a combination trial and so that then causes the need for the FDA to make a recommendation about that IND. And I think officially, it would be considered a partial hold in that case. And they've asked us not to launch any new studies with 1625, so that IND would be implicated as being a hold. But as we've said, they're letting us continue dosing in -007 and even enroll new subject. So you're correct in that. In practice, it doesn't really sound like a hold, but from an IND perspective, from the regulatory administrative perspective, it is.

Milind S. Deshpande

Just to add to what David said, this doesn't really change anything in terms of the conduct of -007 trial. We will complete dosing in -007 trial. We will also complete enrollment in that study. So from an operational point of view, as far as -007 is concerned, nothing has changed.

Operator

Our next question will come from Matthew Harrison with UBS.

Matthew Harrison - UBS Investment Bank, Research Division

I guess as a follow-up to what Rachel was asking, can you give us -- so it sounds like the 300 and the 50-fold threshold changes on the PK, can you give us the range that you had seen for these patients? I mean, it sounds like some lower range. And can you just help us understand sort of what that range is and then what ranges -- I mean, what's the highest sort of PK exposure that you've seen in trials without REYATAZ?

Milind S. Deshpande

Yes, thanks for all the questions, Matthew. And as David mentioned, we don't have the full PK data yet, but the lowest fold increase that we have seen is about 60 fold.

David Apelian

Well, I think, with the additional samples, Milind, what we're seeing is that not that we're testing the patient that didn't have the higher ALT elevations, we're seeing the mean is kind of hovering around 60 at this point. So while it won't be as high as 350, which is the most extreme exposure we saw in the early tested patients, we suspect the number is going to come up to a very high multiple somewhere, probably above 50, but around 60 fold is what we're thinking right now based on the data coming in.

Matthew Harrison - UBS Investment Bank, Research Division

And that's above the 200 milligram dose or the 400 milligram dose?

David Apelian

Well, we actually have an internal control on this study, which -- or the patients, the same patients who receive sovaprevir alone, so it's actually a very good control in this setting. And if you're looking at comparisons to the 400- and 200-milligram dose, I believe that's going to be a about a 60-fold difference to the 400-milligram dose that we've seen independently. So -- but I'm mentioning this is as the 60-fold increase of what we're seeing within study in same patients who got sovaprevir monotherapy before they embarked on the combination period of the study. So it's a very well-controlled comparison.

Matthew Harrison - UBS Investment Bank, Research Division

So just on clarity, sort of 60 to 350 range that you're speaking about is versus the 300-milligram tablet that was used in the sovaprevir-only portion of the study?

David Apelian

That's our best estimate as of today and I don't think that number is going to change dramatically because the majority of data then, so we're still gathering the final samples and get the final analysis done. But as you can see, these are not marginal changes, exposure. These are pretty profound changes. So it's not like, it's a little 60% increase and you're looking at something on the margins. This is a pretty distinctive increased exposure.

Matthew Harrison - UBS Investment Bank, Research Division

And then, as just another follow-up to one of Rachel's questions, in terms of the clinical hold and sort of the potential implications of that, if -- I mean, so it sounds like you need to provide some additional data to the FDA, which you've sort of outlined a timetable to do. If they're not satisfied with that data, I mean what are the -- I guess what I'm trying to understand is what are the potential implications if they decide either a it's a more serious issue or not and it sounds like you have to resolve this before you can start any additional study beyond -007?

Milind S. Deshpande

Matt, we have very good clarity in terms of what the FDA is asking for. We, as I said, we received a letter from the agency last Friday and in that, they have asked for a very clear data set that we will provide to them. And that -- those data sets really are adapt to fold from the ongoing clinical study, which is the drug-drug interaction study, as well as an integrated summary of all the clinical studies that have been done with sovaprevir. So these are the 2 things that the FDA have asked. So we have good clarity on what the agency is asking for. [indiscernible] are fairly straightforward for us to put together and I believe that we can provide this information to the FDA in a timely fashion.

Matthew Harrison - UBS Investment Bank, Research Division

Okay. And then just to be clear on another comment you made, have you seen any ALT increases in the 301, 1625 combo studies, or you none of any grade?

David Apelian

No, we've been checking this in realtime as you might imagine. We haven't seen any Grade 1 elevations or higher in -007. We looked at the safety profile in terms of AEs as well and the study is very clean. So that was one of the first things we communicated to the agency and it's something we're going to obviously track really closely going forward. But in fact, we haven't seen anything of note in terms of safety in -007.

Operator

Our next question will come from Brian Skorney with Robert W. Baird.

Brian P. Skorney - Robert W. Baird & Co. Incorporated, Research Division

I guess most of my questions have been answered already, but just kind of looking at the sovaprevir exposures that you saw in the atazanavir, ritonavir DDI study. Could you kind of contrast what exposures you're seeing in the other DDI studies? I mean, you've seen anything that even has marginal increases in 1625 exposures are getting anywhere near what you're seeing with the REYATAZ combo. And also when we think kind of about our cytotoxicity in preclinical animal models, at what levels of sovaprevir would you start expecting to see some sort of significant liver effect and is that correlated in sort of with what you're seeing here?

Milind S. Deshpande

Thanks, Brian. I'll address that clinical question first. In all the drug-drug interaction studies that we have completed so far, we have not seen any effect on the pharmacokinetics characteristics of sovaprevir. So that's the short answer and the long answer. I mean, there was really nothing in any of the DDI studies that we have completed today that showed any PK interactions with the other drugs. That was tested in combination with sovaprevir. In terms of the nonclinical studies that have been completed, we have toxicity studies done with sovaprevir for 9 months in 2 species. And in all the studies that we have done, again, we have achieved very high exposures and demonstrated high safety margins with 1625. So I don't think that there is anything that the FDA in the -- on the side of toxicity updates or the toxicity studies that were done with sovaprevir that could have -- that suggest that we would see these increases in ALT.

David Apelian

And, Milind, I would only expand on the fact that this is not the kind of exposure you would ever design into a trial brand, as you might imagine, right, but the fact that it happened and the fact that we're now looking at these exposures that are in very high multiples of the intended exposure and the fact that not a single one of these cases even qualified as an SAE and we didn't see signs of decompensation either from lab values or from clinical presentation in these patients is kind of remarkable and it gives us at least a feeling exposure that we actually have some clinical data in. So it's not the kind of trial you'd ever design intentionally, but the data as you think could be useful now in modeling exposure to these ALT findings, and I think that has spaced above our target exposures in the patient population are going to be very clear with a lot of headspace above -- we can't predict that we would ever get near these exposures but the 200- and 400-milligram dose in the HCV population.

Brian P. Skorney - Robert W. Baird & Co. Incorporated, Research Division

I mean, it just sounds like you're attributing the ALT specifically to sovaprevir so I'm just trying to understand -- I mean is it just because there's so much plasma exposure of the drug, you're assuming it because it sounds like you're saying that there's a pretty significant increase in atazanavir as well and I know there's at least some background history that could lead to some low rate of ALT elevations. So how do you disconnect what's sovaprevir and what's atazanavir?

Milind S. Deshpande

I think it is possible that the increases in ALT that we are seeing are a combination of increases in exposures of atazanavir, as well as increases in exposures of sovaprevir, provided that remains a possibility, but I don't think that it is important to sort that out for the overall clinical development of sovaprevir.

David Apelian

Yes, I think we do this is a DDI-specific finding and atazanavir was increased by about 50% in this preliminary PK testing so -- and we know that the atazanavir has potential ALT elevations as part of its labeled information. So it may have contributed to this and at the point, we want to just clearly identify this as a DDI-specific finding confirm as we have that we haven't seen this type of ALT elevations in our other either DDI studies or clinical HCV trials. So I think that's the most important point.

Brian P. Skorney - Robert W. Baird & Co. Incorporated, Research Division

And just one of the points you brought up, David, about the separation between the 2 INDs and sort of the sovaprevir IND being on hold by the 3102 combo not, I mean have you already discussed with the FDA that -007 remain open? Or is there a risk that once they reference the hold on sovaprevir that they could also put a hold on the 3102 IND for a combo?

David Apelian

No, that was part of their explicit feedback to us is that we could keep the -007 patients on dosing and complete the enrollment of segment 1 of -007. That was an explicit recommendation to them and the context of this whole conversation. So we're not presuming anything here. We had a lengthy discussion with them and realtime follow up on that point.

Operator

Our next question will come from the line of Katherine Xu with William Blair.

Y. Katherine Xu - William Blair & Company L.L.C., Research Division

I'm just wondering, is this something atazanavir- and sovaprevir-specific kind of interaction? How would this impact supposedly if you go with -- go forward with your combo. Is HIV patients to be excluded from the label. I mean from a development perspective, how would this impact your strategy?

David Apelian

I'll take that one, Katherine. I think there are still a good ways forward in HIV-coinfected patients, namely 1 major category as to do this in combination with something like ATRIPLA or there's not a PI or boosted PI and then we could reevaluate in which circumstance we would use 1625 in combination with the PI that present perhaps less risk of this. Not all the PIs have ALT increases part of their profile for one thing. And we could reassess how to dose, in combination with PI potentially, to keep that class in the mix. But even if we just went ahead with an ATRIPLA combination going forward, that would still address a major component of the HIV-coinfected population. So we still think there's a good way for us to address that important segment, the high unmet need segment of the population.

Y. Katherine Xu - William Blair & Company L.L.C., Research Division

So why did you do this study? Were we looking for ABT 450? It's look like they didn't do it with atazanavir and ritonavir. So what -- is this a routine study for you guys to do for DDI, for the industry to do?

Milind S. Deshpande

Yes, I mean atazanavir is the most widely used PI for treatment of HIV. When we chose these drugs that we wanted to study for drug-drug interactions for HIV, HCV core infected patient population, first of all, we assess the profile of sovaprevir on its own. Also, look very carefully at the drug that we wanted to study the interactions. And the selection of drugs was based on feedback that we got from 3 KOLs who are the leading treaters for HIV-, HCV-coinfected patients. So it was really based on assessment of the profile of sovaprevir as we have seen today or the assessment of the profile of the other drugs that we're going to be using in combination with sovaprevir. And also, the selection of the drugs that were taken into DDI that was based on the feedback that we got from the 3 most known KOLs who are involved in treating HIV-, HCV-coinfected patients.

Y. Katherine Xu - William Blair & Company L.L.C., Research Division

I

So if there were something specific between the 2 PIs, do you think going forward -- I mean, how many DDI studies do you have to do, just thinking about it, the potential or drug that you could run into in these patients that you would be able to really well characterize the DDI problems that the label could assist us so that the label is reasonable, from a safety perspective?

David Apelian

Yes, I think there a reasonable way forward in HIV. I think -- for example, ATRIPLA, in the U.S., I believe, is the dominant regimen used in the market. And, for example, atazanavir is probably a -- while one of the more widely used PIs, that I don't think it is higher than 10% of the HIV market, HIV-coinfected market, would be -- probably reflect similar numbers. So I think there's enough options for us to do a solid HIV coinfection development program and obviously now, learning what we have learned from the atazanavir interaction, and as we get the full PK data, we'll have a better idea of how -- if and how to approach the boosted PI class as part of that strategy. But I think the important point is that we do see a way forward in HIV co-infection and we just need to be prudent in how we did the PI development.

Operator

Our next question will come from the line of Phil Nadeau with Cowen and Company.

Philip Nadeau - Cowen and Company, LLC, Research Division

I do want to follow up on one that was just asked by Katherine and that's how generalizable is this drug-drug interaction? It seems like the FDA's going to want you to understand the exact mechanism here and how many drugs outside of the realm of HIV could also induce such a large increase in drug exposures. So one, do you -- what DDI studies do you plan to do to kind of further flush this out? Has that been increased by this news. And then, two, is it also the impression that you're going to have to understand the mechanism here before the drug can be approved?

David Apelian

Well, I think, again, the HIV-coinfected population is a special population, an important one, and it's certainly one that we want to advance at the timing of the registrational filing, so -- but I think we will have time to sort this out, figure out the best way forward with any HIV drug that could have a potential DDI effects on sovaprevir. So obviously, this is something we're going to be paying close attention to in having an ongoing dialogue with the agency on the best way to proceed. So I think it's just going to be, for us now, to get the PK data to look at -- by exacting exactly what happened and what the trends were for the atazanavir trial. And then using that information to have the best HIV-coinfection plan that we possibly can have.

Milind S. Deshpande

One of the studies that we have already completed, but not have the full data set, is the drug-drug interaction study with ketoconazole, which is also a [indiscernible] for inhibitor soap. [indiscernible] questions filling out in terms of mechanistically understanding what's going on here. Obviously, if we will study sovaprevir in combination with another CYP3A4 inhibitor, which is ketoconazole. That study is already complete and we will be looking at that data. And mechanistically, the other thing that is happening probably with atazanavir is the effect on transporters. And we have completed a number of strategic transporters. So [indiscernible] is an inhibitor of PDP and after [indiscernible] is a substrate for OATP transporters and you don't see the effect -- we didn't see any effect in these 2 drug-drug interaction studies. So I think the key study is really trying to understand what is the effect of CYP3A4 inhibitor and sovaprevir and that study has already been done.

Philip Nadeau - Cowen and Company, LLC, Research Division

Okay, and Milind, you have been around drug development for a long time, how many drugs have been approved with a PK profile like this where there is maybe a somewhat rare chance, but some drug-drug interactions might induce such high increases in plasma exposure?

Milind S. Deshpande

Yes, there are instances where drug-drug has been approved. Obviously, there are -- there will be various indication of using that drug with the other drug where you see these increases in PK value. Again, the important thing to note here is that the margins that we are seeing as compared to the 200-milligram or the 400-milligram doses that you are using in clinical trials is very, very significant. If you were looking at multiples of 2- to 5-fold or even 10-fold, that becomes a tough proposition. But here, we are looking at exposure margins of more than 50-folds. So I don't think that this would be an issue.

Philip Nadeau - Cowen and Company, LLC, Research Division

Okay, and last question for me, were any other side effects increase at these very high exposures? Were there other adverse events that maybe didn't prompt the clinical hold, but were notable anyway, given the high exposures?

David Apelian

No, there were no notable clinical event. We obviously looked at the AE profile, as well as the lab data, and we didn't we didn't see any clinically significant findings. So this was really a distinct feature of the presentation in the atazanavir combo trial.

Operator

Our next question will come from the line of Howard Liang with Leerink Swann.

Howard Liang - Leerink Swann LLC, Research Division

Is the clinical hold is -- or is the sensitivity partly because you're likely -- may have some also bilirubin-increased needs patients because I think atazanavir causes a lot of those I think in maturity of the patients?

David Apelian

Well, we did observe bilirubin increases that were largely driven by indirect bilirubin and as we mentioned, the atazanavir exposure was increased by about 50% and that was not at all the focus of the conversation we had with the FDA. The effect appear to be distinct and independent of each other and that the bili increases preceded ALT increases and the bilirubin resolution well proceeded the ALT resolution. And as I said, we didn't see any laboratory evidence of decompensation. So they were distinct -- they appear to be distinctive signals and the behavior for bilirubin was consistent with the atazanavir profile.

Howard Liang - Leerink Swann LLC, Research Division

Okay. Do we -- I don't know if you already said it and I have missed it, is there a study done with sovaprevir just with ritonavir? Do we know whether it's boosted by ritonavir?

Milind S. Deshpande

Howard, the study that we just completed was with ketoconazole, which is also a CYP 3-year fold inhibitor like ritonavir.

Howard Liang - Leerink Swann LLC, Research Division

And there's no interaction there?

Milind S. Deshpande

That study is just completed, so we don't know the results yet.

Operator

Our next question will come from the line of Chris Richard with Merlin Nexus.

Christian Richard - Merlin Nexus

All my questions have been asked.

Operator

Our next question will come from the line of Jason Kolbert with Maxim Group.

Jason Kolbert - Maxim Group LLC, Research Division

Yes, most my questions have been asked, but I'd like to see if you could elaborate just a little bit more about mechanistically what do you think is tripping the higher exposure of both drugs in the plasma? I mean, theoretically, what interaction is it. We've been dancing around this. Is it ritonavir having an effect on sovaprevir? Or what do you think is going on here?

David Apelian

Jason, I think the -- it's potentially a combination of effects here. I mean, the fact that ritonavir is in play. It does implicate the [indiscernible] to some extent, but the fact that atazanavir and sovaprevir could share [indiscernible] borders could have affected levels of both agents. And so there could be multiple potential targets that were in play here that gave us distinctive finding in this DDI study. So as Milind mentioned, having the ketoconazole data completed fairly soon will help us to dissect [indiscernible] parts of that because that's a pretty select inhibition of ketoconazole and it will give us some insights about what other role atazanavir may have played in the interference of the CDI. So -- but it very well may be more than one thing that happen in this particular combination.

Jason Kolbert - Maxim Group LLC, Research Division

Okay, David, I understand that. And so in your communications with the FDA, was there scrutiny that none of the patients in the current Phase II trial are currently HIV positive, so therefore you're not worried about an atazanavir interaction?

David Apelian

Yes. I mean, what was clearly, I think, their intermediate interest in ours was to look at the safety comprehensively across our program. We obviously want to see that -007 safety in realtime to confirm that in fact, the safety was -- the safety profile was clean and it was safe on lab NAE data and the risk of exposure to something like ritonavir-boosted atazanavir would be highly unusual on this setting. And just to be clear, we have exclusion in that study for CYP3A4 inhibitors, for example, because that was an anticipated theoretical interaction that we wanted to avoid in our clinical trial. So we're already taking precautions in the -007 program to avoid those kinds of potential interactions that would be unintended in the hep C population, for example.

Jason Kolbert - Maxim Group LLC, Research Division

And my last question is in hep C population, then, particularly a niche population where you're dealing with patients that might have end-stage liver disease or liver decompensation, what other drugs might those patients be on that might be suspect now in terms of a DDI interaction?

David Apelian

Well, I think that's a great question. I think that's something we're going to really obviously think very thoroughly about, not only to the other comment that those patients might be taking but what role of a more serious liver decompensation might play in clearance and we need to be aware of that in just making sure we dose patients appropriately. So you could think about drugs that would be used in [indiscernible] transplant setting. Those are things we'd have to consider. So obviously, we're going to learn what we can from the PK data we get today to make sure we do as safe and vigilant program for hepatic decompensation as you possibly can and really look at different grades, different shades of decompensation, whether melt scores or try a few stores to get a better appreciation for the risk and the functional reserve in the patients before we treat them. So I think it's going to become an important part of the complementary program alongside our well-compensated hep C patients.

Operator

Our next question will come from Brian Skorney with Robert W. Baird.

Brian P. Skorney - Robert W. Baird & Co. Incorporated, Research Division

I just wanted to know, given that sovaprevir has a subject-exquisite liver partitioning, the increases in exposures you're talking about are just plasma, correct? What would you model to be the liver exposure increases that would correlate with the 50x increase in plasma?

Milind S. Deshpande

Brian, that's a great question. One of the things -- there are 2 possibilities that the plasma exposures -- the increases in plasma exposures are reflective of the increased exposures in the liver as well and the second possibility is that you are seeing increased plasma exposures because the uptick of sovaprevir is reduced. The uptick of sovaprevir into the liver is reduced that's why you are seeing in increases in plasma concentrations. My guess is that after some point, the very short liver-to-plasma ratios will tend to be the same or the increased partitioning that we see of sovaprevir into the liver would tend to flatten out after a certain exposure in plasma. And we have seen that in animal studies as well. So if you have low exposures in plasma, then the liver-to-plasma-ratio is going to be high. But as the doses increase and the plasma exposures increase, obviously the liver to plasma ratios tend to decrease. So I don't think that in this case, we will see the same level of increases in the liver, or the liver-to-plasma-ratios, as we see with low plasma exposures.

Operator

And we do have one additional questioner on the phone queue and it comes from the line of Brian Abrahams with Wells Fargo Securities.

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

Just taking the follow-ups. Just a couple of real quick clarifications. What's the lowest fold increase in sovaprevir exposure relative to the 400-milligram dose that you've seen in a patient who had an ALT elevation in this study?

David Apelian

I don't have the exact number, Brian, but I can tell you that in that initial set of patients, we expedited the full changes were all very high in the 50 or higher range multiple with the highest that we saw was up to 350 over to 200 and up to 50 over to 400. We didn't see, I think, sub-10 multiples in any of those first set of patient that had the high ALTs. So that was based on the first subset of patients that we tested that had the ALT elevations. So, I think -- but clearly looking at something that's not a marginal increase, it's a high multiple increase in the exposure. And as we said, we're going to get the full PK data shortly. This was based on the preliminary data that we had received and expedited in communications with the FDA. But when we saw multiples that high, we knew we were dealing with a real effect and now it's just a matter of getting the complete data in to get the refined numbers of the total data set.

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

Okay, and next, have you confirmed that there's no issues with the drug substance, of either drugs, used in this study, just because, I would think if the mechanism for the drug-drug interaction here is multi-factorial, as I guess the working hypothesis is, you might see some smaller but real changes in exposure in some of your other studies. So do you know that the drug substance used in this study, if there wasn't something wrong with that?

David Apelian

Well, just looking at the data itself and looking at the within study controls, we didn't see that kind of variability in the monotherapy sovaprevir arm. So that would suggest to me that the drug was behaving as expected in the context of monotherapy. So just on its state, we didn't see increased excursions around what we would have expected. We didn't study -- I think, in fact, it's the same patients.

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

Okay, so there wasn't a different batch of drug given to these patients -- these volunteers in the part 3 of the study? Okay. And then lastly, I guess, I'm just wondering how far along you are in terms of patient exposures in the -007 study. I think you talked about patients being through 6 weeks, but maybe you can quantify that a little bit more in terms of how many patients are through 2 weeks, which is where you started to see issues in the drug-drug interaction study and further along than that?

David Apelian

I can tell you that we have up to 6 weeks of exposure now in the 200-milligram group and that enrollment was pretty tight in terms of getting all other patients in quickly. So I suspect that the mean exposure there is not far below 6 weeks in that group and we have up to 3 weeks of exposure in the 400-milligram group. So the first group has 15 patients on treatment. The second group has 13, and we're enrolling 2 additional patients into the 400-milligram group. So that's the ballpark on the exposure of -007 at this point.

Operator

And at this time, I'm showing no additional questioners in queue. I'd like to turn the program back over to Dr. Glenn Schulman. Please go ahead.

Glenn Schulman

Thanks, Jerry [ph]. Actually, I'd pass it along to Dr. Deshpande for a couple of closing comments.

Milind S. Deshpande

Again, I would like to thank all of you for participating in this call. And in closing, I just want to reiterate that we remain confident in our compounds and their development path towards market, including sovaprevir, which we believe continues to be safe, well tolerated and potent agent for treatment of HCV.

Regarding the current DDI studies, we believe that we have clarity regarding what FDA would like to see, with respect to the DDI issue, and we expect to deliver those things in a timely fashion. Our timelines overall remain unchanged for our combination trial, which is ongoing, which is the -007 trial, and we also believe that our long-term clinical development path for a clear combination remains intact and that we will be able to initiate registrational studies with sovaprevir and 3102 as planned during the second half of 2014.

And with that, I'll hand back it over to Glenn.

Glenn Schulman

All right. Thanks, everyone. If you have any follow-up questions or need anything, we'll be in the office. Feel free to give us a call or an email.

Operator

Thank you, gentlemen, and thank you, ladies and gentlemen for your participation. This does conclude today's conference. Thank you. You may now all disconnect.

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