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Vertex Pharmaceuticals Incorporated (NASDAQ:VRTX)

Phase II Results for VX-661 Conference

April 18, 2013 4:30 pm ET

Executives

Michael Partridge - Senior Director of Strategic Communications

Jeffrey M. Leiden - Chairman, Chief Executive Officer and President

Peter R. Mueller - Chief Scientific Officer, Executive Vice President of Global Research & Development and Member of The Scientific Advisory Board

Ian F. Smith - Chief Financial Officer and Executive Vice President

Eric Olson

Analysts

Geoffrey C. Porges - Sanford C. Bernstein & Co., LLC., Research Division

Geoffrey C. Meacham - JP Morgan Chase & Co, Research Division

Omar Saad - ISI Group Inc., Research Division

Rachel L. McMinn - BofA Merrill Lynch, Research Division

Michael J. Yee - RBC Capital Markets, LLC, Research Division

Liisa A. Bayko - JMP Securities LLC, Research Division

Yaron Werber - Citigroup Inc, Research Division

Terence C. Flynn - Goldman Sachs Group Inc., Research Division

Matthew Roden - UBS Investment Bank, Research Division

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

Ying Huang - Barclays Capital, Research Division

Alethia Young - Deutsche Bank AG, Research Division

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

Howard Liang - Leerink Swann LLC, Research Division

Koon Ching

Philip Nadeau - Cowen and Company, LLC, Research Division

Operator

Good day, ladies and gentlemen, and welcome to the Vertex Phase II results for VX-661 conference call [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the call over to Michael Partridge. You may begin.

Michael Partridge

Thank you, everyone, for dialing in today. This afternoon, we are pleased to announce Phase II results for VX-661 dosed alone and in combination with ivacaftor for 28 days in patients who are homozygous for the F508del mutation.

With me on the call today are Jeff Leiden, our Chairman and CEO, and Peter Mueller, Chief Scientific Officer. After prepared remarks, we will be joined by Eric Olson, cystic fibrosis disease area research lead, and Ian Smith, CFO, and we will take your questions. We anticipate concluding the call before 5:30 p.m. and we will be available in our offices following the call.

Before we begin, I'll remind you that the information discussed on this conference call includes forward-looking statements, which are subject to the risks and uncertainties discussed in detail in our reports, including our 10-K and 10-Q reports, which have been filed with the Securities and Exchange Commission, and are also discussed in our press release today. These statements, including without limitation, those regarding KALYDECO and the ongoing discovery and development and potential commercialization of Vertex's cystic fibrosis drug candidates, are based on management's current assumptions. All are subject to risks and uncertainties that could cause actual outcomes and events to differ materially.

During the call, our speakers will be referring to data and graphs contained on the webcast slides. For those of you dialing in, it may be helpful for you to go to the events section of our website and access the webcast slides now, if you haven't done so already. I'll now turn it over to Jeff.

Jeffrey M. Leiden

Thanks, Michael. Good afternoon, everyone. As most of you know, Vertex has had a long-standing and broad strategy to develop breakthrough drugs that address the underlying genetic defects that cause cystic fibrosis. Our overall goal is to develop a portfolio of medicines that will enable us to offer effective treatment to the vast majority of patients with this serious and debilitating genetic disease.

Today, I'll briefly review that strategy and then summarize our significant progress in discovering and developing our CF medicines, in order to provide context for the Phase II clinical results for VX-661 that Peter will discuss today. Our CF strategy has 3 parts: First, we aim to use KALYDECO monotherapy to treat up to 10% to 15% of the 70,000 patients with CF worldwide.

Last year, we launched KALYDECO, known generically as ivacaftor, for CF patients with a G551D mutation. We believe there are approximately 2,000 patients aged 6 and older globally with this type of CF. Today, the vast majority of G551D patients in the U.S. are receiving KALYDECO, and we continue to work to ensure access for G551D patients in Europe and Canada.

During the last several months, we've achieved reimbursement in a number of key markets outside the U.S., and we believe this will drive further access to KALYDECO for more patients this year. Over the next several years our goal is to expand the number of CF patients that we treat with ivacaftor monotherapy. Towards this end we are currently conducting a number of clinical studies of ivacaftor monotherapy, including first Phase III study in patients with other gating mutations, these are similar mutations to the G551D. This study is now fully enrolled, and we expect data in the second half of the year.

Second, a Phase III study in people with the R117H mutation, R117H is a specific type of residual function mutation this study continues to enroll. Third, a study of children ages 2 through 5 who have a G551D or a gating mutation. All of these studies are studies that, if positive, could help to expand the label for KALYDECO. We are also conducting a clinical study in patients with residual CFTR function. This study includes several different types of less common mutations, as well as R117H, and the goal here is the be able to define more broadly, the types of patients who may benefit from ivacaftor alone.

The first results from these trials will be available in the second half of this year, and we continue to have productive discussions with the USFDA about how the breakthrough designation of ivacaftor may help us accelerate its development to provide access to patients beyond G551D. If these studies are successful, we may have the opportunity to use ivacaftor monotherapy to treat up to 10% to 15% of the estimated 70,000 CF patients worldwide.

The second key component of our CF strategy and one that can also significantly further expand the patients we may treat is advancing the combination of ivacaftor and a corrector molecule for the treatment of Delta 508 homozygous CF patients. We believe that there are an additional 30,000 people or more with this type of CF worldwide.

In late February, we announced that we are initiating a Phase III program under the Breakthrough Therapy Designation for ivacaftor, in combination with the corrector molecule, VX-809. This program includes 2 studies, totaling approximately, 1,000 patients homozygous for Delta 508, who will be treated for 6 months. This registration program is based on the data we received from a Phase II study that we competed last year.

Today, we are announcing results from another Phase II study, this was a study of ivacaftor in combination with VX-661, a second corrector molecule. As Peter will discuss in more detail in a moment, these new results provide further validation for our strategy of combining a corrector with ivacaftor in Delta 508 homozygous patients.

Finally, it's worth noting that in addition to VX-809 and VX-661, we have advanced into development a third first generation corrector molecule, called VX-983. VX-983 has just completed a single ascending dose Phase I study in healthy volunteers, and is now in a multiple ascending dose study also in healthy volunteers. We plan to advance VX-983 into a Phase II study in Delta 508 patients in combination with ivacaftor in the second half of 2013, pending discussions with regulators.

The third and final part of our current CF strategy is to address the additional 20,000 or so CF patients who are heterozygous for the Delta 508 mutation and to further enhance the clinical benefit for all patients that we may treat. Towards this end, we are working to advance second-generation corrector molecules out of research that we plan to combine with ivacaftor and a first-generation corrector, such as VX-809, 661 or 983.

I'm very pleased with the progress we've achieved in CF over the last year, but we have not done this alone. I want to personally thank all of those involved in the development of our CF medicines, particularly, the patients who volunteered for our clinical trials, as well as their families, physicians and care teams. The Cystic Fibrosis Foundation, which has also played a key role in helping us to develop our medicines for people with CF and our employees who have worked so hard to develop these novel medicines to help people with CF around the world.

I'll have more comments to make later in the call, but now I'd like to turn it over to Peter, to review the VX-661 Phase II clinical results.

Peter R. Mueller

Thank you, Jeff, and good afternoon to everybody. It is a real pleasure to talk with you this afternoon about our progress in developing new medicines for people with cystic fibrosis and to highlight VX-661, in particular.

A few words to describe VX-661 before we review the trial design and the data. VX-661 is a product of our CF direct recovery efforts that are centered at our San Diego research site. This is the same research platform that produced KALYDECO and VX-809 and the corrector molecule VX-983 that Jeff mentioned earlier. We began clinical development of VX-661 in 2010, and we initiated the first study in people with CF in March 2012. This is the study we are reporting on today.

VX-661 has a number of similarities to VX-809, a molecule you may be more familiar with. It is from the same chemical class as VX-809, and our data indicates that it acts at the same step in the CFTR collection pathway. In vitro, VX-661 showed similar activity in restoring CFTR function in combination with ivacaftor, when compared to VX-809 in combination with ivacaftor.

Let me characterize VX-661 preclinically, we noticed VX-661 did not show the potential for a drug, drug infraction with ivacaftor, meaning, that we did not have to increase the dose for ivacaftor, as we do with VX-809. Today, we are reporting topline results from Part A of the Phase II study.

A schematic of Part A of the VX-661 study is shown on Slide 6. This was a double-blind randomized placebo-controlled dose escalation study of VX-661 dosed alone and in combination with ivacaftor for 28 days. It was designed to look at 4 different doses up to 150-milligram of VX-661 dosed once-daily. The final combination dose group completed treatment in March, and they have also now completed 28-day posttreatment follow-up. Now we are reporting the topline results.

A total of 128 patients were dosed in the trial. Our primary focus was on the evaluation and further validation of the CFTR corrector potentiator combination therapy approach in Delta 508 homozygous patients, as well as identifying a therapeutically relevant dose for VX-661 in combination with ivacaftor.

All of the in vitro and clinical data we have obtained to date indicate that a combination of a CFTR potentiator and a CFTR corrector is necessary to maximize the increase in CFTR protein function in Delta 508 patients, which we believe will drive fundamental clinical improvement in this disease.

The combination arms were designed to enroll more patients than the monotherapy arms. Within each treatment arm, a few patients were randomized to placebo, which created a culled placebo group to compare with the treatment arms.

I will point out that within this study, all treatment groups recruited new patients, whether placebo, monotherapy or combination therapy doses, this is very different from the Phase II study we conducted with VX-809 in combination with ivacaftor. The results for VX-689 in combination with ivacaftor demonstrated a dose-dependent improvement in percent predicted FEV1 versus placebo, and in the 2 highest combination dosing arms, we achieved statistically significant increases in FEV.

The bar chart on Slide 7 provides the data for each VX-661 dose arms in monotherapy and in combination. First, the monotherapy arms. From our prior in vitro and clinical work, targeting Delta 508 CF patients, we did not expect to see meaningful clinical improvements with the correct monotherapy, and this expectation was confirmed as the monotherapy arms of the VX-661 trial. Variable responses in lung function were observed in all the VX-661 monotherapy dosing groups. The increases were not dose-dependent, there was variability between patients and within dose groups. There were no statistically significant improvement of FEV1 in any of the monotherapy dosing groups at Day 28.

In contrast, the mean FEV1 for each combination dose group increased during the study. And even though the study was small, the top 2 dose groups were statistically significant versus placebo at the end of 28 days.

At the top 2 doses, the increases in relative percent predicted FEV1 were 9.0% and 7.5%, respectively, representing a meaningful clinical improvement for these patients. In contrast, the placebo group had a mean relative improvement of 0.03% and was essentially flat.

What is equally striking, in the evaluation of the patients treated with combination therapy, is the decrease in FEV1 that occurs during the 28-day post-treatment washout period. At the end of a day -- of a 28-day posttreatment washout period, all combination dose groups had returned close to baseline and are similar to placebo. The data shown here were gathered post-dosing, and were not part of the group specified statistical analysis plan, have then further reinforced the activity seen in these arms during the first 28-day dosing period.

Slide 9 provides an individual patient visualization of the statistical significance that we achieved with the 100-milligram and 150-milligram combination dose groups, which were the 2 highest doses we tested in the trial compared to placebo. This waterfall block indicates the relative change in FEV1 for each patient at Day 28. You can see a high proportion of patients in the 100-milligram and 150-milligram dose groups with a greater than 5% relative improvement, or any kind of improvement during the 28-day study, compared to the expected normal distribution of placebo patients around their own baseline FEV.

When you look at just the 100-milligram and 150-milligram dose groups, you can see just how many patients have a positive response. Between the top combination dose groups, 19 of 31, or about 60% of patients have a relative FEV1 improvement of 5% or more.

The table shown in Slide 11 summarizes the complete lung function results expressed as relative and absolute change in FEV1 for the combination dose arms compared to placebo. I would like to emphasize that the mean FEV1 improvement achieved in this study in 28 days is clinically relevant.

Some additional observations. Obviously, we measured also sweat chloride in this trial. As with previous studies of VX-809, we observed, modest statistically significant decreases in sweat chloride with VX-661 monotherapy and in combination with ivacaftor, supporting the view that the clinical activity we are observing results from correcting CFTR function, which is the underlying mechanism of disease.

However, as with VX-809, there appears to be no correlation between sweat chloride and clinical effect. Improvement in FEV1 responses were observed early in treatment, and the mean relative FEV1 improvements for the highest combination dose group were statistically significant versus placebo at days 14, 21 and 28. In combination dose groups, FEV1 declined towards baseline after dosing was stopped.

From a safety perspective, all doses were generally well-tolerated and had similar safety profiles, the most common adverse events were respiratory in nature. Overall, we are very pleased with the clinical results for VX-661. VX-661, in combination with ivacaftor, demonstrated a statistically significant and dose-dependent increase in FEV1, at the 2 highest doses over 28 days of treatment. The results of this study support the strategy of combining a corrector and potentiator to treat Delta 508 CF patients.

VX-661 alone, and in combination with ivacaftor, was generally well tolerated over 28 days. This is VX-661's first trial in patient, and we are still early in our evaluation of this particular molecule. Our plan is to conduct additional studies of VX-661, in combination with ivacaftor, to further evaluate its potential for late-stage development, pending regulatory discussions.

I will now turn the call back over to Jeff

Jeffrey M. Leiden

Thanks, Peter. I want to conclude the call with a few specific remarks about our near-term CF development strategy and how we think about the development of CFTR correctors in general. At Vertex, we believe in pursuing multiple molecules and treatment regimens at the same time, with a goal of bringing forward the best regimens for patients.

As we think ahead to future regimens, we believe it is worth evaluating additional correctors to identify the best possible future combinations, which could involve more than 1 corrector. This is really the development objective for molecules like VX-661 and for VX-983, which is profiled on Slide 15.

Despite the significant success and progress to VX-809, both VX-661 and VX-983, offer a potential advantage for future triple combination-type regimens, because they do not exhibit drug-drug interactions with ivacaftor. VX-983 is in the same chemical class as 661 and 809, and shows comparable activity in vitro, and it acts on the same step of the corrector pathway. We've now completed a single ascending dose Phase I study of VX-983 in healthy volunteers, and we plan to advance to a 28-day combination study of VX-983 and ivacaftor, in Delta 508 homozygous patients later this year.

VX-661 and VX-983 are close in their development timelines, and our plan is to prioritize one of these compounds in 2014 for development in combination with ivacaftor and/or in potential dual corrector combinations.

So in summary, we're continuing to make excellent progress in our CF strategy. KALYDECO is on the market in the U.S., Europe and Canada, and we expect to see the first data in patients outside of G551D later this year. With Delta 508 homozygous patients, we're very pleased with VX-809, which is far out in front, the Phase II trials have now opened to screening, with a potential for an NDA submission next year.

Finally, we continue to progress both VX-661 and VX-983, as well as second-generation correctors for triple combination therapy approaches, with a goal of maximizing benefits in Delta 508 patients. Over to you, Michael.

Michael Partridge

Thank you, Jeff. We will now open up the call to questions.

Question-and-Answer Session

Operator

[Operator Instructions] The first question is from Geoffrey Porges of Bernstein.

Geoffrey C. Porges - Sanford C. Bernstein & Co., LLC., Research Division

A bunch of questions, but one is, is it -- is there any possibility that you could dose KALYDECO in combination with 661 on a once-daily basis? That would certainly facilitate going forward with a single tablet regimen and that might be particularly intriguing. And then could you comment on the trend between Day 14, Day 21 and 28, was it straight up to 14, and then flat? Or were there still some sign of increase? And then I'll get back in the queue. I'm sure there's lots of other questions.

Ian F. Smith

Geoff, Peter will take the dosing question, and then we'll hand over to Eric to talk about the pattern of response questions.

Peter R. Mueller

So Geoff, thanks for the question and the nice comments you make about the progress. And I must say I'm excited as you are that, first of all, VX-661 works, and also that San Diego produces compounds. I think this is really great. And this is sort of a reflection of our innovation potential in research here in Vertex. What I wanted to tell you, so, all the combination stuff that we have in mind, whether it's 809 and 770, or 661 and 770, or any other combinations that we sort of do later, are set up in a way that we will do a one pill type of approach and do co-formulation. So we're working diligently on all of those molecules to be able to do that.

Geoffrey C. Porges - Sanford C. Bernstein & Co., LLC., Research Division

And Peter, could you considerably give KALYDECO on a once-daily basis?

Ian F. Smith

Same answer, Geoff. I mean we're working towards kind of formulations of those, but at this point, it is twice-a-day compound, and we do work towards optimizing formulations and so we'll certainly give it consideration of how it might combine with 809 or 661 as we move forward.

Geoffrey C. Porges - Sanford C. Bernstein & Co., LLC., Research Division

Okay. And then the trend over time?

Eric Olson

Yes, Geoff, this is Eric. First of all, the response that we stated was rapid and consistent from Days 14 to 28. The statistical significance, as Peter said, at the highest dose at Days 14, 21, 28. And at the 100-milligram dose, statistical significance at 14 and 28, so we just missed it at Day 21. So both those top doses got a rapid response and was consistent through day 28.

Geoffrey C. Porges - Sanford C. Bernstein & Co., LLC., Research Division

And would you say there was any trend to improvement at Day 28? Or was it pretty much plateauing over the last couple of weeks?

Eric Olson

Yes. It was a short study, 28 days, and we'll see what happens on a longer treatment.

Operator

The next question is from Geoff Meacham of JPMorgan.

Geoffrey C. Meacham - JP Morgan Chase & Co, Research Division

So that's how you validate Phase II data is with the -- I wanted to ask you a little bit about the monotherapy piece. You didn't see the decline in the first 28 days with 661 than you do with 809, and just maybe any thoughts on those comparisons? And then a bigger picture question, I know it's difficult to compare the 2, but how would you envision, if 661 has higher potency that you see in other studies, would you guys take this into a heterozygous population, where 809 didn't show as robust an effect, and leave 809 in the homozygous?

Ian F. Smith

Geoff, we'll have to split that question. So Eric will take the first part of the question, and then Jeff can talk to the broader strategy we have with all the molecules that we've mentioned on the call today.

Eric Olson

Yes. So just to remind everybody, what he's referring to, in the 809 study in that monotherapy portion, the first 28 days of 809, we saw a decline in FEV1. And we didn't see that in the study. And of course, what we've learned from all of our in vitro data and now data from these 2 clinical studies, these 2 regimens, is that a combination regimen is the path forward. And each of them now have shown statistically significant and clinically meaningful increases. And it's really the combination that we're going to be focused on. And probably not worth speculating too much about mechanism of cost than in 809.

Ian F. Smith

Jeff, do you want to take the broader strategy?

Jeffrey M. Leiden

Yes, Geoff, thanks for asking the strategic question. I guess I would start of by saying that our approach all along in CF and our belief has been that different patient populations here will be optimally treated with different combinations of drugs. And obviously, KALYDECO has done a very nice job with G551D and we're looking to expand that with monotherapy. In the homozygous patients, we're really pleased with the 809 ivacaftor combination and our ability to take that forward quickly under breakthrough status. Now we have 661, which clearly shows activity. You mentioned the 661 was more potent than 809, I do want to be careful to correct that. We don't really believe that it's more potent. We don't have many evidence that says it is. And in fact, to me, one of the most remarkable things when you compare this data, despite the fact these were 2 different studies, 2 different drugs, and 2 different patient populations, is that the combination result is remarkably similar, right? I mean, we saw 7.5% to 9% relative increase in FEV1 here with the 2 highest dose groups and the 600-milligram dose group, for example, we saw, again, a 9% to -- 9% or so, to 12%, depending on how you looked at it, relative increase in 809. So remarkable similarities. I think as we go forward, we are in a nice position now of understanding how to use each combination to best address each patient population. That's what we'll be doing over the next short period of time.

Geoffrey C. Meacham - JP Morgan Chase & Co, Research Division

And any thoughts, Jeff, on how -- or maybe, Peter, how you would envision a small, but potentially, fast Phase IIb just to get -- what steps, I guess, are do you guys envision that are needed to get into a pivotal with 661?

Jeffrey M. Leiden

Well, we really don't know fully yet, Geoff. This is the first human data that we have with the molecule. And so our plan is, over the rest of this year, to conduct some additional studies of 661, to talk with regulators of course, to try to understand what the best path forward for the molecule is.

Ian F. Smith

That said, Geoff, we'll be in better position to let you know what our plans are, development plans are, with 661, once we've had those discussions. And just to set people's expectations, we'd anticipate coming back to you in the second half of this year with those plans.

Operator

Next question is from Mark Schoenebaum of ISI Group.

Omar Saad - ISI Group Inc., Research Division

This is Omar, filling in for Mark. I had a couple of data questions, actually. So the first one was, I noticed there's a dose response in the combo portion, but it seems like there's an inverse dose response in the monotherapy portion, just trying to understand if we're thinking about that correctly. And then secondly, on the sweat chloride, stats like benefit, could you possibly quantify that? We just want to be able to comp this versus KALYDECO or versus the 809 monotherapy?

Ian F. Smith

Maybe, I'll take that first question on monotherapy because it is just a function of the data and the small arm that's in that study. You've noticed the data we provided is not statistically significant in the monotherapy, and I assume you're talking about inverse dose response because in the 10-milligram monotherapy dosing arm, we did -- we reported a 4.5% FEV improvement. That was actually influenced by 1 particular patient within that arm, that had a very high FEV response. And when you put 1 patient in particular, in a very small end, it really drives up the mean. But it wasn't statistically significant and that's why today, you hear us focusing on the combination therapy. We see a sort of variable response with monotherapy and none of those groups were statistically significant. And then to the latter part of your question, Eric?

Eric Olson

Yes. Just -- sweat chloride, certainly is a valuable biomarker of CFTR mediated chloride transport and it's one that we've -- you know we've routinely used in our studies. And so, well, it's an important marker for the biochemical mechanism of action, what we've learned, is that it did not correlate very well with changes in FEV. With that said, we did see a decrease in sweat chloride, as stated in the release, and that supports our conclusion that we're targeting the basic defect. And of course, just to reiterate, the most important outcome, that we feel is the most meaningful for everyone, the patients, families, physicians and regulatory agencies, is the improvement in pulmonary function.

Operator

The next question is from Rachel McMinn of Bank of America.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

A couple of questions. Just, it looks like you do have -- that you've hit a nice, kind of peaked dose with the 100mg dose based on the FEV1 data, in other words, going up doesn't buy you anymore. But I'm curious, from a PK perspective, if that data is also supportive of that? And then secondly, you keep saying you're going to do additional 661 studies, but I'm wondering if you could provide any kind of hints or ideas as to what those next studies would look like? And then finally, when you talk about 983 and how we think about your broader strategy, I'm wondering if we should be thinking about you guys' running head-to-head studies as with any of these earlier stage molecules that you can, I guess, prioritize the best one.

Peter R. Mueller

So Rachel, thanks for the question. Eric will take the question on expression dose response and then maybe we could -- Jeff can respond to both next kind of studies for 661 and 983, again, from a managed portfolio approach and more options these provide us.

Eric Olson

Yes, Rachel. So first of all, the -- we don't have all the PK data yet from, especially, the last -- that last group. So it's a little premature to start speculating about kind of PK/PD relationships. But I certainly feel this is encouraging that we're into a dose range that, based on our vitro data and our Phase I data that we -- from this program that -- and everything else we've learned about CFTR modulation, that we're in a dose range, that we think it gives us a good target in moving forward in future studies.

Jeffrey M. Leiden

And Rachel, this is Jeff. Thanks for the question about the future studies. In terms of the additional studies of 661, as I said, we've just received this data. We need to talk with regulators about it and understand what the next step studies are to evaluate its potential for future late-stage development. With respect to 983, I mentioned that our plan is to go to a 28-day combination study later this year in Delta 508 homozygous patients. And then the third part of the strategy, as I mentioned, will be to bring the second-generation correctors, which are currently pre-clinical into the clinic, and then combine them with one or more first-generation correctors in ivacaftor, both for the Delta 508 homozygous patients. But also, we want to look at that in the heterozygous patients.

Rachel L. McMinn - BofA Merrill Lynch, Research Division

And maybe just a follow-up then, do you think 983 is more potent than 661? I'm just -- after looking at the really amazing data from 661, I'm just wondering how could 983 be better if it's from the same chemical class targeting the same mechanism. What's the hook on that one?

Peter R. Mueller

I think it's not necessarily just the potency. We have to look into the overall profile of the molecule. And I think all of those molecules have different metabolism and different PK/PD profiles, which then enables us to put the right molecules together for the benefit of the populations we want to study.

Operator

The next question is from Michael Yee of RBC Capital Markets.

Michael J. Yee - RBC Capital Markets, LLC, Research Division

I wanted to re-ask you, how you think the data on -- in combination from day 28 to 56, when that was dosed in combination, compares to what you're seeing here from day 0 to 28 for 661? When we look at the day 28 to 56 in combination, obviously, there's a rapid increase of 6 and 6.5 for the 40 mg BID. so there's a rapid and very high absolute benefit, and that's actually even better than the 661 from day 0 to 28. So maybe clarify how you think the 2 data compares. And then my second question is, there are 2 websites, clinical trial websites that show 661 being offered as well in heterozygous, is that just incorrect? Or do you plan to look at 661 in heterozygous?

Ian F. Smith

We'll split those up, Mike, if you don't mind. But sorry, Eric will take the final [ph] question. And then as we think about, again, the strategy going froward in heterozygous specifically, Jeff will take.

Eric Olson

Yes. So just to remind you of what we saw with the -- with 908 is the -- for example, the 600-milligram combination dose from day 28 to 56, that relative mean versus placebo is the 12.8%, highly statistically significant; and from day 0 to 56 was 9.2%. And in this study, at the 100-milligram, we saw a 9% improvement, so very, very comparable. Small studies and, again, a cautious -- against -- trying to compare across studies, different design, different people. But the important thing is each of these 2 studies with 2 corrector molecules in combination are showing very comparable improvement in FEV.

Jeffrey M. Leiden

And then with respect to your second question in terms of the strategy, as you know, everything that we've seen so far has taught us, I think, that a single first-generation corrector, be it 809 or 661 plus ivacaftor, is effective in Delta 508 homozygous patients. And so that's the first area that we're going to focus on, most prominently with 809 going forward in Phase III. We are very interested, of course, in treating heterozygotes. So far, what we've learned is we think it's going to be more difficult to treat the heterozygotes than the homozygotes. And that's why we're really focused on the 3-drug approach, the second-generation corrector plus the first-generation corrector and ivacaftor, for that population.

Operator

The next question is from Liisa Bayko of JMP Securities.

Liisa A. Bayko - JMP Securities LLC, Research Division

Two questions. The first is, can you maybe describe the pattern of response in the first 14 days? Because we know in the other study is was sort of on a decline pattern and then when you put the combination together, it did go straight up. So I'm just curious about that first 2-week period. And then also could you comment on -- a little bit more specifically about the weight gain?

Eric Olson

Yes, this is Eric. So like we stated in the release, from day 14 to day 28, we saw this consistent response and probably, for this kind of study looking at additional time points, probably not a lot of value at this point so...

Ian F. Smith

And Liisa, I would just add, Eric did, in his commentary to an earlier question, did add the pattern of response for the 100-milligram dose group as well, which was similar to that in the 150 and it actually hit statistical significance on, I believe, day 14 and day 28. And actually, the only day it missed was on day 21. And coincidentally, it did on an absolute perspective but not on a relative. So it just shows you that the pattern of response between those 2 dose groups is very similar. And we're seeing this early onset of action. So it's very pleasing.

Liisa A. Bayko - JMP Securities LLC, Research Division

That's great. But I'm just trying to narrow down on the first 2 weeks. Was that -- was there -- was it just sort of straight up to day 14? Or was there an initial dip and then it came up because of maybe coughing and that kind of thing or -- I'm just trying to understand the shape of the curve for the entire period.

Ian F. Smith

Yes. I mean, additional data on this will be coming at a future medical conference. But you can anticipate it headed up towards day 14. But more disclosures on this at a later medical conference, where people will actually plot the curves, I'm sure. But we're helping you understand what the shape of those are today by helping you understand that there is statistical significance at day 14, 21 and 28 and a similar response in the 100-milligram dose group as well.

Liisa A. Bayko - JMP Securities LLC, Research Division

Okay, that's great. And what conference will that be at? Have you decided yet?

Ian F. Smith

We'd rather not describe the data, which is coming to specific conference is. There's a couple that's coming later this year. Stay tuned.

Liisa A. Bayko - JMP Securities LLC, Research Division

All right. And then any more granularity on weight gain will be great.

Ian F. Smith

I'll just say we didn't measure weight gain in this study. It was 28 days.

Operator

The next question is from Yaron Werber of Citi.

Yaron Werber - Citigroup Inc, Research Division

So just a couple of questions really for kind of Peter and Fred. With respect to 983, I'm really trying to figure out sort of -- I don't know if you can help us understand a little bit. Pre-clinically, what are you seeing in terms of potentiation of the channel activity, sort of at the surface of the channel when you measure it in your in vitro assays? And does it have a differential activity at the nucleotide-binding domain or near the ICL4 loop that maybe can explain potentially a greater potency? And then I have a follow-up, too. I'm just trying to understand mechanistically how it's different.

Peter R. Mueller

Sorry, Yaron. So mechanistically, it's not different. That's the short answer. I think it acts pretty much the same way 661 and 809 does in terms of correction folding pathway that leads through expression of the protein on the surface. There is no -- it's the same binding site area, so that's what you're asking, that's the first question. So no difference. I think in terms of potency, it is in vitro, pretty much comparable to what you see with 809. I think there's not a big difference between the 2, between the normal standard deviation. And I think the bigger question is at the end of the day, it has a very different metabolism than 809, for example. Because there is no induction potential on other type of things that you have to correct later on. And so that gives you a different option in terms of combining different molecules. There's different profiles. It's that sort of high level what the differences are.

Yaron Werber - Citigroup Inc, Research Division

And then just in terms of -- in the patient -- I mean it's very hard to ask this question because essentially, everybody responded. It looks like, based on your response curve, who was on therapy. But in the patients who didn't have, let's say, an optimal response, do you have any -- in your models, is there any correlation between exposure and response? Or is there any relationship between speed of onset of response and ultimate response? I'm trying to get a sense -- is it fully optimized? Or they're just tend to be slow responders. Or is it either you respond or you don't?

Peter R. Mueller

Yaron, that's a very good question. And I say we just got the data very recently, and so we will basically dig in deeper into those questions, especially the PK/PD. And then we might be able to answer some of these as we move forward. So at this point in time, I have no information that could give you any help here unfortunately.

Yaron Werber - Citigroup Inc, Research Division

The final question. And anything -- so what's your latest thoughts, now that you have this data and the last 809 data? And what happened in the initial 809 studies with respect to exacerbation in that first 2 weeks to 4 weeks?

Eric Olson

Yes, this is Eric. What we saw in 809 was, in that first 28 days, a decrease in FEV. And we don't have an explanation. In terms of -- we didn't really measure exacerbations the way you would define exacerbations in that study. It's too short.

Yaron Werber - Citigroup Inc, Research Division

Okay. What -- I guess, what I meant is, in respect to coughing, with some of those pulmonary exacerbations, the way I think it was described, it almost looked like it might have been symptomatic of response.

Eric Olson

Yes, we don't understand what the mechanism. We don't know the mechanism of that. And again, we'll see what happens in the Phase III, but we're doing combination, not mono so...

Peter R. Mueller

The only thing we can say is, respiratory rise, we see similar side effects in the 28 studies in all of those regimens that we have ever tested. And we don't know the mechanistic background of that. But I think it's very similar across the different combinations that we ever tested.

Operator

The next question is from Terence Flynn of Goldman Sachs.

Terence C. Flynn - Goldman Sachs Group Inc., Research Division

Two questions for me. And so the first is, can you give us the follow-up data post treatment for the 661 monotherapy arms? I noticed you gave us that for the combo, but I didn't see it in the release for the monotherapy arms. And then also, can you tell us the percent of patients in the combo, the low-dose combo arms, that had above a 5% relative improvement in FEV? I noticed you gave that to us for the high-dose groups and placebo, but I didn't see it in there for the 2 low-dose combo arms.

Ian F. Smith

Thanks for the question, Terence. In terms of the post-treatment period for monotherapy, we actually didn't measure it. So we don't have that data. And as far as the responders are concerned, responder analysis, we provided you with the data of what we thought was the most meaningful data on this call, and specifically, those 2 high-dose groups that was the purpose of this study, with the dose-escalating study. There may be more data at future medical conferences that I mentioned before, but we hope they we're providing you with all the relevant data on this call tonight and more data to follow up that will just confirm what we're communicating this evening.

Terence C. Flynn - Goldman Sachs Group Inc., Research Division

Okay. And I guess one question for Eric, just I know you and I have talked about this before, but just the potential that what you're seeing is being driven by KALYDECO alone versus the combo, just would be curious to get your thoughts, given the data you've got now from 2 separate studies.

Eric Olson

I think it's from the studies, from the in vitro work, I think it's clear that the effect is due to the combination.

Peter R. Mueller

See the monotherapy didn't show a statistically significant benefit. That answers part of the question.

Operator

The next question is from Matt Roden of UBS.

Matthew Roden - UBS Investment Bank, Research Division

So first question is on safety. Just for the sake of completeness, can you describe whether or not there's any dose dependents on the frequency of adverse events in the study? Was there anything new at all, that there's any sort of signal attributable to drug? And then secondly, we're gratified to see another corrector 983 coming through. I was wondering though if you could update us on your thinking on the triple combo approaches and when we should expect to see an IAD [ph]in advancement with the triple combo.

Eric Olson

Yes, this is Eric. Yes, there were no dose dependency on the adverse events.

Jeffrey M. Leiden

And in terms of the triple combo, I think we said all along, and continues to be the case, is that the second-generation correctors are pre-clinical. And our goal is to bring one or more of them into the clinic by the end of next year.

Operator

The next question is from Brian Abrahams of Wells Fargo Securities.

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

I know patients who are cycling on antibiotics, in this study, were synched to start their cycle at the beginning of the 28-day period then cycle off. I'm wondering if you could talk about the proportion of patients who are cycling on antibiotics in this study and whether there were any differences between the 100 and 150-mg arms and placebo. And then I have a quick follow-up.

Eric Olson

Yes. This is Eric. This early, we just haven't analyzed all that data yet.

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

Got it. And then can you maybe talk about how this -- obviously, it's hard to compare across studies. But how the population here compared to the population enrolled in the 600 once a day and 400 twice a day groups for the Phase II 809 KALYDECO study?

Eric Olson

Yes. They were generally very similar as you might expect for an adult population with these 2 mutations. Again, the included criteria was similar kind of a range of FEV between 40 and 90. This group -- they were similar across the dose groups, pretty evenly matched in terms of baseline characteristics and placebo and pretty similar to what we saw in 809 although the FEV in this group just tended to be just a little bit lower than in our 809 studies, but that's probably just a different study.

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

Okay. And then just one last quick question, based on this data, is accelerated approval something that you might consider exploring with the FDA? Obviously, there's much increasing regulatory openness to accepting accelerated approval on small data sets for significant unmet needs.

Jeffrey M. Leiden

Yes. This is Jeff, Brian. Obviously, we've had a lot of experience talking with the FDA since we got the 2 breakthrough status designations for ivacaftor and for 809, which we're really pleased with. And as I said, what we need to do here is to complete the analysis of this data, put it together into a package and go talk to regulators about next step.

Operator

The next question is from Ying Huang of Barclays.

Ying Huang - Barclays Capital, Research Division

Two questions for maybe Peter and Eric. First of all, do you think you need to actually increase the dose at all from here from 150? And also if so, do you have any toxicology data to support a higher dose than this? Secondly, if you look at 100 versus 150, I think there's one other question before me, that was saying that maybe there's no doses on here reached a plateau. But then how much do you think the baseline FEV played a role here? Because based on my calculation, it seems you had a average baseline FEV1, 53% from the 100-milligram dose cohort and then and 60% from the 150-milligram dose cohort. So there's a 7% difference in FEV1 beginning for these 2 dose cohorts. Does that play a role in the relative FEV1 improvement from baseline or not?

Ian F. Smith

So Ying, appreciate all those questions. And the reason I'm going to answer is not because I have the answer but just to let you know that everything you've asked -- this data, we've just received it. And when you're asking about kind of dose levels, next steps, whether there's a marginal difference in the baseline, that affects the 100 versus 150, to me, there's really a lot of details in this study that we still need to understand as we move forward. We're really happy with this result, and we've got to go and have discussion with regulatory authorities to have a better understanding of what our next steps are. And we'll be back to you later this year to help you understand exactly what those steps are. And I apologize I can't, at this point, answer. Or we can't answer those questions with the granularity you're asking but, at some point, later this year.

Operator

The next question is from Robyn Karnauskas of Deutsche Bank.

Alethia Young - Deutsche Bank AG, Research Division

This is Alethia for Robyn. Two questions. One, kind of what -- can you give us a flavor of the status of the enrollment of the Phase III trial that's ongoing? And just kind of -- is there -- do you think that this study could increase excitement around it and it could roll faster? Or are there just rate-limiting steps? And then I guess the second question is just around your second-generation correctors, like -- philosophically, like, what are you screening for to improve and enhance in thinking about combining with, like, 2 very strong first-generation correctors that we've seen already?

Ian F. Smith

We'll split that up, if you don't mind. And Peter can give you a brief update in the Phase III, and then Jeff will take the second piece of the question.

Peter R. Mueller

So I think after we have had our breakthrough discussion with the agency, which was by end of February, we -- in ultra speed, opened all the sites in many countries in the world. And so I think enrollment has gone incredibly well. And no, I'm not seeing here any limitations. So I hope that we have a patient on drug relatively soon.

Jeffrey M. Leiden

In terms of the second-generation correctors, as you would imagine, there are 2 primary things we're looking at there. One is, what is their potency in combination with the first-generation correctors and ivacaftor on both homozygous and heterozygous cells? That's sort of the primary screen, if you will. And then the second one, as Peter mentioned before, is we do feel it's very important that we come up with molecules that can be combined into a single pill. And so we're looking at the properties of these molecules from a formulation standpoint as well.

Operator

The next question is from Katherine Xu of William Blair.

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

I have 2 questions. One question is why did the KALYDECO plus 661 combo study take so long? It took a year. It looks like it was -- did the KALYDECO plus 809 was shorter as of Phase II study? The other one is, in this study, you used KALYDECO at 150 milligrams per -- BID. For KALYDECO monotherapy, that's 100. And if you look at monotherapy in G551D, 150 was actually worse. So the reason why you increased to 150 for the KALYDECO-809 combo is because of the interaction. And now, with 661, if there's no interaction or less interaction between the 2, are you still using 150 for KALYDECO? Are you thinking about looking at 100? Or just optimize that? And how does it work?

Ian F. Smith

Thanks for that question, Katherine. We'll split it into 2. In terms of the duration of the study, you're correct. It started in March of last year, and we're reporting the data this -- in April of this year. This was a kind of a linear dose ascending study that had monotherapy at low dose, moving to combination of that low dose and then moving to higher dose of monotherapy and then onwards and stepping up -- all the way up, including placebo as well. The data has to be analyzed between each one of those steps, whether monotherapy going to combination or combination then going up to a higher monotherapy and the -- and to do a study of this importance and of that nature, it just takes that amount of time. So -- but we're very happy with the results today.

Eric Olson

And just a reminder that KALYDECO, the commercial dose is 150 milligrams, and that's the dose that we used in the study.

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

Sorry, I might have -- got confused myself. So what was the dose used in the 809 study then? 809 and KALYDECO combo?

Ian F. Smith

The 809 and KALYDECO combination was 250. But that is, as Peter has mentioned early on this call, is that we do have a PK interaction between 809 and KALYDECO. So we dosed KALYDECO up in that combination. So KALYDECO is dosed at 250 milligrams with VX-809. We don't have that interaction with VX-661. And therefore, we're able to use the marketed dose of ivacaftor.

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

I got it. I just -- I mismemorized the 250. Yes, that's correct in -- sorry about that.

Operator

The next question is from Howard Liang of Leerink Swann.

Howard Liang - Leerink Swann LLC, Research Division

Sweat chloride data -- is the sweat chloride change on monotherapy greater than the combo like of the case in VX-809?

Eric Olson

Yes, so this is Eric. Yes, so we did see some sweat chloride decrease in monotherapy, again, reinforcing the mechanism of action. It was comparable to what we saw with 809.

Ian F. Smith

And you're correct that the same thing was seen with the combination as well.

Howard Liang - Leerink Swann LLC, Research Division

Okay, great. Just on the post-treatment data, did you measure any point before 28 days, after end of the treatment or after the 28 days?

Ian F. Smith

What -- the honest answer, Howard, is we may have done. I'm not sure. But we reported the day 56. We saw that for 28 days post treatment, we thought that was meaningful to help people understand an off-drug effect. It gave a 28-day period washout, post drug, post treatment. And I think the data helps you understand that there was an on-treatment effect, and then this return towards baseline helps to understand the magnitude of that effect.

Jeffrey M. Leiden

Howard, this is Jeff. The one other thing I'd add that for me was particularly meaningful about that data that we really learned something from was the consistency of the response across all the dose groups. So we saw the same kind of return close to baseline in all the dose groups.

Howard Liang - Leerink Swann LLC, Research Division

I guess my question is, did it return very quickly? Or is this still going -- is there's still further return? Because all of the groups are in a very narrow range from 0.5 to 0.8. Is that the new -- is that a permanent enhancement of FEV1? Or is that going to 0 at some point or just measured narrow?

Jeffrey M. Leiden

Yes. Howard, just to be clear, we really don't ascribe any difference between 0 and 0.5 in a study this size. And my interpretation of that is there is no significant difference in any of those groups or the placebo group, frankly.

Operator

The next question is from Ravi Mehrotra of Credit Suisse.

Koon Ching

This is Koon, asking question on behalf of Ravi. And I just had a quick question on the monotherapy, the higher doses. Could you tell us if in terms of the -- there was an improvement in FEV1. I know it's not significant. But was there a trend in that most of the patients appear to be increasing? Or was it really scattered or influenced by just one patient in particular?

Ian F. Smith

So Koon, thanks for the questions. I think we mentioned this earlier on the call. And when you look at the monotherapy result, it is variable. We don't see a dose-dependent response and is non-statistical and is variable amongst the patients, hence, the non-statistical response. Other than that, we're not trying to interpret this data. As we say, this is about combination therapy, and we're really happy with that result.

Operator

The next question is from Phil Nadeau of Cowen and Company.

Philip Nadeau - Cowen and Company, LLC, Research Division

Just 2 quick questions. First, how many baseline FEV1 measures did you take? And then second, did you look at any symptomatic improvements in the patients? And if so, did you see anything interesting, any trends or any signals?

Ian F. Smith

Yes. And I'll just quickly close on that question, and then I'll actually hand it over to Jeff for some closing remarks. But no, we didn't take those symptomatic measures in this study. With the 28-day study, we've reported results, the FEV was a measure of sweat chloride. We've reported the results of the key measures of this result. And also have given you some other data to understand in terms of the waterfall plot to help you understand the context of the top line data. There's more data that will come from the study. It will be at the future medical conference. We'll be happy to work with you at that point. But we're really happy with these results today. And I'll hand it over to Jeff for some closing remarks, given that we're approaching 5:30.

Jeffrey M. Leiden

Thanks, Ian. And thanks to all of you for joining the call and for your questions today. I guess, I would just end by saying that we are really pleased with this data. And the main reason we're pleased is because we think it really arbors goes well for patients with CF. And we've had a very longstanding goal here, more than 10 years to try to address the underlying genetic mechanism of this disease. And I think today's data is one more very important step forward. This leaves us feeling very encouraged that we are cracking the code of the disease, and we're going to be able to offer treatment to more patients and that's our goal. I think it also validates our strategy of combining a corrector with a potentiator. And that has obvious strategic importance to us, as we think about the 809 ivacaftor trial. As Ian said, we will be providing more data at scientific meetings. But as I look at this data, I think it does provide a clear answer to the strategy and to the story. So thanks again for your attention and for your questions.

Michael Partridge

So this is Michael. Thanks again for your kind comments on the call and all of your emails as well. We will be in the office tonight if you have additional questions. Thanks.

Operator

Ladies and gentlemen, this concludes today's program. You may now disconnect. Good day.

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