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Vertex Pharmaceuticals, Inc. (NASDAQ:VRTX)

Q2 2012 Earnings Call

July 30, 2012 5:00 p.m. EDT

Executives

Michael Partridge – VP, IR

Jeff Leiden – Chair, President and CEO

Ian Smith – EVP and CFO

Peter Mueller – EVP, Global Research and Development, and Chief Scientific Officer

Robert Kauffman – SVP and Chief Medical Officer

Analysts

Geoff Porges – Sanford Bernstein

Rachel McMinn – Bank of America-Merrill Lynch

Mark Schoenebaum – ISI Group

Yaron Werber – Citigroup

Geoff Meacham – JPMorgan

Matt Roden – UBS

Liisa Bayko – JMP Securities

Terence Flynn – Goldman Sachs

Tom Russo – Robert W. Baird

Ying Huang – Barclays Capital

Brian Abrahams – Wells Fargo Securities

David Friedman – Morgan Stanley

Katherine Xu – William Blair

Howard Liang – Leerink Swann

Michael Yee – RBC Capital Markets

Ed Tenthoff – Piper Jaffray

Phil Nadeau – Cowen and Co.

Brian Skorney – Brean Murray

Alan Carr – Needham & Co.

Operator

Good day, ladies and gentlemen and welcome to Vertex Pharmaceuticals, Incorporated second quarter 2012 financial results conference call.

[Operator Instructions]. As a reminder, this conference is being recorded. Now I'll turn the conference over to Michael Partridge, Vice President of Investor Relations. Please begin.

Michael Partridge

Good evening and welcome to Vertex's second quarter 2012 conference call.

Vertex continued to make progress in the second quarter of 2012 to build our global business. With our approved medicines, in its first full quarter, Kalydeco achieved $46 million in US sales, reflecting increased uptake in people with CF who have the G551D mutation. We also announced on Friday that we have received approval of Kalydeco in the EU.

Incivek, for the treatment of hepatitis C, reported sales of $328 million in the second quarter. We continue to lead the market in hepatitis C, approximately 70% to 75% of new DAA prescriptions written in the US are for Incivek. However, the number of patients initiating treatment for hepatitis C has declined compared to late 2011 and early 2012. Therefore, we have revised our 2012 guidance for total Incivek net revenues today.

Highlighting our progress in R&D, in cystic fibrosis, with clinical results and study initiations, we advanced our efforts to be able to expand the number of CF patients we may ultimately treat. And in hepatitis C we today announced promising seven-day viral kinetic data for our first nucleotide analog ALS-2200 that we licensed from Alios BioPharma.

To discuss these and other developments on the call tonight, we have Dr. Jeff Leiden, CEO and Chairman; Ian Smith, CFO; and Dr. Peter Mueller, Head of Research and Development and Chief Scientific Officer. After the prepared remarks, Bob Kauffman, Vertex's Chief Medical Officer, will join us, and we will take your questions.

We expect to conclude the call as close to 6:00 p.m. as we can manage. To help us do that, we would ask that you please limit your questions to one with a related follow-up.

I will note that 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. These statements, including without limitation those regarding the market launch of Incivek and Kalydeco and our guidance are based on management's current assumptions and are subject to risks and uncertainties that could cause actual outcomes and events to differ materially.

GAAP and non-GAAP financial measures will be discussed on this call. Information regarding our use of these measures and a reconciliation of non-GAAP to GAAP is available in our second quarter 2012 financial press release which is on our website.

Thank you. And I will now turn the call over to Jeff.

Jeff Leiden

Thank you, Michael. Good evening, everyone.

2012 has been a very dynamic and productive year for our business. During the last seven months we have delivered a series of important advancements. For cystic fibrosis, the approval and successful launch of Kalydeco in the US, m more recent approval of Kalydeco in Europe, and positive Phase II data for the VX-809 plus Kalydeco combination in delta 508 homozygous patients that supports progressing to a pivotal program; and now in hepatitis C, very impressive seven-day viral kinetic data for ALS-2200, our nucleotide analogue.

With these advancements, all made since the start of this year, we are demonstrating our consistent ability to discover, develop and commercialize multiple transformative medicines, which in turn represents a strong foundation for the sustainable long-term growth that we expect to create with our business.

During the last few months I've been working closely with the cystic fibrosis and hepatitis C franchise teams at Vertex. I'll provide a perspective on how we are positioned in these markets and also strategically how we are planning on extending and enhancing our presence in the treatment of these diseases. I'll also highlight for you what I think are the tangible markers for our progress as a business that we will ask you to focus on in the months and years ahead. After that, Ian will review our financial performance, our 2012 guidance and discuss how we're prioritizing investment in our business. Then Peter is going to provide you with a more detailed update on data and recent developments in our pipeline.

Beginning with cystic fibrosis, Vertex is seeking to fundamentally change the outlook for people with this disease, and we have made excellent progress toward the goal this year. Kalydeco, which was approved earlier in the year in the US for G551D CF patients age six years and older, has been rapidly adopted in the US as a groundbreaking new medicine that addresses the underlying cause of the disease in these patients.

The launch of Kalydeco has exceeded our expectations. We are currently treating a significant number of G551D patients, and we expect additional G551D patients to begin treatment in 2012, including patients who are rolling off the PERSIST Phase III extension study. Our field teams have done an excellent job with the launch, working to educate physicians and caregivers about Kalydeco and helping eligible patients and their families get the medicine. Last week we received approval in the EU for Kalydeco for G551D patients, and our team there is working to make Kalydeco available as soon as possible in multiple countries.

We also believe that we can significantly expand the CF population that is addressable with Kalydeco alone. And towards that end, we have initiated additional monotherapy studies that Peter will discuss in his remarks. If our strategy is successful, these studies could increase the addressable population from the current 4% to 8% to 10% of the CF population, and potentially more as we consider the applicability of Kalydeco to certain other people with CF.

During this quarter we also produced clinical data that provided convincing insights into how we may be able to treat a much greater number of people with CF, the homozygous delta 508 population. Specifically, we reported Phase II combination data for VX-809 and Kalydeco, which support moving into pivotal development, targeting delta508 homozygous patients early next year. If successful with these development efforts, we could potentially address 60% or more of the cystic fibrosis population with our different medicines.

CF is a serious genetic disease, and I'm very proud that our team is at the forefront in developing potentially life-changing medicines for patients and their families. We're committed to being a leader in cystic fibrosis and continuing to work closely with the CF Foundation, patient groups, physicians and patients and their families around the world to develop additional breakthrough medicines and to provide hope.

Let me now turn to hepatitis C. We are leaders today in the treatment of this disease, and with the portfolio of novel medicines we have in development, we think we are well-positioned to continue to deliver new regimens to the treatment of hepatitis C. I'll make comments on Incivek's recent performance and near-term outlook. We've learned about this evolving market in recent months and I want to share our thinking in terms of how we're approaching our commercial efforts. I'll also talk about our ongoing plans to develop all oral treatment regimens for the future, which I think is very promising based on today's announcement about our new program.

Let me start with Incivek and two things that have not changed in the first half of this year, Incivek market share and persistence rates. First, market positions.

Incivek has been and remains the leading direct-acting antiviral or DAA. Seventy to 75% of Genotype 1 patients who initiate therapy with a DAA in the Unites States continue to initiate treatment with Incivek. This position, which we have maintained since the launch of the drug, and which we expect to maintain, speaks to strong execution by our commercial team as well as to the benefit that this treatment provides to those with hepatitis C.

Second, persistence rates, that is the number of patients completing 12 weeks of treatment with Incivek. Persistence rates for Incivek remained strong, and this has been consistent since launch, which once again speaks to the benefit of Incivek and the execution of our commercial team. What has changed in this market is the number of hepatitis C patients initiating treatment, which I'll refer to as the treatment rate. This treatment rate is changing faster than we expected compared to earlier this year, and this is the reason for our revised guidance that Ian will talk about during his remarks.

I'd like to describe the pattern that we've observed to provide some perspective for you on the 13 months since Incivek was approved. Soon after launch in the fall of 2011, the annualized treatment rate for all Genotype 1 patients had increased to approximately 90,000 to 105,000 patients per year, due in large part to the influx of warehouse patients seeking treatment with the newly approved DAAs.

During the first four months of 2012, this treatment rate stabilized at approximately 70,000 to 75,000 Genotype 1 patients per year. The guidance range that we set in February and reiterated in April was based upon this relatively stable treatment rate, adjusted downward for anticipated seasonality and potential for fewer patients to start treatment as the year progressed as well as on our stable share of this market and our persistence rates. However, in May and June, the number of people with hepatitis C initiating any type of therapy substantially decreased by 20% to 25% when compared to the first four months of this year.

We attribute this decrease in the overall hepatitis market to two main factors. First, physicians deferring treatment of patients, especially those with less advanced liver disease, following the presentation of multiple sets of mid-stage results for oral combination therapies at this year's EASL conference in April. And second, an increase in the number of ongoing and planned clinical trials in hepatitis C, which has drawn in increasing numbers of patients.

The timing and impact of these factors has been difficult to predict and forecast, especially the deferral of treatment in some patients. Based on this change in treatment pattern, we are adapting our marketing efforts for Incivek and we have also revised our 2012 Incivek revenue guidance. As I mentioned, we believe that expectations of future all-oral regimens are an important factor in the decreased treatment rates we are seeing over the last few months. Therefore, I would also like to provide some perspective on Vertex's potential to participate in the evolution of these all-oral therapies.

Based on the Alios data we reported today, we are moving quickly to develop all-oral regimens for hepatitis C that we believe could make a major difference for patients and be highly competitive as hepatitis C treatment continues to evolve. We're very encouraged by the clinical potency of ALS-2200. The compound has shown excellent tolerability to date. Therefore, we believe ALS-2200 could be a central component for future all-oral combination regimens. Our guiding principle in the development of all-oral regimens is that we want to do what's best for patients.

Our new Alios data, coupled with the evolving regulatory pathways, opens the field for us to pursue multiple options. Our key imperatives with our all-oral development program are, first, evaluate combination regimens with our own DAAs and consider combination regimens with other companies' DAAs. And second, gather as much Phase II data as quickly as possible and in parallel to enable us to pick the best regimen or regimens to take forward into a pivotal program next year.

Most specifically, our approach will be to initiate smaller Phase II studies of ALS-2200 plus multiple other therapies this year to design -- to guide the design of a pivotal trial. Given the many unknowns concerning different all-oral combinations, we believe it will be important to design our pivotal program based upon efficacy and safety data from these Phase II studies. With these Phase II data in hand in the first half of next year, we will then target the initiation of a pivotal program starting in late 2013, which we believe represents the best and shortest duration regimen or regimens for people with hepatitis C. Peter will talk more about our data and our plans in a moment.

In summary, during the last year, we have seen a significant evolution in our business at Vertex. Our teams have produced a series of major clinical and commercial achievements that have markedly enhanced the foundation of the business going forward. These achievements which speak to Vertex's ability to consistently discover, develop and commercialize multiple breakthrough medicines are the foundation upon which we will build a sustainable, growing global business over the years to come. I look forward to updating you as we go.

I'll now turn it over to Ian.

Ian Smith

Thank you, Jeff. Good evening to everyone.

Financially, 2012 is demonstrating that we have a diverse revenue base with multiple sources. These revenues remain significant and are important to enable reinvestments in our pipeline for future growth and value-creation in multiple diseases.

Now to the results. In second quarter 2012, total revenues were approximately $418 million compared to approximately $114 million in the same quarter of last year. The key components of these second quarter revenues are as follows.

First, we reported approximately $328 million of Incivek net product revenues. This reflects a strong April, and then a decrease in the number of new patients initiating treatment, most notably in May and June, as Jeff has already described.

Second, we recorded $46 million of net product revenues from Kalydeco, which reflects the first full quarter of sales since launch in February earlier this year. This reflects strong patient demand, the connectivity of the CF community, and the broad awareness of the importance of Kalydeco. We expect this revenue stream to grow as more people start and maintain treatment with Kalydeco. We have now received approval in Europe to add to this revenue base and provide further growth. We foresee a sustainable, long-term and growing revenue base from Kalydeco.

Third, we received $33 million of royalty revenues, including $28 million of Incivo royalty revenue from J&J. We expect our Incivo royalties will continue to contribute positively to our financial results during 2012 given that Incivo is now available in more than 25 countries.

And finally, we received collaborative revenues of $12 million. These revenues primarily fund R&D activities where we have relationships in the areas of hepatitis C and cystic fibrosis.

The GAAP net loss attributable to Vertex was $65 million in the second quarter of 2012 or approximately $0.31 per share. The non-GAAP net income was approximately $100 million or $0.46 per diluted share. The non-GAAP income includes three charges, $31 million excludes three charges -- my apologies, $31 million in stock compensation, $56 million related to increase in the fair value of the expected future payments under our Alios collaboration following the positive viral kinetic data announced today, and a $78 million charge in the cost of product revenues to reserve against the potential excess Incivek inventory.

And now to 2012 financial guidance. Based on the recent decline in the number of hepatitis C patients initiating treatment, we have revised our 2012 forecast for a total annual Incivek revenues to $1.1 billion to $1.25 billion. This range reflects recent decline in patients initiating treatment, which Jeff noted.

Now, to our operating expenses. Based upon the achievements of multiple successful proof-of-concept studies in cystic fibrosis, HCV and RA, respectively being VX-809 and Kalydeco combination results reported in the second quarter, the viral kinetic results in ALS-2200 announced today, and the results of the X-509 in rheumatoid arthritis last year, we have increased and accelerated our investment into these high-priority programs. These monies were significant.

Despite this increased investment, we have maintained our operating expense guidance for 2012 of $1.03 billion to $1.13 billion, which we provided on our February 2 call. We accomplished this by prioritizing and reducing expenses, specifically with significant reductions in G&A spend and aligning our commercial spend to follow future demand in the markets we’re in. These expense reductions have enabled us to reallocate resources towards and within R&D to support the acceleration of these programs yet maintain our operating expense guidance.

In summary, we continue to derive a significant revenue and cash flow from Incivek sale and Incivo royalties. Kalydeco continues to exceed our expectations, and with the clinical results in hepatitis C and CF, we hope to expand our presence and the number of people we can treat over the long term.

Now with viral kinetic data announced today for ALS-2200, our nucleotide analog for hepatitis C, we have the potential to participate in the high-value HCV market with all-oral combinations. We accomplished all of this while generating earnings and cash flow to end the quarter with approximately $1.2 billion of cash and equivalents.

I will now turn the call over to Peter.

Peter Mueller

Thank you, Ian, and good evening, everybody. My remarks will cover some of the pipeline advances that we have made in recent months, most notably in the areas of CF and hepatitis C. In cystic fibrosis, during the second quarter we announced results from a Phase II study of the corrector VX-809 in combination with Kalydeco. We are very pleased with the results we obtained, and they support the start of a pivotal program early next year.

To briefly summarize the key data again, the top dose of VX-809, 600 mg once daily, showed a mean absolute improvement in FEV1 of 3.4% over the 56-day course of the study compared to baseline, and a 6.7% improvement in FEV1 over the placebo arm for the same time period. Both of these were statistically significant with P values of 0.03 and 0.002 respectively.

To us, the most important data comes from the period between Day 28 and Day 56 which was when the patients were actually receiving VX-809 and Kalydeco in combination. A distinct pattern emerged between Day 28 and Day 56. All the dose arms involving VX-809 and Kalydeco in combination improved over this time period while the placebo arm declined. The 600 mg dose showed the best response of its in-subject mean absolute improvement in FEV1 of 6.1% over this time period with a P value of less than 0.001 and a mean absolute improvement in FEV1 compared to placebo of 8.6%, also with a P value of less than 0.001.

More than half of the patients in the 600-mg once daily arm experienced the greater than 5% absolute improvement in FEV1 during this period. VX-809 was better tolerated as a single agent and in combination with Kalydeco. Adverse events and severe adverse events were similar between VX-809 and placebo groups.

We have analyzed the data many different ways, by dose, versus placebo, versus baseline, and on an individual patient basis. All of these analyses performed in combination with Kalydeco was well-tolerated and associated with significant clinical activity. We expect that the investigators will present additional Phase II combination data at a medical conference this fall.

We continue to make progress in designing a pivotal program in the delta 508 homozygous patients 12 years and older, and are on track to initiate a global pivotal program in the early part of 2013 pending discussions with regulatory authorities. Our goal is to confirm the results of cohort two of the Phase II study by evaluating 600 mg once daily of VX-809 and potentially other doses in combination with Kalydeco twice a day.

We have also initiated two important new Phase III studies of Kalydeco monotherapy. The first is a 40-patient study in patients with at least one copy of the R117H mutation and the second is a 20-patient crossover study in patients with a non-G551D gating mutation.

These are both six months studies, with primary endpoints of FEV1 and safety. We anticipate having results of both studies next year, with the goal of generating data that will support an expansion of Kalydeco's label to address these populations. Just last week, we received approval of Kalydeco in the EU for G551D patients aged six and older. I'm proud of the efforts of our team to achieve this first European approval for a Vertex medicine.

I would also like to comment on our second CFTR corrector, VX-661. A Phase II study is ongoing exploring the corrector VX-661 in combination with Kalydeco in CF patients who are homozygous with delta 508. This study is designed as a dose escalation, placebo-controlled study. Part A of the study, which we initiated earlier this year, is evaluating different doses of VX-661 alone or in combination with Kalydeco for 28 days in approximately 100 patients in total. The design is different than the Phase II VX-809 study, reflecting the earlier state of development for VX-661. This is our first trial of VX-661 in patients. We expect to conclude all dosing and follow-up in Part A of VX-661 study before we discuss results publicly and we anticipate that this will take place in 2013.

Now, turning to hepatitis C. Today we announced seven-day viral kinetic results for ALS-2200, a nucleotide analog that was licensed from Alios last year. These are very encouraging results that allow us to move rapidly into Phase II all-oral studies later this year. We achieved a median reduction of 4.54 log in HCV RNA from baseline in the seven-day trial with a 200 mg once-a-day dose. The activity was consistent among patients, with a range of 3.81 to 5.08 logs after seven days of treatment. The initial drop in viral load in this dose group was steep, 3.85 logs after three days and ALS-2200 was also well-tolerated. There were no FAEs or dropouts.

From here, we are advancing rapidly to all-oral, interferon-free combination studies. We expect to begin two clinical studies with compounds within our own portfolio in the second half of this year. First, a Phase II 12-week study of ALS-2200 in combination with Incivek in Genotype 1 patients. Second, also a Phase II study 12 weeks of ALS-2200 in combination with ribavirin in Genotype 1 patients. These studies will evaluate safety and efficacy as measured by SVR 4 and SVR 12 and should enable us to move into advanced studies.

As Jeff mentioned, we will consider regimens with our own compounds as well as the merits of combining ALS-2200 with other leading direct antivirals currently in development. We will work towards the best target regimens for the different patient populations in hepatitis C.

In summary, our efforts in cystic fibrosis reflect the conviction that we can leverage our R&D experience, scientific knowledge and capabilities to make a big difference in the lives of many patients with cystic fibrosis, and our ongoing efforts in hepatitis C demonstrate our commitment to continued innovation in this area. I would like to thank our development teams who have executed extremely well to advance and broaden our pipeline in the last 12 months.

Before I finish, I will just highlight one more high-priority program, our JAK3 inhibitor VX-509. We established proof-of-concept to rheumatoid arthritis last year and advanced this program now into Phase IIb to study VX-509 on a background of methotrexate. We are enrolling now and we expect to initiate studies in other immune-mediated inflammatory diseases beginning in 2013.

Beyond hepatitis C, CF and RA, we have important programs in development targeting flu, epilepsy and other diseases. I look forward to reporting on our progress in those areas in upcoming quarters.

I will now turn it back over to Michael.

Michael Partridge

Thank you, Peter.

That now concludes our prepared remarks. Tyrone, we’d like to open up the call to questions.

Question-and-Answer Session

Operator

Thank you. [Operator Instructions].

We have a question from Geoff Porges of Bernstein. Your line is open.

Geoff Porges

Thank you very much, and congratulations on another important discovery or at least development program. Well done. Just a few questions on the Alios nukes. The first is just, and they’re all sort of technical questions. It’s the first we learn much about them. Peter, can you tell us whether there's any CYP3A or CYP4A metabolism there or likely interactions?

Secondly, if you would soft of cast a wide net, what would be your preference for a combination with the nukes given the profile that you've seen so far? You conspicuously didn't mention 222, and I wonder if we should read anything into that. And lastly, is there any dose response worth pursuing to a higher dose than the 200? Thanks. I'll get back in the queue.

Bob Kauffman

Jeff, this is Bob. I'll try to take those questions, not exactly in the order that you gave them. But let's just say for 222 it was not knowingly omitted, for sure. We're certainly looking at ways of folding that into our development. We've mentioned the two potential Phase II studies that we're planning. There may well be other Phase II studies in more difficult to treat populations where somewhat larger number of compounds combined together might be useful, and that's likely where you'll see 222 come in. We also could combine it with one of the nukes, and there would be no reason not to do that. It's just that we've chosen Incivek as the initial one that we're going to pursue.

In terms of dose response, yes, we're going to be exploring that more with some PK/PD analysis to try to figure out if it makes any sense to go higher, and we certainly could do that if we choose to.

In terms of CYP metabolism, at this point we don't know that much about these compounds. They've just obviously been in very short-term studies. But in general, nukes have not really had major drug interactions with other compounds, and we would expect these to be similar. Obviously we'll see what we get in future studies.

George Porges

Thanks very much. I'll jump back in the queue.

Operator

Thank you. Our next question is from Rachel McMinn of Bank of America-Merrill Lynch. Your line is open.

Rachel McMinn – Bank of America-Merrill Lynch

Yeah, thanks very much. And I also had a couple of Alios questions. I guess I wanted to better understand why you're interested in doing separate studies, one with telaprevir and one with ribavirin, but not looking to do triple? And just make sure that the ribavirin study is going to be in Genotype 1 and understand that rationale.

And then is this nuke, the adenosine, can you just tell us what the base is? And should we presume that because you've made the decision to go forward, that if you're -- I guess are there any inferences to make on the other Alios nukes? So if the data looks just as strong, are you planning on, you know, how would that influence your clinical decisions going forward? Thanks.

Bob Kauffman

So, Rachel, this is Bob. Maybe I'll take the last one first, and just say that clearly we have the data for ALS-2200 in our hand right now and our plan is to move as quickly as we can with that compound. If all goes well with the 2158 and we have another compound, obviously we'll fold that into development when it comes along, and that could be in the setting of either nuke combinations or combinations of each one with other compounds. I wouldn't otherwise read anything into it except just the two studies are just not running completely in parallel with each other. In terms of the structure, we haven't revealed that, so I won't say much more about that.

In terms of the ribavirin study, yes, we do plan to do all of our work in Genotype 1. We see that as where the biggest unmet medical need is at this point, and so we would pursue that. One of the reasons to do the ribarivin plus 2200 study is obviously part of the goal of Phase II is to gather some additional well-needed safety data on the compounds and longer duration, and we just want to clean the system we can to be able to tease out the safety profile of 2200 from the other compound. And just the recent separate studies is really just convenience rather than folding everything into one humongous thing. It just is easier to manage separate studies.

Rachel McMinn – Bank of America-Merrill Lynch

And I guess I don’t -- yeah, I'm still unclear why you wouldn't just run triples. If you have an arm without PI-1 with PI, then why wouldn't you run all three together?

Bob Kauffman Just our preference to do it this way.

Jeff Leiden

Rachel, this is Jeff. Obviously we've just received this data and we're thinking through it. It gives us a lot of optionality, as you pointed out, with respect to our own compounds, and as we've said, we'll consider combining 2200 with other folks' compounds as well. And so I just want to be clear that part of what you're hearing is an evolution of our thinking as we understand what the true optionality here is. And I think the important thing to take away from this is that our plan is to do multiple Phase II studies quickly in order to pick the best combination that we can take forward into Phase III based on actual efficacy and safety data.

Rachel McMinn – Bank of America-Merrill Lynch

Great. Thank you very much.

Operator

Thank you. Our next question is from Mark Schoenebaum of ISI Group. Your line is open.

Mark Schoenebaum – ISI Group

Hey, guys. Thanks for taking the question. A quick one, do you guys have the data in-house for 2158? I don’t know if you -- you may have mentioned and I may have just missed it.

And then on, maybe on CF, on the 661 trial, can you just be really clear, is there an interim or is there not an interim in that trial? And what changed that caused you guys to move the timelines out from this year to next year? And also on that, can you remind us of the design? And give us -- and then also on the combo, can you give us an update on when you're actually going to meet with the FDA to talk about a Phase III design? Thanks.

Bob Kauffman

I'll take the 2158 question, and that is the study is ongoing, it's still blinded, so there's nothing really much that I can say about it.

Peter Mueller

So with respect to 661, Mark, it's a complicated study, it's adaptive trial design. So we will have some data as we go along, and we want to see the entirety of the data before we basically make any statement to the outer world obviously, and that takes a while. So it's not a linear type of design. It's an adaptive trial design to make sure that we look at the compound from different angles and get sort of a good feeling about dosing and combinability with 809.

So we hope that if everything goes well, that we can provide you data in 2013. That's for this piece. In terms of -- what was the other question that you had?

Mark Schoenebaum – ISI Group

Oh, just the Phase III on the combo, when you may meet with the FDA?

Peter Mueller

Yeah. So, basically towards the fourth quarter this year we will have a meeting and then talk about how we go forward that is needed to initiate the trial at the beginning of 2013.

Mark Schoenebaum – ISI Group

And can I just slip one, for Ian? Ian, if revenues decline next -- I know you're not giving 2013 guidance, but just a general philosophical question, if revenues continue to decline into 2013, what -- how should we be thinking about our 2013 expense modeling?

Jeff Leiden

Actually, to the expense question, Mark, I think you can expect us to look at it the same way that we have this year. What we're trying to communicate on this call is a very active program, specifically in our G&A area this year as well as being nimble as we see markets change and adapt to our marketing programs as well. That's allowed us to maintain the guidance that we have this year despite the increased investments in the priority two programs.

As we go into 2013, we have to have a good understanding. We'll get more data and more understanding of the market. But in terms of philosophical question, we're trying to minimize the G&A, the SG&A in our business to the extent we can to prioritize our investment into R&D into these high-value programs.

Mark Schoenebaum – ISI Group

Thank you.

Jeff Leiden

Mark, this is Jeff. Maybe just to add even a bit higher level view, because Ian reviewed the pure financial considerations, I think our vision and our strategy has been quite consistent, which is that we're trying to build a global, multi-product business that can produce long-term growth. Obviously we've made some important and impressive progress this year on our late-stage pipeline. As we go into 2013, I think we want to continue to invest in that pipeline to maximize value, and we'll do so. But we've also said that we're going to be financially very disciplined, both in terms of prioritizing programs and in terms of controlling our expenses. And that's our plan, and we'll give you more insight on that as all the pieces of the puzzle from both the revenue and expense side come together later this year.

Mark Schoenebaum – ISI Group

Thank you.

Operator

Thank you. Our next question is from Yaron Werber of Citi. Your line is open.

Jeff Leiden

Yaron, are you there? Are you on mute?

Operator

He has two lines in. Let's try the next line.

Jeff Leiden

Yaron, are you there?

Yaron Werber – Citigroup

Yes. I'm here. Can you hear me okay?

Jeff Leiden

Yes. We can.

Yaron Werber – Citigroup

Okay, great. So, a few questions, if you don't mind, on the Alios nukes. One, any sense you can give us what was the breakdown between 1A and 1B in that study? Second question, did you see any breakthrough at all on therapy? And then three, what's the metabolism of the nuke? Are they metabolized by the liver at all? Just give us a little bit of sense what you're seeing in animals.

Bob Kauffman

Yeah. So this is Bob. As you saw in our release, the patient population was primarily Genotype 1B. That's likely just geographically based. The study was conducted primarily in Eastern and Western Europe.

In terms of breakthroughs, there were none on therapy. Yeah. There were no breakthroughs on therapy. And metabolism we haven't really talked about very much, so there's not much to say about those. These are nucleotide pro-drugs, and so they are metabolized as they get into the liver through first-pass metabolism into the active compounds.

Just in terms of the 1A/1B breakdown, I'll just say that in general for the nukes there really hasn't been any real difference in activity between Genotype 1A and 1B clinically. In vitro for these compounds there's no real difference between them. And when you look at the data and the trial, even though there were just a couple of people with Genotype 1A, the viral declines were really indistinguishable from the Genotype 1B patients. So we don't really anticipate there being any big difference there.

Yaron Werber – Citigroup

And maybe just a last question, how do you -- give us a little bit of a sense, I mean, you have a lot of work to do. I mean this data is fantastic, but you have data on eight patients at seven days. At this point you need to do the drug-drug interactions, you need to have several hundred patients on drug before you can move into pivotal. We're just trying to understand how is it possible that you can start a pivotal study within 16 months or so?

Jeff Leiden

Yeah. So the way we do it is to move as quickly as we can into a broad Phase II program that will give us the safety database that we need. And we don't disagree with your numbers that it'll be hundreds of patients required, and we anticipate gaining those in various combinations in a series of Phase II studies, perhaps in different patient populations, to basically try to define the right regimens for the right patients. And that is how we will go forward, and we anticipate to be on move quickly. There's a great demand for patients to enter trials with nukes because of their potential advantages. We don't expect any difficulties with recruitment. And so we'll move along quickly.

Peter Mueller

Yeah. And Yaron, as we go forward. Now when you really look into how those drugs normally proceed, we have really an option here by end of next year to basically enter into a pivotal program. And the nice thing, as Jeff alluded to, is we will have numerous evaluations of different combinations in different patient populations that gives us a good sense what is the best regimen for a particular population if you want to move forward. And I think our decision will be data driven and safety data driven, and so we go forward by end of next year with a solid pivotal program, and I think that gives us an option to be a player in the field.

Operator

Thank you. Our next question is from Geoff Meacham of JPMorgan. Your line is open.

Yaron Werber – Citigroup

Good afternoon, guys. Thanks for taking the question. For Kalydeco and the R117H pivotal, it looks to be a six-month study. I'm curious if there's an interim, say, three months, and then if you guys are thinking initially that your delta F homozygous combo study will also be six months, or have you any preliminary discussions with the FDA that it still will have to be a 12-month pivotal? And I have one follow-up.

Peter Mueller

Okay. So, Geoff, hi. This is Peter, so I'll take that. With respect to the monotherapy Kalydeco labeled extension studies, 117 and the gating, the non-551D gating, both of them will be six-month studies without any interims. So we are not doing interims here, it's a small patient population, you don't want to disturb the integrity of the trial by doing interims, so we are not doing this. So the data will be available in the course of next year. And then we will basically file an SNDA to get a label extension. So that's for this part.

In terms of the combo 809 for 12 years and older, we are currently planning a study that has, from a global point of view, the ability to produce one-year safety and one-year efficacy data. And we might, depending on and pending on discussions with the regulatory agencies, we have an option in GS maybe to start an earlier rolling submission as we did with Kalydeco, and that could be on the base of half-a-year data point. But I think that needs to be discussed with the regulatory agencies.

Yaron Werber – Citigroup

Got you. And just the follow-up is on the hep C franchise. So I'm curious if you guys have some sort of ROI target for hep C. I'm just trying to get a sense maybe at a higher level, I mean what magnitude investment you're willing to make given the current dynamics of the market and the landscape. Thanks.

Jeff Leiden

Yeah, it's a good question. Obviously this is a very dynamic, very competitive market. And rather than going to ROI details, I would say what we've said before, which is that we need to be convinced that we have winning regimens that will allow us to address large parts or large portions of this market going forward.

I think as you probably remember, we said that our new data needs to be competitive with anything out there in order to move forward. We feel it is, which is why we're going to move forward. And we'll make the same kinds of decisions as we go and collect our Phase II data prior to moving into Phase III to make sure again that we're not chasing the market with a second-rate or non-competitive regimen. But we think that the new data we provided today is a good start.

Yaron Werber – Citigroup

Okay. Thanks.

Operator

Thank you. Our next question is from Matt Roden of UBS. Your line is open.

Matt Roden – UBS

Great. Thanks very much and congrats on the Alios data here. So on the hep C program, a couple of quick questions here. Can you talk about the baseline characteristics a little bit, maybe the IL-28 genotype, BMI, things like that, just so that we can maybe help assess the degree of difficulty if you will in this study? Secondly, if you can speak to any treatment emergent adverse events in the study.

And then for planning purposes, as you move into a pivotal study, is it your assumption that if there is a new standard of care established by that time in the overall space, whether or not you would actually have to run up against an active control or whether or not you'd sort of take advantage of the progressiveness that the FDA is taking forward in the current hep C studies.

Bob Kauffman

So, Matt, this is Bob. I'll take those. In terms of baseline characteristics, there's nothing particularly notable about them. The IL-28B genotype distribution was as you would expect, but we have not yet analyzed the study by IL-28B individual subject, so I can't really say too much about that, nor by any other baseline factors. So that will be coming as we look at the data. Obviously it's very fresh so we don't have a whole lot of additional analyses.

In terms of adverse events, they were sort of typical for a Phase I study, is all I can say, and obviously we'll provide more information when these data are presented at a medical conference.

In terms of the regulatory strategy, I think it's just a little bit early to say at this point. The FDA, as they have done publicly in a number of settings, has indicated a great deal of flexibility in the development of all-orals. We hope to take advantage of that. It may help us to speed up our program, but it's really premature to think about comparators and sort of all that part of it. Obviously we'll gain more information as we go along.

Peter Mueller And I want to just add two comments to that. So first of all, from a baseline point of view, viral RNA, it's pretty high, it's six-point-ish something. That means it's hard to treat patients in general. So that means we really pick hard to treat people. That's number one. And on top of that, I want to just make sure that we all understand there were no severe adverse events in the entire study, which is actually an important outcome too.

Matt Roden – UBS

Okay, great. And then related -- I guess as a follow-up on the last question, and that is, is it safe to assume or should we infer that since you're continuing to invest in hepatitis C with an early stage asset here, that it's your view that the commercial market will be more sustainable under sort of all-oral standards of care as opposed to the sort of rapid rise and rapid decline of the treatment rate both ten years ago and again in your experience with peg, ribavirin and telaprevir.

Jeff Leiden

Yeah, this is Jeff. Our view is that this is a large market that will likely evolve into multiple segments, some of which will be large, and that one or all would come, there's a very nice commercial opportunity, there's also a great opportunity to treat more patients which is very, very important. And so as we look at it, as I said, once we see our Phase II data, I think we'll be in a good position to conclude whether we have, let's call it winning or first-rate regimens that can address some of these large patient populations. And if we do, that's a worthwhile investment for us and it's a worthwhile investment for patients.

Matt Roden – UBS

Thanks very much.

Operator

Thank you. Our next question is from Liisa Bayko of JMP Securities. Your line is open.

Liisa Bayko – JMP Securities

Hi. Thanks for taking my question. When we think about the combination with Incivek and the Alios nuke, could you maybe talk about the type of regimen or dosing that you're thinking about for Incivek? Are you going to be considering daily dosing and lower doses than currently available? How should we think about that?

Bob Kauffman

This is Bob. We'll likely be dosing Incivek twice-a-day dosing in the combination studies. In general, principles of the antiviral therapy are that you don't generally lower the doses of each of the agents. You obviously need them to cover the variants for the other. So I would not anticipate any different dosing of Incivek than we're currently using.

Liisa Bayko – JMP Securities

And along with the lines, timing wise, I guess 12 weeks is -- I'm just trying to think about if there's a way to make the safety or tolerability a little bit more tolerable in the combination?

Bob Kauffman

Yeah. So just a quick word on that, obviously we had a little bit of a window into the safety profile of Incivek without peg-interferon and [disease] study dual arms. And it was actually quite a bit more favorable, as you'd expect, than what we saw with the triple therapy and it gives us some amount of confidence that we'll be able to design tolerable regimens. And clearly we'll confirm that when we combine them with the nukes. But that is one of the goals, of course, of Phase II is to get that information. And we are looking at 12 weeks as our primary development path.

Liisa Bayko – JMP Securities

Okay, thanks. And then just a question on the CF program, are you considering higher doses of 809 currently? Are you exploring any? And then I just wanted to understand the launch plan in Europe. In what sequence will you be rolling out in countries, sort of timing, and how should we think about price? Thanks.

Peter Mueller

So I take, Liisa, the first thing with the dosing. So as we said, I think there are two aspects of the pivotal trials. Number one is you have to confirm what they have seen in cohort two in Phase II, just the 600 mg once-a-day and Kalydeco 250 mg twice a day. And we actually plan, because we see from the response that we might not have maxed out yet. We will try several other dose regimens that are higher on the VX-809. And one of them, as we always said, could be a BID 400 mg. So that gives you a higher exposure and hopefully then a better translation into the correction. But that's what we are trying to do.

Jeff Leiden

And Liisa, this is Jeff. I'll take your question on the commercial launch in Europe. First, as I think we mentioned before, we've been planning for this launch, so the entire commercial organization is in place in Europe. We're focusing on the four major countries with most of the G551D patients, which is Germany, France, UK and Ireland, initially, although we may roll it out in additional countries over time as we identify these patients, or they identify to us.

As I'm sure you know, the way reimbursement works in Europe is a little different. It's negotiated country by country. And we are just beginning those discussions now with each of the countries. It's therefore early to talk about price, and we'll keep you informed as we go. But as I've said before, we view the value -- the pricing of our medicines with respect to their value to the patient, and we think that, based on our data, this is a very valuable medicine for G551D patients.

Operator

Thank you. Our next question is from Terence Flynn of Goldman Sachs. Your line is open.

Terence Flynn – Goldman Sachs

Hi. Thanks for taking the question. Just was wondering if you can give us any update on how many of the patients have rolled over from PERSIST onto commercial Kalydeco, and if all of them have rolled over? And then any details on the gross to net this quarter for Kalydeco? And then I have one follow-up.

Jeff Leiden

Yeah, this is Jeff, so I'll take those two first. With respect to the rollover, we're not providing a detailed information on the patient numbers. They started rolling over in May and they will continue to roll over, most of them actually, in the third and the fourth quarter. So far the rollovers are going well, Terence, in the sense of it's been a fairly easy process to move patients over.

Your other question was on the gross to net for Kalydeco. And again, we haven't disclosed the number. The gross to net for Kalydeco is really based mostly on payer mix, and the payer mix is about 70% commercial, 20% government, 10% other. That may change a little bit over time as we get more government-funded patients on the drug, but we don't anticipate it'll be a major change.

Terence Flynn – Goldman Sachs

Okay. And then, have you guys looked at any of the PK/PD data yet from the Kalydeco-809 Phase II trial? And where are you on that front, I guess?

Peter Mueller

Obviously, we're looking at those data constantly. We will basically present some of them most likely in a conference later this year.

Terence Flynn – Goldman Sachs

Okay. Any details you can share with us?

Peter Mueller

No. Not at this given point in time. I think what I indicated is that we go for higher-dose regimens, which gives you an indication that we have a confidence that we'll reach exposure levels that are covered by our safety ranges. And that's I think the most we can say at this given point in time.

Terence Flynn – Goldman Sachs

Okay. Thanks a lot.

Operator

Thank you. Our next question is from Tom Russo of Baird. You're line is open.

Tom Russo – Robert W. Baird

Good afternoon and congrats on the great results for the nuke. First question, and then a follow-up, I just wanted to get a little more granular thoughts on cross-company collaborations, maybe the appetite that you have, mechanisms that you'd favor, how advanced any conversations you've already had are, and whether one or more of the Phase II trials that you're talking about could be adapted to accommodate outside compounds?

Jeff Leiden

Yeah, this is Jeff. We're not going to comment on any sort of specific discussions or strategies there. I would really just go back to what I said originally, which is our goal is to find the best regimen or regimens per patient. We think there's still a fair amount unknown about what those regimens are, and our goal is to learn more about that. And I think the classes of molecules one would combine with the nuke are pretty obvious at this point. So they don't bear really reiterating.

But it is our plan to go forward with our own drugs in combination with the nukes. And as I said, we would consider combining them with drugs of other companies as well.

Tom Russo – Robert W. Baird

Okay. And then, the other question, I don't think we've really seen or heard much on the preclinical for the nukes yet. Is there anything that you can say on the dose-limiting talks or how close -- how much coverage you have in terms of the therapeutic window versus the 200 mg that we're seeing today?

Peter Mueller

It's Peter speaking, Tom. I think there will be data in the upcoming conference that basically describes the preclinical profile. We have spoken a little bit about that in the earlier days and I want to repeat that. So we did a careful evaluation quickly before we made a decision to pursue Alios nukes. And on that base safety was an important component. And as I said then, I say now, it was, from a preclinical point of view, one of the safest, if not the safest, nukes that we have sort of seen in the landscape out there. And I think it was part of the decision to go forward.

Tom Russo – Robert W. Baird

Okay. Thanks, Peter.

Operator

Thank you. Our next question is from Ying Huang of Barclays. Your line is open.

Ying Huang – Barclays Capital

Thanks. Congratulations also on your nuke data. My first question is for Bob. Can you confirm that in the Phase 1 trial, for the placebo-treated patients, they're also predominantly Genotype 1b?

And then I have a question for Ian. The excess I guess inventory, $78 million, is that all accumulated from 2Q of this year? Thanks.

Bob Kauffman

So, just a quick answer, yes, the placebo subjects were predominantly 1B.

Jeff Leiden

And Ying, to your question on inventory, it's actually the inventory we built over quite a long period based on our expectations of the market and consistent with how we've communicated on this call. We have seen a change in that market and decline in treatment rates which has resulted with us reserving against potential for excess inventory.

Ying Huang – Barclays Capital

Thanks. And then if I can squeeze one more for Peter. You guys have sufficient toxicology data to support 12 weeks study in human now?

Peter Mueller

Yes, we do. Twelve weeks is all basically ready to go, and as we go forward we will provide actually six months tox data to have longer treatment regimens possibilities if we decided so.

Ying Huang – Barclays Capital

Great. Thanks.

Jeff Leiden

Thanks, Ying.

Operator

Thank you. Our next question is from Brian Abrahams of Wells Fargo Securities. Your line is open.

Brian Abrahams – Wells Fargo Securities

Hi. Thanks for taking my questions, and my congrats as well on the Alios nuke data. Question on the Kalydeco-809 combo, recognizing that the design is still evolving, I was wondering if you could talk about how you might be thinking about inclusion criteria for a Phase III versus a Phase II. I guess I'm just wondering if there's anything you're seeing as you continue to look at the Phase II data that might be suggestive of ways you might further reach the population. And then just on Kalydeco pricing, can you confirm that the ultra-orphan status whether or not with the ultra-orphan status Kalydeco you still need to go through the value assessment processes in Germany and the UK? Thanks.

Peter Mueller

So, Brian, in terms of inclusion and learning something from a Phase II towards Phase III, I think there is a broad population that we will include it. Obviously as we said, first, homozygous and we will not have any particular, let's say, exclusions, and just it's probably for all homozygous delta 508 patients in a certain age group. That's sort of basically what drives the selection of the patients. We have to go with 12 years and older to go on a fast track because that's what we have tested in Phase II. That's the only sort of marker in a way that we have, and then that's the usual selection of people that have sometimes contraindications in terms of their co-medication which they can go, that's normal.

But I think broad population for almost everybody in the age group for 12 years and older. That's sort of what I can say to this process.

Jeff Leiden

Yeah, Brian, in terms of Kalydeco reimbursement in Europe, again, as you know, whether it's orphan or not, it does need to go through the German value process. And you may have seen that recently the UK has been changing its rules around the value process. And we're just talking with the UK about whether we will come under the new rules or the old rules since they're literally changing over the last couple of weeks. So I just can't give you a final answer on that yet.

Brian Abrahams – Wells Fargo Securities

Thanks very much.

Operator

Thank you. Our next question is from David Friedman of Morgan Stanley. Your line is open.

David Friedman – Morgan Stanley

Thanks for taking my question. It's actually just around the R&D. Is there any way that you guys could discuss or in just general buckets what the R&D breakdown is in terms of hep C, CF, basic research and other?

Jeff Leiden No, we haven't actually broken it down that way. And so I think what we said today is that our philosophy, our strategy, if you will, is to reinvest in the most promising late-stage programs and we consider CF, [HC/B] and [JAKB] to be promising programs. We clearly need to continue to invest in research, otherwise we won't have future late-stage programs. And then we take a very, very careful look as we get to proof-of-concept with the earlier development compounds to make sure that we have transformative medicines that we're bringing to the late-stage pipeline.

David Friedman – Morgan Stanley

All right. Thanks.

Operator

Thank you. Our next question is from Katherine Xu of William Blair. Your line is open.

Katherine Xu – William Blair

Great. Good afternoon. I'm just wondering, so if you look at the hep C competitive space, you have Gilead already having a co-formulated double combo going into Phase III in the end of this year. So if you are going to Phase III a year later, are you targeting a profile of a pan-genotypic combo or do you think you can still go with Genotype 1 only combo that your analysis can still be successful?

Jeff Leiden

Yeah, obviously we don't comment on what Gilead is doing, so I can just tell you what our strategy is. And as I said, we plan to test multiple all-oral regimens in Phase II between now and the first half of next year in multiple small studies, and based on both safety and efficacy results, we think that's going to allow us to design a single or multiple pivotal trials which will go in parallel with a high probability of success. Aand we can do that by that end of next year.

Katherine Xu – William Blair

But do you think that'll be a pan-genotypic combo or is that a target profile you're going with, or you're just Genotype 1 only is okay as well?

Bob Kauffman

Katherine, this is Bob. I mean, our initial strategy really is Genotype 1 specific that we still believe is the major unmet need. I think if you look around the world at all the markets and all the various genotype distributions, it still comes out that Genotype is probably still the most valuable proposition.

Katherine Xu – William Blair

Got it. And then a follow-up if I may, for 25 -- is that 18, the other nuke, what is taking so long --

Peter Mueller 2158.

Bob Kauffman

2158.

Katherine Xu – William Blair

2158, thank you. What is taking so long? I'm just curious. I thought both studies were started around the same time. And then what is taking longer for the other one?

Bob Kauffman

It's not so long. Basically the studies -- the 2158 study started about a month later than the 2200 study. Obviously running one program on time is hard, running two programs exactly in parallel is almost impossible. And recruitment has been just a little bit slower than we expected in the countries where it's being run. So we do expect the data sometime in the next couple of months.

Katherine Xu – William Blair

Thank you.

Operator

Thank you. Our next question is from Howard Liang of Leerink Swann. Your line is open.

Howard Liang – Leerink Swann Thanks very much. The Incivo royalties down quarter over quarter, can you give some color where your partner is in European launch and whether we should expect our line to increase over time?

Jeff Leiden

So, hi, this is Ian. As I mentioned in my remarks, we've been -- well, Incivo has now been approved in over 25 countries, in most of the major European countries and certainly in the major countries. So they're at that early stage of launch, a lot of those approvals have been this year. So we'll look to see how they perform in those markets.

Howard Liang – Leerink Swann

Great. And I think you said that you're interested in combining 2200 with other nukes. Would that be with 2158 or other experimental nukes?

Bob Kauffman

This is Bob. Our goal would be potentially to combine 2158 and 2200 together. We haven't really thought of that other nukes at this point. And obviously, we won't know the feasibility of that till we have the 2158 data.

Howard Liang – Leerink Swann

Thank you.

Operator

Thank you. Our next question is from Michael Yee of RBC Capital Markets. Your line is open.

Michael Yee – RBC Capital Markets

Thanks. On 661, I don’t think the answer was fully clear. Can you just better describe the adaptive design? You got a lot questions on that and I'm trying to understand what actually triggers a read-out. Is that safety, is it an efficacy time point? Maybe explain a little bit better, because I thought as you -- it was [dose] question, so the longer it goes, the higher doses you're going at.

Michael Partridge

Michael, this is Michael. I'll just point out that there is a slide in the webcast that has a bit of a graphic that describes kind of how the doses escalate a little bit, and other features in the design. But I'll let Peter...

Okay. So Peter says the slide describes it pretty well.

Michael Yee – RBC Capital Markets

Okay. Then let me ask one last question then. On the 809 combo on Phase III, you said you could look at higher doses. What data do you have to support higher doses? They were never touched on in Phase II. So, just wondering how that's possible in Phase III.

Peter Mueller

We have obviously Phase I data that basically measured exposure levels. And that is linked to safety in humans but also in animals. And that gives us basically, by using PK/PD modeling, the opportunity to select different doses that are within that safety range.

Michael Yee – RBC Capital Markets

Okay, that's helpful. Thanks.

Peter Mueller

And Michael, we'll give you a call and walk you through the slide and describe for you how 661 works. And we find that most of the questions regarding the 661 study is once data are available, and the design will help you understand that the final data will be available in 2013.

Michael Yee – RBC Capital Markets

That's why I asked. Thanks.

Operator

Thank you. We have a question from Ed Tenthoff of Piper Jaffray. Your line is open.

Ed Tenthoff – Piper Jaffray

Thank you very much for taking the question. In first quarter of Kalydeco launch, you said that estimated roughly 60% of patients were, of G551D patients in the US, were on drug. How has that changed in the second quarter? Has that increased, and can you provide what that level is?

Jeff Leiden

Yeah, this is Jeff. As we said on our first quarter call, we are not going to provide numbers of patients going forward. Just to clarify what we said, we said 600 patients in the US at the end of the first quarter. And as I said today, the number has increased, and we anticipate it will continue to increase both as we identify new G551D patients and as G551D patients roll over from PERSIST.

Ed Tenthoff – Piper Jaffray

Great, thanks. And then, for Ian, just real quickly, with the focus of more on R&D, does that change the breakdown in R&D in that $690 million to $760 million guidance that you've given?

Jeff Leiden

The relative weighting of those two remains similar.

Ed Tenthoff – Piper Jaffray

Okay, thanks.

Operator

Thank you. Your next question is from Phil Nadeau of Cowen and Company. Your line is open.

Phil Nadeau – Cowen and Co.

Good afternoon. Thanks for taking my question. Just to, Jeff, at the risk of asking something that you just said you're not going to answer, as you've launched in the US, have you found, or is there anything that has changed your mind on the number of G551D patients in the US? Do you still think that's about 1,100 patients? And a similar question about the four companies you, four countries you mentioned earlier, is 1,000 to 1,100 patients approximately the right number of G551D patients in those four countries?

Jeff Leiden

Yeah, good question, Phil. So in the US, nothing has changed our estimate of 1,000 to 1,100. Our best estimate in Europe is also around 1,000 to 1,100, although I always put the caveat on this, Phil, that, as you know, the genotyping in Europe is not as advanced as it is here and so the precision of the 1,000 to 1,100 in Europe is a little bit less than what we know in the US.

Phil Nadeau – Cowen and Co.

And did you have any compassionate use program in Europe that has enrolled patients? Are there any patients on drug today?

Jeff Leiden

Yeah, there are. We have a program in France that's enrolled some patients as part of an ATU program, and we anticipate those patients will roll over to commercial drug now that it's approved.

Phil Nadeau – Cowen and Co.

Okay. Would you care to tell us how many patients that is?

Jeff Leiden

No. We haven't disclosed how many patients that is. It's a small number.

Phil Nadeau – Cowen and Co.

Okay. Thanks for taking my questions.

Operator

Thank you. Our next question is from Brian Skorney of Breen Murray. Your line is open.

Brian Skorney – Brean Murray

Hey. Good afternoon, guys. Thanks for taking the question, and congrats on the data from the Alios nuke. I guess just to kind of dig in a little bit more on the molecule with the understanding you're not ready to talk about the structure, but just in terms of maybe a little bit of a comparison to the resistance of this drug compared to the other nukes which I think are -- all have the two [meta] nucleoside backbone. I'm just wondering what -- is it a totally different structure than that? And in preclinical studies, have you been able to select for resistance? And what sort of mutations would confer resistance to this drug? Thanks.

Bob Kauffman

This is Bob. I really can't talk at all about the structures. I will just say that these compounds have a very high barrier to resistance and therefore, are excellent combinations for other drugs, much like the other nukes that have been described.

Brian Skorney – Brean Murray

Thanks.

Bob Kauffman

There will be a bit more detail coming out at a medical conference later on, on some of these issues.

Brian Skorney – Brean Murray

Okay. I'll wait for them.

Bob Kauffman

Okay.

Michael Yee – RBC Capital Markets

Operator, this is Michael. We're now about 10 minutes past our planned stop time for the call, so in the interest of everybody's time we will take just two more questions. Thanks.

Operator

Thank you. Our next question is from Ravi Mehrotra of Credit Suisse. Your line is open.

Unidentified Participant

Hi. Congrats on the data. This is actually [Kuhn] calling on behalf of Ravi. I just had a quick question regarding your -- one of the trials for the Alios nukes which is the -- with ribavirin. I just wanted to know if there was anything in the data that you'd seen that would suggest that your nuke with ribavirin might give you better results than what we've seen so far. Thanks.

Bob Kauffman

This is Bob. That's obviously why we're going to do the study, is to find out. Clearly, the properties that we've seen so far, very high level of antiviral activity would make it potentially a good companion with ribavirin. As I said, both efficacy wise and safety wise we think it's a good trial to do.

Unidentified Participant

Okay. Thanks.

Peter Mueller

The other things that's impressive what we said in the call is it had a very steep decline from a viral kinetic point of view, is 3.85 log drop in three days, which is a good indicator that you might have a good chance for a combination and good trial outcome at the end of the day.

Operator

Thank you. Our next question, final question, is from Alan Carr of Needham & Company. Your line is open.

Alan Carr – Needham & Co.

Hi, thanks for taking my question. Any sense of off-label use, other genotypes, patients using Kalydeco? Thanks.

Jeff Leiden

Yeah, this is Jeff. As you know, Alan, we only promote Kalydeco for labeled indication, which is G551D greater than six, and we don't track or keep track of any off-label use. So I really don't have any data on off-label use.

Alan Carr – Needham & Co.

Thanks.

Michael Partridge

So, thanks very much, everybody, for joining us tonight. I think everybody got to ask at least one question. If you didn't get your follow-up or you have additional questions, we're in the office, happy to talk further tonight. Thanks very much for tuning in.

Operator

Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may now disconnect. Have a wonderful day.

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