Amicus Therapeutics Inc (FOLD) 2011 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Amicus Therapeutics fourth-quarter and full-year 2011 results conference call. At this time all participants are in a listen-only mode. Later we will conduct a question-and-answer session with instructions following at that time.

(Operator Instructions)

As a reminder, this conference call is being recorded. Now I'll turn the conference over to Sara Pellegrino, of Investor Relations for Amicus. Please begin.

Good afternoon, and thank you for joining our conference call to discuss our fourth-quarter and full-year 2011 financial results. Speaking on today's call, we have John Crowley, our Chairman and Chief Executive Officer; Bradley Campbell, our Chief Business Officer; and Daphne Quimi, our Corporate Controller. They are joined by Pol Boudes, our Chief Medical Officer, and David Lockhart, our Chief Scientific Officer, who are available to participate in the Q&A session.

As a reminder this conference call will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 relating to the business operations and financial condition of Amicus, including but not limited to, pre-clinical and clinical development of Amicus candidate drug products, the timing and reporting of results from pre-clinical studies and clinical trials evaluating Amicus candidate drug products, and the projected cash position of the Company. Words such as, but not limited to, believe, expect, anticipate, estimate, intend, likely, should, and could, and similar expressions are words identifying forward-looking statements. Although Amicus believes the expectations reflected in such forward-looking statements are based upon reasonable assumptions, there can be no assurance that its expectations will be realized. Actual results could differ materially from those projected in Amicus' forward-looking statements due to numerous known and unknown risks and uncertainties, including the risk factors described in our annual report on Form 10-K for the year ended December 31, 2010, and other public filings with the Securities and Exchange Commission. Amicus does not undertake any obligation to publicly update any forward-looking statements to reflect events or circumstances after the date on which any such statement is made or to reflect the occurrence of unanticipated events. At this time, it is my pleasure to turn the call over to John Crowley, Chairman and Chief Executive Officer of Amicus.

Great, thank you, Sara. Good evening everybody. We are indeed off to a great start in 2012. I think a lot of that going back just over the last several weeks, at and around the JPMorgan conference with the release of some of the data with the combination, even proof of concept, Study in 013. I think, though, as we think about the strong start to 2012 with some of the new data, the new strategy that we have articulated, you can look back to 2011.

And if I can, I'd like to begin just for a moment and reflect back on what we did in 2011 that we think lays such a strong foundation for 2012. Of course one of the primary drivers of value for shareholders at Amicus is our Fabry program with the migalastat and with that the 011 Study for monotherapy approval of the drug. Enrollment of that study into and through the end of 2011 was a critical part of our success both in building relationships and bridges with the physician community in addition to providing the success hopefully as we look to data in Q3 of 2012 for that program. So enrollment in 011 very important. Likewise we've laid the foundation for 012 and 013, two separate studies that we'll be talking about on this call, as well, together with continuing pre-clinical work to further strengthen the program for migalastat for Fabry as well as the broad technology here at Amicus.

In 2011 we also continued to build upon the deal that we had signed at the end of 2010 with GSK Rare Diseases. 2011 was a terrific year in building on that working partnership that we strengthened and advanced with our partners at GSK. And in addition, we spent a lot of time, and I've had a chance to talk to a lot of you over the last few months about the work that our Management team and our Board did at Amicus in taking the data that we were gathering, looking at the value that we planned to create at Amicus and thinking about from a strategic standpoint, where do we want to invest our capital going forward. So doing all the work around that strategic plan and then putting it in place at the end of 2011, beginning of 2012, was a critical part of the foundation that we laid in 2011.

Let me talk a little bit about the 011 Study. I'd like to update you little bit on that Phase III global registration study. Again, this is for migalastat as a monotherapy for Fabry disease together with our collaborator, GSK. We reiterate here today that we anticipate announcing results from this Phase III Study, the 011 Study, also known as our FACETS Study in the third quarter of this year. We have talked and we began this year talking about the confidence that we have in the 011 Study, a couple of different points to reiterate together with some new information here. One is the Phase II experience. Again, this is a drug that's been through several years and continues with an extension study in Phase II, more than 90 patient years of experience with migalastat. 17 patients continuing on therapy with migalastat as the only monotherapy for their Fabry disease. Again, we've previously seen positive results on both renal and urine GL3 clearance, again GL3 clearance in urine being a key biomarker in Fabry disease. And in terms of Phase II experience, we've also seen long-term trends towards stabilization of kidney function.

One other important area of confidence for us is the strict entry criteria for all of these patients with Fabry disease. In our Phase III Study, they have to have been naive to ERT or had no ERT in the last six months. They have to have amenable mutation to respond to the migalastat as a monotherapy. And we further enriched the population for study purposes by requiring that every patient in this study have a urine GL3 level at or above four times the upper level of normal. We've also used another area of confidence in this study as an improved histological methodology, that's the use of the BLISS methodology, a more advanced, sensitive, and objective measure of the inclusion bodies, a methodology developed by Dr. Barisoni, a close collaborator with our team at Amicus and GSK. And then also what we've observed in Phase III to date.

We do have some new numbers to update you on. We had previously indicated of course 67 patients enrolled in this study. We now know that 45 patients to date have completed the six-month primary treatment arm. We know that all 45 of those patients have elected to continue into a six-month treatment extension. So for those patients who had been randomized to migalastat, they continued on migalastat. For those patients in the placebo arm for the first six months, they crossed over and entered the migalastat treatment. So 67 enrolled, 45 having completed the six-month treatment period. All 45 electing to go into the six-month treatment arm.

As we sit here today, we have now had 28 people complete at least a year of study, six months primary treatment and six months extension. Of those 28, we know that all 28 have elected to go into the open-label extension study after one year in study. Of those 28, 26 continue ongoing. And as I indicated at the JPMorgan conference, again, those are the two patients who didn't elect to continue past that one year of treatment withdrew for personal reasons, not drug-related reasons. So we think that bodes well for 011 Study, and we'll continue to provide updates as necessary.

We also in reference to patient disposition, we know we have updates on how we got to the 67 people in this study. Many of you were at the WORLD Conference for Lysosomal Disease Scientific Symposium in San Diego last week. We presented, Dr. Bichet, on Amicus' behalf presented some data regarding the screening of patients into the study. I'll reiterate that here. Again, we screened a total of 180 patients at 37 sites on 5 different continents to enroll the 67 patients meeting all of the entry criteria. Again, exceeding our original target of 60. Again, at WORLD last week, Dr, Bichet presented information on the first 140 patients screened in the Study 011. The data was as of July of 2011. And Dr. Bichet showed that a majority of the subjects who presented had missense mutations, and that a majority of these missense mutations were amenable to migalastat monotherapy and that they were potentially eligible for Study 011. So again, we think that's terrific news in terms of what we've learned about this study, in terms of screening, potential patient populations who might be available, and again, we continue to believe that 40% to 50% of people living with Fabry disease could be amenable to migalastat as a monotherapy for the treatment of their Fabry disease.

Moving to Study 012 and 013, I'll turn it over to Brad for more color here, Brad Campbell. Before I do that, just to remind people, the 012 Study is also a Phase III Study with migalastat, it will satisfy our US Phase IV commitment as well as a commitment for approval with the EMEA and Europe. This is a 50 patient study with a 2-1 randomization, migalastat to people remaining on enzyme therapy, either Fabrazyme or Replagal. It is an 18-month study where the primary end point is looking at noninferiority of people switching to migalastat compared to people remaining on ERT in terms of kidney function, as measured by estimated GFR. And that study is currently enrolling throughout the course of this year.

And then our 013 Study again, a very important part of Amicus as we go forward in that leveraging the chaperone technology. We believe to address potentially many of the deficiencies with the enzyme replacement therapies including protein and stability and the immunogenicity brought on by many of these ERTs. So a very important study for us. Brad will talk more about what we've learned to date and what some of the plans are going forward. With that, let me turn the call over to Bradley Campbell, who is our Chief Business Officer.

Great, thanks John. Hello, everybody. Before I get into the details of the chaperone ERT combination programs, I'd just like to echo John's excitement about our Phase III Fabry program and the significant opportunity that we believe exists for migalastat as a monotherapy. We're all eagerly anticipating the results of a study that we hope could lead to an important new treatment option for a number of Fabry patients.

With that, let me shift gears to our chaperone ERT combination platform. Right now we're evaluating several chaperone ERT combinations in Phase II studies in Fabry and Pompe and pre-clinical studies in Gaucher and other undisclosed LSD's where we believe there's a significant opportunity to improve current ERT products. As a reminder, as part of our Fabry collaboration with GSK, we're developing migalastat as a monotherapy in combination with ERT. However, outside the Fabry program, we own exclusive rights to all of our other assets.

As we've described before when co-administered with ERT, pharmacological chaperones are designed to bind to and stabilize the infused recombinant enzyme in the circulation of patients on ERT regardless of their mutation type. Pre-clinical chaperone ERT co-administration studies in animal models of Fabry, Pompe, and Gaucher have all shown that a pharmacological chaperone can selectively bind to and stabilize the enzyme, prevent deactivation in the circulation and increase uptake of active enzyme into key tissues of disease. In addition, in Fabry and Pompe animal models, we've shown that this increased activity and tissue uptake have led to greater substrate reduction than ERT alone.

Based on these pre-clinical data that we've generated so far, we're conducting two Phase II open-label studies, one for Fabry and one for Pompe to evaluate our first two chaperone ERT combinations in the clinic. Patients in each study will be compared to themselves at two subsequent ERT infusions, ERT alone followed by ERT co-administered with a single oral dose of the chaperone. Both studies are designed to evaluate safety and whether the presence of a chaperone can increase active enzyme in plasma and in key tissues, skin for Fabry patients and muscle for Pompe patients, compared to ERT alone.

As a reminder, in January and again last week at the LDN WORLD symposium we presented positive preliminary results from Study 013 which is the Phase II co-administration study for Fabry. These data describe the first 7 patients in Study 013, who received either full- or half-dose Fabrazyme co-administered with migalastat at 150 milligrams. We're very encouraged to see that co-administration increased the uptake of active enzyme in plasma and skin versus Fabrazyme alone and that the magnitude of these increases was consistent with what we saw in Fabry and knockout mice in pre-clinical studies. As John mentioned, Paul and David are on the call today. We can walk you through additional details during the Q&A session. But I will note that from a timing perspective, we expect to complete the study in the first half of this year. Final study results will include migalastat at oral doses at 150 milligrams and 450 milligrams, co-administered with half- and full-dose Fabrazyme as well as Replagal.

So following closely behind Study 013 is our Phase II Pompe Study 010, which is investigating ERT co-administered with four different doses of AT2220 in approximately 16 male or female Pompe patients. Preliminary results from this study are anticipated during the first half of the year. And given the challenges that still exist for Pompe patients on ERT, many of which were highlighted at the WORLD symposium last week, we believe our chaperone ERT combination approach has the potential to address several of these limitations. For example, formation of antibodies in Pompe patients undergoing ERT infusions is believed to adversely affect both the safety and efficacy of alglucosidase alfa over time, causing some patients to withdraw from treatment. Pre-clinical results to date suggest that AT2220 when co-administered with ERT may mitigate the immunogenicity induced by the ERT for Pompe disease. Importantly these pre-clinical findings form the basis for a grant that was awarded to Amicus by the Muscular Dystrophy Association which will support our further investigation of the effect of AT2220 on ERT-specific immunogenicity this year.

In addition to our Phase II combination programs in Fabry and Pompe, we've also conducted pre-clinical studies of two pharmacological chaperones, AT2101 and AT3375, in combination with ERT in animal models of Gaucher disease. So as a reminder, AT3375 is our next generation chaperone targeting the GCase enzyme deficient in Gaucher disease and it was designed to improve upon the properties of AT2101. Mutations in the GBA1 gene that encodes for GCase enzyme are the most common genetic risk factor known for Parkinson's Disease. Therefore in addition to conducting further pre-clinical studies of AT3375 co-administered with ERT, given its ability to cross the blood-brain barrier and other properties, we're also continuing to investigate AT3375 as a monotherapy for Parkinson's Disease in Gaucher patients and Gaucher carriers and potentially the broader Parkinson's population, as well. By the end of 2012 we expect to complete pre-clinical and IND-enabling studies of AT3375 which are funded in part by a grant the Michael J. Fox Foundation. Also of note, the Fox Foundation recently announced that during the first quarter of 2012, Amicus will be one of the initial awardees to have a project featured as part of their partnering program which is designed to proactively showcase promising research results in the Fox Foundation's portfolio for funders who may wish to invest in their continued development. Now that we've gone over some of the highlights of our development programs, I'll turn the call over to Daphne Quimi, who is our Corporate Controller, who will review the financial results for the fourth quarter and full year 2011. Daphne?

Thanks Bradley, and good afternoon, everyone. Before I turn to the fourth-quarter 2011 and full-year financial results, I will quickly comment on our cash position and reiterate the full-year 2012 financial guidance that we announced during the JPMorgan conference in January. Cash, cash equivalents, and marketable securities total $56 million at December 31, 2011, and $60 million at the beginning of 2012, compared to $70 million at September 30, 2011, and $107 million at December 31, 2010. We anticipate that our current cash position will be sufficient to fund operations into the middle of the third quarter of 2013. This projection includes anticipated Fabry program reimbursements and development milestones but excludes potential regulatory milestones under our agreement with GSK. As a reminder, we are eligible to receive up to $170 million in development, regulatory, and commercial milestones, as well as tiered double-digit royalties on global sales of migalastat. We expect full-year 2012 operating expenses to total $37 million to $43 million, net of anticipated cost sharing and milestones related to the GSK collaboration.

Turning to the financial results, I will be referring to table one in our press release which is available on our corporate web site at www.amicustherapeutics.com. Additional details can also be found in our Form 10-K to be filed in the next few weeks. Total revenue was $5.6 million in the fourth quarter of 2011 compared to $0.9 million in the prior-year period. For the full year 2011 total revenue was $21.4 million compared to $0.9 million in full year 2010. Our total revenue consists of research and collaboration revenues recognized under our collaboration with GSK from migalastat. Research revenue reflects reimbursement from GSK related to our agreement to share total development costs for migalastat. Amicus and GSK equally share development costs for migalastat in 2011 and GSK will be responsible for 75% of these costs in 2012 and beyond, subject to annual and aggregate caps. Each quarter GSK reimburses us for the portion of our actual spend that exceeds our obligations. Amicus and GSK reconcile each party spend for the migalastat program on a quarterly basis to ensure that costs are shared in accordance with this arrangement.

Research revenue for the fourth quarter of 2011 was $4 million compared to $4.1 million in the third quarter of 2011. Quarter-over-quarter, GSK incurred a higher percentage of total migalastat costs relative to Amicus. So we were reimbursed at a lower amount. Research revenue is expected to fluctuate quarter-to-quarter relative to our proportion of total migalastat expenses and the percentage we're responsible for paying under the agreement. As of December 31, 2011, we have recognized a total of $14.8 million as research revenue under the GSK agreement. Collaboration revenue for the fourth quarter of 2011 was $1.7 million and reflected the recognized portion of the $33.2 million up-front payment received from GSK upon signing the agreement. The total up-front consideration consisting of a $30 million license fee and a $3.2 million premium on GSK's equities investment is being recognized on a straight-line basis. As of December 31, 2011, we have recognized a total of $7.5 million of the GSK up-front payment as collaboration revenue since the inception of the agreement.

Total operating expenses in the fourth quarter of 2011 were $18.7 million, an increase from $17.5 million in the prior-year period due to higher research and development expenses. For the full year 2011, total operating expenses were $72.3 million compared to $56.8 million for the full year 2010, primarily as a result of higher expenses for research and development as well as one-time stock-based compensation expense and severance items. Net of cost sharing related to the GSK agreement, full-year 2011 operating expenses of $47.2 million were below our projected guidance range of $50 million to $55 million.

Research and development or R&D expenses were $14.4 million in the fourth quarter, including $800,000 of stock-based compensation expense. Compared to $13.2 million in R&D expenses, including $700,000 of stock-based compensation expense in the prior-year period. Full-year R&D expenses were $50.9 million, including $2.9 million of stock-based compensation expense, compared to $39 million in R&D expenses, including $2.6 million stock-based compensation expense for the full year of 2010. The increases in the fourth-quarter and full-year 2011 R&D expenses were primarily as a result of higher contract research and manufacturing costs within the Fabry program.

General and administrative or G&A expenses for the fourth quarter of 2011 were $3.9 million, including $700,000 of stock-based compensation expense, compared to G&A expenses of $3.8 million, including $800,000 stock-based compensation expense in the prior period. The increase in the fourth quarter was primarily due to increased recruiting costs and professional fees. G&A expenses for the full year 2011 were $19.9 million, including $5.8 million of stock-based compensation expense, compared to G&A expenses of $15.7 million including $3.6 million of stock-based compensation expense in the prior period. The increase corresponds to an additional stock option compensation expense to modify the term of our Chief Executive Officer's stock option grants in connection with his amended employment agreement, and the stock-based compensation expense and severance payment incurred with the departure of our former President in August, 2011. Net interest for the fourth quarter of 2011 consisted of net interest expense of $3,000 compared to net interest expense of $22,000 in the comparable quarter last year. Net interest for the full year 2011 consisted of net interest income of $12,000 compared to net-interest expense of $104,000 for the full year of 2010. Lower net-interest expense during the fourth quarter and full year 2011 were due to less outstanding debt on our secured loan.

For the fourth quarter of 2011, we reported a nonoperating gain of $742,000 related to the change in the fair value of our warrant liability compared to a loss of $946,000 for the change in the fair value of our warrant liability during the fourth quarter of last year. For the full year 2011, we reported a nonoperating gain of $2.8 million related to the change in the fair value of our warrant liability, compared to a loss of $1.4 million for the change in the fair value of our warrant liability during the prior-year full period. Warrants issued in connection with our March 2010 registered direct offering of common stock were recorded as a liability at their fair value on the issuance date. The fair value of these warrants increased or decreased with the change in our stock price, and we report the change at each reporting date until these warrants are exercised or expire. Net loss attributable to common stockholders for the three months ended December 31, 2011, was $8.7 million or $0.25 per share, compared to a net loss of $15.1 million or $0.48 per share for the same period in 2010. Weighted average common shares outstanding were $34.6 million and $31.3 million for the three months ended December 31, 2011, and December 31, 2010, respectively. Net loss attributable to common stockholders for the 12 months ended December 31, 2011, was $44.4 million or $1.28 per share compared to a net loss of $54.9 million or $1.98 per share, for the same period in 2010. Weighted average common shares outstanding were 34.6 million and 27.7 million for the 12 months ended December 31, 2011, and December 31, 2010, respectively.

This summarizes our key financials for the fourth quarter and full year 2011. I will also be available to answer questions during the Q&A session of this call. With that I turn things back to John.

Great. Thank you, Daphne. Hopefully everybody can see that there's a lot of excitement here at Amicus building for all of our programs and the advancement of the technology. We've seen a great appreciation in our equity over the last month, and that's certainly a good thing and hopefully representative of a lot of the great work being done here at Amicus. But we've got much, much more work to do through the course of this year. Through 2012, we will deliver some very important clinical as well as pre-clinical data on multiple of our programs. But we'll also be providing continued dialogue with the investment community and continued perspective on our strategies for how we'll leverage our technology and our programs going forward. In every case with the same goal, and that's to develop therapies for people living with these rare diseases. So with that, we'll turn it back and happy to take your questions.

Thank you, ladies and gentlemen.

(Operator Instructions)

Ritu Baral, Canaccord.

Hi, everyone. Thanks for taking the question. I wanted to ask about the combo therapy programs, both Fabry and Pompe and sort of how they relate to each other. We are getting -- I'm assuming based on the timeline, Fabry's data, additional Fabry's data first. Could you talk to the read-through that we should get from the Fabry's program to Pompe's and how the two enzyme therapies compare and contrast and how the chaperone benefit to either ERT should compare and contrast.

I think there were multiple questions there. As a prior litigator I probably should have objected to the question in principal. I will try to answer it as best I can and certainly ask David or Pol to weigh in, as well. I think if you step back and think it, what we're talking about here is several fundamental limitations of these first generation therapies. So enzyme replacement therapies have been around for several decades. They've offered enormous benefit for a lot of patients. We've seen in different diseases different levels of efficacy for sure.

If you take it to what we're doing in Fabry and what we're doing in Pompe disease, obviously two different diseases, two different enzymes. But the same fundamental problem in that you're taking large amounts of protein made in bioreactors in multi-hour infusions and taking from a lyophilized powder, reconstituting it into an infusion bag, and putting enormous amounts of protein then into infusion bag and into patient from plasma and hoping then through the whole process of receptor-mediated endocytosis that it ends up getting taken up into the lysosome of target tissues. The challenge is several fold with the ERTs. One is primarily that the enzymes that we're dealing with are enzymes that we all without disease naturally make and that live in the lysosome. The lysosome pH is more like 5, a highly acidified compartment. When you are putting it in the bag at neutral pH, at 6, 6.5 or so, then when it hits the plasma at pH 7.3 they become very, very unstable proteins. They lose a tremendous amount of their activity, they not only become less potent, we think as you're seeing them begin to unfold and come apart in infusion bag as well as in plasma that you're actually seeing a heightened level of immunogenicity that's attributed to this whole phenomenon.

We think we have a very unique tool set to address that in that using a small molecule to bind to the active site of the ERT promotes its conformational stability, essentially keeps it bound, active, and stable so that you have a much more potent enzyme. By doing that we think we have the potential to dramatically reduce the immune profile of these ERTs. We're looking at this as both a co-administration like we're doing now in the clinic in Pompe and Fabry, but also considering in pre clinical studies the direct co-formulation, actually mixing the chaperones directly with the ERTs. So again, we see this along a continuum of development. If you look at what we've proved in these first six patients and the data that we've seen is strong proof of concepts that a small molecule that's orally bio available on board in plasma can stabilize an ERT product. We've seen that now with a 150 milligram low dose of migalastat with Fabrazyme. We have more work to do and as you've alluded to Ritu, by the middle part of this year we'll have additional preliminary data with Replagal. And then also we need to look at the higher dose of migalastat, as we're now exploring in the clinic, the 450 milligram dose with Fabrazyme. Important proof of concept for the potential expansion of this molecule and its use in direct administration with the enzyme therapies in Fabry.

But we do think there is a spillover effect in terms of the broad proof of concept of using these molecules directly with ERT. That's where we become even more hopeful that this could be a potential therapeutic option in Pompe. As you know, we're in the clinic with our AT2220 chaperone for the Pompe enzyme. Patients are currently being treated. We have not seen any of the data. We'll be able to report that data by the middle part this year, though. And again, we think that will be further proof of concept, not just for that specific drug program which, again, we own completely. It's not partnered with GSK, but we think even further validation for the broad use of this technology. So hopefully that's not too long of an answer to several of your questions.

Sure. And do you see alpha glucosidase as being more immunogenetic than galactosidase and the interaction between 2220 and glucosidase, are there lessons to be learned from migalastat and the Fabry enzyme?

It seems from the literature and from talking to physicians, and in our experience, the Fabry ERTs seem to be less immunogenic than Pompe. But still you see immune responses in virtually all patients in Fabry disease. We do think the immunology of the ERT and the immunogenictiy of any of the currently marketed ERTs could be a very important factor in terms of the therapeutic efficacy. Again, we'll have to explore that in the clinic and see what impact we can have. We're, obviously from what we've seen and from what others have seen, the Pompe enzyme, the myozyme, lumizyme market seems to be very, very immunogenic. They do have a black box warning, there was anaphylaxis associated with them in the clinical studies. But even more so, we think that some of the immune response that you're seeing actually impedes therapeutic efficacy due to the immune response created by this unfolded, unstable enzyme in blood. That was part of the grant that we were just given from the MDA that Brad referred to. We're going to explore that, and again I think that will be part of the important pre clinical data that we'll have this year as well as the clinical data from the 010 Study. If there's an area where we think we can have an impact in Pompe, I think it's twofold. I think the protein potency as well as the immunogenicity, so we'll continue to explore those.

One more question and I'll hop back in the queue. 012 enrollment. Are there lessons learned from the FACET Study? Do you see it being more efficient, you seem to have given it sort of shorter timelines than what we experienced with FACET?

Yes, it's a little bit smaller study. It's a 50-patient study. There are no biopsies, so I think that helps a great deal in terms of patient interest getting into the study. You know, there is no placebo arm. I think that's important. People will either stay on ERT or go on to our drugs. So I think all those weigh in favor. And then yes, we've learned a lot, and we've built a lot of relationships.

One of our key learnings is to enroll studies with the right patients, you have to screen a lot of patients and to do that, you have to open a lot of clinical site. We're well on the path in the 012 Study. If you remember, when we did the 011 Study, we did that prior to the GSK relationship. 012 really got up and going last year. And we've done a lot of that work together with GSK. So in a lot of the geographies, where we might not have a strong presence we're seeing great participation from our partners at GSK helping us make sure we can have the right reach globally.

Great. Thanks.

Joseph Schwartz, Leerink Swann.

Hi, thank you. There was some striking data on the deleterious effects of immunogenicity at WORLD in areas like Pompe. I'm wondering when will we be able to get some data on your ability to sero revert I guess or how do you expect to study the ability of the chaperone technology to translate the improved denaturation profile and serum half life on antibodies?

I think, you know, we're looking at -- I'll ask David and Pol to add some color, as well, Joe. But again, we're looking at that with continued pre clinical work. So a lot of the work that we're doing with the MDA grant and the data that will be generated through this year will characterize the immunogenicity of myozyme, lumizyme products and also what we might be able to do to mitigate that specifically with the addition of our drug. There are a number of ongoing pre clinical studies at Amicus, and we hope to have more of that data through the year to talk about what we might be able to do to mitigate that response. The 010 Study, just to remind you, of course, is a short-term PK/PD Study. Although we'll evaluate some of the potential immunogenicity involved. In a short-term study we wouldn't expect to see that we'd have any changes there. And Pol, David, if you have color to add, please --

Joe, the -- one of the key measurements in pre clinical studies is you can look at a t-cell response in human t-cells. So we'll be doing that over the course this year, and that is part of the muscular dystrophy grant. As John said in this first -- in the first clinical study since it's only a single delivery of the small molecule in combination with the ERT, we don't expect to see anything in particular reducing the antibody titers. In the next set of studies where we have longer term treatment, we'll be able to see if patients who start with a measurable antibody titer can show a reduction with time. So that just requires the repeat dosing studies that will be coming after this first single dose study.

Okay. Great. That's very helpful, thanks. As a followup, how do you envision the regulatory pathway for combination therapy? Would it have similar end points do you think as monotherapy but you just want to show an effect on top of ERT, or is there some other potential way to bring it to market?

You know, we are looking at other potential avenues in terms of broadening the label, Joe. We do think that the monotherapy program for migalastat will be the foundation for the launch. We can envision multiple different ways to move very quickly from this PK/PD Phase II Study, the 013 Study, to a confirmatory Phase III Study. In every case what we want to be able to show is that the addition of the chaperone provides a better benefit for patients, that essentially superiority over ERT alone. And there may be different ways that we can measure that. It may include some of the end points that we've used before. Things like GL3, we think that could be a study that, a urine GL3 input in a short-term study could be particular appropriate. We will also look at other potential end points including ones related to immunogenicity which may end up be approvable end points potentially.

Okay. Great. Thanks again.

You bet.

Jeff Meacham, JPMorgan.

Hi, this is Anupam Rama, in for Jeff Meacham. Just a quick question. In the female patient study at WORLD, there were a few patients that showed improvement in left ventricular mass. Could you just kind of help us understand that improvement and put it into context as to what that means for Fabry patients and are there certain mutations that are associated with left ventricular mass? Thanks.

Yes, David, do you want to comment? Then I'll ask Pol to follow up with any other thoughts.

It just -- to point out that cardiac abnormalities are very common in Fabry disease. It's a whole host of different abnormalities. And of course being able to see some normal --even some normalization of any of those would be a very positive sign. I'm not -- we shouldn't over interpret what we've seen so far. But we do find it encouraging whenever there's any normalization of an abnormality in any of the key organs of disease. So I think that it's interesting, but we do have to be careful not to overstate that quite yet.

Great. Thanks for taking our question.

Okay, you bet. Thanks, Anupam.

(Operator Instructions)

Ritu Baral, Canaccord.

Hi, guys. Of course I have a follow-up question.

Of course.

Going back to the WORLD data, we also saw some interesting Fabry's incidents and prevalence data. Can you tell us what you think about sort of the much, much higher incidence rates seen in some of the infant screening studies presented at the conference versus sort of what's generally accepted as prevalence?

Yes, if you look at the textbook literature, Ritu, it says that the incidence of Fabry is about one in 40,000 or 50,000 and that there are 5,000-plus people in the developed world. That characterizes I think the classical early onset form of the disease, the disease, for instance, that Genzyme studied, that segment of the disease in its confirmatory studies almost a decade ago for Fabrazyme. But if you really look at it, it's like many genetic diseases, where there is a broad spectrum of symptoms and a broad spectrum of onset of disease. I think what these epidemiology studies and screening studies are showing is that Fabry is indeed a much, much more prevalent disorder than people had traditionally thought. The studies that were presented at World showed I think one -- the one from the Illinois screening showed a one in 1,700 incidence. Others that have been published from Taiwan and other geographies over the last couple of years have shown one in 3,000, one in 4,000. Which make this much more akin to the prevalence you see in something like a Duchenne muscular dystrophy or cystic fibrosis. If those continue to play out, it could end up being that Fabry together with CF and a few others is among the most prevalent human genetic disorders out there.

You're starting to see Fabry diagnosed in cardiac clinics, and there was some presentations about that at World, where people have never suspected Fabry before. People with undiagnosed left ventricular hypertrophies for instance, other cardio myopathies. You're seeing it in renal clinics where people are finding Fabry where they have never looked for it before. Again, this is a phenomenon and a series of studies that's been developed over the last couple of years. It's one that Amicus and GSK are very much interested in. Particularly because many of these studies have shown that the ability to find this Fabry disease in people at such an early stage usually translates with these people having a late -- what's traditionally thought to be a late onset form of the disease. Where they would be symptomatic at certain points in their life, but they would have the pathology of disease throughout their life. And many, many of those mutations, a clear majority, seem to be the type of mutations that would be amenable to chaperone monotherapy. It's something we're very, very interested in.

As far as the screening programs and potential increased diagnosis, how -- how do you see that impacting the Fabry market as far as timing? And do you see that sort of kicking in the next couple of years? Is it more of a 5-year process or a 10-year process?

You know, I couldn't tell you exactly how long it would be, Ritu. It's something we've -- we have been thinking about even prior to the WORLD meeting with GSK for sure. Others, I mean, Shire, Genzyme has done a very good jobs at beginning to explore some of those other potential patient populations. As we look at our forecast internally, we've been very conservative about what the chaperone monotherapy population could be. Again, whatever that number is, we still believe that migalastat is appropriate for 40% to 50% of people with Fabry. I think as more and more people are diagnosed, if it really is that prevalent of a disease, finding them earlier is only going to be a good thing. And having an option of a therapy like migalastat is only going to be a good thing.

And final question. Looking at the responsiveness rates in the WORLD data that you guys presented, with the assumption that there is some selection bias in those 80% and 85% figures, how much of it do you think is patients, say, in the US or Europe who already know what their mutation is, and whether they're missense or whether they're on your sort of list of responsive mutations? I mean, do most Fabry patients know their exact mutation, and where they fall on your responsiveness charts?

I want to make sure I understand your -- you mean in terms of the -- how they got into the study?

Yes. As far as screening dynamics --

Yes.

From what I understand, many at least US Fabry patients know their exact mutation and can look on one of the many charts that you've provided to the Fabry community and say, oh, I'm responsive, I should enter. But at the same time, you're finding new mutations. So I'm just sort of wondering how that dynamic shakes out both as far as known and unknown mutations, as well as US and ex-US.

I think it shifted a bit in a favorable direction, Ritu. We don't mean to imply that because of this screening study you can extrapolate that to say that 80% plus of people could be amenable to the chaperone as the monotherapy. I think there was some selection bias where people, whether patients or the physician knew that the Amicus Phase II Study had been successful in people with missense mutations broadly. And that certain like the R301Q are a little more prevalent in Fabry patients. So some of those patients very well may have presented knowing some of that.

But I can tell you, and Dr. Bichet went through this in his presentation. Again, we have quite a range of mutations presented in this study. Of the 67 patients, there are 59 unique missense mutations that are confirmed, and 13 of those were newly discovered mutations. And in a lot of the geographies outside of the United States, and again, a majority of these patients are outside the US, people presented not knowing at all what their mutations are. I think as we look at this, as we try to be conservative, discounting some of these numbers for some preselection bias, we still are very comfortable with our prediction that roughly half of people living with Fabry will be amenable to the chaperone as a monotherapy.

But I think -- this is Brad. I think your logic initially is probably right, that in general in the US and Europe and probably Japan there's a little bit more awareness of mutation type either by the patient or physician. And as you go to the more developing countries, that's less true. Not a perfect correlation, but as John said, we think the numbers will still hold. And then as you get into the newborn screening and other kinds of high-risk screening populations, if we do uncover those more late onset types of mutations, then you'd expect that number to go up over time.

And Ritu, it wasn't -- it clearly wasn't complete preselection either. There were, out of the first 140, there were 13 mutations that were completely new, they had never even been reported before. And they were ones that we had never seen, we had never tested. And once we knew -- once we got the information, then we tested them. But the patient actually brought the mutation in the door for the first time before it was even known to us. And there were also more than 20 patients in that first 140 who did not have missense mutations. It wasn't even just a selection for people with known -- who were known to have a missense mutation as a fair number who were screened did not even have missense mutations or did not have single missense mutations.

Great, thanks for the color, guys.

You bet.

Bill Tanner, Lazard Capital.

Thank you for taking the question. John, for you, on the 011 Study, I know the inclusion criteria, either ERT naive, or not having been treated for six months prior. I'm wondering if you can make any comments as to which are most of the patients truly naive or have they just not been treated? And I have a followup.

You know, I have to follow up with you, Bill. I don't have the exact split. I could tell you that we saw in Phase II that it was about a split between previously naive and people who had been off for a period of time. In this study given that a lot of the patients came from outside the United States, I'm pretty sure that the majority of them had not been on ERT. Pol?

Yes, that's right.

That's correct. So a majority of the patients had never been on ERT. I don't have the exact numbers for you, Bill, but we can get that.

I'm sorry.

I was going to say with the shortage, I would be careful to draw too many conclusions there because that just sort of confounded the background of what the patients were going through.

And then how should we just think about the severity of the disease for the patient that are enrolled? I mean, I guess the most obvious inference of patients wanting to stay on in the open label or the extension part is that it's working or they feel good or both I guess. Just -- curious on the severity of it in -- that their disease in terms of really needing to be in therapy such as someone who would have been on Replagal or Fabrazyme and had to get off, well, I guess Fabrazyme because of the shortage and really needed the ERT.

No, absolutely. Two things that are really important about this study, one is that it is the largest Fabry disease study, pivotal study ever conducted with 67 patients. And the second thing more relevant to your comment, Bill, is that what we're studying is a true representation of the spectrum of patients living with Fabry disease. And we have a couple of dozen males in the study, we have females. It's important especially given that the population consists of a significant number of females. We have many, many patients in this study who would be considered at the severe end of Fabry disease in terms of their symptoms. In every case a patient is certainly symptomatic. They have Fabry disease. And because we put in that GL3 criteria, that they have to have at least four times the upper limit of normal to get in the study, there's not a straight correlation between the urine GL3 and the severity of the disease but there's a general correlation. Because of that, this is I think not only a broad representation of patients but certainly patients who are very symptomatic with their Fabry disease.

Last question, is there a stopping rule then for patients who go on to the open label or the extension in terms of their GL3 clearance going down or kidney function getting poorer? What's the -- any criteria there?

No.

Any rule there?

No, I don't believe so.

It's Pol. There is no stopping rule. It's up to the physician of the patient to decide what's going to happen.

Okay. All right, thank you.

Yes, you bet.

Thank you. There are no more questions at this time. I would like to turn the call over to management for any closing remarks.

That's all we have. That was a great call. Great, great questions. Again, off to a great start for the year, but a lot more work to do. Great. Thank you, good night.

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