Amicus Therapeutics, Inc. (FOLD) Q4 2011 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to the Amicus Therapeutics Fourth Quarter and Full Year 2011 Results Conference Call.[Operator Instructions] 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. Here on today’s call we have John Crowley, our Chairman and Chief Executive Office; 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 preclinical and clinical development of Amicus candidate drug products, the timing and reporting of results from preclinical 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’s forward-looking statement due to numerous known and unknown risks and uncertainties, including the risk factors described in our Annual Report on Form-10K 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 is going back just over the last several weeks, at and around the JP Morgan conference, with the release of some of the data with the combinations, even proof of concept study in 013. I think as we think about the strong start to 2012 with some of the new data, the new strategy that we’ve 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 laid such a strong foundation for 2012. Of course, one of the primary drivers of value for shareholders at Amicus, as 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 successes, 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 laid the foundation for 012 and 013, 2 separate studies we’ll be talking about on this call as well, together with continuing preclinical 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 have 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 and 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 a little bit on that Phase 3 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 3 study, the 011 study, also known as our FACET study in the third quarter of this year. We have talked and we begin 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 2 experience. Again, this is a drug that’s been through several years and continues with an extension study in Phase 2, 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 previously seen positive results on both renal and urine GL-3 clearance, again GL-3 clearance in urine being a key biomarker in Fabry disease. And in terms of Phase 2 experience, we’ve also seen long term tends 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 3 study. They have to have been naïve to ERT or had no ERT in the last 6 months. They have to have amenable mutation to respond to the migalastat as a monotherapy. And we further enrich the population for study purposes, by requiring that every patient in this study at the urine GL-3 level, at or above 4 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 methodologies, a more advanced, sensitive and objective measure of the inclusion bodies. A methodology developed by Dr. Berenson, a close collaborator with our team at Amicus and GSK and then also what we’ve observed in Phase 3 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 6-month primary treatment arm. We know that all 45 of those patients have elected to continue into a 6-month treatment extension. So for those patients who had been randomized to migalastat, they were continued on migalastat. For those patients in the Placebo arm for the first 6 months, they crossed over and entered to migalastat treatment. So 67 enrolled, 45 having completed the 6-month treatment period, all 45 electing to go into the 6-month treatment arm. As we sit here today, we’ve now had 28 people completing at least a year of study, 6-month primary treatment and 6-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 JP Morgan conference, again those are the 2 patients who did not elect to continue past that 1 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, the Lysosomal Disease Scientific Symposium, San Diego last week. We presented Dr. Bichet on Amicus. We have presented some data regarding the screening of patients into that study and 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 population that 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. Now before I do that, just to remind people, the 012 study is also a Phase 3 study. With migalastat it will satisfy our U.S. Phase 4 commitment, as well as the commitment for approval with the EMEA in Europe. This is a 50 patient study with a 2:1 randomization, migalastat, 2 people remaining on enzyme therapy, either Fabrazyme or Replagal. It is an 18 month study, where the primary end point is looking at non-inferiority 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, and that’s leveraging the chaperone technology, we believe to address potentially many of the deficiencies with the enzyme replacement therapies, including protein 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 learnt to-date and what some of the plans are going forward. So 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 of our Phase 3 Fabry program and the significant opportunity that we believe exists for migalastat as a monotherapy. We are 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 chaperon ERT combination platform. Right now we are evaluating several chaperone-ERT combinations and Phase 2 studies in Fabry and Pompe and preclinical studies in Gaucher and other undisclosed LSDs, where we believe there is a significant opportunity to improve current ERT products. As a reminder, as part of our Fabry collaboration with GSK, we are developing migalastat as a monotherapy and in combination with ERT, however outside the Fabry program, we own exclusive rights to all of our other assets. As we have 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. Preclinical chaperone-ERT and 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 in tissue uptake has led to greater substrate reduction than ERT alone. Based on these preclinical data that we’ve generated so far, we are conducting 2 Phase 2 open label studies, 1 for Fabry and 1 for Pompe, to evaluate our first 2 chaperone ERT combinations in the clinic. Patients in each study will be compared to themselves at 2 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 and 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 2 co-administration study for Fabry. These data describe that for 7 patients in Study 013 who received either full or half dose Fabrazyme co-administered with migalastat at 150 mg. We were 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 knock-out mice in preclinical studies. As John mentioned, Pol and David are on the call today and 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 this study in the first half of this year. Final study results will include migalastat at oral doses of 150 mg and 450 mg, co-administered with half and full dose Fabrazyme as well as Replagal. So following closely behind Study 013 is our Phase 2 Pompe Study 010, which is investigating ERT co-administered with 4 different doses of AT2220 and 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, the 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. Preclinical results to-date suggest that AT2220 when co-administered with ERT may mitigate the immunogenicity induced by the ERT for Pompe disease. Importantly these preclinical 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 2 combination programs in Fabry and Pompe, we’ve also conducted preclinical studies of 2 pharmacological chaperones, AT2101 and AT3375 in combination with ERT and 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. So therefore in addition to conducting further preclinical studies of AT3375 co-administered with ERT. Given its ability to cross the blood brain-barrier and other properties, we are 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 preclinical and IND-enabling studies of AT3375, which are funded in part by a grant from 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. So 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 totaled $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 reimbursement 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 1 in our press release, which is available on our corporate website at www.amicustheraputics.com. Additional details can also be found in our Form-10K 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 cost for migalastat. Amicus and GSK equally shared 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’s 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 $4.0 million compared to $4.1 million in the third quarter of 2011. Quarter-over-quarter, GSK incurred a higher percentage of total migalastat cost 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 are 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 upfront payment received from GSK upon signing the agreement. The total upfront 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 upfront 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 expenses, 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 of 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 cost 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 of stock based compensation expense in the prior period. The increase in the fourth quarter was primarily due to increased recruiting cost 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 expense 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 stock option grant, 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 2011 we reported a non-operating 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 [ph] liability during the fourth quarter of last year. For the full year 2011 we reported a non-operating 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 a change in our stock price and we report the change at each reporting data until these warrants are exercised or expire. Net loss attributable to common stockholders for the 3 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 3 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. So 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 dialog 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. [Operator Instructions]. We have a question from Ritu Baral of Canaccord.

Thanks for taking the question. I wanted to ask about the combo therapy programs, both Fabry and Pompe’s and sort of how they relate to each other. I’m assuming based on the timeline of 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 2 enzyme therapies compare and contrast and how the chaperone benefits to either ERT should compare and contrast?

I think there were multiple there. As a prior litigator, I probably should have objected to the questions if possible, but 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 about it, what we are 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 benefits for a lot of patients. We’ve seen in different diseases, different levels of efficacy for sure. If you take it to what we are doing in Fabry and what we are doing in Pompe disease, obviously 2 different disease, 2 different enzymes, but the same fundamental problem, and that you are taking large amounts of protein made in bioreactors in multi hour infusion and taking it from a lyophilized powder, reconstituting it into an infusion bag and putting enormous amounts of protein then into infusion bag and indentation from plasma and hoping then through the whole process of receptor-mediated endocytosis that it ends up getting taking up in to the liposome of target tissues. The challenge is several folds with the ERTs. One is, primary that the enzymes that we are dealing with are enzymes that we all without disease naturally make and that live in the liposome. The liposome pH is more like 5, a highly acidified compartment when you’re putting it into the infusion bag at pH, neutral pH of 6, 6.5 or so and then when it hits the plasma at pH 7.3, it becomes a very, very unstable protein. 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 fusion bag as well as in plasma, that you are actually seeing a heightened level of immunogenicity that’s attributed to this whole phenomena. We think we have a very unique tool set to address that and that using a small molecule to bind to the active side of the ERT promotes the conformational stability, essentially keeps it sound, active and stable, so that you have a much more potent enzyme and by doing that, we think we have the potential to dramatically reduce the immune profile of these ERTs. We are looking at this as both a co-administration like we are doing now in the clinic in Pompe and Fabry, but also considering in preclinical 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 proved in these first 6 patients and the data that we’ve seen, is strong proof of concept that a small molecule that’s orally bio-available, onboard in plasma, can stabilize an ERT product. We’ve seen that now with a 150 mg low dose of migalastat with Fabrazyme. We have more work to do and as you 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 are now exploring in the clinic the 450 mg dose of migalastat with Fabrazyme. We have more work to do, and as you alluded to Ritu, by the middle part of this year, we’ll have additional preliminary data with Repligal and then also we need to look at the higher dose of migalistat as we’re now exploring in the clinic, the 450mg dose of migalistat with Fabrazyme. So 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 and that’s where we become even more hopeful that this could be a potential therapeutic option in Pompe. As you know, we are 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 will be able to report that data by the middle part of this year though and again, we think that will be a further proof of concept, not just for that specific drug program, which again we own completely, it’s not partnering 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

No. Do you see alpha-glucosidase as being more immunogenetic than galactosidase and the interaction between 2220 and glucosidase, are there lessons to be learnt from migalastat and the Fabry enzyme?

It seems from the literature and from talking to physicians and in our experience, the Fabry ERT seems to be less immunogenetic than Pompe, but still we see immune responses in virtually all patients in Fabry disease. So we do think the immunology of the ERT and the immunogeneticy of any of the currently marketed ERTs could be a very important factor in terms of the therapeutic efficacy and again, we will have to explore that in a clinic and see what impact we can have. Obviously, from what we’ve seen and from what others have seen, the Pompe enzyme, the myozyme, lumizyme enzyme, that’s in a few markets seemed to be very, very immunogenic. They do have a black box warning, there was anaphylactic with them in the clinical studies, but even more so we think that some of the immune response that you are seeing actually impedes the therapeutic efficacy due to the immune response created by this unfolded, unstable enzyme in blood and that was part of the grant that we were just given from the NDA that Brad referred to. We are going to explore that and again, I think that will be part of the important preclinical data that we’ll have this year, as well as the clinical data from the 010 studies. So if there is an area where we think we can have an impact in Pompe, I think it’s twofold. I think its protein potency as well as the immunogenicity, so we’ll continue to explore this.

And one more question and I’ll hop back in the queue. 012 enrollment, are there lessons learnt from the FACET study? Do you see it being more efficient and 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. There is no placebo arm. I think that’s important. People will either stay on ERT or go on to our drug. So I think all those weigh in favor and yes we’ve learnt a lot and we’ve built a lot of relationships. One of our key learning is to enroll these studies with the right patient, you have to screen a lot of patients and to do that you have to open a lot of clinical sites and we are well on that path in the 012 study and it’s also, if you remember when we started 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 lot of the geographies where we might not have a strong presence, we are seeing great participation from our partners at GSK, helping us make sure we can have the right reach globally.

Thank you. Our next question is from Joseph Schwartz from Leerink Swann.

There was some striking data on the laterius effects of immunogenicity at WORLD in areas like Pompe and I’m wondering, when will we be able to get some data on your ability to zero [ph] revert I guess or how do you expect to study the ability of the chaperone technology, to translate, improve the maturation profile and serum half-life on antibodies?

I think we are looking at it and I’ll ask David and Pol to add some color as well Joe, but again, we are looking at that with continued preclinical work, so a lot of the work that we are doing with the NDA 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 preclinical 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 PKPD study, although we’ll evaluate some of the potential immunogenicity involved in a short term study, we wouldn’t expect to see that we have any changes there and Pol, Dave, do you have any color to add to it – please.

Joe, one of the key measurements in preclinical studies is you can look at a T-Cell response in human T-Cells. So we’ll be doing that over the course of this year and that is part of the Muscular Dystrophy Grant. As John said in the first clinical study, since its 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, but in the next set of studies where we have longer term treatment, we’ll be able to see in 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 does study.

Okay great. That’s very helpful, thanks. And then as a follow-up, 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.?

No, 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 PKPD Phase 2 study, the 013 study, to a confirmatory Phase 3 study, but 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 is essentially superiority over ERP 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 GL-3. We think that could be a study that where urine GL-3 input in a short term study could be particularly appropriate, but we will also look at other potential end points, including ones related to immunogenicity, which may end up being a provable end point potentially.

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

This is Anupam Rama in for Geoff Meacham. Just a quick question. In the female patient study at WORLD, there were few patients that showed improvement in left ventricular mass. Can you just kind of help us understanding that improvement and put it into context and what that means for Fabry patients and I’m assuming its mutations that are sort of associated with less ventricular mass. Thanks.

David, do you want to comment and I’ll ask Pol to follow-up with any other thoughts.

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, even some normalization of any of those would be a very positive sign. We shouldn’t over interpret what we’ve seen so far, but we do find it encouraging whenever there is 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 carefully not to overstate that quite yet.

[Operator Instructions] We have a follow up from Ritu Baral of Canaccord.

Of course, I have a follow-up question.

Carry on.

Going back to the world data, we also saw some interesting Fabry’s incidence and prevalence data. Can you tell us what you think about sort of the much, much higher incidence rate seen in some of the instant screening studies presented at the conference versus sort of what’s generally accepted as prevalent.

If you look at the text of literature Ritu, it says that the incidence of Fabry is about 1 in 40,000 or 1 in 50,000 and that there are 5000-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. And I think what these epidemiology studies and screening studies are showing is that Fabry is indeed a much, much more prevalent disorder than people have traditionally thought. The studies that were presented at WORLD showed -- I think the 1 from the Illinois screening showed that 1 in 1700 incidents. Others that have been published from Taiwan and other geographies over the last couple of years have shown 1 in 3,000, 1 in 4,000, which make us much more akin to the prevalence you see in something like a Duchenne muscular dystrophy or cystic fibrosis and 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 are starting to see Fabry diagnosed in cardiac clinics and there were some presentations about that at WORLD. For people that never suspected Fabry before, people with undiagnosed, left ventricular hypertrophies for instances, other cardiomyopathies. You are seeing it in renal clinicians where people are finding Fabry where they have never looked for it before and 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 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 with clear majority seem to be the type of mutations that would amenable to chaperone monotherapy. So it’s something we are very, very interested in.

As far as the screening programs and potential increased diagnose, 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?

I couldn’t tell you exactly how long it would be Ritu, but it’s something we have been thinking about even prior to the WORLD meeting with GFK for sure. Others, I mean Shire, Genzyme has done a very good job at beginning to explore some of those other potential patient populations. So as we look at our forecasts 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. So 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 are mis-sends or whether they are on your sort of list of responses 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 question. You mean in terms of how they got into the study?

Yes, as far as screening dynamics, I mean from what I understand there were many, many at least U.S. Fabry patients know their exact mutation and can look on one of the many charts that you provided to the Fabry’s community and say, "Oh, I’m responsive, I should enter," but at the same time your 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 the U.S. and x U.S.

I think it shifted it a bit in a favorable direction Ritu. We don’t mean to imply that because of the screening study you can extrapolate that to say that 80 plus percent of people could be amenable to the chaperones and monotherapy. I think there was some selection bias where patients or their physicians knew that the Amicus Phase II study has been successful and people with missense mutations broadly and that’s certainly like the R301Q, 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 U.S., people presented not knowing at all what their mutations are. So I think as we look at this, as we try to be conservative, discounting some of these numbers for some pre selection bias. We still are very confirmable with our predictions, that roughly half of the people living with Fabry will be amenable to the chaperone of the monotherapy.

This is Brad. I think your logic initially is probably right, that in general in the U.S. and Europe and probably Japan, there is a little bit more awareness of mutation type either by the patient or the physician and as we go to the more developing countries, that’s less true and it’s 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 other 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 pre-selection either. Out of the 140, they were 13 mutations that were completely new. They have 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 it us. And there were also more than 20 patients in that first 140 who did not have missense mutations. So it wasn’t even just a selection for people with known, who have known to have a missense mutations as a fair number who were screened did now even have missense mutations or did not have a single missense mutation.

Thank you. Your next question is from Bill Tanner of Lazard Capital.

Thanks for taking the question. John, for you, just on 011 study, I know that the inclusion criteria, they are ERT naïve or not having been treated for 6-months prior and I’m wondering if you can make any comment as to which -- are most of the patients truly naïve or have they just not been treated and I have a follow up.

I have to follow-up with you, because I don’t have the exact list, but I could tell you we saw in Phase 2, that it was about a split between previously naïve and people who had been on [ph] 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. I don’t know Pol.

Yes, that’s right.

Yes, that’s correct. So a majority of the patients had never been of ERT. I don’t have the exact numbers for your Bill, but we can get that.

Go ahead, I’m sorry.

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

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

Yes. No absolutely. Two things that are really important about this study. One is, that either it’s the largest Fabry disease study -- pivotal study every 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 a spectrum of patients living with Fabry disease and we have a couple of dozen males in this study, we have females, so it’s important, especially given that the population consists of a significant number of females. So we have some 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 diseases and because we put in that GL-3 criteria, that they have to have at least 4 times the upper limit of normal to get in the study, there is not a straight correlation between the urine GL-3 and the various disease, but there is a general correlation. So 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.

And I guess, last question, is there a stopping rule then for patients who go on to the open label by the extension in terms of the GL-3 clearance going down or kidney function getting poorer. What’s the -- any criteria there? Any rule there?

No, I don’t believe so.

It’s Pol and there is no stopping rule. It’s up to the physician and the patient to decide what’s going to happen.

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

Well, that’s all we have. That was a great call. Great, great questions. So 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.