Amicus Therapeutics Inc (FOLD) 2012 Q3 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Amicus Therapeutics Third Quarter 2012 Results Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time.

(Operator Instructions)

As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference, Ms. Sara Pelligrino, Associate Director of Investor Relations. Ma'am, you may begin.

Good afternoon and thank you for joining our conference call to discuss our third quarter of 2012 financial results. Speaking on today's call we have John Crowley, our Chairman and Chief Executive Officer; Bradley Campbell, our Chief Business Officer; Pol Boudes, our Chief Medical Officer; David Lockhart, our Chief Scientific Officer; and Chip Baird, our Chief Financial Officer. They are all available to participate in the Q&A session as well.

Today's prepared remarks coincide with the slide presentation that is now available on our corporate website at www.amicusrx.com. The slides are located in the investor section under events and presentations, right below the webcast link to today's call.

On slide two, we have a reference to forward looking statements. This conference call and presentation contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 relating to business operations and financial conditions 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; the projected cash position for the Company; and business development and other transactions activities.

Words such as, but not limited to, look forward to, believe, expect, anticipate, estimate, intend, plan, would, should and could, and similar expressions or words identify 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 quarterly report on Form 10Q for the quarter ended June 30, 2012.

All forward looking statements are qualified in their entirety by this cautionary statement, and Amicus undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof.

So 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, and thank you for joining us on our Q3 conference call. I'll direct you to the agenda slide, slide number three of the presentation. I'll begin the presentation and go through some of the major corporate highlights for Amicus, and then the bulk of the presentation I'll turn over to some of our senior team at Amicus who I'm joined by here this evening.

The Fabry Monotherapy Program updates, I'll cover briefly and then turn over some of the clinical, including some of the data -- very exciting data from the American Society of Nephrology Meeting in San Diego this past weekend, to our Chief Medical Officer, Dr. Pol Boudes.

And then, we also have our Chief Business Officer, Bradley Campbell, as well as our Chief Scientific Officer, Dr. David Lockhart, who will go through some additional results, especially in our Chaperone-ERT Program for both Fabry and Pompe.

I'll then turn the call over to Chip, our Chief Financial Officer, and Chip will take us through the 3Q '12 financial results and fiscal year '12 guidance, and then I'll conclude the call with upcoming milestones and final remarks.

Just briefly, to turn your attention to slide number four, you'll see the headline of this slide is related to the hurricane, the super storm Sandy that struck the East Coast and particularly devastated New Jersey last week. You'll see the headline there, that the Amicus New Jersey facility and operations remain intact and fully functional.

I just want to assure everybody on this call that we certainly at Amicus took this, as with all natural disaster threats, very seriously at Amicus. We came through the storm thankfully fine. We are fully functional and operational.

The picture that you see on that slide was actually taken this morning from in front of our building, so you can see some of the work going on at Amicus. We have a 300 kilowatt generator that powered the facility. Thankfully, we only lost our power for a short while. We did our facilities team in the building here throughout.

We did have backup contingency plans if any of our experiments needed to be moved to places with power, including transferring some of that to a GSK facility temporarily. Thankfully, we didn't have to do that. We were only out of the building Monday and Tuesday during the storm and then back on the facility on Wednesday.

So Amicus thankfully made it through the storm well. Certainly, many of our communities, including the communities that many of our employees live in, were particularly affected and many of our Amicus team are helping to volunteer through the Red Cross and other agencies. And for any of you interested in helping any of our friends here in New Jersey, would certainly encourage you through whatever means you can to add your support. But again, thankfully Amicus came through this storm.

Turning to slide number five, I'll just give you a brief overview of some of the corporate highlights. So, it's been a great quarter for our Fabry Monotherapy Program, and I think this really reflects not just the significant progress within that program, but also the clinical execution.

For many of you who attended my presentation earlier in the year at the JPMorgan conference, we highlighted some of the pillars of strength and value as we saw it for 2012 for Amicus and one of those was our global clinical expertise. And that's something that I think is really reflective in these 3Q results.

Again, with Study 011, our Fabry Monotherapy Study, the first our Phase IIIs for Fabry Monotherapy, Migalastat, we have our 12-month analysis plan completed and will go through that with you on this call, which will be an update. We are also reiterating our guidance to expect the six-month data by the end of this year; we're expecting that to come in December. And we're also now issuing guidance that we will have the 12-month biopsy data analyzed and released in the first half of 2013.

You saw the release recently, too, about our Study 012, and that's our switch study, moving people from enzyme replacement therapy to Migalastat as a monotherapy, again, people with responsive mutations in Fabry. We achieved the target enrollment. In fact, we actually over enrolled that study ahead of schedule with final enrollments expected in this quarter, as well as the updated Phase II extension study results that were just presented this past weekend that Dr. Boudes will take us through here shortly.

So, Fabry Phase II study in combination. The 013 study enrollment is now complete for both the Fabrazyme and the Replagal. We will have updated preliminary results November 8 at the American Society of Human Genetics Meeting by the end of this week.

We continue to make great progress as well with our Pompe Program. We have some good data here in the slides to share with you as well. Positive preliminary result in cohorts one, two and three that were presented in October at the World Muscle Society Meeting in Australia. And we also expect to have not only enrollment complete, as it is now, but all four cohort data reports, including that last fourth cohort that's the highest dose cohort, by the end of this quarter.

And also -- and Dave Lockhart will take us through the immunogenicity work that we've been doing, especially with the Antitope data that looks increasingly compelling as well.

Just to highlight a little bit, too, about the corporate and financial strength, we think we're in a very good position financially, especially with the cash raised through our extended collaboration with GSK in the middle part of this year and, of course, our equity fund raised back in Q1. So we end Q3 with just over $106 million cash or cash equivalents on hand. And we think that gives us a lot of flexibility to continue to advance the Fabry program, but also to make sure that we advance the technology fully.

And really, as we've said, with the financing at the beginning of the year, to fully invest in leveraging this core technology for the development of combination programs directly with enzyme replacement therapies, including building the [biologic] of expertise and capacity in the Company to be able to develop these next-generation enzyme replacement therapies. So, good financial strength in the Company.

I'll turn your attention to the next slide, slide number six, which talks a little bit about the global Phase III registration studies, again, two different studies -- the 011, for approval in the United States, a placebo-controlled study. That study also overenrolled 67 patients. In the next slide, I'll go through the updated disposition on where we are with those patients. But that study continues to go extremely well, again, with data from the six-month primary treatment period expected in the fourth quarter of this year, in December, as well as the 12-month analysis plan now completed, and we'll go through that as well.

Study 012, that again is our switch study, comparing ERT to Migalastat. It's a 1.5 to 1 randomization and we now have 57 patients enrolled in that study. If you'll recall, the target was 50, so at 57 we think that reflects the enthusiasm in the community. Also in this study, you'll see we have a significant number of males in this study.

We are reporting this evening that we have 24 males and 33 females enrolled in that study, again, with final enrollment expected by the end of this year. And that's an 18-month study looking at kidney function as a clinical endpoint.

Slide number seven, we have some of the updated patient disposition from the last time we updated this several months ago. As we stated on the last conference call, the six-month primary treatment period was completed in June of this year in 63 out of 67 patients. So with that study, to the primary endpoint of six months, we have only a handful of patients, equaling a 6% dropout rate, so lower than we had anticipated, together with the higher enrollment in this study.

All of those 63 patients who went into the six-month follow-up period continued on Migalastat or they were switched from placebo to Migalastat if they had been in that arm. Both patients and physicians remained blinded as to whether they were on Migalastat or placebo during the first six months, but they all know now that they are on Migalastat after the six-month period.

51 of those 63 patients have now completed the six-month follow-up period and have received their month 12 biopsies. And as we sit here this evening, 49 of 51 of those patients are currently enrolled in the ongoing voluntary extension studies, which include a study 011 treatment extension followed by a separate long-term extension study.

So, increasingly good news about the patients' dispositions, more patient experience with the drug, and, at least in terms of safety and compliance, we're very pleased with where we are with these patient numbers. And, like many of you, we very much are looking forward to and eagerly awaiting the un-blinding of the six-month data once we have those last patients out of the 12-month part of the study, which, again, we expect in December of this year.

Let me go ahead to the next two slides and turn the discussion to our Chief Medical Officer, Dr. Pol Boudes, who will talk to us about the six and 12-month now analysis planned as well as the data that you presented, Pol, this weekend that graphically on slide nine, I think, shows a very impressive story with GL-3 clearance. So, Pol, I'll turn it to you.

Thank you very much, John. Hello, everyone, and good evening. As John mentioned, the momentum with enrollment and patient disposition in our Phase III Fabry Monotherapy studies gives us great confidence in the program.

Slide eight provides additional details on the six and 12-months analysis for Study 011. During the last quarter's conference call, we discussed our encouraging Type C meeting with the FDA, specifically, the agency's willingness to consider both the six and the 12-months efficacy as well as safety. As a reminder, the primary endpoint is interstitial capillary GL-3 at six months and we will compare the number of responders on Migalastat Hydrochloride versus placebo at month six.

12-month descriptive comparisons include various analysis to support the six-month data and are outlined in the bullets here, so you can see we will have a very robust data set at month 12 for this comparison, including 12 months of data in the initial Migalastat group as well as the six months of data in the group that crossed over from placebo to Migalastat and, of course, initial safety data as patients continue with Migalastat in the six-months extension and the open-label extension studies.

Turning to slide nine, you will see updated results that John mentioned from our Phase II extension study of Migalastat Monotherapy, also known as Study 205, which I presented over the weekend at the American Society of Nephrology Kidney Week in San Diego. Below is the snapshot of changes in interstitial capillary GL-3 in eight variable patients who had baseline kidney biopsy from the primary Phase II study as well as Study 205.

The follow-up biopsies in Study 205 were taken at various time points and individual patient values are plotted here. The median treatment duration in Study 205 prior to biopsy was 60 weeks. And that's 60 weeks just in study 205 in addition to prior treatments in the primary Phase II studies. As we indicated [at the Congress] and in this morning's press release, there was a 78% median decrease in interstitial capillary GL-3 in patients with amenable mutation and 114% median increase among patients with non-amenable mutation.

This is the longest-term data presented in patients on Migalastat to date and gives us further confidence in the program. I will now turn things over to Bradley to review patient disposition in the Phase II and Phase II extension studies.

Great. Thanks, Pol, and good evening, everybody. I'll refer you now to slide 10, which gives a quick overview of who makes up that data set from Study 205. I'll refer you to this morning's press release for further detail on the design of those four Phase II studies, but this essentially shows the patient disposition from the original 27 patients who enrolled in our four Phase II studies, down to the 17 patients who completed Study 205 with an average of 5.2 years on Migalastat as their only treatment for their Fabry disease. So again, as Pol and John mentioned, very encouraging data ahead of the un-blinding of the six-month [O and 1] results later this year.

So with that, let me transition the conversation to our Chaperone ERT Combination Platform on slide 11. This highlights our continuum of innovation where we seek to deliver new patients to -- new benefits to patients along this continuum. In Fabry disease, for example, where upwards of 50% of the population have an amendable genetic mutation, we hope they can take Chaperone monotherapy with Migalastat as their only treatment for their Fabry disease.

However, for patients who lack the appropriate genetic mutations, who have to stay on enzyme replacement therapy, we believe the direct combination of Migalastat plus their ERT can make their enzyme replacement therapy better.

And this is now more than just a preclinical concept as we've continued to generate positive initial clinical data throughout the year in our Fabry co-administration studies looking at Migalastat plus or minus Replagal or Fabrazyme at various doses as well as our Chaperone AT2220 for Pompe disease and our Study 010 looking at AT2220 plus or minus Myozyme and Lumizyme.

So with that, let me turn it over to Pol and to David, who will walk us through some of that exciting data from our Pompe program.

Thanks, Brad. So, beginning on slide 12, I will highlight results presented last month during the World Muscle Society Congress, which are from the first three cohorts in our open-label Phase II Study 010.

This study is a drug-drug interaction study investigating four ascending does goals of our Chaperone AT2220 co-administered with ERT -- in this case, recombinant GAA enzyme. Co-administration is being compared to ERT alone during two subsequent infusions.

In addition to safety, we are looking at uptake of active recombinant GAA enzyme into plasma and into muscle tissue with and without our Chaperone AT2220. Slide 12 shows increased uptakes of active enzyme in plasma, which was observed in 16 out of 16 patients enrolled in the first three dose cohorts. Among these patients, co-administration increased active recombinant GAA enzyme in plasma up to 2.64 versus ERT alone.

Now, on slide 13, we show the muscle biopsies from cohort two and cohort three, which were taken in each patient either three or seven days following each infusion. The results on this slide suggests that co-administration increases recombinant GAA enzyme uptake into muscle versus ERT alone. These results are an important next step for the Pompe ERT combination program and/or ongoing design of subsequent repeat dose studies. In addition, the fourth and highest dose cohort in study 010 is now fully enrolled and results from all four cohorts continue to be anticipated in the fourth quarter of this year.

Before I hand over the call to David to discuss our ex vivo studies on ERT immunogenicity, just a quick reminder that updated [preliminary] result from study 013, or Phase II Chaperone ERT Study for Fabry Disease, will be included in a poster at the American Society of Human Genetics, or ASHG, this Thursday on November 8.

Study 013 is an open-label drug-drug interaction study investigating a single oral dose of Migalastat Hydrochloride, either 150 milligrams or 450 milligrams co-administered with Fabrazyme or Replagal in 23 males with Fabry disease. David?

Thanks, Pol. I'm going to talk about the immunogenicity part of the equation, and we've talked about this before and how it's important for Pompe as well as for other diseases in the presence of ERT treatment. In particular, patients who are given ERT develop antibodies and the antibodies, of course, interact directly with the infused protein and that can lead to safety problems and it can also reduce the efficacy of the infused enzyme.

So, we had been doing some studies, as we described before, in animals and we saw very interesting -- some interesting findings, but, of course, it's difficult to interpret studies in animals when you're using a human version of a therapeutic protein. So we moved to the studies with a Company called Antitope, and it's called an EpiScreen assay. And what it measures is a response, a proliferation response, in human T-cells, derived from different human beings with different HLA types.

And so the T-cell response -- the T-cell proliferation response is a necessary part of the human antibody response. And in the plot on slide 14, our data that were generated by Antitope, showing what is seen with other human therapeutic proteins -- and this is what gives us confidence that this read-out is actually meaningful in terms of a human antibody response -- the plot shows the clinical immunogenicity on the X axis. And what this means is it's the fraction of patients who, when given these various therapeutic proteins, develop antibodies.

And on the Y axis is the T-cell proliferation response as measured in this ex vivo assay. So, for example, 50% on the Y axis would mean that 50% of the cells derived from different people with different HLA types show a T-cell proliferation response and the other 50% do not. So you can see there's actually a range with different human therapeutic proteins, with the highest being up around 40% of a response in the EpiScreen assay.

So, no one had ever done this with Myozyme and Lumizyme, the ERTs for Pompe disease, so we did. In fact, we got a grant from the Muscular Dystrophy Association to do that. And so what we measured was the T-cell response that is elicited with Myozyme and Lumizyme under different conditions and also in the presence or absence of AT2220, our pharmacological Chaperone that's designed to bind to and stabilize the enzyme, particularly in the circulation.

So the summary is here. You can see all the known therapeutic proteins more to the left of the plot. And on the right you can see that Myozyme and Lumizyme alone elicited a T-cell response at a pretty high rate. They are actually near the highest, although not larger than some, but they are near the highest of any of the human therapeutic proteins that have been measured.

Down below, kind of giving away the punch line -- I'll show you this in more detail in a second -- but you can see that Myozyme and Lumizyme in the presence of AT2220 have a level that is significantly reduced in terms of the T-cell response. And, in fact, it's down near the dashed line, which is generally considered -- this isn't proven, but it's generally considered to be the point at which there essentially is not a worry about the antibody response.

So you can see that the addition of 2220 basically takes Myozyme and Lumizyme from being about as high as any human therapeutic -- current human therapeutic proteins are in this assay and bringing them down to a level that's essentially at the level that is considered to not be a very sizeable antibody response.

If you go to the next slide, on slide 15, this is showing it a little bit more detail. The hashed bars are the ones with Myozyme or Lumizyme alone, the four hashed bars to the left of the plot.

You can see there's Myozyme, Lumizyme, Lumizyme that was allowed to sit around at 27 degrees for a while, and Lumizyme that was incubated at 37 degrees to essentially completely unfold it. And you can see that either Myozyme or Lumizyme elicits a strong T-cell response. And if you let Lumizyme sit around at elevated temperatures, that gets, if anything, a little bit worse.

And then, the smaller bars that are next to those four are those experiments that in the presence of either 2220 alone -- just to show that 2220 does not elicit a T-cell response on its own -- and then the next three show Myozyme plus 2220 and Lumizyme plus 2220, or Lumizyme incubated at 27 degrees with 2220. And you can see that in all three of those cases the presence of AT2220 significantly reduces the T-cell proliferation response.

So that is extremely encouraging. That was, in fact, what we were hoping to see. There does not seem to be a significant difference between Myozyme and Lumizyme in this respect. They're not identical, but they are similar. And also, on the far right is a very important control.

A33 is another control protein, completely unrelated to Myozyme and Lumizyme, that is known to elicit a T-cell response. We redid that as a positive control. We see a T-cell response; and in the presence of AT2220, that T-cell response is not reduced. So AT2220 is clearly not having some general effect. It is not something that blocks T-cell proliferation and the effect is, in fact, specific for the Pompe enzyme, either the Myozyme or Lumizyme form.

So, very promising so far. The next step is to supplement this work with very similar studies, except using cells that are derived from Pompe patients. So these are Pompe patients that have been part of our Phase II combination study. So we will have Pompe patients with known genotypes, with known HLA types, with known antibody titers, and we will see how their cells -- how their T-cells respond to the presence of Myozyme and Lumizyme with and without the presence of 2220. That will be an important addition to the study. Okay?

Great. Thanks, David. I'll turn it over to Chip Baird, our Chief Financial Officer.

Great. Thanks, John, and good evening, everyone. I'll start on slide 16 by reviewing our third quarter results for the three months ending September 30, 2012. Alternatively, these results appear in tables one and two in the press release we issued earlier today and additional details can be found in our 10-Q, which will be filed later on this evening.

Our third quarter results reflect updated revenue recognition accounting in conjunction with the expanded GSK collaboration which we entered in July of this year. Payments received from GSK under the agreement are now being recorded in the deferred reimbursements account on the balance sheet. On September 30, 2012, the deferred reimbursements balance was $27.2 million. This amount includes $4.5 million cash reimbursed per shared global development cost in Migalastat during the third quarter 2012 and the $22.7 million unrecognized balance of the upfront license payment.

Prior to the third quarter of this year, quarterly cash reimbursements were recorded as research revenue and the upfront payment was being amortized each quarter in collaboration revenue. So although we show no research revenue in the third quarter of 2012, we earned $4.5 million in collaboration reimbursement from GSK.

This compares favorable to the $4.1 million research revenue for the three months ending September 30, 2011. I'll provide a little more information on this updated revenue recognition accounting, which importantly does not impact cash, on the next slide.

Moving down the P&L, total operating expenses for the third quarter totaled $16.9 million, compared to $18.9 million in the year-ago period. The year-over-year decrease was primarily attributed to lower research and development expenses related to our Fabry program.

Net loss attributable to common shareholders in the third quarter was $16.3 million, or $0.34 per share, compared to a net loss of $9.8 million, or $0.28 per share, in the year-ago period. The difference in the year-ago period is attributed to the change in revenue recognition under the expanded GSK collaboration.

So moving to slide 17, I'll summarize the change in revenue recognition accounting under the expanded GSK collaboration. Prior to the third quarter of this year, payments received from GSK under our cost-sharing arrangement for the development of Migalastat were recognized as revenue. In the year-ago period, $4.1 million under the GSK cost-sharing arrangement was recognized as research revenue.

In the third quarter of this year, under the expanded agreement, $4.5 million of comparable GSK reimbursements were recognized, but in this case they reside in the deferred reimbursements account on the balance sheet. So the cost-sharing arrangement remains the same, the deal economics remain the same, and there is no cash impact in the accounting change of revenue recognition.

Also impacted with this accounting change is the upfront cash license payment received from GSK back in 2010. Previously, we amortized this on a straight-line basis each quarter. Now, we record that unrecognized balance of that upfront consideration from GSK in the same deferred reimbursement account, which was $22.7 million on September 30.

So if you move to the right-hand side of the slide here, on slide 17, the cost share from GSK in the third quarter and the unrecognized balance of upfront consideration total up to that deferred reimbursement balance of $27.2 million as of September 30, which is circled in green.

So going forward on a quarterly basis, the deferred reimbursements balance will increase by the amount of reimbursement that GSK will pay to Amicus for ongoing share development costs. Any future milestones payable by Amicus to GSK will be debited against this balance of deferred reimbursements.

And before I turn it back to John to wrap things up, I'd like to briefly tough on our current cash position and reiterate our full year operating guidance on slide 18. Cash, cash equivalents, and marketable securities as of September 30 totaled $106 million, compared to $56 million at the end of last year. We continue to expect to end the year with more than $90 million in cash, cash equivalents, and marketable securities, which we will expect to fund our current operating plan beyond 2013.

In addition, we continue to expect full year 2012 operating expenses to fall within that upper end of the previously guided range of $37 million to $43 million net of anticipated cost-sharing related to the GSK collaboration. Just as a reminder, GSK is responsible for 75% of development costs for Migalastat monotherapy and co-administration in 2012. During the third quarter of this year, GSK also began investing in 60% of the development cost for our preclinical Chaperone ERT co-formulated product.

This summarizes our key financials for the third quarter and the full year 2012 guidance. I'll be available for the Q&A session if there are additional questions, particularly around the GSK accounting. And with that, I'll turn it back to John.

Great. Thank you, Chip. Thanks, everyone, on the Amicus team for their presentation. I will just end here on slide 19, as you can see, again building shareholder value as the theme, consistent with our mission to deliver the highest quality therapies for people living with rare and orphan diseases. We're very pleased with 2012. It has been a transformational year for Amicus indeed, in many different ways.

This slide here with our milestone is very similar to the slide that I showed in January at the JPMorgan conference, just with the addition of some new work and new programs that we've begun this year and announced this year at Amicus. The checkmarks in Fabry are milestones that we've already delivered and achieved, including some of the enrollment achievements within these programs for Study 012 and 013.

But we still have to deliver, of course, the final 013 data, additional preliminary data, I should say, for Q4 of this year. That will come by the end of the year, as well as the Phase III Study 011 results for six-month data, which we eagerly await. We're also announcing, of course, on this call , as I did in the beginning, that the Phase III Study 011 12-month data, according to the plan that Pol discussed, will be in the first half of 2013. Which is important, because that gets to reconfirming that the six-month endpoint is the primary endpoint of this study.

But ,as the FDA indicated this past summer, they are willing to consider safety and efficacy in this study, so having the 12-month data we think will further confirm what we hope to be good data at the six-month. And, in addition, the 12-month data could potentially in itself support the filing application here in the United States for Migalastat in Fabry disease.

So many, many different moving parts to the Fabry program. Again, we have our co-formulation program with our partners at JCR Pharmaceuticals and GSK that advances. We expect by the end of this year or early next year to have some updated news on that as well. Many different pieces of Fabry that continue to move forward, but so does our Pompe program. And Pol and David did an excellent job of taking us through some of the Phase II studies as well as the important preclinical and scientific work.

And what's really important there, I think people need to make sure we keep in mind, is that with this combination approach, the use of Chaperones together with enzyme replacement therapies, either as a co-administration with existing therapies or co-developed with our own proprietary next-generation enzyme replacement therapy products, but there are two very important pieces to where we think it could be of benefit to patients, two different parts of the mechanism of action, again, the notion that the small molecule combined with the ERT product can confer additional stability on the ERT product.

So step one -- or one part of the mechanism of action is the increased binding -- the increased activity of the ERT protein through the binding of the small molecule, which we believe could lead to increased uptake of the ERT, of course, having a good therapeutic outcome for patients. But also, the second part of the binding of the small molecule to the ERT product, and that's to reduce the immune profile and the immunogenicity of these proteins. So, more data continues to come in. We'll have more here with the cohort four data in Pompe by the end of this year.

And finally, we have our Parkinson's program. We haven't talked much about that lately, but a busy part of our R&D efforts here at Amicus, again, with that important link and increasingly recognized link between the Gaucher enzyme and Parkinson's. And we'll have some additional data completed by the end of this year with our lead molecule in Parkinson's.

So, continues to be an exciting year and certainly an exciting couple of weeks coming up for Amicus and our shareholders. And with that, operator, we're happy to take any questions.

(Operator Instructions). Our first question comes from the line of Ritu Baral with Canaccord. Your line is open.

Hi, guys. Thanks for taking the question. Glad to hear you guys are all doing okay over there. As we look forward to the six-month data, can you give us an idea of what, in addition to the top-line responder analysis, you might have available by December? Specifically, could we see something like the inclusion graph that we saw in the extension Phase II slide that you put up? I believe it was slide nine, the reduction in GL-3 inclusion?

Yes. Ritu, we are working with GSK to figure out once we do un-blind that study, exactly how we want to present it. We've indicated that we will have the top-line data. You'll certainly know the results of the study. The exact level of detail, we're not quite sure about. Much of that would be presented at a scientific conference in the first quarter, but we'll try to be as detailed as we can, being respectful of science -- the scientific symposia and GSK's needs as well.

Got you. And in the study flow you mentioned that there were two patients who elected not to go from the six-month extension into the open-label portion. What was the reason behind that?

In neither case was it related to drug or any problems with the drug, and in neither case did the physician recommend they come off drug. My understanding is that in both cases it was the patient's choice, related to travel with the study and compliance.

I see. So it wasn't like they've chosen to go onto enzyme or anything like that?

Honestly, I don't know what happened to them afterwards, if they went on to enzyme or not. I don't believe they did, but --

We don't know?

Yes, but I can't confirm that.

Got you. And then, the last question and I'll hop back in to queue. On slide 13, I believe, this was the Pompe combination study, we saw some very strong ghost response in plasma levels, but we see a little more variability when we start going into activity in the muscles. And granted, we're speaking about very, very small ends here, but what should we sort of keep in mind as far as the pharmacodynamics between plasma levels of the combination therapy and then the muscle activity enzyme levels that we're looking at on this slide?

Yes, go ahead. I'll let David comment on that.

Hi, Ritu. This is David. The data from the muscle biopsies is noisier, and it's expected to be noisier because it's a single -- remember, it's only from a single time point, either day three or day seven, and it's a biopsy from a complex tissue and one that is compromised in people with Pompe disease. So we expect it to be noisier than what we're seeing in the plasma, where we get to average over points that are taken every two hours over a 24-hour period.

The encouraging thing -- if I can describe a little analysis that we did recently, if you look at the overall data from cohorts two and three, and you take the data that we have for the biopsies at both day three and day seven, there are data for 11 patients, where we have ERT alone or ERT plus 2220. If we do that, six of the 11 showed an increase and, probably more importantly, the five values that were the largest in magnitude, both in a relative and an absolute sense, were all increases.

Okay.

So did that make sense? So there were 11 measurements, and the five biggest changes observed for any of the 11 patients were all increases.

Got you.

So that gives us confidence that there is a clear overall effect and that we can see an increased uptake in the muscle. But we aren't able to assign the quantitative values and be able to say that this patient is 20% better than that patient, just given the vagaries of the muscle biopsies.

And is there any sort of, I guess, mechanism behind why the overall activity levels look lower at day seven than day three?

Yes, there is a very good reason for that. And we saw that in the animals as well. It's related to the half-life of the enzyme once it gets taken up into lysosomes. So the half-life of the enzyme is days, so at day three it's pretty much peaked and by day seven it's starting to be turned over. So even these lysosomal enzymes, guess where they get turned over? They get turned over in the lysosome. So when GAA gets taken up into lysosomes themselves, any given molecule tends to have a half-life of somewhere between three and six to seven days.

So for the biopsies at day three, it's been taken up and there should be close to the maximum amount. By day seven, depending on the tissue, you're already out at least one or sometimes even two or more half-lives. So it should be lower at that point.

So that also -- the fact that the values at day seven are lower overall than what we see at day three is actually encouraging. That gives us more confidence that the biopsies are a readout that is not being dominated by the noise.

Got it. Great. Thanks for the taking the question, guys.

Great. And, of course, Ritu, we're looking forward to here shortly getting the cohort four data and hopefully that will continue to trend positively. Great. Thank you.

And our next question comes from the line of Anupam Rama with JPMorgan. Your line is open.

Hey, guys. Thank for taking the question. With the 013 results being presented at the genetics meeting later in the week, can you talk about where you are in the planning process for a potential multi-dose study and potential timing of initiation of that study? Thanks.

Yes, that's something that we are actively planning with our colleagues at GSK. In fact, Marc Dunoyer is here, the Head of GSK Rare Diseases, all day today and all day tomorrow with us on a number of these program plans. So we've spent a lot of time thinking about that. We don't yet have guidance for that Anupam. I think at the beginning of the year, in 2013, we'll be able to provide a very clear view of how we see that program as a co-administration with either Fabrazyme or Replagal.

At a very high level, we see that as a multi-dose study, longer-term study. Now, whether that is a study that would be sufficient to expand the label or not, that's something that we need to look at this final data set here and combine that with some regulatory discussion. But I hope very shortly to have a point of view on that.

The good news is the data is very positive and gives us a reason to believe that this is going to be of significant benefit for patients. We'll have the poster presentation the end of this week, and I'm eager to talk to you after we have the specific data out there.

Great. Thanks for taking our question.

You bet.

Thank you. Our next question comes from the line of Bill Tanner with Lazard Capital Markets. Your line is open.

Hi. Thanks for taking the question, maybe for you, John, or anybody on your team. If I just think about the patient disposition in the 011 study and apply Occam's razor, just looking at the retention, what would cause this trial to actually fail? Because one would assume that there's a relationship between patients wanting to stay in the trial and the way they feel that that would be somewhat related to the therapeutic effect of the drug.

Yes, look -- there's two questions, really, though. I think, one, your question of what would cause the study to fail, and secondly, what would give an indication as to whether or not the drug is working?

If you take the totality of everything we know, we've had patients from the Phase II extension study, every one of whom have been on that drug for five to six years, in some cases I think six-and-a-half years now. So those patients, you have 17 of the 23 go into that study. Years later, you have 16 and 17 still taking Migalastat as their only treatment for Fabry disease, never having gone to or gone back to ERT. And now that we have this long-term data, this biopsy data, we're very excited about, that Pol presented this past weekend.

And if you extrapolate that, take it forward then to the 011 study, certainly we're very pleased with compliance, the safety profile, whatever we can and can't read into this study. We're going to look at the data and see where that takes us. We're very convinced that this is a good drug for people with amenable mutations. We're very convinced that we designed the very best study to show that.

So, where the study could go wrong? Obviously, you could have some variability in the biopsies, in where the samples were taken and how they're read. However, and we've been through this with lots of folks, with ourselves a lot as well, that we've controlled for that as best we can -- the size of the biopsy samples, the number of biopsies, the number of capillaries taken, the quantitative nature of the Barisoni methodology.

So, all in, we feel really, really good about this study. There are a lot of studies that you kind of dread getting to that final data point and turning over the big card; we're actually very, very much looking forward to it. We think the drug is hopefully about to help a lot of people with these amenable mutations and we think we designed a very good study to show that. And hopefully, we'll meet the P-value at the primary endpoint. And then, we're also eager to see the 12-month data together with the 012 study.

I think the fact that we're able to get people -- two-thirds of the people who presented for that study to agree to give up ERT, their only drug for a fatal genetic disease, for a study that doesn't even yet have its pivotal data, is pretty remarkable in drug development, so the size of the patient population we're studying with 57 people enrolled in 012.

So if you take a step back and take the totality of it, we feel really good about this program. I'll let -- David or someone else want to comment?

Hi, Bill, this is David. The thing that -- the worst thing that could make a trial fail is safety. Unfortunately, we don't have any concerns on that front.

Yes.

But that's the most important thing. The second most important thing is potentially something that maybe went by a little too quickly in the session today. It's on slide nine. So, the thing that is worse -- the worst thing for the P-value is having patients in the placebo group crossing over and scoring as responders. And remember, there are females in this study, and females with Fabry disease are mosaic, so you're taking a small biopsy of an inhomogeneous tissue and there can be noise.

So that's why slide nine is really important. Look at the three on the right. Those are all three females. They have had biopsies approximately a year apart. They have non-amenable mutations, so they're sort of our surrogate for being the placebo group. And not one of them would have scored as a responder.

So on the left-hand side are the people with responsive mutations. And four out of five show a reduction of 50% of more. Five out of five show a reduction; four out of five were 50% or more. Go to the right. We have three females, which is the hardest possible case. Those are ones with non-amenable mutations, so we don't expect them to show a reduction. With three out of three, they do not score as responders.

So it's four out of five on the left, zero for three on the right, which is exactly what -- if those proportions hold up, it won't -- I don't know what the P-value will be, but there will be a lot of zeros after the decimal point.

So I think that part of slide nine is really the most -- one of the most important new bits of data that we're showing.

Right. And for John or the rest of the team, just in terms of the FDA, what's -- and I appreciate that this is, I guess, theorizing or hypothesizing how flexible the FDA might be. If the Company -- if the trial "fails," but you see -- obviously, you've had good retention.

And then perhaps in some subgroups presumably you could approach the FDA to see how willing they would be to be flexible. But let's say they were not. This is something that if the data are sufficiently encouraging in a subset of patients, you would think about revisiting?

Absolutely. I think, yes -- there are a lot of ways we think to get this drug approved. Certainly, the fastest and cleanest path would be for all of the zeroes on the P-value at the end of the year.

Right.

But then also, remember, this was -- and this -- we designed this study and designed the biostatistics around this, including the primary endpoint and the nature of the biopsies, in a pre-PDUFA V world. Now, post PDUFA V, and I worked very closely as a bio board member, helping to make sure that we had very strong language in there, new pathways for accelerated approval specific to diseases with unmet medical need, especially in the orphan world.

So I think what you're seeing from FDA, I think you've seen it with a number of our peer companies just in the past few months, is an increasing openness from FDA to consider the dramatic unmet needs in some of these diseases and to take the totality of the data. We hope that's not the argument that we have to lead with, but in addition to the six-month data we'll have the 12-month data. In addition to all of that, we'll have the 012 study, again, that's now already fully enrolled with a clinical endpoint. So that's yet another way to potentially get the drug approved.

We have a significant number of secondary and tertiary endpoints, including urine GL-3, that we could look at. So I think, yes, there are a lot different ways, if we were to miss the P-value on this study at six months, that we could still get this drug approved, especially as we sit here tonight. You've got well over 100 people around the world who are taking Migalastat as their only medicine for Fabry, many of whom have given up their lifeline of ERT to take that drug.

So hopefully we'll have a very, very strong body of evidence to move toward approval, but one step at a time. Let's turn over this big card in the next couple of weeks and see where we're at then.

Yes. Okay, thanks. Good luck with that.

Yes, thank you. Thank you, Bill.

Thank you. (Operator Instructions). Our next question is a follow-up from the line of Ritu Baral from Canaccord. Your line is open.

Thanks for taking the follow-up, guys. Can you discuss a little further what the regulatory path for the combo therapy program might look like? Is there any potential at any point to have to do some sort of factorial study? And right now, would the plan be to move forward with approved enzymes? And at what point might the JCR enzymes come into play?

Yes. So there are a lot of factors that we'll have to look at. Obviously, we think that Migalastat will get approved first as a monotherapy for Fabry disease. We do think that for persons with non-amenable mutations who would still need to take one of the approved ERTs, Replagal or Fabrazyme, that we can improve the characteristics of those drugs.

Now, whether we would move for an extensive Phase III program to expand the label, or whether we would do a study to help inform doctors about the drug-drug interaction and how they might be used together, we haven't made that decision yet. There's a couple of other pieces of data that we need to get yet, Ritu. And one of those is something within our control, and that's how quickly we think we can move our own proprietary next-generation ERT that, again, combines Migalastat with our proprietary ERT from our partners at JCR and GSK.

So, again, just indulge us another month or two to have that plan pull together, and I'm confident by the beginning of the year in 2013 we'll be able to articulate a pretty clear path forward for that program.

Got it. And last question, I guess, what was the strategy behind the shift in accounting? Chip, if you could address that? Is there anything new as part of the agreement or any other new accounting rules that, I guess --?

Ritu, I have to tell you, Chip was eagerly hoping that somebody would ask him a question about the details of FASB Accounting Rules that prompted this change. So, Chip, have at it.

Thanks, Ritu. No, it's really a function of the subtle change in the collaboration as we expanded it back in July. So under the old collaboration, most of the payments were flowing from GSK to Amicus. And now, under the new collaboration, there's the potential in the future that Amicus could owe GSK some milestones, mostly related to approval and sales-based milestones around the co-formulation product.

But as a result of that, that puts us into a different revenue recognition category with regard to [AFC] and the different accounting standards there. So that really is what mediated the change, and that's something we've gotten buy-in with [ENY on] and [Dante's International Office] on. So we really just wanted to make sure that that's not the big story here, that the [Gaucher effect], there's no change, deal economics, there's no change, and so that's really where we stand today.

Okay, that makes sense. Thanks. I thought I heard you angling for a question there. If anybody's going to oblige, it's going to be me. So thanks, guys.

Feel free to get back in the queue with further accounting questions. Great.

Thank you. And our next question comes from the line of Mayank Gandhi with Capstone Investments. Your line is open.

Sorry. Good evening. Thank you for -- can you hear me okay?

Yes, we can. Thank you.

Yes, thanks for taking the question. I just want to go back to slide number nine. It's obviously very encouraging data, but if you look on the left side, one of the other takeaways is also that there is a fairly good correlation between the response and the baseline GL-3 inclusion. In other words, patients who have had higher baseline inclusions also seem to be responding stronger and they only felt patient number three has a very low baseline GL-3.

So my question is, in Study 011, how do you actually control for that? Or is there --

So --

Is there any way of controlling for that, I guess?

There is. There's a very good way to control for it. So what we did in that study, which we did not do for these patients that you're looking at on slide nine in the Phase II, what we did to control for this, primarily for the female patients, is to make sure that the patients qualifying, number one, of course, have to have Fabry disease.

Number two, they have to have one of the known responsive genotypes to make them amenable to this treatment. And number three, specific to your question, they have to present with a minimum threshold of GL-3 burden in -- we measure it in urine, but it correlations very tightly with the GL-3 in kidney, as you'd see on biopsy.

So that's how we controlled for it. They have to have at least four times the upper limit of normal of GL-3 as they screen for this study. And what that meant in practice, because men typically have a higher load of GL-3 in the kidney with Fabry disease, about two-thirds of the men who presented with amenable mutations passed the GL-3 screen. Only one-third of the females who presented had sufficient GL-3 load to qualify them for this study.

So for patient, I guess, number there herein the middle, who showed the mean 34% decrease, while that's a good decrease admittedly, it's from a very low baseline already, it's very likely that that patient would not have qualified for our Phase III study. So that's how we control for that.

One important part of the analysis is that every patient is compared to themselves. So wherever you start to score as a responder, there has to be a 50% reduction from wherever you start. So if somebody starts higher, in an absolute sense they have to come down -- they have to have a larger absolute reduction and it has to be more than 50% in order to score as a responder. Similarly, if they start at a lower level, then they have to come down less in an absolute sense, and it just has to be 50% or more from wherever they started.

And when you look at the -- I actually would be careful saying that the ones who started higher showed a bigger response. There is essentially a floor here, just based on -- if you take a biopsy and you stain the material and you do microscopy, there can be things that are occasionally scored as potential inclusions. So that a minimum score could be expected to be a little bit above zero, around 0.1 to 0.2, and that was seen in the paper that we've published already with Professor Barisoni.

So my interpretation of these is that for most of the patients they're basically getting near full clearance, that it's coming down essentially as far as it can come down. So if you start higher, it's a larger difference, but that's because there's a floor. Does that make sense?

Thank you. And I'm not showing any further questions at this time. I'd like to turn the call back over to Mr. John Crowley for closing remarks.

Great. So, thank you, operator. Thank you, everybody, for listening. Thanks to the analysts for the questions. It was a very, very strong Q3, it's been a terrific 2012, and I'm hopeful that it will be a terrific Q4. And I'm expecting that by the end of the year we'll have a chance to all speak again. Thank you.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone, have a wonderful day.