Amicus Therapeutics Inc (FOLD) 2012 Q1 法說會逐字稿

Good day, and welcome to the Amicus Therapeutics First Quarter 2012 Earnings Conference Call. (Operator Instructions) As a reminder, this conference call is being recorded. I would now like to introduce the host for today's conference, Ms. Sara Pellegrino, Director of Investor Relations. Please go ahead, ma'am.

Good afternoon, and thank you for joining our conference call to discuss our first quarter 2012 financial results. Speaking on today's call, we have John Crowley, our Chairman and Chief Executive Officer; Bradley Campbell, our Chief Business Officer; and Chip Baird; our Chief Financial Officer. They are joined by Pol Boudes, our Chief Medical Officer, and David Lockhart, our Chief Scientific Officer, who are also 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 for the Company.

Words such as, but not limited to, believe, expect, anticipate, estimate, intend, likely, should and could, and similar expressions are words identifying forward-looking statements. Although Amicus believes the expectations reflected in such forward-looking statements are based upon reasonable assumptions, there can be no assurance that its expectations will be realized.

Actual results could differ materially from those projected in Amicus' forward-looking statements due to numerous known and unknown risks and uncertainties, including the risk factors described in our annual report on Form 10-K for the year ended December 31, 2011, 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.

Good evening, everybody, and welcome to this, our first quarter 2012 conference call. I am happy, as always, to lead the call, and let me begin by welcoming Chip Baird, who has been with us for nearly a month as our Chief Financial Officer. Chip comes to us after spending the last decade with PTC Therapeutics, so great experience in the rare disease area, and welcome, Chip, and we'll hear shortly from Chip on some of the financials.

After I walk us through some of the recent corporate milestones and specifically in our progress in our Fabry Phase III studies in migalastat as a monotherapy, I will turn it over to Bradley Campbell, our Chief Business Officer. Brad will be providing a status update on our chaperone-ERT combination products, and before I close out the call, Chip again will review the first quarter financials.

So, a very exciting quarter for Amicus. As you all know, in March of this year we successfully raised $62 million in net proceeds from a public offering. It was very strong demand and broad participation. We saw several important new shareholders come into Amicus as long-term investors, we hope. And also we saw some of our long-term shareholders also continue buying shares in Amicus through this offering, and I'd like to welcome any of you to today's call.

We began the year in January at the JPMorgan conference outlining our corporate strategy, our current portfolio, and some very important positive preliminary results from the Phase II study of our pharmacological chaperone migalastat co-administered with enzyme replacement therapy, Fabrazyme, for Fabry disease, known as our Study 013, a very important milestone to the Company. And since that time we have made terrific progress executing against that business strategy and our business plan, and we've done that against a backdrop of continued momentum in the rare and orphan disease area.

I will tell you, I haven't been in this field for a long time. It was very exciting to see the interim results that Vertex announced this week, that molecule, a chaperone against a misfolded protein target in a rare genetic disease, CF. So, we think yet another example of the potential for chaperone therapy, and, again, a very significant development broadly within the rare and orphan disease field. So, the great momentum continues.

Let me highlight a couple of key corporate milestones before I get into some of the more detailed review of the Fabry programs. So, again, solid momentum in all of our ongoing studies. Very importantly and hopefully you've got the press release in front of you, you'll see first a terrific momentum in the enrollment of our Phase III study, 012. That is our second Phase III study. We've announced that we now have a majority of patients already enrolled in that Phase III Study 012. Again, that is our second Phase III study of migalastat as a monotherapy for Fabry disease. And we have achieved this against the heightened global interest for the switching study since the first of the year. So, very, very welcome advancement for the Company and for that program.

Secondly, we have continued to make good progress in our Phase II Study 013, our study of migalastat co-administered with ERTs for Fabry disease. Our current enrollment in that study now includes both patients on Fabrazyme as well as Replagal patients we are treating.

Third, we have now seen two out of four dose cohort groups that have completed enrollment in our Phase II Study 010, as we sit here today. And, again, that's our second chaperone-ERT combination study investigating AT2220 co-administered with the ERT for Pompe disease.

And, finally, we are seeing -- we are currently evaluating the potential for that molecule, AT2220, the Pompe chaperone, to mitigate the ERT-mediated immunogenicity through our ongoing work to define the relative immunogenicity of lumizyme with and without our chaperone.

So, those are some very high level overviews. We are fortunate to have a very strong cash position as we work toward completion of our ongoing studies. We do continue to plan late-stage chaperone-ERT studies, which is very important for how we think about the next stage of development for that important aspect of the technology. And we also continue to work closely alongside our partners at GSK on the necessary activities to prepare the NDA for migalastat as a monotherapy for Fabry disease.

The proceeds from our recent offerings strengthened our balance sheet considerably and will support it as we move along the continuum of innovation with the goal of delivering constant advancements to the patient community in the rare and orphan diseases and, in particular, as we advance closer toward becoming a fully integrated biopharmaceutical company.

There are, of course, many expected milestones to look forward to throughout 2012 from Amicus. We look forward to the consistent strength in patient disposition, especially from our Study 011, and I'll have an update here shortly on where we stand with patient disposition in that study currently.

Also, significant progress with Study 012 enrollment that we can see right now continuing to support our confidence in migalastat as a potential monotherapy for Fabry disease, and to demonstrate the strength of our collaboration with GSK.

So, if we can, let's spend just a few minutes talking about our two separate Phase III registration studies for migalastat as a monotherapy study, studies we refer to as Study 011 and Study 012, respectively, both of which are being conducted with GSK.

Both of these studies are investigating migalastat at an oral dose of 150 mg, administered every other day to Fabry patients identified as having alpha-Gal mutations amenable to migalastat as a monotherapy.

So, for Study 011, or what we refer to as our FACET study, again, a US registration study of migalastat at the oral dose of 150 milligrams every other day. This is a six-month randomized, placebo-controlled study. We had targeted 60 patients enrolled. We enrolled 67. We expect to have the results from this study in the third quarter of this year, reconfirming that guidance previously. We expect that data to support an NDA in the United States.

As a reminder, Study 011 will look at a primary surrogate endpoint, the change in interstitial capillary GL-3 at six months. We designed this study based on direct feedback from the FDA to use the placebo arm and to use the same surrogate endpoint in the same organ in the same cell type that was previously used to support the current conditional approval, the only US approval ever granted for the standard of care ERT in the United States for Fabrazyme.

The Agency also informed us that we were eligible for accelerated approval. We are also confident, based on other elements of this study, including our strict entry criteria, the fully quantitative histological methodology for reading the kidney biopsies, the low study dropout rate, and what we have seen to be a high convergence of patients into our extension studies from the 011 Study, all of that giving us continued confidence in the success of this study.

We do monitor the progress of patients in the Phase III and the Phase III extension studies currently underway, as well as our ongoing Phase II extension study. The patient disposition, as we've talked about before, remains impressive in that study. As a reminder, in the Phase II extension study, as we call our Study 205, 17 patients have been receiving migalastat, some now for more than six years, as the only therapy to directly treat their Fabry disease. Approximately half of the patients enrolled in one of our Phase II studies had been previously enrolled on ERT. And the patients in the extension study who were previously enrolled on ERT, not a one of them has elected to switch back to ERT. So, we think that gives us a great encouragement for the patient experience in that study.

Last quarter I reported patient disposition in our Phase III Study 011, as of January 31, 2012. I'm pleased to provide an update as of April 30, 2012, so very recent data. Again, this Study 011 enrolled 67 patients, 24 males, 43 females. As of April 30, 54 of the 67 patients have completed six months of primary treatment in that study. A number of patients still ongoing in that first six-month period. All 54 of those patients who continued in the six-month treatment extension arm, so of the 54 who completed, all 54, 100% conversion now, have completed the initial six months of treatment. 40 of these 54 patients have completed Study 011. Again, we have others still ongoing in that study.

Now, of those 40, 38 continue in the long-term extension study. So, what I reported back in January, that in that long-term extension study, only 2 patients have withdrawn, and both for personal reasons, those are still the only two people to withdraw from the long-term extension study.

And although we are still blinded to this study, we also remain greatly encouraged, by now more than 150 patient years of experience to date. As I mentioned, we expect to announce Phase III results in the third quarter.

Let me turn now to Study 012. That is our ATTRACT study. It is a registration study of migalastat monotherapy to support approval in the EU as well as satisfying our US Phase IV requirements under subpart H for accelerated approval.

Similar to our FACET study, this study will investigate migalastat 150 milligrams given every other day in patients with amenable mutations. Based on feedback from the EMEA, a difference in the feedback we received from FDA, of course, Study 012 is a randomized open label study to compare migalastat to ERT, either Fabrazyme or Replagal, and as a primary clinical endpoint. That endpoint is kidney function measured by GFR at 18 months. The objective is to show noninferiority using descriptive statistics.

The target enrollment in this study is 50 patients with a 1.5-to-1 randomization rate, drug to -- migalastat-to-ERT. So, we would expect to have 30 patients who began on ERT to switch to migalastat, and 20 patients to remain on ERT.

As of today, as we sit here, a majority of these patients are already enrolled and recruitment is currently underway at 25 clinical sites around the globe. This reflects a significant uptake in the new sites and the pace of enrollment since the beginning of the year. The study, as you know, got going in the second half of 2011.

When we began this year, there were only 10 clinical sites that had been initiated in this 012 Study, and 2 patients randomized. So, tremendous momentum throughout the quarter into this call. We are still guiding toward full enrollment by year end. If that changes, of course, we'll update, but right now that is the current guidance.

We are certainly very encouraged by the interest in patients in switching from ERT to migalastat to be in this study, and thankfully the resolution of the ERT shortage, especially here in the United States, is certainly helping our enrollment.

When we began dosing patients in this study last fall amidst the Fabrazyme supply shortage, we had anticipated that this would be an ex-US study, because our entry criteria specifies that the patient be on at least 80% of the labeled dose of ERT, among other inclusion criteria. Since that shortage has resolved and US patients are now returning to full dose ERT, we do now have patients enrolled and are experiencing increased activity at sites here in the United States.

So, this overall activity in enrollment in Study 012 is tremendously encouraging. It is tracking ahead of our expectations and we are confident in meeting that target to dose the final patient by the end of this year.

So, just a brief summary before I turn it over to Brad. Our Phase III registration studies are certainly helping to shape the opportunity for migalastat as a monotherapy for Fabry disease. We continue to believe it will address approximately 40% to 50% of the total Fabry population based on genotype.

For people with Fabry with amenable mutations, migalastat has the potential, we believe to become a once every-other-day oral alternative to the current standard of care, which is a biweekly ERT infusion. But our overall goal, of course, is to address the entire Fabry population.

In our Phase II study of migalastat in combination with ERT is an important step toward potentially improving ERT outcomes for Fabry patients with nonamenable mutations, who would need to remain on ERT and who would seek a better treatment.

The use of pharmacological chaperones in combination with ERT may potentially help improve patient outcomes with the ERT. The chaperone-ERT therapy also has the potential to address some of the limitations that exist with the current standard of care, the ERTs, for all LSDs, issues including protein instability and immunogenicity specifically.

We are examining this right now in our ongoing Phase II studies in both Fabry and Pompe. We believe we have the potential to apply the same next-generation treatment approach with additional chaperone-ERT combinations for other lysosomal disorders. We seek to do that along this continuum of innovation that we have described for several months now. Our goal at every point along that continuum is to strive to improve upon the current treatment paradigm in order to make these patients lives better.

So, with that, let me hand the call over to Bradley, to talk more about our chaperone-ERT combination program, the most important aspect of our pipeline and technology.

Thanks, John. Good evening, everybody. Let me just reiterate one thing, that while we do believe the enzyme replacement therapies were an important first step in the treatment of lysosomal storage disorders, our vision is to use the chaperone-ERT combination platform to create better therapies for patients with LSDs.

Our top priority is to improve efficacy and potentially reduce immunogenicity by combining ETs with our specific pharmacological chaperones. And along our continuum of innovation, this might include combinations with next-generation ERTs or perhaps improve delivery modalities, but we are first and foremost looking for significant improvements with the existing standard of care ERTs.

Right now we are evaluating chaperone-ERT combinations in Phase II studies, in Fabry and Pompe, and in preclinical studies, in Gaucher and other undisclosed LSD targets, where there is a significant opportunity to improve current ERT products. A reminder under our Fabry collaboration with GSK, we are developing migalastat as a monotherapy and in combination with ERT, but we retain exclusive rights to all of our other programs.

So, most of you are familiar with this by now, but when co-administered with ERT, pharmacological chaperones are designed to bind to and stabilize the infused recombinant enzyme in the circulation of patients as they receive their ERT. Because the chaperone is binding to the recombinant enzyme rather than the patient's own enzyme, this approach has the potential to improve ERT outcomes regardless of the patient's mutation type.

Preclinical chaperone-ERT combination studies in animal models of Fabry, Pompe and Gaucher have shown that a pharmacological chaperone can effectively bind to and stabilize the recombinant enzyme, prevent deactivation in circulation, increase uptake of active enzyme to key tissues of disease. In addition, in Fabry and Pompe animal models, we have shown that this increased activity and tissue uptake has led to greater substrate reduction than ERT alone.

Based on the preclinical data we generated so far, we are conducting two Phase II open label studies, one for Fabry and one for Pompe, to evaluate our first two chaperone-ERT combinations in the clinic. While our Fabry monotherapy studies investigating an oral every-other-day dosing regimen to chaperone a patient's own enzyme, our co-administration studies are using an oral chaperone only just prior to ERT infusion to improve the stability of the ERT while it is in the circulation.

So, patients in each study will be compared to themselves at two subsequent ERT infusions. Patients will first receive their ERT alone, and then just prior to their next ERT infusion, receive a single oral dose of the chaperone. Both of these studies are designed to evaluate safety and whether the presence of a chaperone increases active enzyme in plasma and in key tissues -- skin for Fabry and muscle for Pompe compared to ERT alone.

In the beginning of the year you will recall that we presented positive preliminary results from Study 013, the Phase II study of migalastat co-administered with ERT for Fabry disease. These data described the first seven subjects in Study 013 who received either full or half-dose Fabrazyme co-administered with migalastat at 150 mg. We are very encouraged to see the co-administration increased uptake of active enzyme in plasma and skin versus Fabrazyme alone, and that the magnitude of these increases were consistent with what we saw in Fabry knockout mice.

Right now we have patients enrolled in Study 013 to receive full dose Fabrazyme co-administered with migalastat at 450 mg, as well as Replagal co-administered with migalastat.

We currently expect to provide an update from this study in the third quarter of 2012, and to present final results at the fall of 2012 scientific conference.

And although we did design this study to be as flexible as possible, given the change in dynamics in the Fabry marketplace, it has been influenced by recent events so let me quickly highlight two of them.

The first relates to the ERT supply shortage, which, as you know, has recently resolved. So, when we completed the first group of patients on migalastat 150 milligrams co-administered with half-dose Fabrazyme at 0.5 milligram per kilogram every other week, or full-dose Fabrazyme at 1 milligram per kilogram administered once per month. Now that patients are able to return to their labeled dose, our higher dose of migalastat 450 milligrams is being co-administered with Fabrazyme in patients who are receiving their normal dose of 1 milligram per kilogram every other week.

The second factor impacting Study 0l3 is the withdrawal of the BLA submission for Replagal. So, now that Replagal is not expected to receive US marketing approval, we will not be enrolling patients on Replagal in the US for Study 013. However while we don't expect Replagal to impact development timelines, it is still a priority for us to look at migalastat in combination with Replagal in ex-US markets, because our collaboration with GSK, as well as our commitment to the Fabry patients and the Fabry community is truly global.

So, we are designing with GSK a repeat dose global study of migalastat co-administered with ERT as the next step in US and global development.

I am going to switch gears a little bit and talk about Pompe disease, where we are also leveraging the chaperone-ERT platform potential. Here, as you know, we are currently running a second Phase II study, Study 010, of chaperone AT2220 co-administered with ERT for patients with Pompe disease. Our Pompe study investigating the ERT myozyme or lumizyme co-administered with 4 ascending doses of AT2220 in approximately 22 male or female patients.

Since we dosed the first patient in December of last year, the study has been very quick to enroll. We have completed enrollment for 2 of the 4 ascending dose groups of AT2220 co-administered with ERT. We were given a green light from our independent Data Safety and Monitoring Board, or DSMB, after the first group completed to move into the second AT2220 dose group. And now the DSMB is scheduled to reconvene next week to review the data from that group.

Patients are already lined up at clinical sites to enroll in the third dose group, and we remain on track for preliminary results in the second quarter of this year, so great progress there.

A little bit more detail for safety purposes in the first two dose groups. We do conduct muscle biopsies 7 days following ERT alone, and 7 days after chaperone-ERT co-administration in order to evaluate uptake of active enzyme into tissue with and without the chaperone, and the amount of AT2220 in muscle. This is a slight difference from the design of the Fabry study, where we're looking in the Pompe study at 7-day biopsies not for enhanced ERT tissue uptake, but rather to ensure that our small molecules largely cleared for muscle tissue.

However, for three patients in the second dose group and for all patients in the next two dose groups, we will be looking at day 3 and day 7 muscle biopsies to compare uptake of active enzyme in tissue with and without AT2220.

That day 3 biopsy was added based on our very encouraging results from the Fabry Study 013, and also in Pompe knockout mice, where we saw greater uptake of active enzyme in tissue in the presence of the chaperone versus ERT alone. Our objective in Study 010 is to replicate in humans what we saw in those animal models.

In parallel with Study 010, we are also evaluating whether the addition of our chaperone AT2220 can mitigate or reduce the immunogenicity of myozyme or lumizyme by stabilizing the enzyme in its properly folded active form. Immune responses occur in a majority of Pompe patients receiving myozyme infusions, which have the potential to limit treatment outcomes with this ERT.

And as part of the grant from the Muscular Dystrophy Association, we are using blood samples from healthy volunteers and from Pompe patients from our Study 010, to determine if particular human leukocyte antigen types, or HLA types, are predictive of clinical immunogenicity to ERT.

So, during the third quarter we expect to have more information on the relative immunogenicity of myozyme and lumizyme with and without AT2220. It is our hope that these results can further guide our investigation of AT2220 on immune response to ERT and future clinical studies.

So, as you can see, there is a lot of momentum along our chaperone-ERT combination platform with multiple additional readouts anticipated throughout the remainder of the year. And with that, I'll turn the call over to our Chief Financial Officer, Chip Baird, who will review our financial results for the first quarter and full year 2012. Chip?

Great. Thanks, Bradley, and good afternoon, everyone. I'm very excited to be here today on my first quarterly call as the CFO of Amicus. Before I turn toward the first quarter of 2012 financial results, I'd like to comment on our cash position and reiterate the full year 2012 financial guidance that we first announced during the JPMorgan conference in January.

Cash and cash equivalents and marketable securities at March 31 totaled $108.2 million compared to $60 million at the beginning of 2012.

Our current cash position includes the $62 million in net proceeds raised in our public offering of common stock, which closed in early March of this year and significantly strengthened our balance sheet.

We continue to expect full year 2012 operating expenses will total between $37 million to $43 million net of anticipated cost-sharing and milestones related to GSK collaboration. As a reminder, GSK is responsible for 75% of the development costs for migalastat in 2012 and beyond, subject to annual and aggregate caps.

We are also 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.

Turning to the financial results, I'll be referring to table 1 in our press release, which is available on our corporate website at www.amicustherapeutics.com. Additional details can also be found in our Form 10-Q to be filed later today.

Turning to the P&L, total revenue was $7.8 million for the first quarter of 2012 compared to $6 million in the prior period. Our total revenue consists of research and collaboration revenues recognized under our collaboration with GSK for migalastat.

Research revenue for the first quarter 2012 was $6.1 million, up from $4.3 million in the year-ago period. The increase is due to a higher reimbursement rate from GSK for share development costs from migalastat, which was 50% in 2011 and 75% in 2012 and beyond.

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 the costs are shared in accordance with this arrangement. Under this arrangement, research revenues are expected to fluctuate quarter-to-quarter relative to our proportional of total migalastat expenses and the percentage we are responsible for paying under the agreement.

Collaboration revenue for the first quarter of 2012 was $1.7 million and reflected the 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 equity investment is being recognized on a straight line basis.

Switching to the expense side of the P&L. Total operating expenses in the first quarter of 2012 were $18.5 million, an increase from $16 million in the prior year period. Operating expenses consist of research and development as well as general and administrative expenses.

Research and development expenses were $14 million in the first quarter of 2012, including $873,000 of stock-based compensation expense compared to $11.1 million in R&D expenses, including $652,000 of noncash stock-based compensation expense in the prior year period. The year-over-year increase in R&D expense was primarily attributable to higher contract research and manufacturing costs within the Fabry program.

General and administrative expense for the first quarter of 2012 were $4.1 million, including $515,000 of noncash stock-based compensation expense, compared to G&A expenses of $4.4 million including $765,000 of stock-based compensation expense in the prior period.

The decrease in the first quarter of 2012 expenses was primarily due to lower personnel costs, consulting and professional fees.

Nonoperating expenses consist primarily of the change in the fair value of the warrant liability, which was a $2.4 million noncash expense in the first quarter of 2012 as compared to a noncash expense of $3.4 million in the first quarter of 2011. Warrants issued in connection with our March 2010 registered direct offering of common stock were recorded as liability at the fair market value on issuance date. The fair value of these warrants increases or decreases with the change in our stock price.

In our financial statements we record the difference between fair value on the issuance date and our closing stock price at each reporting date until the warrants are exercised or expire.

Finally, net loss attributable to common shareholders for the three months ended March 31, 2012 was $13.1 million, or $0.35 per share compared to a net loss of $13.4 million, or $0.39 per share for the same period in 2011. Weighted average common shares outstanding were 37.9 million and 34.5 million for the three months ended March 31, 2012 and 2011, respectively.

This summarizes our key financials for the first quarter and full year 2012. I will also be available to answer questions during the Q&A session of the call. And with that I'll turn things back to John.

Great. Thanks, Chip. So, hopefully everybody can see a lot of momentum at Amicus for all of our ongoing studies, and we certainly have a full calendar of upcoming milestones expected throughout 2012. We continue to move toward our vision of becoming a fully integrated biopharmaceutical company. As I have discussed with many of you, we do intend to be a company that has strengths from research and development all the way, one day, to sales and marketing.

We do continue to advance and leverage our core technology platform to develop chaperone monotherapy and chaperone-ERT combination therapies. We have a terrific collaboration with GSK rare diseases, and we continue to strengthen that relationship, and we continue with GSK to move toward our shared vision to deliver benefits to patients and their families who are affected by these rare and orphan diseases.

And so with everything we just covered on the call today and for all of our efforts, and for everybody here at Amicus, we sit here today with a market capitalization of just over $200 million. As Chip indicated, we have a cash position at the end of Q1 of just over $108 million. So, today approximately an implied program and technology value of just over $100 million for all of the clinical and preclinical activities here at Amicus. We think this represents a terrific value proposition for investors today and one that we continue to hope to drive forward in the many months and years to come. With that, Operator, we are happy to take questions.

Thank you. (Operator Instructions) We have a question from Ritu Baral with Canaccord Genuity. Please go ahead.

Hi, guys. Thanks for taking the question. First question, what do you think is driving the much, much faster 012 enrollment, the ATTRACT trial enrollment versus 011? Is it just the entry criteria difference or is it the shortage as well? What factors should we be thinking of?

No, this was a study, as we talked about, Ritu, we were concerned about enrollment timelines here, because it's a big deal to ask people to come off of an existing therapy, lifesaving therapy for a fatal genetic disease and to come on to migalastat as their only therapy for Fabry. That's a big deal difference in 011. And although, yes, you're correct, we don't have biopsies here.

This, I think, speaks to hopefully the now more than 150 years of safety data and patient data. The strength of those 17 people who continue now for some of the more than six years. I think it's just the totality of the experience and the data, and the ongoing momentum in the studies, I think. Hopefully, success builds on success. I think obviously patients and physicians look, just as you guys do, to the patient disposition in the current 011 study. We are very much blinded to that data, so we don't know any of the results. But what we do know is that patients, at least from a tolerability standpoint, seem to be having a good experience, and the 100% conversion into the extension study is pretty remarkable. And I think all those factors come into play.

And I can tell you, also, too, we've learned a lot from the execution side, and our clinical operations team has done a remarkable job together with GSK at making sure that we are on top of every item in terms of clinical research and operations to ensure that everything within our control is controlled for. So, all those experiences I think bode very well.

Is there significant trial site overlap between the two studies?

There is significant overlap, but there are a number of those 25 studies that are new sites, but there is a significant amount of overlap.

And next question. On the Pompe program, can you talk a little bit or be -- give some description as to the doses that you're using in the dose ascension? Are we looking at sort of doubling and tripling, or are we talking about more incremental steps up in dosing?

No, I think it's the former. Without giving specifics, I don't think it's on clinicaltrials.gov. We just have indicated we're starting at a low dose moving to a higher dose. That higher dose is still quite a bit lower than what we used years ago as a monotherapy. But we are moving up, in some cases doubling the dose, so significant.

And also very important to remember, very consistent with the animal studies that we did. In many ways what we're doing in the 010 Pompe study, just like we did in the Fabry 013 is hoping to recreate in patients the very positive results that we saw in animals in terms of the safety of the interaction of small molecule in the ERT, the enhanced tissue uptake, and in this case we're not looking specifically at substrate reduction, but a surrogate marker like plasma, increased plasma activity, the ERT is very important.

And remember that, as I know you know, the dose that we're using is much lower than what we used in the monotherapy study with AT2220, and then also the dosing regimen is very different. The drug is only given once every two weeks prior to the infusion as opposed to three times a week as it was with the monotherapy. So, the overall amount of drug used in the combo is far less than what was used previously.

I just want to clarify, too, and Bradley went into great detail, too, on the biopsies. Again, we're very concerned with safety here. We want to make sure, as excited as we are about the data for the animal studies, we want to make sure as we translate this hopefully into people with Fabry that we do it in a very measured fashion.

So, as Brad indicated, just to reiterate, the first patients who had the biopsies only had the biopsies at baseline and then at day 7, where we were looking primarily for the presence of the small molecule. And then when we went to the second cohort, we had some patients -- everybody at baseline, some patients at day 3 and some patients at day 7, and (inaudible).

Was there a particular observation that triggered the addition of the day 3 biopsy, or was it something in the pharmacokinetics?

I'm sorry, could you repeat that?

Was there something in the -- in your observation of the first cohort that triggered the addition of the day 3, or was it something in the sort of pharmacokinetics of the drug?

No, actually, it was the very positive experience in the 013 Study, where we saw the day 2 biopsies significantly enhanced tissue uptake of the Fabrazyme. That gave us great encouragement in the proof of concept, and that's when we went back and amended the protocol to include day 3 biopsies. And just to clarify, too, Pol just passed me a short note here. They are not baseline biopsies for these patients; it's day 3 and day 7. Go ahead and clarify, Pol.

Yes, you compare -- each patient is going to be compared with the same timing, so you compare the patient with the same data. So, your day 3 patients are day 7 patients. You're going to have the first biopsy without the chaperone and the second biopsy with the chaperone.

And so the direct comparison there is ERT alone or ERT plus the small molecule.

Right. Yes, sorry I missed those. So, each patient gets two muscle biopsies total. Yes, I'm sorry, I missed those.

And, too, it's just a matter of balancing out how many biopsies can you reasonably do in a study like this, and so that's what we were trying to balance from the safety in the second biopsy.

Great. And last question and I'll hop back in the queue. You mentioned briefly, or you referred to the next study in the Fabry combination therapy. Can you give any more detail about what it might look like? How many arms? Would you have to look at the two components separately in that study, or would it be a simple two-arm study?

That is exactly what we're thinking through right now. We can think very simply, what we're trying to prove is that the addition, the oral administration of the chaperone here, migalastat, has a better outcome for patients than ERT alone.

So, it might be as simple as a two-arm study -- one arm on ERT alone, one arm ERT plus co-administration of the chaperone. The important thing is that unlike the 0l3 Study, it will be repeat dosing. The exact endpoint we're not clear on. There's a couple of different ones that we could look to. Obviously, we'd like to default to the one that is not only dispositive, but the one that might provide the most insight as to the change that we would expect to see.

Great. Thanks for taking the question, guys.

Yes, always. Thank you.

Thank you. And our next question is from the line of Joseph Schwartz with Leerink Swann. Please go ahead.

Hi. Thank you very much. I was wondering, just continuing on the Pompe combination study theme, what types of patients are you enrolling? What kinds of Pompe patients are these? Early or late onset patients? Are they naive or treatment-experienced? Are they patients with antibodies that have formed yet, or not?

I'll let Pol Boudes, our CMO, comment on that, Joe.

The patients we are enrolling are late onset patients. There are adult patients, and they are treated with ERT. So, they are not naive patients.

And remember, Joe, one of the important parts of the study is that we are studying patients who are on ERT, and we don't change their ERT regimen at all. All we do is add in -- on one of their infusions we add in a pre-oral dose of the small molecule. So, patients on ERT, we don't preselect based on titer, on antibody titer, we don't preselect based on mutation. They are on ERT and we leave their ERT regimen alone; we just add on, on top of that, a pre-oral dose of the small molecule.

Okay. Will you be able to see what, assuming you capture that information, what kinds of responses or how the responses vary based on whether a patient has a certain level of antibodies or not?

so, this is just a single administration study. So, we are measuring their titers and we will be able to tell if the antibody titer affects the circulated -- the effect on the PK or the uptake. But this is only a single administration study, so we don't expect to see changes in glycogen or other functional measures in this study.

Yes, right, okay. And then what muscles are you biopsying?

The quad.

Okay. And do you have any milestones from -- if the 011 Study is successful and you hit your primary endpoint, I think you're entitled to some milestones from GSK. Do you have that embedded in your financial guidance for 2012? I forget.

Yes. Remember, again, it's $170 million in total milestones. We've guided, Joe, that roughly half of them are clinical and regulatory milestones. The other half are sales commercial milestones for 011. We've also stated that we don't expect any significant milestones this year.

We are eligible for some, but the larger one related to some of the end-stage clinical and regulatory triggers, like the ones you've just indicated, the ones that would be expected to be in the tens of millions of dollars, we don't expect those in 2012. And likewise in all of our cash guidance, we never include any of the milestones.

That's very helpful, thank you. Can I just sneak one more in on the --

By all means.

-- thank you -- the two chaperones which you are developing for Gaucher, AT2101 and 3375. How do they differ? Is one better or different than the other in any meaningful way?

Yes, I'll let David comment.

So, 2101, Plicera was the molecule that we developed initially for monotherapy for Gaucher. That one is also a good candidate for possible use in the combo. AT3375 is a newer molecule that we had developed in part as part of our Parkinson's work. It has greater brain penetration. It is just as potent. In terms of the molecular interaction it is more potent in vivo. And it is a synthetic derivative of AT2101. So, they are related molecules in the same chemical class, but 3375 was selected because of some properties that we were looking for, brain penetrants and exit from cells and tissue and the lysosome.

If it's more potent, would it be tougher or easier to dose it in order to not overdose it and have it be an inhibitor, or does it not work like that?

It may mean that the dose that we can use is lower, but that, of course, will -- that is in the process of being tested. So, it is possible that the dose could be lower. And it leaves cells and tissues and lysosomes more quickly, so that could make it so we have less of any inhibition from the molecule so that we get a greater effect from the enzyme, from the additional enzyme.

And so would you maybe then dose it every day, do you think? Is that a possibility, unlike the (inaudible)?

So, I the context of the combo, it would still be given just as a pre-oral dose initially when the infusion, just before the infusion. So, as a combo therapy, the dosing is very different and so that would just be prior to the start of the infusion so that it can help stabilize the infused enzyme. So, it wouldn't be given every other day or multiple times a week; it would only be given once every other week with the infusion.

Very helpful. Thank you very much.

Thanks, Joe. Have a great night.

Thank you. (Operator Instructions). And our next question is from the line of Anupam Rama with JP Morgan. Please go ahead. Please check your mute button.

Sorry, I was on mute. Hi, guys. Thanks for taking our question. Coming out of the WORLD meeting, one of the questions we get a lot is about the amenable mutations for migalastat. If I remember correctly, if you look at the baseline data, the percentage of amenable mutations from migalastat was a little bit higher than sort of the 40%, 50% that you've quoted. Can you comment a little bit about how we should think about that and if the baseline data are reflective of what you might see outside of the clinical trial setting? Thanks.

Go ahead, David.

So, from the pharmacogenetics work, we've determined that it's around 60% of the missense mutations are -- can show an effect with the small molecule when tested in cells outside the body. And then in Fabry disease, around 60% to 65% of the mutations are missense. So, that leads us to say that about 35% to 40% of the mutations in the world are likely to be amenable to the small molecule in vivo.

I think you are referring to the Phase III baseline numbers. In that case, remember that physicians already knew that this was a monotherapy study for pharmacological chaperone, so they already knew to be looking for missense mutations, when the mutation was known. So, there was already some selection bias based on what they already knew. But they were not selecting patients for screening based strictly on our pharmacogenetic table.

So, in fact, there were patients that came in with mutations that were not amenable. There were patients who came in with mutations that had never been seen before. We actually found 15 mutations that had never been reported in the literature for a Fabry patient. So, it was a larger percentage than you would get if you just randomly selected Fabry patients from the population. That's why the number in the Phase III screening was larger.

But our estimate of saying that if you took the entire Fabry population, we still estimate, based on everything we know, that the small molecule should be appropriate for, as a monotherapy, for between 40% and 50% of the Fabry population. And that percentage, we believe, is actually growing with time, because with time it's clear that Fabry disease is probably more common than was previously thought. Maybe as large in some studies as 1 in 2,000 or so in the population. And these additional patients that are being found with much higher frequency have missense mutations, and those mutations that are being found are more likely to be amenable missense mutations.

So, if you take the Fabry population as it exists now, probably around 35% or so, and with time, as more of the later onset patients are being found, they are with high probability missense, and they are higher probability amenable missense, and that's how the percentage grows to upwards of around 50%.

Great. Thanks for taking our question.

And we have a follow-up from the line of Ritu Baral with Canaccord. Please go ahead.

Hi, guys. Thanks for taking the follow-up. Just in reference to the immunogenicity study that you are doing with 2220, ultimately what do you, I guess, think at this point the clinical benefit for 2220 will be based on, reduction in immunogenicity or increased potency? What do you think will ultimately -- do you suspect ultimately it will be more important?

I don't know about more important, Ritu. I think they're both very important and it's important to remember they're both very related. They go with each other. The immunogenicity of these proteins, especially lumizyme, isn't necessarily -- it's not tolerated by patients, even though lumizyme does, I believe, have a black box warning and there is some anaphylaxis associated with it. Typically, that can be managed.

The greater concern around immune response to these proteins are the antibodies that are triggered can attach to the ERT and take them to non-target tissue, non-target organs. So, in the case of Pompe, the antibodies are really rendering much of the ERT not effective in dealing with the course of the disease. It is taking it to places other than [normal]. That's why it's so important in these studies that we're doing right now and, again, that we've announced just here tonight, that we're going to have the data in Q3, the (inaudible) and other studies that we'll be able to categorize first, what is the immunogenicity in the immune profile of the lumizyme ERT? And then, secondly, at varying dose concentrations with our chaperone, can we mitigate that immune response? And that is going to be a very, very important series of findings that will help guide what that next series of clinical studies should be.

Great. Thanks for taking the follow-up.

Yes. And let me just add, again, we don't think this is limited just to lumizyme. We think this is going to be a problem with any Pompe ERT that we see in development today, either in the clinic or the ones that we know of in preclinical development. And, again, it's the same phenomenon, although maybe to different degrees, than we've seen with any of the ERTs that we've tested in any of the lysosomal storage disorders.

Thank you. This concludes the Q&A portion of today's conference call. Thank you for your participation in the Amicus Therapeutics First Quarter 2012 Earnings Conference Call. This does conclude the program and you may now disconnect. Thank you and have a wonderful day.

Great. Thank you all for listening. Have a good night.