Amicus Therapeutics Inc (FOLD) 2012 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Amicus Therapeutics full-year 2012 results conference call. At this time, all participants are in a listen-only month. And later, we will conduct a question-and-answer session and instructions will follow at that time.

(Operator instructions)

As a reminder, this conference may be recorded.

I would now like to introduce your host for today's conference, Sara Pellegrino. Ma'am, you may begin.

Good evening and thank you for joining our conference call to discuss our full-year 2012 financial results.

Speaking on today's call, we have John Crowley, Chairman and Chief Executive Officer; and Chip Baird, our Chief Financial Officer. Bradley Campbell, our Chief Business Officer, and David Lockhart, our Chief Scientific Officer, are also on today's call and available to participate in the Q&A session.

Today's remarks coincide with the slide presentation that now is 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 2, you will find a reference to our Safe Harbor statement. This conference call contains 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 clinical trials evaluating Amicus candidate drug products.

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 events through 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, 2012. All forward-looking statements are qualified in their entirety by this cautionary statement and Amicus undertakes no obligation to revise or update this presentation to reflect events or circumstances after the date hereof.

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, and good evening, everybody. It is a pleasure as always.

We will recap where we were in 2012 and much of my discussion here before I turn it over to Chip for the financial overview will be focused on where we are today and what we see as some of the key milestones as we head forward into 2013, which, as we have indicated through a number of investor meetings with many of you over the last several weeks, will be an incredibly important year where I really believe we are finally going to realize in the clinic the true potential of these drugs being developed. And again, for a number of years, what we have sought to do is to use this pharmacological chaperone technology to make medicines, to build drugs that can fundamentally change people's lives. And, as we ended 2012, we had the first glimpse into the most significant of the clinical studies we have ever done in Fabry disease and, of course, that is Migalastat for our monotherapy.

So if you look and on the agenda slide here on Slide 3, you will see I will begin with Migalastat monotherapy for Fabry, an overview, give you the current state of that program and what to expect as we head into this year. I'll also then highlight the new CHART, our Chaperone-Advanced Replacement Therapy platform technology, our proprietary platform, and where that stands in now multiple programs, including the clinical data, as well. And then, of course, turn it over to Chip for financial results in fiscal year 2012, and also for guidance on fiscal year '13. And, of course, my full team will be here and happy as always to take any questions. So, as we started to do last year, we've used PowerPoint slides so for those of you who have your computer handy, feel free, of course, to join along. I am on Slide 4.

And here what we really want to highlight is where we are in Study 011. And as you remember, as we ended 2012, we shared the preliminary data, or the interim data, from Stage 1 of Study 011. And that again, a 60-person study, 30 people randomized to placebos, 30 people randomized to Migalastat. Looking on a primary endpoint to see if we would see meaningful changes and statistical changes, placebo versus the active group. On that interim analysis, we saw encouraging data. And if you recall, we ended that study with 59 people having completed this 12-month period. 57 of those persons voluntarily elected to continue into the next year of the extension study. And as we sit here today, all 57 people continue on that drug, on Migalastat, as their only treatment, disease-modifying treatment for Fabry disease.

So I won't reiterate much of what we have talked about over the last couple of months in a couple of calls, as well as numerous presentations, including the updated data that we saw from the WORLD meeting back in Orlando in the middle of February. Again, I will just reiterate that what we saw was encouraging, and certainly merits continued study of the drug. We, in looking at that data, of course, looked at the primary endpoint where we did not achieve statistical significance at the six-month period of the Stage 1 analysis, but again, on a post-hoc analysis, as you saw, we did see changes above a 0.3 inclusion body cut off.

Beyond that, though -- beyond the yes/no responder analysis, what we actually saw was, looking at the total amount of GL-3 analyzed as a continuous variable, we saw very encouraging trends, as well, almost meeting statistical significance even on this interim look. Again, a median reduction of 41% versus just 6% in the placebo group. We also, of course, saw encouraging kidney function data as measured by estimated GFR after six months, and a very favorable safety profile with no treatment-related adverse events.

Again, we see patient compliance to be strong. As we've indicated over the last couple of weeks, we are spending a significant amount of time internally with our partners at GSK, with some key consultants, and now engaging the FDA in a review of the interim data, as well as looking forward to the 12-month data. It is important to remember that the people in this study, we have already collected all of their 12-month data and samples, including those very important biopsies. The analysis of those biopsies is ongoing by the pathologists. We are of course blinded to it. Moreover, we have not yet locked the database in that study.

So as we engage in the further analysis of the data that we do have on the Stage 1 data set, we are also now working again with all those constituencies to make sure that as we look forward to the 12-month data, that we are looking at the right data, the right data sets, again with an eye toward the 6 and 12-month data, efficacy, and safety to support conditional approval of Migalastat for people with amenable mutations with Fabry disease.

So we continue to be encouraged. We think based on the work that we are doing, the encouraging data that we have seen to date, and these ongoing discussions with FDA, we have previously guided that the 12-month data would be late 2Q or early Q3. It is smarter now and we are now guiding to expect this in the third quarter. And again it is very important to note that we continue to collect the data in a blinded fashion. And we will not be unblinded, and once we are, of course, in a very timely fashion, as we have done before, we'll release it in a top-line manner.

We want to make sure that we have the ability to put together the most compelling and rigorous data set possible once we see that 12-month set of data. And it is also important to remember now, as we are working on potentially even further revising the statistical analysis plan at 12 months, that again we want to do that in the most rigorous of fashions.

Also, too, I will note that when it comes to the patients for whom this drug would be appropriate, that we expect to seek a label for patients with amenable mutations. And we do not anticipate that we will have any label restriction for baseline interstitial capillary GL-3. Of course, that is not practical as kidney functions are almost never done in a clinical practice.

So we're moving forward. We are in good shape on Study 011 and we're very much looking forward to seeing that data. If it is consistent with what we saw in Phase 2, we would hope to be able to see that for patients who have been on Migalastat for the full 12 months of that study, that compared to 6 months, that they continued to show clearance of GL-3 in those kidney cells and, importantly, for people who switched from placebo to Migalastat, that we started to see a change in direction of their total amount of GL-3, particularly as we look at it over time on that continuous variable. So again, the persistence and durability of the effect of this medicine is critically important to evaluating the full safety and efficacy.

I will just note briefly, and again, still following along on this Slide 4 here, that our Study 012 continues to go very well. That is our second study for approval for Fabry disease for Migalastat. That was the study designed -- looking at a primary clinical outcome, 18-month study, looking at a direct measure of kidney function by iohexol GFR, again, over that 18 -month treatment period. If you recall from 2012, looking back, we saw rapid enrollment of those patients. Every one of them had been stable on either Fabrazyme or Replagal as their only treatments for Fabry disease. And we had a 1.5 to 1 randomization again.

So 36 of those patients who enrolled of the 60, stopping completely their ERT treatment and moving over to Migalastat. And as we are on this call here today, we continue to see very high compliance in that study, which we think is very encouraging to date. And again, that data, given that it is an 18-month study, last patient in was December of '12, the data is anticipated in the second half of 2014. So that is where we are in the Migalastat monotherapy program.

Let me highlight on Slide 5 where we are in the combination therapies. And again, if you remember, the whole concept here is that we are using small molecule chaperones to stabilize human recombinant proteins, bioreactor-made enzymes, either used as co-administration, as you will see at the top there, chaperones or proprietary chaperones, together with currently marketed ERTs, where the second application of this CHART platform technology is in the development of our own proprietary next-generation enzyme replacement therapies. And again, those are ERTs co-formulated with our proprietary chaperones and our proprietary enzymes. And that all fits into the continuum of innovation that we have described before.

And the third application that you see on that slide there, 5, is using the CHART platform technology to develop next-generation enzyme replacement therapies that have the potential for improved delivery regimen. And if you recall, a couple of months ago at the JPMorgan conference, I had opportunity to share for the first time some of the very promising data we have showing the ability to use these small molecules directly co-formulated with ERT to stabilize the ERT to such a degree that we may well be able to deliver these enzyme subcutaneously.

And I'll just highlight -- we did at the Cowen conference last week have an opportunity to roll out this branding of the platform technology, again using CHART as Chaperone-Advanced Replacement Therapy. The logo, I will comment our team here at Amicus for coming up with this internally. The logo here showing the forward-looking motion, again charting the future, for what we think could be the future of these treatment paradigms in a Lysosomal Storage Disorders, and the ribbon structures also looking forward, representing the protein with a small dot, of course, at the active site, or nexus of the protein.

So a clever logo and one hopefully that we will continue to be able to use very effectively with all of our key constituencies, patients, physicians, key scientists, and of course the investment community. And again, we really think that this has the potential to be the greatest value driver for Amicus in the years to come, the ability to leverage this CHART platform.

If you turn to Slide 6, we'll talk a little bit about where we are for Pompe disease. If you remember, again at the beginning of January, we had the opportunity to share the proof-of-concept data from our Phase II study, or Study 010, and that was our drug, AT2220. It was orally co-administered in a single dose together with Myozyme or Lumizyme, the currently marketed ERTs for Pompe disease. The results of that study demonstrated that the co-administration increased uptake of the Pompe enzyme with the a recombinant GAA intramuscle compared to the ERT alone.

And again, in preclinical studies of that molecule co-administered with the ERT and co-formulated with ERT, we also saw increased enzyme uptake into tissue, which also translated to further reduction of the glycogen compared to the ERT alone. So we have moved forward and last year, we actually, when we first saw the early pieces of this data looking so positive, we, at risk, began a project to formulate this molecule in an IV formulation. And we're doing that, because we actually have preclinical data that it could potentially have an even improved PK profile. And also, a very practical consideration that, of course, since patients will still be receiving their ERT, it is no added burden to the patients and moreover, it will actually allow better control of the administration of the drug and also many patients, particularly the children with Pompe, are actually unable to take oral medications.

So that, again, excellent proof of concept. This will be a very important study for Amicus, this next co-administration study using the CHART technology, it will be a repeat-dose clinical study. We are guiding again that this is expected to begin in the third quarter of this year. Manufacturing of the drug is completed. It is now in its final preclinical studies and tox studies. And the protocol development is nearly complete. We expect this to be a repeat-dose study, approximately 12 to maybe 24 weeks in duration. We will look at safety and PK in muscle. We expect people who have never been on ERT before to be in this study, as well as treatment-experienced people. So this will give us a very important data set. Again, seeing can we change in a positive way the PK profile of Myozyme or Lumizyme, can we enhance their tissue uptake? And we will also, of course, look up at the immunogenicity and what impact the chaperone addition might have on affecting the immune response to ERT.

So, that is the co-administration and that is a program we fully intend to develop moving forward as a separate program. We also have on the continuum of innovation, our next-generation enzyme replacement therapy that is a proprietary ERT that we are developing here at Amicus. And that is one that will be co-formulated with the chaperone together with other changes to the ERT that we think might improve its profile and its ability to target muscle tissues. So, much work continues in the monotherapy, and more and more, a good part of Amicus is focused on advancing our CHART technologies, both in the co-administration setting, as well as co-formulation with our own proprietary next-generation enzyme replacement therapies.

So that is my overview of the programs. I will now turn it over to Chip and Chip can take us through the fiscal year '12 financial highlights and the guidance for this year. So, Chip, all yours.

Great, thanks John, and good afternoon, everyone.

I will start today's financial discussion with a few comments on our current cash position and guidance and here I am on Slide 7. As previously announced at the JPMorgan conference in January, we began 2013 in a strong balance sheet position with $99.1 million in cash, as compared to $55.7 million at the beginning of 2012. For the full-year 2012, net operating expenses were $40.7 million. This amount was net of cash reimbursed by GSK who shared global development of Migalastat and I'm pleased to report that was within our guidance range of $37 million to $43 million.

Looking ahead, we continue to estimate full-year 2013 net cash spend of between $52 million to $58 million. And again, that is net of anticipated cost sharing under the GSK collaboration. As a reminder, GSK is responsible for 60% of the global development costs for Migalastat in 2013 and beyond, and our current cash position, along with these anticipated GSK reimbursements, projected to fund our operating plan into the second half of 2014.

Turning it over to Slide 8, you'll find a snapshot of our full-year financial results, which also appear in Tables 1 and 2 of today's press release, which we put out after market close. Additional details can be found in our annual report on Form 10-K, which will be filed later this evening. For the 12 months ended December 31, 2012, total revenue was $18.4 million. That's compared to $21.4 million in the year-ago full period. The slight year-over-year decrease is attributed to a change in revenue recognition accounting at the expanded GSK collaboration. This accounting change does not impact cash and we will explain more detail on this in the following slides.

Operating expenses for the full-year 2012 totaled $71.3 million compared to $72.3 million in the full-year 2011. The year-over-year decrease in expenses was primarily attributed to lower research and development expense, as well as a decrease in personnel costs.

Moving down to P&L, we had a nonoperating income of $901,000 in the full-year 2012 compared to nonoperating income of $2.8 million in the year-ago period. The change in nonoperating income, which importantly is a non-cash item, is primarily due to the change in valuation of our warrant liability.

Finally, net loss attributable to common shareholders in the full-year 2012 was $48.8 million compared to a net loss of $44.4 million in the full-year 2011. The wider net loss versus the year-ago period is attributable principally to the change in the revenue recognition under the expanded GSK collaboration. Our per share basis for the 2012 net loss was $1.07 compared to a net loss of $1.28 in 2011. The narrower net loss per share versus the year-ago period reflects an increase in the shares outstanding as a result of our March 2012 follow-on public offering and shares issued in conjunction with the GSK collaboration expansion in July of 2012. As of December 31, 2012, we had 49.6 million shares outstanding.

Finally, turning our attention to slide 9, I will provide a brief reminder on the change in revenue recognition accounting under the GSK collaboration. So, beginning in the third quarter of 2012, payments received from GSK under the agreement are being recorded in the deferred reimbursements account on the balance sheet. Deferred reimbursements balance on December 31, 2012 totaled $30.4 million. And that consists of $7.7 million in cash reimbursed by GSK under the Fabry cost-sharing arrangement during the second half of 2012, as well as $22.7 million for the unrecognized balance of the upfront payment and premium on equity received under the original GSK collaboration in October of 2010.

Previously, research reimbursements from GSK were recognized as research revenue and a straight-line amortization of the total upfront considerations was recognized each quarter as collaboration revenue. So while the recognition of these payments under the expanded GSK collaboration has changed, there's no cash impact and the mechanics of the cost-sharing arrangement remain the same. This summarizes our key financials for the full-year 2012, as well as our full-year of 2013 guidance. More information on our financials will be available in the 10-K, which again, will be available later this evening.

I'm happy to address questions during the Q&A session but for now I will turn it back to John.

Great. Thanks, Chip.

So I will go ahead and end here on Slide number 10, which is our milestones for 2013. Again, these are the clinical milestones that we are going to focus on in the Company. And as we look to make a difference for people with these diseases, which is so important to us, as well as, of course, building significant shareholder value, we see these as the three key drivers of value, hopefully this year. Again, the first being the Migalastat monotherapy program for Fabry disease. We've already delivered the full Study 011 interim data in the science platform presentation of WORLD. Again, now guiding for third-quarter 2013 for the top-line Study 011 12-month data, or the Stage 2 data, that will be very important. And, again, we are moving that to Q3 to give us the time to continue to work with the FDA.

We are fortunate that the study was designed that we have an inter rim look at the data. It has told us much about how the drug is working. It also now gives us an opportunity to potentially make yet further changes to the statistical analysis plan, which I think will be important to understand the full effect of the safety and efficacy of the medicine. And, also, too, realizing that the FDA has already guided that they will look to the entirety of the data from both of those stages.

So we think that is very encouraging and we glad that we have a little bit extra time to complete those regulatory discussions, as well as then to analyze the data once it's unblinded to us in the third quarter. And, of course, we will be able to top-line release that very quickly after we look at it and digest the data. We still plan for a pre-NDA meeting based on that 12-month data. That meeting to discuss a US regulatory pathway approval. We expect that in mid-2013. So that is the Migalastat monotherapy program. Two major milestones still to achieve there.

The Pompe ERT co-administration program, our second clinical program of significance this year, again very encouraging data that we saw, the positive data at the WORLD meeting in February, already delivered and everything in the Pompe program now geared toward the initiation of that repeat-dose clinical study in Q3 of 2013. And then our third program, again using that CHART technology, we intend to move forward still with the next-generation enzyme replacement therapy product in Fabry disease. That is the product that we are developing with GSK and with JCR Pharmaceuticals, our partners in Japan. That is Migalastat, our chaperone, combined with the JCR enzyme, the cell line JR-051 that is on track for IND submission in the fourth quarter of 2013, and we expect entry into the clinic in the first quarter of 2014.

So lots of work still to do. Of course, there's an awful lot of research and development at Amicus ongoing. Particularly, the application of the CHART platform technology to other programs and other rare diseases that we have not yet disclosed. And we think that we have the potential through this year, as data is generated, to begin to talk more about those programs. But on Slide 10, we wanted to focus on the major clinical milestones.

And with that, operator, that is all we have and we're happy to take questions.

(Operator instructions)

Ritu Baral, Canaccord Genuity

Thanks for taking the question. I just wanted to drill down further on the 12-month data that could come out, especially the potential changes to the statistical analysis plan that you discussed.

What are some of those potential changes? Is filtering by baseline inclusions number one of them? And whatever you guys decide, and decide prospectively to analyze the data, how are you prospectively decide to analyze the data, would you run it by FDA even before the Q3 12-month data?

Yes. The short answer is yes, Ritu. If you remember -- if you look back historically over the last year in this program, we had that type-C meeting last summer. And that was the first time the FDA had indicated that we could consider safety and efficacy at both 6 and 12 months -- in fact, referring to 6 months as Stage I and 12 months as Stage II.

Through the fall of last year and 2012, we then worked with the FDA. We proposed three additional pre-specified statistical comparisons. And we have gone through those before, happy to review those again. But that is already agreed to for the 12-month data set.

What we are looking at now is based on the six-month data as we know it, can there be or should there be any other changes to the statistical analysis plan or different statistical comparisons. I don't want to comment specifically on what we are discussing with FDA. I want to preserve the integrity of those conversations. So I will leave it at that, but once we have that guidance, we will be able to release it outward.

And just as a follow-up, because of the change at the six-month point, the conversion of placebo patients to active, we will have -- will we have hazard ratios for certain measures, even if we don't have p-values? And how historically has FDA looked at hazard ratios from small orphan trials?

I am not as familiar with that, Ritu. David, if you want to comment? Or we can certainly follow-up.

Yes. This is David.

So, we're still doing statistics -- and sometimes people use the word descriptive statistics and it sounds like it is a less-than-rigorous comparison. But that is not what we mean here. There's still direct comparisons, there's still calculations of means and medians.

And with the hazard ratio, comparable is to say the 95% confidence interval, so standard errors, confidence intervals and those sorts of things can be calculated. The sensitivity is just to calculating a formal p-value, as technically that means there was a formal hypothesis testing. So if anything is post-hoc, there is sensitivity to calling it a hypothesis testing with a p-value. But essentially the same information comes analyses with the confidence intervals.

And again, it is important, Ritu, to remember that what we are seeking here is that conditional approval. So looking for conditional approval based on a surrogate marker or markers likely to predict clinical benefits and we think GL-3 is an excellent one. And certainly the cell types and the tissues that we're looking at in the kidney are the very relevant ones that we think will be likely to predict clinical benefit. And we just want to make sure that as we look at the entirety of the data, that we are able to pre-specify as many of those statistical comparisons as we can.

And there are two things that are important to be reminded of. One is that there's a lot more data when we have the 12-month collection because at that point, the patients who were on drug for the first six months stay on drug. And so we will have data for those patients for 12 full months. And then also, the patients who were originally on placebo cross over to drug. So in effect we have nearly twice as many patients -- we will have data for nearly twice as many patients on drug for at least six months.

So it gives us two things. One is data for nearly twice as many patients. And it gives us data, not only for a 6-month treatment period, but also a 12-month treatment period.

And as we saw in the Phase II studies, there was an effect at 6 months but that that effect was larger at 12 months. And that is also what is seen with ERT. So there is reason to believe that the effect could be even larger for the patients who have been on drug for 12 months, not just 6 so we can do that direct comparison. In addition we have nearly twice as many patients with at least a six-month treatment period.

Great, thanks for taking the question.

Anupam Rama, JPMorgan

Thanks so much for taking the question. Just on the repeat-dose study for Pompe, which is expected to start in 3Q, what sort of preclinical work or next steps need to be completed before the start of that study?

Yes, again the manufacturing, we had to do the formulation work moving from the oral formulation to the IV formulation. That is completed. The GMP manufacture is completed. The aseptic fill finish is completed for the drug material. And then it is just in the last of its toxicology studies.

Brad, do you want to--?

No that's a fair characterization. Of course the other elements of starting up a study are on the clinical operational side. So working with the sites, which we've already identified, getting protocols approved, going through IRBs, those kinds of things. So it's really more in the clinical operations mode.

Yes it's actually exciting to see that program now. We were all here about 2 months ago when the contract manufacturer had a live video feed from their aseptic fill finish facility. And that was just an idea about 10 months ago at the Company, that it would be best to deliver this in an IV formulation for a host of reasons. And an enormous amount of work here internally at Amicus to make that happen.

Again, remember of course, as you know, Anupam, this is an un-partnered program, so we're doing all of this with our internal resources and our key vendors. So it is exciting to see this move forward and now we're only a quarter or two away from this going into patients in a repeat-dose study. And obviously, very, very excited to see the data coming out of that open label study.

Great. Thanks so much for taking our question.

Kim Lee, Janney Capital Markets

Good afternoon. A quick question for you. What was the thinking that was behind the pushing out of the read-out for the Stage II of the trial? Was it some discussions with the FDA? And if so, what has been that feedback? Thanks.

Yes. No, again, we had been guiding to late Q2, early Q3. We think it is prudent now that we say it's Q3. And it is really, with all the data that we have, Kim, at six months, all the internal analysis that we have done, working with the pathologist to make sure that we have all the right types and numbers of pathology reads, together with the ongoing discussions with FDA and, under type-C guidance, those are timelines that are in the two-month or so period. So that will take some time to complete that.

So again, it's actually -- I consider it very much a positive. Obviously, we would love to have all of the data sooner rather than later. But the fact that six-month data really was so encouraging, especially as we've dug deeper into it, on areas like looking at the overall GL-3 level on the continuous variable. And just making sure that we do everything possible and take a little bit extra time so that we can analyze that data as comprehensively as possible. And to set up as diligent a briefing package as we can into the FDA for that pre-NDA meeting.

Yes, the only other thing I would add, John, is from an operational perspective, remember we have collected all of those biopsies, those were collected in December -- or by the end of December last year. And we are still blind to the data. I know John mentioned both of those things, but as John said it's not an operational issue, more it's just making sure that we get it right and we have the appropriate discussions and that we prepare appropriately for--.

Yes, to me this is a strategic decision to take those extra couple of weeks. And I think it is actually quite positive that we are engaging the FDA in this interim period between the 6 and the 12-month data. So I think it is very positive.

And what--?

Hopefully, it will set us up even better. Go ahead, Kim, I'm sorry.

Oh, no, that's okay. And what -- so you are in discussions with the FDA currently and then can you help us understand what kind of guidance they are providing for you between now and your read out in Q3? Thanks.

I can't comment on specific guidance from the Agency and the nature of the discussions. Only to state that we are sharing the data, we're proposing ideas for potential changes to not take away from, but to add to the pre-specified statistical comparisons. So that when we look and we describe what is the entirety of the data, we understand -- the regulators understand, investors, physicians -- really all the interested parties understand just how well we hope this drug is working and therefore how convincing of a package we can put together for that pre-NDA meeting.

So it is time well spent. Thankfully, we have got good data to look at.

Great, thanks.

Joseph Schwartz, Leerink Swann.

So when will the FDA see 12-month data? And how do you anticipate updating investors once they have seen it and then that meeting has taken place and you're able to share with us whatever clarity you can out of that interaction?

Sure, so Joe, in the third quarter, we would expect to be able to top-line that data. And as before, the full data set would be presented at a science conference, most likely in the early part of the fall, I would suspect. And then in terms of the FDA, we intend to move, once we analyze that data, very, very quickly into the pre-NDA discussions with FDA.

So you think about the monotherapy program, there is really three gates that's here that we have to get through. It is going to be the 12 month data in Q3. It is going to be the pre-NDA discussion after that. And then we are still on track and all the other work that we need to do is on track, assuming that the 12-month data looks where we need it be, to file the NDA by the end of the fourth quarter. So those are the three gates that we'll need to get through to continue to de-risk that program.

Okay, great. And then can I ask one follow-up on that IV AT2220 study in combination with the market ERTs? I was curious, you said it was going to run for around 12 to 24 weeks.

How many patients do you anticipate enrolling and how long do you think it will take to do that? And then, what kind of immune response tests do you anticipate you will be able to analyze? And will there be a ERT monotherapy arm as a control?

All right, Joe, that's four questions. Let me make sure I got them.

So it's a number of patients. Again, we are still developing the protocols but it is fair to say this it's probably going to be about 18 to 24 patients -- again, some on ERT, some naive to ERT. We do expect afterwards that there will be an extension arm.

I think your second question was the time to enrollment. We expect this to enroll very, very quickly. We're not asking anybody to come off of their ERT. We are only adding an investigational medicine to explore whether we can change the PK profile, enhance the tissue uptake, and potentially affect the immune profile of the ERT in a positive way.

So we think there will be significant interest. I can tell you we are talking to the key opinion leaders in the world, all of whom were investigators for the Myozyme pivotal studies and we are very excited about the data that they've seen, including the clinical data.

And if you remember, too, for Study 010, even though it was basically a Phase-II-A PK study and it included multiple muscle biopsies, no chance to take the medicine, our chaperone more than once, we enrolled that study very, very rapidly. In fact, we had to turn some patients away. The people living with Pompe disease are really, really eager for next-generation therapies that can either enhance the efficacy or safety of their current medicine or potentially lead to the development of next-generation ERTs.

And I know it and I live it and I don't worry about enrollment of this study. We will do it in a rigorous fashion, but we will enroll the study in a very, very expedited manner.

You had a question, too, also about immunogenicity -- I was just scribbling down your questions quick. I apologize but immunogencity was your third question, Joe?

Yes, thanks. Sorry to include so many, but the immunogenicity aspect is obviously important and then we have ERT monotherapy as a control?

Yes. That is not clear that we will need a monotherapy control right now. But we are looking at that -- again, we will have the final protocols in the next short while here.

But, again, since we're looking at ERT-experienced patients, and remember, of course, in Pompe, you have 100% zero conversion. So everybody develops antibodies that is known to the ERT. We will have many of those patients in this study.

We will look on a number of different parameters, including T-cell response antibodies, to see if the addition of the chaperone and co-administration has any impact. We need to investigate that. And then we also look at ERT-naive patients, if the medicine is co-administered with ERT, the chaperone with the ERT, what impact if any does that have on the immune response. So we will look at all the multiple parameters to measure the immunologic response. And then your -- I wouldn't stop there -- did I?

That was it. Thanks very much. Extremely helpful.

Greg Wade, Wedbush.

So the results of the 12-month study are complicated. You have got patients who had responded, which could either continue to respond or fail; patients who had failed to respond who could respond or continue to fail; and then the same in the placebo group. So there's three potential outcomes per group that you have already of responders and non-responders. So I'm curious what you would prospectively define as a successful enough result at this 12-month time point to continue the program forward.

And then secondly, if I might squeeze another one in. The amenable mutation assessment has not really been predictive of response at this point. And I'm just curious as to what the Company is doing in order to create sufficiently robust commercial tests that would allow you to identify those patients whom, if you do go forward with the program, might best be treated with Migalastat? Thanks.

Yes, let me address that last question first and I'll ask David and Bradley to add any color that is necessary. Actually, we think it is actually one of the most powerful aspects of the technology is the very personalized medicine aspect of the monotherapy, where, if you recall, we had developed the constructs of every known mutation that can cause Fabry disease -- over 500 and even in the course of enrolling this study, discovered several dozen new mutations that can cause Fabry. And we're actually very confident that we can predict with nearly 100% certainty, who is appropriate to this medicine based on that now GLP assay.

So the amenable versus non-amenable is critically important to us and we think we have had very good evidence. And I think you'd indicated that we didn't see evidence before -- I'm a little confused about that because if you look at our Phase II data that was presented at the American Society of Nephrology back in the fall, we actually had patients who had non-amenable mutations. And they actually showed an overall increase in their GL-3 levels compared to a 78% median reduction in the GL-3 in people with amenable mutations.

So I don't think that is quite right, but maybe I missed something. So, I don't know, David or Bradley, if you want add any color on that point? And then I'll come back to your first part, Greg. I'm sorry. If there's nothing there, so let me get--

Actually, John, so John is correct, that the -- from the Phase II, we do have evidence that we have the in-vitro study, mutation-by-mutation does appear to be meaningful in terms of the response in vivo when patients with the different mutations get the drug. We will have similar data from Phase III. We have not shared the patient-by-patient data yet, but we do have patients in the Phase III study who have mutations that, based on the GLP pharmacogenetics assay are non-amenable.

So we are able to compare those with the pre-identified non-amenable mutations versus those that are amenable. And when we share the patient-by-patient data, we will be able to compare those two groups and see whether there is good predictive power with the pharmacogenetics work. Is that what you were asking, Greg?

Well, everyone in the Phase III study was identified as having an amenable mutation but your response rate was not 100%. So I'm a little confused?

The confusion comes from the fact that when we were enrolling that study, we had an R&D assay that was the basis of the inclusion. And we tried to be inclusive. And so there are patients who went into that study, who then, when the full set of 531 assays were transferred to the CRO so that that could be done under GLP conditions, so every single one of the 531 were rechecked. There were some that had previously scored as amenable that were now determined to be not amenable.

We agree with the assessment of the CRO, done under the GLP conditions. And so, those are, by the criteria we defined before the study started, they do not meet the amenable status criteria. And so, they were let in, because of the R&D assay, but with the GLP assay, they are not amenable. And so that is why they were in there, it was just a matter of time and the switching of the assay to a GLP setting outside of Amicus. So they effectively serve as the control for the ability to predict based on that assay.

So let me just be clear that the vast majority of the patients in this study do have amenable mutations and the small number who don't, obviously, we are still analyzing. But I think, maybe if I can just get to the first part of your question because it is very important, Greg, and a very good question around what to expect at 12 months and how do we know that that is going to support approval of this drug.

We know the drug works. It has been in patients now more than 200 years of patient data, some people more than 7 years on the drug. We think the compliance rate -- the fact that the 57 of 59 people who agreed to go in the extension study in December before the six-month data was released, every one of them has continued on in the study.

So there is really three things we need to show at 12 months advancing from 6 months. First, we need to show that the effect of the medicine is persistent and durable. So, for instance, a lot of different ways and perhaps offline, we can go through the more detailed comparison.

But what we need to show is for people who were on the drug for six months, when you add another six months of treatment, is that persistent and durable, does it continue? Is it even greater an effect? If it is consistent with our Phase II data, it should be. And again, for people who were on placebo, when they switch, you start to see a change in the trend.

And in the primary endpoint for six months, we had looked at a peer responder analysis. As you saw with the post-hoc analysis, made sense that a cut of 0.3 and above -- that explained that unexpected placebo response. But much more importantly, for 12 months, we needed to show that this entirety of the data on this biochemical endpoint supports that we see a persistent and durable change first.

Secondly, that the change in the magnitude of change we're showing is meaningful. And we think it is actually quite encouraging, at six months that the Migalastat-treated group was already at a 41% median reduction. We think in talking to all the experts in the field, that if that were to continue, that that would indeed be a meaningful change likely to predict clinical benefit.

And, of course, thirdly, we need to show that the drug continues to have a strong safety profile, which thankfully it really does. When we put all of that together, we are hoping that all of that data will lead to a strong package for FDA seeking conditional approval.

Ritu Baral, Canaccord Genuity.

Thanks for taking the follow-up, guys. One thing that is not in your upcoming catalysts is a plan to take a sole Migalastat formulation -- so Migalastat alone -- into potential combo use. Can you take us through the strategy around that decision? Why bring it forward as a combo only as part of co-formulation?

Because we think it will be a better option for patients, Ritu, number one. And number two, our co-formulation program has essentially caught up with co-administration.

So we think the 013 study, with excellent proof-of-concept, again showing, of course, we can change the PK profile, the tissue uptake of both Fabrazyme and Replagal. And we did that in the patients -- all the patients for whom it was tested. Over the last two months, we have worked with GSK. We have had many long meetings assessing whether we should move that into a pivotal study for co-administration.

And given how advanced the ERT, and how well the ERT co-formulated product looks pretty clinically to be performing and how well the manufacturing is going, it does not make sense to run those programs in parallel giving that the next-generation ERT for people with these non-amenable mutations is still need to take ERT. It should be, and we think it has significant potential, to be a better therapeutic outcome than just the co-administered chaperone with other ERTs.

So we think it is a very important then to bifurcate the program -- Migalastat and monotherapy for Fabry disease for 30% to 50% of the patient population with any one of these amenable mutations. And for the other 50% or more of the population, we will have an IND, we intend by the end of this year for the next-generation ERT. So I hope that make sense.

Yes. Thanks for taking the follow-up.

Thank you. And at this time, I'm not showing any further questions. I would like to turn the call back to Management for any further remarks.

No, that's all we have, operator. Everybody, thanks for listening, and always available to speak as needed. Have a great evening.

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

Thank you.

You're welcome.