Amicus Therapeutics' CEO Presents Lysosomal Disease Network WORLD Symposium Data Highlights Conference (Transcript)

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Amicus Therapeutics, Inc. (NASDAQ:FOLD) Lysosomal Disease Network WORLD Symposium Data Highlights Conference Call February 15, 2013 11:30 AM ET


Sara Pellegrino - Associate Director, Investor Relations

John Crowley - Chairman & CEO

David Lockhart - Chief Scientific Officer


Ritu Baral - Canaccord

Anupam Rama - JP Morgan

Michael Smith - Leerink Swann


Good day ladies and gentlemen and welcome to the Amicus Therapeutics Lysosomal Disease Network WORLD Symposium Data Highlights Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time. (Operator Instructions) As a reminder, this conference call is being recorded.

I would now like to introduce your host for today's conference, Ms. Sara Pellegrino, Director of Investor Relations. Ma’am you may begin.

Sara Pellegrino

Thank you. Good morning. And thank you for joining our conference call to highlight the data presented this week at the Lysosomal Storage Disease Network WORLD Symposium in Orlando. Speaking on today's call we have, John Crowley our Chairman and Chief Executive Officer; David Lockhart, our Chief Scientific Officer and Dr. (inaudible) our lead clinical consultant. Bradley Campbell, our Chief Business Officer and Chip Baird our Chief Financial Officer are also here with us and available to participate in the Q&A session.

Today's prepared remarks coincide with the slide presentation that is now available on our corporate website at The slides are located at the Investors section under Events and Presentations right below the webcast link to today's call.

On slide two we have referenced forward-looking statements. This presentation 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, may, 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 these expectations will be realized.

Actual results could differ materially from those projected in Amicus’ forward-looking statements due to numerous known and unknown risks and uncertainties including the risk factors described in our quarterly report on Form 10-Q for the quarter ended June 30, 2012. All forward-looking statements are qualified in their entirety by this cautionary statement and Amicus undertakes no obligation to revise or update this presentation to reflect events or circumstances after the date hereof.

With that, I would like to turn the call over to John Crowley our Chairman and Chief Executive Officer.

John Crowley

Great Sara, thank you and good morning everybody. I know from our pre-review a few moments ago with the operator that we have quite an audience on the call which I think is a very good thing. We are here in Orlando at the Lysosomal Disease Network WORLD Symposium and as Sara indicated I am joined by the senior members of our team. It has been an excellent conference for us here at Amicus.

If you look at slide three, it will give an overview of the platform presentations including the two presented this morning as well as some very important posters for us and you can see across the board is from our monotherapy program in Fabry to the co-administration program especially that’s a very, very important data presented on Pompe this morning as well as the posters including the Pompe co-formulation which I think is a very important expression of our significant work in developing next-generation enzyme replacement therapies.

Obviously, a very, very strong interest in our migalastat monotherapy program, lets say presentation that we worked with the investigative Dr. Ezgu and our partners at GSK to present in clear and transparent fashion as we could. We have quite a bit of data here to go through, data taken from that presentation. I will say, I am quite surprised that markets reaction to that presentation, whether it's confusion, perception, rumors, I am not sure, but I think our attempt today is to in as transparent manner present what we think are very, very important and positive data around the nature of the primary endpoint with the clearance of the GL-3 and we will take you through some of the slides as well as with the secondary endpoints including what seems to be while early trends toward positive changes in kidney function.

So we hope by the end of this call and then going through again our Pompe data that you will be increasingly confident as we are that migalastat for monotherapy in the patients with a amenable mutations for whom it's intended to benefit is having a good effect. Certainly, deserves to continue to be studied and we look forward to the 12-month data, but I think this data will be make it even more clear why we are very encouraged.

So with that said, if we can turn to slide five and I’ll turn it over to David to go through the data. David, go ahead please.

David Lockhart

So I am going to go through the data from the Phase III from the first six months of the Phase III study and the molecule, I will probably refer to it as migalastat and potentially AT1001, a line of those of the same molecules and also there is the GR number connected with GSK.

So if you go to slide six, just a quick reminder of the study design. The study is a 12 month study which is followed by an open label extension after that. There are kidney biopsies at base line and at six months and at 12 months. For the first six months of the study the patients are randomized to either placebo or to receive a 150 milligrams every other day of migalastat. They were stratified by sex to make sure that we had comparable numbers of males and females in the two groups. So the data that we are going to be talking about today is for the six month period. We can say that all of the patients have completed the 12 months of study, but we are still obliging to those data. So this will be a discussion of the first stage, the six months results.

To just jump right in to the primary endpoint, as a reminder, this endpoint is related to what was used for the approval of Fabrazyme in Phase III with some modifications that are appropriate for the patient population that we are studying; that we believe is representative of the Fabry patient population as it exists in the world today. So this is a measure of the load of GL-3 which is the primary storage material in Fabry disease and a particular cell type in the kidney, so it’s interstitial capillary GL-3 also the same cell type used for Fabrazyme for the Phase III study.

And so the primary endpoint at six months was a measure of a 50% of greater reduction in interstitial capillary GL-3 and you can see the results and we can say clearly that we missed the primary endpoint; although, there was a larger affect in the treated group than in the placebo group, the P value was not less than 0.5. Importantly, and something we haven’t necessarily specified before you can see the overall results are in favor of migalastat versus placebo.

If those are broken up into the results for males and females you can see that the results are comparable, sometimes its thought that perhaps the males which show a bigger affect than the females and that there would be noise in one group than the other but in fact the differences that we observed in the overall group is not driven primarily by either the males and females; the results are somewhat similar.

So that’s the primary endpoint which we’ve described before, let me go to slide eight, which shows a secondary analysis of that same endpoint and it really is the same readout, but instead of looking at the reduction as a responder analysis, where a person have to show you reduction of 50% or more, instead its just using the quantitative scores.

So this is a measure of the median percent change from base line in the same interstitial capillary GL-3 that was used for the previous slide, but that’s a continuous variable. And you can see again, the results are clear here and that they are, if you look at the overall the entire population mITT population that is 30 in the treated under placebo group, the number that, the reason that adds up to 60 instead of 67 is that only for patients who completed the six months period and had both a baseline and a six months biopsy or carry out biopsy.

So you can see here that there is good separation between the treated group and the placebo group, minus 40.8% versus minus 6.3%. There is a fair amount of variation in those numbers which is why the p-value is still 0.09, so closer to 0.05 it's still not achieving statistical significance and that's because there are differences between individuals based on their level of response as well as how much signal there was at baseline.

So, again, clearly a nice trend in the direction of the treated group. Again, if you look at males and females separately the values are similar to the overall so that reduction, that greater reduction in the treated group that's staying when we look at all patients is not driven particularly by either of the males or females. Both groups are behaving similarly.

So if we go to slide nine, this shows various subgroup analyses, just looking at the patients as defined by different categories, by gender by age, race and also by proteinuria BMI and so on. You can see that overall the trends are in favor of migalastat for all of these different subgroups. One of the most subgroups that we'll talk about in more detail in a couple of slides and that an analysis that was discussed in more detail with the talk this morning is the one at the bottom showing that groups that had either less than a score of 0.3 interstitial capillary inclusions per capillary or those that had greater than 0.3.

And you can see that for that bottom category, the patients who had at least 0.3 inclusions per capillary show a greater reduction as measured by the primary analysis than in the placebo group. And that difference is greater for those who have greater than 0.3 as opposed to those that are less than 0.3. And this is an extremely important point which is why I'll discuss this in more detail in the next couple of slides.

One other thing to mention just as an important fact in the study is that patients with Fabry disease who have proteinuria, it is becoming standard of care that those patients go on ACE inhibitors or ARBs. And it was specified that patients could be on ACE inhibitors or ARBs in the study but that they have to be on a stable treatment regiment that was supposed to remain consistent during the study and we did find that there were more patients on ACE inhibitors and ARBs in the placebo group than in the treated group.

All right, let's go to slide 10, this makes it clear that what we think is happening with the interstitial capillary GL-3 reduction. Remember this is a responder analysis and we saw that the median reduction in the treated group was about 40% but to be a responder, a patient had to show a reduction of 50% or more. So the fact that the median is 40% makes it clear that they were clearly a number of patients who showed reduction of 30%, 35% and 40% and so on, but who did not cross over the 50% cut off.

But also it became clear to us that when the baseline levels of interstitial capillary GL-3 are too low, it maybe very difficult to even detect reliably a 50% reduction just because of issues signal-to-noise. Basically, when the signal is too small, it's difficult to reliably detect a reduction in the signal that starts out small and that is not large compared to the noise.

So you can think of the 0.3 as essentially a cut point, an idea that’s commonly used in titer measurements and so on, where you can say that’s not the limit of detection of what you are trying to read out, but it is the point at which you believe there is significant signal to noise in order to detect a reliable change.

And so, in order to look at that more systematically, we did a sensitivity analysis where we look at a whole series of potential cut point. The 0.3 was one that we had actually previously described in our conversations with the FDA and it was where we believe a reasonable cut point would be, but for this analysis we looked at cut points of zero which means no cut points at all, 0.1, 0.2, 0.3 and so on.

And you can see at the 0.3 and above point, that at that point there is a clear separation between the treated group showing a nearly 70% response rate, 7 out of 11 whereas in the placebo group, it was only two out of 14. And in fact, these numbers are very consistent with the numbers that we were using to power the study. We were expecting a 60% to 70% of response rate in the treated group and a less around 20% or so response in the placebo group.

So you can see that when we take the cut point of 0.3 then in fact, we see exactly what we had powered the study for. Importantly also, sometimes some people might expect that when we make that cut but again the effect is being driven entirely by the males in the study but that is not the case of those seven of 11 responders, four of them are males and three of them are females and then the placebo group that two that are called responders even though they didn’t receive drug, it was one of seven males and one of seven males that were the responders.

So what we are seeing with the males and females is very similar and the key cut point here is not related to sex, it’s related to the baseline level of the measure.

And then to the right, you can see those are just subsets of that group at 0.3. If you cut it higher 0.4, you start to lose patients, you start to lose a few more about 0.5 and so on. So to the right, those are essentially subsets of the group at 0.3. So at 0.3 and above, there is a nice separation between the treated group and placebo.

And this is really what we consider to be a very important analysis because it shows that when we are above the noise when we have a good signal-to-noise ratio in the primary measure then we see a difference between the treated group and placebo.

John Crowley

Yeah, great. David that was excellent and I don’t want to overemphasize the point but if there is one slide in this entire deck at least with respect to the migalastat monotherapy program that we think tells the story, what’s really happening on that primary endpoint. We think this captures it very well. It is immediately on the six month stage one analysis, a Post-Hoc Subgroup Analysis but its one we think as entirely rational and one that we actually contemplated sometime ago when designing the study in fact just a little historical perspective.

We have some concern about GL-3 levels being below the level of delectability and within the noise sort of the FDA in our early discussions around the design of this study, the FDA had actually asked if we would consider screening biopsies, in fact to David’s point earlier, we considered it, we said 0.3 would be the direct point relevant based on what the pathologist tell us for rising about the noise here in terms of baseline levels.

But however and then looking at it and talking to the investigators, we realized that they were making enrollment of the study in practical screening biopsies and quite frankly it would that be supported by the IRBs. So we weren't able to do that but I think in some respect this kind of retrospectively does that.

And again to David’s point, I think that the breakpoint of 0.3 and above, it shows on this primary endpoint very clearly the separation between the groups and explains that unexpected placebo effect that we had first articulated back in December with the first reviewing to this data.

We'll come back to this little a bit later, but its also important to remember that to look at six months and of course add 12 months, we will have the patients who are originally on drug, we will then have data for them with 12 months of treatment and for the group that was originally on placebo, they cross over it six months and we will have six months of data for the original placebo group as well.

So the amounts of data that we will have at 12 months will be considerably greater and basically we want to see that the trends that we are seeing at six months are maintained or even improved upon at ‘12 (inaudible).

David Lockhart

And the safety I won't much time on this, we have a lot of history with this drug. We have patients from Phase 2, who are still on drug for as long as seven years, 16 patients remain on drug as part of the Phase 2 open label extension. The safety profile has been good, and you can see the adverse events, you can see that these are things that are generally observed in Fabry patients, the numbers are similar between the placebo and the treated group.

There were no serious adverse events that were deemed by the investigators to be treatment related, no withdrawals were due to drug related adverse events, and so I think the summary of the safety profile continues to look like what we had seen over the previous years of experience.

So if we go to slide 12, I think maybe this slide is about the secondary end points. These have the potential to be supportive of what we see with the primary end point. The urine GL-3 ended up not being particularly meaningful what we saw was a median reduction from base line in both groups, and its important the next point is very important to underscore is that there was quite a bit of variability deserved even before patients with on drug, and exactly why there was this variability we don't know, we can speculate but we don't know for sure.

All we know is that patients differed from themselves significantly even in the absence of drugs. So since there was variation in patients between springing and base line of a mean 1.6 fold, we could not expect to see a difference but in the ballpark of 30% to 40%. So there's really not much we can say from the urine GL-3 measurement at this time.

With renal function, you can see the table, the baseline values are normal, eGFR in these units is around 90. Fabry patients GFR that's anywhere from extremely low 30 and below, as they are approaching end stage renal disease. Sometimes there are patients who are called hyperfiltrators where eGFR is well above 120 or 130.

You can see that in both the placebo and treated group the base line values are very near normal, very near 90 and nicely matched. What we saw over a six month period is that, although I should say, but there are some patients whose baseline GFR is well below normal, and so in those cases what we want to see is an increase in their GFR and all we are able to say at this point is that at six months we did see that the Migalastat Group had a net increase which is the positive direction and the placebo group showed a decrease.

So it’s certainly something that we would phase in the right direction, but it is only a trend. These are only six month’s data, we still need to get the additional data from the 12 month time point. As a reminder the European study is an 18 month study, with GFR as the primary readout. We thought 18 months was the right amount of time to really see a change by that measure.

So all we can say here is that there is a trend that we would say would be in the positive direction, but it is too early to draw further conclusions on that.

John Crowley

Yeah, I think that's well stated David and again in terms of secondary end points overtime, we think this will be a very important one. Obviously, renal function in a kidney disease critically important and just to the point I made earlier in the call about potential confusion, I did get an email from one investor who was very concerned about this eGFR data on renal function and quite frankly had misread the data.

And again to emphasize David’s point, while still early, it was unexpectedly positive and it seems like we're beginning to see a separation from the placebo to the Migalastat Group in the favor of Migalastat. I think that’s a positive, but still early and lots more work to do.

David Lockhart

Yeah, certainly and not in the wrong direction. We should say based on the eGFR, there is no safety signal. So there were patient down the treated group, who showed a significant worsening, meaning a reduction in their eGFR. Also on the Proteinuria area, this is an important read out, it's an important measure of kidney function. Again, too early to say I think the data of 12 months will probably more meaningful than the data from the 012 study. We do not expect to see changes over this time period.

I think just for a context. I know because I have been asked this recently. The question about eGFR regarding what's seen with ERT just to provide information from the published literature on ERT. The basic summary is that in patients whose kidney function is pretty good to start with, what has been seen is a stabilization of GFR overtime, improvement in GFR have not been seen with ERT and also it is seen that if patients have low GFR or have Proteinuria as baseline that they do not even see a good stabilization. So just to put that in to context those are the published literature on with ERT. So John do you want to touch up ongoing.

John Crowley

Yeah I will just highlight the next slide or two. So where are we in this study again the data that we presented for the first time in December and now with a much more color around that data being presented here. This is stage one where the interim analysis of a 12 month study, stage two will be the 12 months data and again remember after six months the patients on placebo transitioned over to migalastat the people who in stage one had been on migalastat continued on migalastat.

We are very encouraged still that of the 59 patients who completed a year of studies stages one and two that 57 of those patients voluntarily elected to continue in the 12 months study 011 extension; so we think that’s very, very good certainly speaks to we think a good safety profile and compliance and we will see once we look at the 12 months data of where are we going from here.

But we think very positive reminder as well that we continue with the study 012 that is the ERT switch study with 60 patients enrolled that study completed enrollment back in the fourth quarter of last year. The primary end point there is kidney function as measured by GFR and very encouraging as well in that study with some patients now over a year treatment in that study. 54 of the 60 remain in the study. Of the six dropouts four actually came from the ERT group, people who didn’t want to comply with the study requirements, only two dropped out of the migalastat arm which is pretty significant as well for patients to completely transition from ERT to our drug.

So we think that’s also encouraging and again a longer term study and the data they are expected in the third quarter of 14.

David Lockhart

John can I just say one thing very quickly about what you will have, when we have the 12 months data, I get ask this a lot. What will you have but more than what you have now. It’s just important to point out that we will have original group, we will have data for 12 months of treatment not just six and its been seen in our phase 2 and also with ERT that changes that occur over six months tend to continue and become greater at 12 months. So there is time dependents to the response.

So our patients for longer treatment time as well as nearly twice as many patients on drug for 6 months, because these original placebo group will cross over. So we will have six months worth of treatment data for nearly double the number of patients as well as 12 months of data for half the patients. So it’s a considerably larger data set.

John Crowley

It will and that’s actually good transition David to slide 14. So the phase 3 and some points, now we have taken this program very far, we are encouraged where we are today and quite frankly we’ve got a couple of important gates throughout this year to move this program forward that we have to move through, the next one being at 12 months data it will be a very robust data set at stage two top line data still expected in the second quarter of 2013.

Once we have that data, it’s made publicly available at least in top line fashion will move very quickly to work with the FDA to discuss in our pre NDA meeting the US approval pathway. We think this is a good drug again for the patients for whom it’s intended to benefit. The FDA again has indicated that they will look at the entirety of the data from stage one and stage two in making the risk benefit analysis.

And again we are thinking conditional approval on a story that’s likely to predict clinical benefit. So we think, we hope of that weighs in our favor and as we move to these gates we will continue our provide update on how the program is progressing.

So with that let's go ahead and transition to our co-administration and again we remain very optimistic and encouraged about the potential for monotherapy in Fabry disease for 30% to 50% of the patients with amenable mutation. We do think that an increasingly valuable and perhaps the most valuable part of our portfolio is the use of the chaperones indirect combination with enzyme replacement therapy either co-administered with existing ERTs or as we are already doing to develop next-generation ERTs that are co-formulated with the chaperone to provide added stability, increasing tissue up tick and we think the potential for reduced immunogenicity of the protein.

So a lot of work has been done and this continues to be very, very important focus for the company and we will have a lot to say about it throughout the course of the year, but a couple of key data were presented throughout this conference, so slide 15, I'll turn it over to David again.

David Lockhart

Yes, on slide 15 we are showing the results from the first clinical study using AT1001 migalastat in combination with ERT. And I can explain the important elements of the combination idea very quickly. Essentially, it’s that enzyme replacement therapy enzymes are lysosomal enzymes. They are very stable at the PH of the lysosome but they are not very stable at the PH of blood.

And so when they are put into blood or high concentration, they have a tendency to unfold, they unfold irreversibly and when the proteins unfold irreversibly they can no longer do a patient any good and the other part of the hypothesis is that unfolded proteins and unfolded proteins that aggregate are bad in terms of immune response.

And so the effect of the small molecule is to keep the protein folded properly in its folded and active form so that more of it in the active form can be taken up into cells and tissues where its needed and so that less of it is in a form that will be recognized by the immune system and elicit an immune response. So that's it in a nutshell, the small molecule stabilizes the enzyme when it comes to circulation to keep it active and to keep it from being immunogenic.

So the initial study, the clinical studies have now been done for both Fabry and Pompe. So on slide 15, that's the Fabry Phase 2 study, it’s a single administration study so you can think of it as a safety PK, PD study and the key readouts are whether the addition of the small molecule given orally prior to the infusion, whether that can lead to more of the active enzyme in the plasma over a 24-hour period and whether it can lead to more of the active enzyme taken up into tissue. In the case of Fabry the tissue we measured was skin.

So on the left hand side are the plasma results and at the top are the data when we gave a pre-oral dose of 150 milligrams of migalastat just prior to the start of the infusion and the bottom panel is with a pre-oral dose of 450 milligrams. There are multiple lines there because we tested patients who were on different ERT regimens. We have people who are on Fabrazyme at either 1 mg/kg which is the label dose or 0.5 mg/kg which was half dose because of the shortage or Replagal on 0.2 mg/kg which is the label dose of Replagal.

The key point here is that in all cases at either 150 or 450 and regardless of whether it was Fabrazyme or Replagal and regardless of the dose, we see a clear increase between 100% increase and as much as 340% increase in the amount of active enzyme. This is a measure of enzyme activity, not just circulating protein, but protein that is active. So it's an increase across the board.

So the next important, that’s good but that’s not where you need the enzyme in the body of the patient. It needs to be in tissue. So we took skin biopsies and we measured the amount of active enzyme in the skin; you might ask why did we do skin? In the animals, we had done skin, kidney and heart; of course a heart or kidney biopsy is more invasive and more dangerous than a skin biopsy and we found in the animals that skin tracked well with kidney and heart. So in patients, we only are doing skin.

So in skin you can see that on the left, that’s ERT alone in the green bar or ERT with a pre-oral dose of either 150 or 450 milligrams of migalastat. You can see again, for all of those groups, there is a clear increase in the amount of active enzyme. The maximum point is with the highest dose, which is Fabrazyme at 1 mg/kg quite naturally because you get more of the enzyme with just the enzyme alone, but that matters increase to even further in the presence of the small molecule.

Similarly at the 450 mg oral dose, again whether it's Replagal whether it's Fabrazyme at either dose, we see a significant increase in the amount of active enzyme in the skin. So this is very encouraging. This is basically the increased amount of active enzyme in the tissue part of the equation and the part of the equation having to do with immune response will have to await the repeat dose studies. We have reported data for the Pompe program, no we haven’t reported, so I guess I won’t say. So we will have to see the immune response part of the equation in future studies.

If you go to slide 16, these plots should look pretty familiar as it is a very similar type of design, but this study is in Pompe patients who are receiving Myozyme or Lumizyme and it’s a different molecule. The molecule here is AT2220, not migalastat and that’s because each molecule is specific for the intended target, so migalastat is not appropriate for Pompe and AT2220 is not appropriate for Fabry.

So similar study as what was shown previously, but given the Pompe patients and on the left is the plasma are under the curve, so this is the total exposure to active enzyme over a 24-hour period with ERT alone on the left or on the right with a pre-oral dose of AT2220 and that’s with doses of 50 milligrams of AT2220, a 100 milligrams, 250 or 600. So you can see that an important part of the study is that each patient is their own control and this is very important because not all Pompe patients have the same amount of residual activity, not all Pompe patients show an increase of exactly the same amount when they get ERT alone and then also there may be some variability in the presence of the small molecule. So in this case each patient is compared to themselves and you can see that the highest dose cohort showed the largest increase followed close behind by the next highest dose cohort and then down to the lowest one. So clear increase in all dose groups, the higher dose groups showing an even larger relative increase.

If you go to the right and Pompe was really an important as how much of the active enzyme can get into muscle; especially the scale of the muscle, so we did muscle biopsies from the clot in the Pompe patients unlike skin biopsies and we can’t take as many muscle biopsies, so in most stations we will only have two, so we are able to look at a muscle biopsy that is taken after ERT alone and then after ERT given with a pre-oral dose of AT2220.

So the data shown in the right hand panel is the days three muscle biopsies in our animal studies that were the affect was essentially maximized, and you can see again in all of the different dose cohorts, but not the 50 milligram dose cohort, there is no clear increase, so that appears to be too low, but if we look at the 100, 250 and the 600, you can see that in all those dose cohorts there was an increase in the amount of active enzyme in the muscle at day three and especially look at the cohort four, the highest dose group, there it’s greater than 100% increase in the amount of active enzyme seen in muscle in Pompe patients following an infusion. So quite striking increase there, comparable to what we saw in animals in all the preclinical studies and just to remind you that level of increase in the animals produced a greater reduction of glycogen, the storage material in the variety of different muscles and also the heart and the diaphragm.

So encouraging results here and the next step is to go beyond this and to do a repeat dose studies so that we can see the effect on repeat doses of ERT in combination with the small molecule as well as have a chance to see effects on antibody titers and other readouts.

John Crowley

And again, David on that point about antibody titers, we think that will be an incredibly important part of the evolving technology here in Pompe disease broadly in the lysosomal storage disorders with this combination technology but the ability to keep these proteins stable, reduce their immune profile we think could make them much more tolerable. We also think it could lead to better therapeutic outcomes for patients.

We have previously provided some data in the Antitope in vitro studies that you indicated, that's in the appendix to this deck. We are not going to go through it here. We did also look at antibody titers are in the process of analyzing that from the Phase 2 study in patients that's not yet ready for public release but as soon as it is we will be able to provide an update and perhaps some glimpse into what the antibody impact could be even in a very short-term setting with the co-administration of a chaperone with the Pompe ERT.

David Lockhart

Yeah, there is a series of talks at beating around right now having to do with the immune response to ERT and just a couple of talks before the Amicus talks P. Kishnani showed that an antibody response for infants is a matter of life and death. If they develop high titers, they lose the response to ERT and typically die within about a year to two years, sometimes even less.

And even in adults who develop high titer antibody that, that significantly reduces the effectiveness of ERT. So it is clear that these issues are very important in ERT with a sizeable subset of the patient population and its something that is currently only addressed by essentially ablating the immune system and in some cases Pompe infants and we are trying to find a way that would be much less aggressive than ablation of the immune system prior to ERT.

On slide 17, we do think that this co-administration of the small molecule, given the molecule orally prior to the start of the infusion has the potential to be a significant improvement in the treatment and that of course has to be proven in the clinical studies, but we also think that's not where we want to stop.

We think that it is possible to do even better than that by coformulating the small molecule with the enzyme even prior to hanging the drug in the bag. So having the two molecules together as soon as the enzyme is reconstituted and so that the two molecules are together in the bag in the infusion line and then in the circulation so where the small molecule is always there to protect the enzyme.

And so what we showed at the meeting was on slide 17. We had a poster showing our first what we call coformulation, that's where the AT2220 is premixed with the enzyme prior to putting it into the Pompe mice in this case and if you look at the left hand panel, this is of course why we do this. If you look at the red curve this shows the Pompe enzyme, this shows Myozyme or Lumizyme in human blood outside the body but in human blood at 37 degrees and you can see that the protein unfolds and it loses activity.

And once the activity has lost, we and no one else has been able to refold the protein and re-obtain that activity. So what's important is to preserve the activity, preserve the protein in its folded active form, and you can see on the green plot that that's exactly what happens with AT2220.

If AT2220 is present in the human blood at 37 degrees, there is no loss of the enzyme activity. So that’s outside the body. The goal is to do that same thing inside the body and so on the right hand side, our studies in vivo studies in the Pompe knockout animals, these animals accumulate glycogen in the heart, and diaphragm, in the tongue, skin, skeletal muscle and so on. We show and we have measured the glycogen and the glycogen reduction with ERT alone and then ERT that is coformulated with AT2220.

So you can see the white bars and all four of the tissue show that the elevated glycogen levels in the knockout animals. If you get ERT alone, that’s the red bar. There is a reduction. So ERT alone can lead to some reduction of the storage material but if you get ERT coformulated with 2220, the reduction is even greater and that’s exactly the goal. Of course, these are lysosomal storage diseases and the primary goal of the treatment is to reduce the storage material as much as possible and the dashed line in each of the four panels there on the right that shows normal level. So getting closer to that dash line is the goal. So essentially normalized glycogen level. So it's the same as it is wild type animal.

John Crowley

Great, thank you David. So I will wrap up with these last two slides. So first just to highlight what's next in our increasingly important Pompe program. Two different halves and two different molecules, we have AT2220 which as David indicated, had been given in oral formulation and that important Phase 2 study that we just went through. Here and it was presented in the oral platform presentation at the world meeting earlier this morning. We continue to move that forward, we think that has very significant potential for all patients on ERT in Pompe.

We have completed the manufacturing in fact we have our (inaudible) finish of this new IV formulation that was completed about a month ago. It’s actually now in its final toxicology studies. We expect that repeat dose study to begin in Q3 of this year. It will be an open label study. In the weeks and months to come, we will be able to provide more clarity about that clinical study but as David indicated, we will look to continue stabilization of the protein and plasma, continued increases we hope an uptake in muscles and very importantly looking at the immune profile and any changes both most likely both in ERT naïve patients as well as ERT experience.

So a very important program for us moving forward into more advanced studies in the middle of this year. And as I indicated in the JPMorgan Conference, we have had very, very good data showing that and even better impact for patients could be the direct coformulation of that chaperone with our own ERT.

We have shown some proof-of-concept standpoint that the existing ERTs Myozyme and Lumizyme very good preclinical data. We are now working in earnest developing our own proprietary enzyme replacement therapy in Pompe disease. We are looking at improving the ERT itself, we are looking at optimizing the glycosylation specifically the level of correlation in the overall (inaudible) based content on that protein as well as other ways to deimmunize what seems to be a very highly immunogenic protein. In addition to all of that, we will incorporate the AT2220 the small molecule essentially as a stabilizing agent and with that and I had shown this data for the first time as well last month at JPMorgan, the addition of a chaperone seems to confer so much stability to the protein that we now have initial evidence that we can potentially develop a subcutaneous formulation of that ERT, so more work to be done there.

As we indicated a few weeks ago, we are now working with Laureate Biopharmaceuticals also in the New Jersey, a contract manufacturing company; we have the contract with them for the manufacture of the ERT. Laureate has great experience and including having previously worked to manufacture the clinical supplies of the [Anova] protein which is the very complex and very successful protein now of course for the Lexicon portfolio.

And my final slide is slide 19, as you can see across these programs so the migalastat monotherapy program that again we need to continue moving through these gates, get more data, engage with the regulators, understand exactly what is the (inaudible) of the data and how it could support conditional approval in the United States where we also continue to work toward in mid 2014 getting the data for the second Phase 3 study as well.

And the plan is still to move forward with FDA discussions to seek approval based on study 011 once we have that 12 months data. And then, I have already commented on Pompe coadministration, Fabry coadministration we think it was excellent proof-of-concept. If you remember back a year ago it’s actually the first proof-our- concept that addition of the chaperone can substantially improved the properties of the ERT, now both ERTs and Fabry.

We are evaluating further development of the coadministration but we think the most likely pack that we will continue to work through, what you see here on the last action on slide 19, and that's the next generation ERT that we are developing with GSK and with our partners in Japan and JCR Pharmaceuticals that is going to design DNA enabling studies, it is scaled now to 2,000 liters, clinical supply is being manufactured and we think it will enter the clinic that next generations Fabry ERT at the end of this year or early 2014. So I know that's quite a lot in about 45 minutes.

We hope that we were able to convey the essence of the data from this morning and we hope especially with respect to the migalastat monotherapy that you can see why we continue to be very encouraged by the data that we see and look forward to gathering more data here the next couple of months.

With that operator I'll turn it back to you and we are happy to take any questions.

Question-and-Answer Session


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

Ritu Baral - Canaccord

John what was the nature of the interaction with the FDA around this 0.3 points on the monotherapy data when they suggested a screening threshold. Was that the number that they proposed and how do you think they would view had they given the randomization and balance.

John Crowley

The concern of course from the start would be that with biopsies you might have a substantial number of patients Ritu, who would have very low level of base line interstitial capillary GL-3. That was the FDA’s concern, it was our concern. We tried to control for it with the urine GL-3 screening criteria again looking for four times the upper limit of normal.

We think it did enrich, but just not enough based on this initial analysis. The 0.3 goes back to the discussions in 2009 with FDA. It was something we actually proposed to the FDA that if we were to do screening biopsies that you accept to cut off at 0.3 and that was based on our discussion with the investigators, specifically the technologist in the study. So they have a history to it. So we didn't just pick that out of the air.

David Lockhart

That was also based on the observations of the signal to noise ratio, at various levels when biopsies were analyzed in the way we are using for Phase 3 and so it’s relatively straightforward to and also our Phase 2 experience of course. But it’s relatively easy to describe with a signal of 0.3 at base line to show a 50% reduction or more you have to go to about 1.5 or lower, at 0.15 or lower.

It was known from the pathologist reading of our samples as well as acute normal samples that have been done previously that there was noise down to of about 0.1 and that a normal kidney could get a signal of about 0.1. So if you start at 0.3 a two fold reduction is 0.15, but the floor is essentially 0.1.

So if you start below 0.3 there's nowhere to go down enough that still gives you a signal that is significant relative to the background. So the genesis of this was all of our experience, the experience of the pathologist, all of our experience from Phase 2 and in fact in our meetings with the FDA that was our suggestion, our suggestion that a good cut point would be 0.3. Their reply was that we should enroll everybody and analyze all the data and so that's what we ended up doing. But that's where that suggestion came from.

John Crowley

Very importantly Ritu to your point now that we've taken this interim look. If you recall that even prior to this interim look, we have made some changes to the 12-month and 6-month statistical analysis plan based on some tight interactions with the FDA over the summer of last year. We expect to engage in continuing dialog. I would say, the FDA has been excellent.

I think it's a reflection of the changes in a post PDSA and post PDUFA 5 world recognizing the complexities in these studies and the nature of these unmet medical needs in trying to work with us to ascertain what is the true risk benefit ratio of the drug. So we will continue with those discussion including potentially further modifications to the 12 months statistical analysis plan.


And I am showing our next question comes from the line of Anupam Rama with JP Morgan. Your line is open.

Anupam Rama - JP Morgan

Just a quick question. Having shared this six month data with the FDA and then also looking to the 12 month data, can you sort of benchmark, sort of what you would be looking for, what would be the most ideal outcome for you to increase your confidence, going in to sort of regulatory discussion and just from an EBIT epidemiological perspective, percent of patient that sort of fall in to the 0.3 threshold or greater for GL3.

John Crowley

I think those are three questions. Let me take them one at a time. First of all, I don’t want to comment on ongoing discussions with the FDA. So in terms of what we've shown the FDA, their comments back, I think it's premature to comment on that except to say that we're in dialog with FDA and we're very encouraged with the FDA, you know, extremely interested in this as a potential therapeutic option.

In terms of your question around, I think it's your third question, I will come back to the second one. But your third question was around the nature of the distribution of baseline GL3 in the population. Quite frankly I think this mirrors the general population where you see quite a bit of variation across the population generally correlated with (inaudible) type of disease but not necessarily and that again was one of the professes of this study to study male, to study female, to study people across the range of symptoms in the disease it does make this one particular end point more challenging and that you do need to have a certain threshold level of Interstitial capillary.

What we did see if you do the math here, it ends up being 25 patients in the study had baseline interstitial capillary GL3 level of 0.3 or higher of those 60 patients. And I want to make sure. What was the second part of your question? I want to make sure I captured all three of them.

So a 12 months we are going to look to quite a bit of the data. For instance we will be able to look at patients who were on placebo for six months who then transitioned over to migalastat for the next six months effectively using them as their own control. We are very interested to see the durability and persistence of effect in patients especially those with measureable levels above that threshold of interstitial capillary GL3 so people that were on migalastat at six months and then continuing for another six months.

So far with this interim look at stage one our experience now in this data is entirely consistent with what we saw in Phase II. We know generally in the Phase II studies the longer people with a minimal mutations were on migalastat, the more durable and the more persistent the effect and that specifically what we would like to be able to show that the 12 months data we’ll see what the data looks like which certainly we think present a stronger case for conditional approval of this drug on that surrogate endpoint.

And in addition there are number of secondary endpoints including kidney function which we highlighted in this call and we think it will be important in building the totality of the data for FDA assessment.


Our next question comes from the line of [Ken Lee with Janney Capital]. Your line is open.

Unidentified Analyst

I have two questions for you; first is how can we handicap outcome of part two based what you now know about ICGL-3 in that post talk analysis. And two if you’ve screened by urine GL-3 but yet you see no significant difference in that secondary endpoint, what gives you comfort that you have the right patience in the study, thanks?

John Crowley

Yeah, so the first part of that question, David you want to fill that one.

David Lockhart

Which was the first one.

John Crowley

You guys ask a lot of questions. Can you just repeat the first part so we are clear on it.


One moment while I open her line. Ken your line is open

Unidentified Analyst

How can we handicap outcome of part two based on what we see now but the post talk ICGL-3. How do we know that you have enough patients, with greater than 0.3 for ICGL-3?

John Crowley

Okay, great, and then second part of the question again, just so we are clear was (inaudible) patients in the studies and I think it is somewhat related to it.

Unidentified Analyst

Right, if you use the screening of your GL-3 but in the secondary end points so far in six months you haven't seen significant difference there, but what gives you comfort that you have the right patients in the study?

John Crowley

Thanks for the clarification.

David Lockhart

Yeah, I think the answer is it’s related to what John said about the last question. So it’s clear that all of our patients don't have enough interstitial capillary GL-3 to reliably measure. What we saw from this first group is that they were 60 who had the paired biopsies and 25 of those had 0.3 or above.

So in effect, it’s about half. So the good news is that even with the half, we are still able to see a clear separation between the treated group and the placebo group and what we want to see at 12 months is that in the group that crossed over that we see something similar to what we saw with this first group and that also for the patients who were on drug for six months to start that when we have their data at 12 months that it shows that the effect is durable and that potentially that there's an even greater reduction, at least in those who had enough to measure at baseline.

And so, the estimate given what we know now with that 0.3 cut points is that it’s roughly half, you know it’s 25 out of 60. So it’s a zip at least with regard to that measure. This isn't true for all the other measures but at least with regard to that measure it’s a zip we have with patient population that is roughly half of the total.


Our next question comes from the line of Michael Smith with Leerink Swann. Your line is open.

Michael Smith - Leerink Swann

I just had a question on the endpoint measure, I mean obviously it makes perfect sense to have a measure that works above the signal-to-noise background, I was just wondering the 0.3 cut off whether you have that subgroup analysis pre-specified with FDA and if not what's the flexibility that FDA have to potentially to…

John Crowley

Yeah, to be clear this is a first part of subgroup analysis. It was not pre-specified. We are looking at several changes to the statistical analysis planned for 12 months. Although, we can't comment on that quite yet; but again, I think very importantly in terms of your question about flexibility, the FDA has already indicated that they will consider the entirety of the data. We think that endpoint is a good surrogate endpoint. We think they actually compared very favorably to placebo on this endpoint. We think it will be an important part of the story but certainly not the only part of the story.

David Lockhart

And can I add one thing too, it’s the reason we put together the analysis on slide 10 to show that we weren't just being totally arbitrary about selecting 0.3 as a cut point. By doing the sensitivity analysis where we show a whole set of possible cut points and showing that the conclusion is similar and that there is a good separation starting at 0.3 but that separation continues above and there was a separation even at 0.2 that got larger at 0.3. That's the purpose of sensitivity analysis, to not just pick one value even though if we had to have picked one, there is a record of saying that's what it should be, but since its post-hoc to say okay suppose it was 0.1 or 0.2 or 0.3 then what would the outcome be and that's the purpose of the analysis on slide 10.

And I think it makes the point clear that is when you get above 0.3, you have 0.3 or above but then you see a separation. That separation is maintained as you go above 0.3 and then eventually it gets to the point where there aren’t too many patients left because there are smaller number of patients who had higher levels of baseline. So again that’s the point of slide 10, it's not just have to be totally arbitrary to plug. 0.3 as the cut point but to show a series of possible cut points.


Our next question is a follow-up from the line of Ritu Baral with Canaccord. Your line is open.

Ritu Baral - Canaccord

On that, given the sort of randomization in (inaudible) you had between placebo and (inaudible) on the baseline above and below 0.3 cut points how (inaudible) when you look at that and we have to overall baseline (inaudible).

David Lockhart

You cut out a little bit there but I think I heard your question. So if we look at the 0.3 and above cut point, there are 25 patients total and that’s 11. So nearly evenly divided, it's not exactly but it's nearly evenly divided in that it's 11 in the treated group and 14 in the placebo group. So at least very nearly evenly divided.

And also when it comes to males and females, there were significant number of votes in that group of 25. So even above that cut point, it still makes it so the two, the treated and placebo group are similar in size and the number of males and females is similar as well. So the only real downside to it is the total end is smaller. So the N in every group is smaller and that’s just a fact of life, but the distribution in terms of the important criteria are similar.


Our final question is a follow up from the line of [Ken Lee] with Janney Capital . Your line is open.

Unidentified Analyst

Just following up on my last question there, based on your powering assumptions of the study, how many patients do you estimate you will need to have that would have to have the cut off at least 0.3?

David Lockhart

Well so remember the primary end point was at six months; our predefined primary end point was at six months and it was based on the interstitial capillary GL3 reduction with the responder analysis for the entire people who had paired biopsies, and we missed that end point there is just no two ways about that.

But we are in the mid-point of the study and that we have more data coming at 12 months. We have a data at six, we have more coming at 12. We believe we are better informed at this point and also the FDA has said clearly to us that their decision is based on a risk benefit ratio and it is based on the totality of the data.

So our job at this point is to analyze the entirety and that includes the primary measures as a responder analysis, the primary measure as we already showed as a continuous variable to look at the set of secondary, tertiary and exploratory analysis to assess the safety of the drugs so that the risk benefit ratio can be assessed and its that entire collection of data and actually also involving the Phase II data and that we have a collection of patients who have now been on drug for more than five years and some as long as seven years. All of that is part of the entirety. There is no single readout, the FDA said there is no readout that is definitive and they also said it’s the entirety of the data across all of the measures.

One thing I think we should say clearly that we haven't yet is what our goal is and what our burden of proof for the study is. We are going for conditional approval, we are not seeking full approval at first, and that's exactly what Fabrazyme has. Even though Fabrazyme has been was approved nearly 10 years ago, it was conditionally approved and its still has conditional approval.

And the burden approved with conditional approval is that your data indicates that your drug is reasonably likely to show clinical benefit. It’s not proof of clinical benefit, that comes in the post approval commitments studies. So our burden approved and our barrier at this point is reasonably likely to predict clinical benefit and also to show that there is a good risk benefit ratio.

John Crowley

I will just wanted to add a little more color. Again it was pre specified, it is a post talk sub group analysis, but if you do set that cut off at 0.3 or higher with the 7/11 responding on Migalastat versus 2/14 on placebo, again though not pre specified it does reach to basic of significant. So we have been in that small number of patients. So we don't think that is going to be what carriers today. We think to David’s point it will be entirety of the data.

David Lockhart

And I think its also good to point out again, just by looking at the numbers the 7/11 versus the 2/14 that shows our risk admittedly and small, but that shows a response in the treated group that is above 60% and it shows a response in the placebo group by the primary readout that is less than 20% and that is in fact what we powered the study to show.

So once we get above the cut point that's what John was saying, this is actually what we expected based on Phase 2. These percentages of responders in the treated and placebo group is actually what we based the powering calculations on. So that does actually match the expectations from the previous study. Unfortunately and it’s smaller, but still the percentages are what we had targeted.


I'm showing no further questions at this time. That ends today's question-and-answer session. Ladies and gentlemen thank you for participating in today's conference. This does conclude the program. And you may all disconnect. Everyone have a great day.

John Crowley

Thank you. Thank you all.

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