Amicus Therapeutics' CEO Presents at 2013 UBS Global Healthcare Conference (Transcript)

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Amicus Therapeutics, Inc. (NASDAQ:FOLD) 2013 UBS Global Healthcare Conference Call May 21, 2013 1:30 PM ET


John Crowley – Chairman and CEO


Matthew Roden - UBS

Matthew Roden - UBS

Good evening everyone. My name is Matt Roden. I am one of biotech analyst here at UBS and I'd like to thank everyone for attending the new UBS Global Healthcare Conference. I am pleased and privileged to introduce Amicus Therapeutics, an innovator in rare and orphan diseases. Speaking on behalf of Amicus is its Chairman and Chief Executive Officer, John Crowley. John was Founder, Chairman and CEO of Novazyme before its acquisition of Genzyme, prior to Amicus. He also has experience as a naval officer and at Bristol-Myers Squibb. But he is probably most well-known for his personal drive to find solutions for rare diseases. Following the presentation there is going to be a break-out in Liberty 3. With that I am pleased to hand it over to John.

John Crowley

Hi, thank you very much Matt for the introduction and good afternoon everybody. I will refer you to slide number two of the Safe Harbor provisions that I will be making forward-looking statements. And then we will begin on slide three with the mission of the company. Amicus is a company that focuses on the rare and orphan diseases, utilizing our core platform technology, for the large pharmacological chaperones which I will explain in a moment and positioning our company at the forefront of developing new next generation therapies in the rare diseases, primarily focused today in the Lysosomal Storage Disorders.

There are four key pillars of value as we see them for shareholders of Amicus. The first is that is a products company. All of our products are home grown from a core technology. The products are in the Lysosomal Storage diseases, including now a pipeline extending into related genetic disorders like genetic Parkinson. So we begin in the products. But again we also have a core platform technology which again I will explain in greater detail, two principal uses of that technology. So Amicus is positioning as a products company with a core platform approach.

Another pillar of value is the strength of our partnerships. 19.9% of Amicus equity is owned by our partners at GSK, through their investment with GSK rare diseases. We are also partnered with GSK in the development of our lead drug, migalastat for Fabry disease.

We also have partnerships with Laureate Pharmaceuticals for the contract manufacture of our next generation enzyme replacement therapy in Pompe disease as well as a Japanese based company, JCR Pharmaceuticals, which we are partnered through our relationship with GSK in the development of a separate next generation protein product in the Fabry area. And then finally our financial strength; we have well more than a year of cash as we are here today. We ended the first quarter of this year with $84.7 million cash on hand.

So let me talk a little bit more about the core technology, the notion of using small molecules as stabilizing agents for human protein. The first use and the first entry into the clinic for Amicus what's now our lead program, migalastat is a mono-therapy for Fabry disease is just that. It's a mono-therapy, it's a pill, orally bio-available small molecule that for patients who have responsive genetic mutations with any number of diseases including Fabry disease can be taken instead of their enzyme replacement therapy.

So if the current paradigm for treatment is for a person, all people with Fabry disease on therapy to take an enzyme replacement therapy when we use our drug as orally available small molecules, people don't have to take that ERT anymore. They can take a pill to replace being hooked up to an intravenous machine, one out of every 14 days of their lives. And again the mechanism here is a small molecule that's designed to bind to target and stabilize at the active site of a person's own enzyme, an enzyme they can't make appropriately because of a genetic mutation.

The second use of our technology is in combination with exogenous enzyme replacement therapy, so the bioreactor made protein. We have taken this into the clinic in two phase IIa studies and we will share those proof-of-concept results here in both Fabry and Pompe disease, but importantly we are also now utilizing these small molecules as stabilizing agents in the formulation of our own proprietary next generation ERT.

So one core technology, one focus in the rare diseases and two separate novel uses of the technology, together with strong intellectual property positions of course. So let me talk a little bit about, because we had these clinical results now for the last couple of months, the use of this CHART platform, that's the Chaperone-Advanced Replacement Therapy. Again the notion that you can use small molecules combined with enzyme replacement therapies to stabilize the ERTs, make them more potent, less immunogenic and we think has the potential to offer a new generation of therapies for people with these diseases.

First use is co-administration, as we did in our first two Phase IIa studies, in Fabry and Pompe disease, literary a small molecule taken just before the beginning of an infusion for patients in Fabry or Pompe. The second use again is making our own enzyme replacement therapies and within the manufacturing and formulation process, including these small molecule stabilizers to provide again enhanced uptake into tissue, higher protein activity and a reduced immune profile, so our own proprietary ERTs coming out of the CHART platform.

And then finally, we have the ability now with the addition of these small molecule stabilizers to deliver these new enzyme replacement therapies through novel routes of administration, such as subcutaneously. As we get towards the end of the presentation I will share with you some pretty neat data in what we have done with Pompe in developing a sub-cu approach there as well as in injection.

So we have quite an advanced product pipeline. The first bars that you see here are our two mono-therapy programs, our Fabry program in two separate Phase III studies. It's designed to address about half of the patients living with Fabry disease to replace their need for enzyme replacement therapy, that's study 011 and study 012 and I will speak more to those studies in a moment, two ongoing Phase III studies and then we had a very R&D effort in Parkinson's, working through a rare genetic disease target, Gaucher disease and it's a program where we have demonstrated pre-clinical proof-of-concept with the use of a small molecule Chaperone and through this year I think we will have more to say about the development of that program.

Those are our mono-therapy programs represented in green. The two gold bars here show you our co-administration therapy programs, literary again combining a small molecule with existing enzyme replacement therapy, either in Fabry or Pompe disease. Fabry is a proof-of-concept as we are ready now in the beginning of 2014 to put our own proprietary ERT, including the Chaperone formulation into the clinic. And Pompe this is a discrete drug development program, a Phase II program that will go into its Phase IIb studies here at in the third quarter of this year.

And then we also have a pretty active R&D effort as we develop our protein capacity and capabilities to make our own next generation ERTs and you see that in Fabry and Pompe as well as in other Lysosomal disorders that we have yet to disclose.

So I will talk for a little bit about our mono-therapy program in Fabry disease. So Fabry disease as many of you know, a therapy currently treated only with enzyme replacement therapy, either the Shire or the Genzyme products, a rare Lysosomal disorder, thought to be about 5,000 to 10,000 people in the developed world, although we think the population maybe significantly higher, affects both males and females and because of the absence of a protein, or the mis-folding of a protein that doesn't work correctly in these patients, the α-Gal protein, a substrate known as GL3, a storage material builds up in the Lysosome disease patients, predominantly in the kidney, but also you see it in heart, skin and in the brain as well. So very severe. Without treatment it is a fatal disorder, typically killing people in their 40s and 50s.

So we have developed this for several years now. We began our Phase III studies again about three years ago. The first of those is an ongoing Phase III study where we enrolled 60 patients, 30 enrolled on migalastat, 30 on placebo for the first six months. After six months the placebo patients crossed over to drug. What you see here are the results on what was the primary endpoint that the study had originally been designed for an interim look at the data at six months. This is the data we revealed in December and it showed that the drug beat placebo. However it didn't reach statistical significance and this is very important to remember that this end point was a pure responder yes-no analysis.

Did patients show a 50% or greater reduction of the storage material, in the interstitial capillaries of the kidney? What we saw was 13 of 32 patients did. However we saw an unexpected placebo response. Well, we looked deeper into the data because we feel very confident that taking a placebo of course isn't going to have a biochemical effect on biopsies in the kidney. We looked deeper at the data and this was a pre-specified secondary analysis of that primary endpoint. So rather an a pure yes-no and an interim look did patients cross an arbitrary line of 50% or greater reduction.

Here we are actually looking at the overall level of GL-3 in these cells as a continued variable. And at six months what we saw was very little change in the placebo group, down about 6.3%. However the migalastat group showed significant decrease, almost even in this interim look reaching statistical significance, again in a small rare disease study, we think very encouraging. It's encouraging as well with about a 41% reduction for migalastat.

Safety continued to look excellent, thankfully in all the drug development here. We have not had a single drug related significant adverse event. The safety profile continues to look very strong for this drug. And again with study 011, we are in the middle of this phase III study. All patients as of December of 2012 have completed one year of treatment at the end of that 59 of the 60 patients completed the treatment. 57 of 59 voluntarily elected to continue with migalastat as their only treatment for Fabry disease. So we think that will lead to a very robust dataset and we think also hopefully speaks to the patient experience and certainly compliance on the drug.

So that extension study is now ongoing. We are still blinded to the 12 months data. All the biopsy samples have been collected. They are in the process of being analyzed. It is a very pain staking analysis by three renal pathologists, literally counting the inclusion bodies per capillary for each of 100s of biopsy samples. We continue to remain blinded to that. We expect that to be unblended in the third quarter and top line data from that 12 months, the stage II analysis of the data to be revealed publicly topline in the third quarter.

With that we would hope then to be able to go to the FDA with a pre-NDA meeting, present the data from the six months and 12-month period of this study, show why we think that depending on what we see of course at 12-months data, why we think the drug is safe and effective and under a risk benefit analysis why we think it should move forward to NDA.

So we have gotten through a couple of gates. We have two very important gates to get through. We see the analysis of the 12 months data in the third quarter and then late in the third quarter or early in the fourth we would expect a pre-NDA exchange with the FDA.

We have a second phase III study with migalastat as a mono-therapy. That study 012, this was a switch study designed for approval in Europe. Also we think could potentially be supportive of a filing in the United States. Designed as a 50 person study we actually over enrolled the study. We had 60 people volunteer. And this was really significant too. It's the only time I am aware of in a rare fatal disorder where you had patients voluntarily electing to give up an approved therapy for their fatal disease to come on to an experimental medicine that didn't yet even have their Phase III data. But we had 60 persons come forward to do that. It was a 1.5 to one randomization, so 36 completely stopped their enzyme replacement therapy and went to migalastat as their only treatment. And 24 went to ERT.

Compliance continues to look excellent. We have only had one person of the 36 withdraw from the study, reasons unrelated to the drug. It was study compliance and convenience. Some of those - many of those now for more than a year having switched completely off of ERT. Again blinded to the data, however in terms of its safety profile and compliance we think this hopefully bodes very well for this study. It is a study not based on a surrogate endpoint like 011, but based on a clinical endpoint, which is kidney function measured by GFR, specifically the Iohexol GFR measure. Last patient out is end of Q2, next year. And we expect that data in the second half of 2014.

So I will talk for the rest of the presentation about what is a piece of Amicus that's of increasing interest to patients, physicians, certainly regulators as well as investors and that's the use of the CHART platform technology again to co-formulate with these enzyme replacement therapies.

So I helped develop these protein therapies, many of them and especially the Pompe therapy in a number of different companies, including my time as a senior vice president at Genzyme in the therapeutics business, really a good first generation therapy. There is a varied degree of response within patient groups across diseases. But what we do know is that when you put a bioreactor made enzyme in an infusion bag and infuse it into a patient, where the pH of the blood is about 7.5 and these are Lysosomal enzymes that like to live in the Lysosome, in that 5.0 low pH environment, the moment they hit plasma they become very unstable.

A good part of it begins to unfold to aggregate which we believe triggers a significant response to the unfolded antigenic protein. Also leads to poor tissue uptake. We think we have a unique toolset to address that problem that's common across all the Lysosomal storage disorders, especially the ones that we are focusing on in Fabry and Pompe to begin.

So this here covers the basic mechanism of action of the CHART. Unlike with the mono-therapy where we are seeking to bind to and boost a patient's own natural enzyme here we are binding to the bioreactor made enzyme, the ERT, in co-administration either someone else's or co-formulation to our own proprietary ERT. And again all the reasons why we think it could be a significant advantage to patients. It is more than a $3.5 billion market. I don't think we have to spend a lot of time on this. And even with more than $3 billion in worldwide sales for the current generation of therapies, there are more than 49 Lysosomal storage disorders. Here you only see about half a dozen or so that are presently being addressed. So even within these diseases with therapies, we think a significant amount of unmet medical need remains.

So our Fabry program. We went into the clinic at the end of 2011 in a pretty straightforward study. We took people with Fabry disease, stable disease who are on either Fabrazyme or Replagal and just prior to their going in for an infusion we measured baseline characteristics, what was the PK profile of their enzyme therapy, what does it look like on skin biopsies in terms of the amount of protein taken off active protein into tissue. We did that for Fabrazyme and Replagal.

And the only difference is when they came back for their second infusion they took a pill about an hour before, it was our chaperone migalastat. It was at two different doses, doses designed to interact with the ERTs, essentially the stabilizing in blood and to alter their PK and we think improve the PK profile.

And what we saw was pretty profound results that in every single patient where we tried this just as it was in animals, we saw a significant change in the PK profile, again depending on the dose of Chaperone given, here is what people started on ERT alone, the different cohorts and you saw anywhere from a doubling to a more than a quadrupling of enzyme activity in blood. So we think very significant for patients.

Skin biopsies are often tough, they are noisy biopsies but even there at the higher doses of enzymes -- I am sorry at the higher doses of the Chaperone especially we saw a significantly higher amounts of active protein. We wouldn't do, we couldn't do in a PK study, kidney biopsies. But we do think skin as an organ of disease, number one. And number two, the skin biopsies are a good surrogate for what could be happening in the kidney. And again the goal is very straightforward, stabilize the protein in blood, increase of activity, allow more active, more functional protein to taken up in key organs of disease.

What we saw in animals and what we didn’t look for in this study in a short term nature is that third step in the mechanism, could you then have a reduced burden of substrate, very clear in animals that you significantly reduce the substrate even further with the addition of a Chaperone. This was a great proof of concept study. But we had been working already for two years with GSK, we were developing a biosimilar to Fabrazyme. We approached them in early 2011, just after we began our mono-therapy program and said we think we can actually improve on the characteristics of this biosimilar.

So the black line that you see here shows the activity over time of Fabrazyme. You can see that whole concept that overtime it doesn't stay stable, it doesn't stay in its optimal active and the JR-051, the JCR and GSK protein was a near mirror image of Fabrazyme. And when we added our Chaperone into the formulation you could see it retained all or even more than a 100% of its activity. This right hand side here, I know it drives my scientists' nuts when we do this but this represents about a 1.5 year of preclinical studies. The key takeaway here being that in looking at animals at heart and kidney, the two key organs in Fabry disease, you see the blue formulation, our next generation ERT with GSK, showing a greater reduction of the substrate even in these reasonably short term animal studies.

So that allowed us to establish proof of concept in animals and to move this program forward. As we sit here today, the material is being made at JCR in Japan, a facility inspected by GSK, it's a program we are developing jointly with GSK, we pay 40% and GSK pays 60% as with our mono-therapy program, it's been scaled successfully to the 2000 leader version and we are on our time line for IND submission at the end of this year and treating patients in a phase I/II study in early 2014. This will be again the first of our next generation proprietary ERTs combined with the Chaperone to be put into the clinic, the first in our pipeline.

What we will also do in the same program for Pompe disease, in many respects Pompe is a more severe disease than Fabry disease, especially in the younger children, can strike just after birth and often they don't live to be about a couple of years old. And this young lady came to visit us at our company last summer, she 4.5 years old. She been on Myozyme for some time. I believe it's helped her but I think there is a lot more unmet medical need for her and many children like her.

So it is a severe neuromuscular disease, again it's Glycogen that builds up in the Lysosome of people living with Pompe disease. It is a drug that's given at 20 to 40 times the dose of the other enzyme replacement therapies for Fabry or Gaucher disease, partly due to its targeting challenges but also we think partly due to the antigenic nature of the protein and this whole problem of protein folding and stabilization and an enzyme I know very well that I helped develop again while at Genzyme.

So we did the same study as we had done in Fabry. We did this one in 2012, just released the results in early 2013 and same thing again for every one of the more than 20 patients in this Phase IIa study, that came in for ERT alone. We measured the profile, the PK profile of the ERT in blood. Two weeks later they came back for their regular infusion. Again the only difference is here they took our specific Chaperone designed to bind to this enzyme. And in every patients we saw from a 50% to more than a doubling of protein activity in plasma.

We took muscle biopsies too from these patients and at the highest dosage of Chaperone we tested we saw more active enzyme in both patients, small and -- about two out of two patients we saw a significantly enhanced enzyme activity into tissue uptake. Again in the quadricep muscle which is keenly involved in Pompe.

So excellent proof-of-concept but unlike Fabry we don't have an ERT that's poised to go in the clinic in the next six to nine months. We have one in development but it's further back in our pipeline, given the unmet need here, the size of the market, the extent to which we think we can effect this protein and potentially enhance its uptake and reduce its immune profile we have made the decision to take this forward as an independent product co-administered to potentially improve the profile of Myozyme and Lumizyme. That study did repeat dose next Phase II will start in the third quarter of this year.

One of the things we have been doing is spending a lot of time understanding the immunogenicity of these proteins. And again the whole notion is that you are taking a bioreactor made enzyme, putting it into blood of these kids or adults with Pompe and generally once every 14 day infusion, infusions that typically last over a six to eight hour period, the enzyme sits in the bag for all of that time and then it hits the blood and we believe becomes even more unstable.

So we wanted to characterize that and we did a series of experiments with some outside contractors where we characterized the immunogenicity and the T-cell proliferation specifically in this in-vitro assay, of Lumizyme the Pompe ERT, Lumizyme at two different temperatures, room temperature in a 27 degrees and then the addition of a Chaperone. What you can see is in the in-vitro assay it stabilized the protein and seemed to elicit a much lower immune response due to the T-cell proliferation.

We are doing a lot more work in preparing for the Phase II study. In the next couple of months we will be able to describe those protocols and where the studies will be conducted and what we expect in terms of exploratory endpoints from that study. But one thing we will look at are infusion associated reaction and the amount of antibodies produced.

We do have our own proprietary next generation ERT. Here is a standard version of the GAA, the Pompe enzyme bioreactor made. And just like in February you see when you add the Chaperone the protein becomes stable, over a 24-hour period retains a 100% of its activity and in animals and heart and other key organs of disease we see a greater reduction of the glycogen substrate.

What we think about development of next generation ERT is we think it gives us a unique opportunity to step back, to learn of the last 10 or 20 years of development and formulation work in the enzyme therapy space. We see that -- we are looking here in Pompe for instance independently at Amicus and again this is a 100% owned Amicus program as is the rest of our pipeline beyond Fabry, that we are looking at this program in terms of not just the addition of a small molecule stabilizer but what can we do to optimize the glycosulation, further de-immunize the protein and other steps that we are taking to reduce the immune profile of own proprietary ERT. We will have more data and more to say about that I think as we get into the second half of this year.

This is one experiment that I did want to share. We showed this first at an investment conference a couple of months ago. We wanted to see just visually what the addition of the Chaperone can do to stabilize this protein. So this is Myozyme and this is actually the control, stay in control, this is after four weeks of 37 degree centigrade, if you leave Myozyme it begins to aggregate become cloudy. With the addition of a Chaperone you see it remains clear which in a very visually striking way shows the addition of the Chaperone and what it can to do to confer stability on the protein.

But we also characterize it that in terms of its PK profile here's Myozyme, when given subcutaneously and that really what this allows us to do to formulate the protein to deliver it sub cu. And you can see the blue are own formulation of Myozyme with the Chaperone. Again you can see significantly enhanced half-life of the protein as well as tissue uptake.

So again in Pompe we have two different paths, two different products, one the Chaperone, co-administered, coming back into the clinic in Q3 of this year and then our next generation ERT with more significant IND enabling studies under way.

So last slide here just highlights some of the data to come, second half of this year we will be busy with the 12 months data coming in February in Q3, the FDA, pre INDA -- pre-NDA meeting we would expect to discuss the U.S. approval pathway. Pompe co-administration into its next Phase II repeat dose study and we will be poised by the end of this year to begin our next generation ERT program in Fabry disease.

So lots going on in Amicus, again with those pillars of strength of a product company, a platform company, a strong balance and some terrific partnership. So thank you for listening. Have a good day.

Question-and-Answer Session

[No Q&A Session for this event]

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