Amicus Therapeutics, Inc. (NASDAQ:FOLD)
32nd Annual JPMorgan Healthcare Conference
January 16, 2014 2:30 PM ET
John F. Crowley – Chairman & Chief Executive Officer
Anupam Rama – JPMorgan Chase & Co.
Anupam Rama – JPMorgan Chase & Co.
Hi, my name is Anupam Rama. I’m part of the JPMorgan biotechnology team. Our next presenting company is Amicus Therapeutics and on behalf of the company is CEO, John Crowley. John?
John F. Crowley
Thank you Anupam and good morning everybody. We are a public company and we will be making forward-looking statements and we will refer you to the Safe Harbor provisions.
We are a company working in the rare and orphan diseases and our mission is quite simple. We are making medicine that will improve patient’s lives. We are not interested in incremental improvements or me-too drugs or biosimilars and you will see that with our new biologics strategy. Our job is to make new medicines that are substantially improve from existing therapies.
So, from a highlight perspective, four key things to highlight, where we believe you will see Amicus to be strongly position to advance in particular our next-generation enzyme replacement therapies for rare diseases beginning in these lysosomal storage diseases.
So, next-generation therapies, a 3-in-3 strategy, three new enzyme replacement therapies in the clinic each of the next three years beginning in 2014 for Fabry, Pompe and then PS-1. Working with our core platform technologies, especially our CHART platform technology that I will talk to you more about as well as our new Callidus Technology through our acquisition of Callidus Biopharma several months ago.
A good cash balance sheet beginning the year with $82 million cash sufficient into the second half of 2015. And our team that spent most of our careers in the rare and orphan diseases. Many of us beginning our careers at Genzyme.
So many of you are familiar with the market for lysosomal storage disorders. Currently now sixth and soon to be more drugs approved. The overall market more than $3.5 billion in enzyme replacement sales for Gaucher, Fabry and other rare lysosomal storage disorders. When you translate this into lives affected you can see what a profound effect these therapies have had on so many people.
Going back to just 1990 when there was a not single drug approved for any lysosomal storage disorder. To just the beginning of the last decade in 2000, so not that too long ago. When the only drug approved was Cerezyme to treat Gaucher disease with fewer than a thousand patients with that rare disease on any therapy. And fast-forward to just a few years ago, now with just those six lysosomal storage disease products treating now more than 7500 patients.
So we come a long way and these first-generation therapies have been very good therapies, varying degrees of efficacy and varying product profiles. But still we think in many of these disease areas especially in the disease like Pompe disease significant unmet need remains and with our new platform technology approaches in the enzyme replacement therapies we have novel ways to treat this.
So I’ll just show you here on these slides it represented a samples of some of the major drawbacks of enzyme replacement therapies today. As you see in many of these studies published studies looking at a range of disorders here in particular we highlight deficiencies for patients being treated with the Fabry enzymes as well as the Pompe enzymes.
Three key problems that we see with LSD products broadly today, again to varying degrees. The first problem is a lack of appropriate enzyme activity and stability. Second is tissue uptake and targeting. Suboptimal tissue uptake and targeting especially in Pompe and again I’ll highlight more of that with some data here shortly. And the third, is the patient ability to tolerate these exogenous proteins and you see that in both tolerability as well as immune responses.
From our product pipeline you will see how we are addressing that today. The pipeline as you will see is divided in two different pieces. The first are a biologics programs utilizing the CHART platform technology, which is a Chaperone-Advanced Replacement Therapy. Our lead preclinical candidate will enter the clinic this year is next-generation enzyme replacement therapy, a Fabry enzyme co-formulated with our proprietary Chaperone.
Second is our Pompe program that will enter the clinic in 2015. And third our program in MPS-I that we expect to enter the clinic the year after. We also continued to advance programs in a monotherapy use. And again this is the use of a small molecule in lieu of any replacement therapy, designed to specifically bind to and stabilize a person’s own natural enzyme.
You see our program the Migalastat HCL program, a small molecule orally bioavailable molecule. That is in two Phase III studies, late-stage Phase III studies both of which will read out in full this year. As well as in earlier stage monotherapy program in Parkinson’s disease that’s will be partnered with Biogen.
So, let me talk in the next two sections about our next-generation ERT’s specifically for Pompe and for Fabry. So, begin in Pompe disease, Pompe of course is a rare progressive neuromuscular disorder and involved the deficiency of the enzyme GAA ranges an onset from severe infant-child forms to still severe adolescent and adult forms, one of the larger lysosomal storage disorders with patient numbers expected in the 5000 to 10,000 pulse range in the developed world. And approved therapy from Genzyme approved in 2006, but we think if that therapy is suboptimal and there is significant room for improvement on a number of different parameters.
Three different challenges we see with the current Pompe ERT that we think we can address. The first is the problem of activity and stability of the enzyme. And it’s important to remember these enzymes, these lysosomal enzymes or once that all of us without disease, we’re making ourselves a little bit all day every day, transported with in cell compartments eventually residing in the lysosome with their job is a housing keeping enzyme essentially to breakdown substrate, in this case glycogen in Pompe.
It’s first challenge relates to the very nature of enzyme replacement therapy, we are taking a bioreactor made enzyme in fusing it into blood with these enzymes never naturally appear in large quantities.
And you’re also taking lysosomal enzyme that likes to live in the low pH environment of the lysosome of that pH 5.0 and putting it in the very high pH environment of the blood of that 7.5. And the result is you see a rapid denaturation of the enzyme replacement product, where denatures begins to aggregate essentially misholds in the blood and we can address that with our CHART platform technology, where we have a small molecule stabilizer that binds to that enzyme and keeps it folded, preventing its denaturation.
The second problem we see with the Pompe ERT is one if targeting. The targeting of this is through the mannose-6-phosphate receptor, which is also shared with the IGF-2 receptor. The current therapy has a low level of mannose-6-phosphate and the uptake into skeletal muscle is very, very inefficient and that only a very small fraction of the infused marketed enzyme product today is actually taking up into muscle cells. So, majority is delivered to other non-target tissues.
The third problem is one of tolerability and immunogenicity. This enzyme is also given and that’s label dose of 20 mgs/kg often times double that dose for many patients especially children.
So you are taking already inherently unstable enzyme in blood that’s not properly targeted. And you are getting it at a very high dose with unless it’s a substantial immune response the vast majority of patients zero converting, developing antibodies in any cases very high antibody titers.
You also see in published literature at least 50% of patients with infusion associated reactions. So, a very difficult enzyme to administer. And we think we now have tool sets that allow us to address all three of these challenges with the currently marketed Pompe ERT.
We do that through complementary platform technologies both the Amicus homegrown CHART platform technology as well as the recently acquired Callidus platform technologies. So, again with CHART the whole notion is that you are using a small molecule that’s design specifically to bind to and establish the GAA protein. It bind the active site, keeps the enzyme replacement product properly folded in the infusion bag, but very importantly in the blood. So, you prevent that denaturation.
That increases enzyme uptake have a more active enzyme into target cells. We’re also think that keeping the enzyme properly folded that it could also improve the tolerability and immune profile of these proteins. So, the CHART platform helps us address the two problems, the one problem of activity and stability and the second problem of immunogenicity and tolerability.
The Callidus Technology helps us with targeting the enzyme to the muscle cells and we do it in two different ways. We do it with the Callidus Technology and experience that allows the enzyme from the start to be uniquely engineered with the high level of mannose-6-phosphate content. The enzyme replacement therapy that we have acquired with the acquisition of Callidus was not only more advance than our own proprietary enzyme, it was also again uniquely engineered to have a very high level of this mannose-6-phosphate.
In addition, the core platform technology from Callidus, takes advantage of something has been known for sometime in the scientific community and that’s the uptake of these enzymes is receptor mediated through the mannose-6-phosphate IGF-2 receptor. So, the Callidus Technology attaches a tagging [more elite] that promotes substantially higher uptake to the enzyme. And importantly, the uptake for mannose-6-phosphate and IGF-2 work in complement to each other and I had a slide that will demonstrate that more clearly.
So, two tool sets. This slide here shows with the CHART technology can do. This is preclinical data and we had several years of published preclinical studies, but just to give you some sense. But you want to be able to prove in these preclinical studies, is two things. First when you see here on the left hand side in heart and skin that the white bars are untreated, the grey bars are GAA alone, the Pompe enzyme and the blue bars represent GAA co-administered with our proprietary Chaperone. And you see very clearly the blue bars much higher enzyme activity. We’re making a more active form of the enzyme.
And then in the right hand side you see, just as activity went up, you want to see the corollary decrease in substrate accumulation. And we see that again with the blue bars with significantly greater Glycogen reduction, and here it represented of tissues of heart and skin. So, strong preclinical proof‐of‐concept.
But we also did a last study last year, where we wanted to see, can we prove an extend this concept and demand. So, we took patients, who are stable on the existing therapy on Lumizyme. We measure their enzyme activity in blood, in plasma. And you see that with the ERT alone, and these four different cohorts, again very tight range of activity of enzyme without Chaperone.
And then you see at the Chaperone co-administrates, the only difference was two weeks later, when the patients came into take their enzyme. They took an oral dose of the Chaperone in hour before, and you see from a 50% to more than a doubling of enzyme activity. So, that proves the concept in 24 of 24 patients that a Chaperone binds to the enzyme, changes its key PK profile, improves its half life.
And we also show again a very small end, but we also saw again especially the highest dose of Chaperone, more enzyme activity at muscle. So, the CHART platform is very important in addressing two of the three challenges, but we know we needed to better target the enzyme to have a better base enzyme.
So, with the acquisition of Callidus, we acquired that Pompe product. We also acquired the platform so great synergies with CHART. Dr. Hung Do who is the founder and Chief Science Officer of Callidus, who had spent quite a bit of time at Genzyme developing their Pompe enzyme, when he and I work together a number of years back also now coming to Amicus as our Senior Vice President of Discovery Biology as well as existing manufacturing relationships.
Importantly this cell line has ready completed tech transfer and is being scaled up for entry into the clinic into 2015. So just a little bit more on the Callidus platform technology because it is the true platform. It is this variant of IGF-2 peptide, the Dr. Hung Do and his colleagues developed, that allows the peptide to be added to GAA, the Pompe enzyme, but it can also be added to any of the lysosomal enzymes and potentially even beyond.
So, this strategy here is that he will conjugate basically add through a linker the peptide to GAA. It does not bind to the insulin receptor as other similar peptides do, it does not bind the IGF-1 which is very important. It has a very high selectivity and binding affinity for the IGF-2, which is again the targeting uptake mechanism for this enzyme.
And just to give you some sense of how significant, the increased targeting and exposure is, in this Myoblast uptake study you can actually see what Lumizyme alone looks like in its affinity for the receptor and how well internalize GAAs into muscle cells.
The red line here represents the base Callidus enzyme with the appropriate glycosylation including significantly higher levels of mannose-6-phosphate. You see an order of magnitude increase of uptake of the enzyme into target muscle tissue. And when you add the Callidus [indiscernible] technology with the variant of IGF-2 peptide, you see even fivefold uptake above that. So, substantially improved uptake.
So, when we talk about the challenges in Pompe, we see this is a very differentiated approach and approach with the CHART and the Callidus Technologies that gives a novel toolset that nobody else developing medicines today for Pompe or any of the lysosomal storage diseases has a [neurosonal].
We have also seen significant preclinical data. We will have more preclinical data on this technology and the approach in Pompe at the world meeting, the Lysosomal Disease Science Meeting in February in San Diego. But just to give you some flavor for, again this is quadriceps a very hard to treat muscle in Pompe in a very significantly affected muscle.
Again the vehicle compared to Lumizyme alone, you see that Lumizyme of course increased activity and a very modest reduction in Glycogen in the study. Here is the Callidus enzyme, which is much improved begin with the better glycosylation and higher level of mannose-6-phosphate. Again the bar goes up with activity and you see a concurrent decrease in the substrate the Glycogen.
And here is the enzyme that proprietary Amicus enzyme the AT‐B200 with the addition of the peptide tag and you see even greater activity as well as greater substrate reduction. So, in this preclinical proof‐of‐concept study, I think good validation of the approach that we are taking in improving the update of the enzyme.
We put this slide together just to give some framework for how we are thinking about developing this next-generation approach and we get a lot of questions about how this is distinct, not just from Lumizyme, the currently marketed drug, but other drugs in development.
And other technology from another company that has an IGF-2 targeting technology, a different than ours and we think ours is very distinct. Neo‐GAA is a product from Genzyme with chemical conjunction a mannose-6-phosphate, moving across the y-axis AT‐B200, which is our Callidus acquired enzyme in Pompe plus AT2220, which is Chaperone. So, a next-generation ERT and then on the right, that proprietary Amicus enzyme further enhanced with the addition of our now Amicus platform technology of the combination with the IGF-2 tagging technology. And you can see in every category, where we think we need substantial improvement, stability activity, targeting an uptake and tolerability and immunogenicity.
We think we just have novel toolsets that may help us address the substantial limitations of the current therapy, but also therapies in development. So, we will see when the data takes us, but preclinical we are very, very pleased with what we have seen today.
And again actually our most advanced program now turning to Fabry disease is our proprietary next-generation enzyme replacement product for patients with Fabry disease. Again Fabry a rare lysosomal storage disorder, GL‐3 the substrates that accumulates leading to renal failure, cardiac failure, oftentimes stroke, very prevalent lysosomal storage disorder in fact based on some recent published studies, we think may actually be not only the most prevalent lysosomal storage diseases, but actually one of the most prevalent human genetic disorders and we think too the current enzyme therapies offer room for improvement.
Just again more preclinical studies, we presented some of this before, they will be more of this preclinical proof-of-concept at the world meeting as well in February. But the grey bar represents the Fabry enzyme without co‐formulation with the Chaperone, the blue bars had the Chaperone. And here you can see in heart and kidney two very important organs involved in Fabry disease, substantially higher enzyme activity with the addition of the proprietary Migalastat, Chaperone in the formulation of the enzyme.
And again that results in much greater substrate reduction. So, we think again at the notion that we are building biobetters a next-generation enzyme therapies, our hope is that this can make a significant difference for people with Fabry disease.
We have also done I showed the Pompe data, but you can also see we did this with Fabrazyme and Replagal varying doses and you saw the proof‐of‐concept here on the left hand side with enhanced plasma activity more than a doubling of enzyme activity in all cohorts, for all patients with Fabry disease.
And again we took skin biopsies so the grey bars on this right hand side show this activity the uptake of active enzyme into skin tissue of people on enzyme replacement therapy alone. And then with the addition here proof‐of‐concept with the oral co-administration of the Chaperone substantially greater activity of the Fabrazyme or Replagal enzymes begin with the addition that Chaperone. So, strong proof‐of‐concept now in man that the addition of a Chaperone makes a difference.
So, this program is now heading into the clinic in 2014. You could see all the work that done on in the last couple of years. The enzyme is manufactured in Japan through our partnership with GSK extended through to JCR Pharmaceuticals is the actual manufacturer. Preclinical data has been presented in the second half of last year. Again more preclinical data to come.
A Phase I study in the first half of this year in help you volunteers of the IV migalastat and then we will enter patient into patients with this next-generation ERT in the second half of this year.
Just a comment briefly here to about our monotherapy programs. And again separate from the development of biologics what we are doing here is using small molecules for patients with very specific predefined genetic mutations that cause their Fabry disease, where they don’t need to take enzyme replacement anymore. They don’t need to take the existing therapies. And quite frankly we don’t believe that they need to take our and advanced ERT for the 30% to 50% of patients with these mutations, we think that we have the drug that will replace the need for enzyme therapy.
We have two separate Phase III studies for FACETS Study and ATTRACT Study. FACETS Study is a Placebo‐controlled study with the placebo patients causing after six months. We will have this Phase III data in Q2 of this year. It will be 12 month biopsy and 24 month clinical data. Again expected in 2Q of this year. So, a very, very rich data set.
And then also we haven’t really talked much about this study in the last couple of years because this had previously been a GSK-owned territory and with the restructuring recently of our agreement with GSK and their move to accepting passive royalties and larger equity stake in Amicus. We now control the study as well as have all commercial rights ex-U.S.
This is the ex-U.S. approval study. Very different from our FACETS Study that we have talked a little bit about before. This is an enzyme replacement therapy switch study 60 patients, 36 of whom completely stopped their enzyme therapy and move to Migalastat is their only treatment for Fabry disease.
18 months study, 24 remaining on ERT is the [comparatour] it’s a non-inferiority study for approval and data accepted in the third quarter. So two very important Phase III studies for us with the monotherapy approach in Fabry disease reading out this year.
And here you can see some of the date that we have and I’ll just highlight on the bottom here you can see. We have 99 patients on the Migalastat today. People living with Fabry, who take our monotherapy Migalastat is their only treatment for Fabry disease. Upto eight years for some of those patients on the drug from our original Phase II patients and in total more than 320 years of patients experience again with a very strong safety profiles to date on this drug.
So, quite a bit of work is done into the study and this will be an important year. We will have the data in Q2 for the U.S. study, Q3 for the ex-U.S. study and we will access that data and determine the right regulatory path going forward. But we are particularly optimistic certainly about the ex-U.S. study that we will be talking about, quite a bit more going forward.
The financial strength again ending the year with $82 million in cash. Our net spend this year will be $54 million to $59 million. Giving us a cash runaway into the second half of 2015 in the land with were we began. And that’s the highlights of Amicus as a company we think really positioned with the right team, the right platform technologies, the right experience and strong balance sheet. That I hope will enable us to make medicines that we believe can substantially improve people’s lives. So that is Amicus. Thanks for listening.
[No Q&A session for this event]
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