Amicus Therapeutics, Inc. (NASDAQ:FOLD)
The 31st Annual J.P. Morgan Healthcare Conference Call
January 9, 2013 6:00 PM ET
John Crowley – Chairman and CEO
Anupam Rama – JP Morgan
We’ll go ahead and get started. My name is Anupam Rama, I’m part of the BioTech team here at JP Morgan. Our next presenting company is Amicus Therapeutics. And presenting on behalf of the company is CEO, John Crowley.
Thank you. Hi, good afternoon, everybody. Thanks for taking time to come to the Annual Amicus Therapeutics presentation. As we are a public company, I’ll refer you to the Safe Harbor Provisions I will be making forward-looking statements.
And I’ll begin with this slide that talks a little about the mission of the company and what we do at Amicus. And that is a company at the forefront of developing next generation medicines in the rear and orphan diseases. And our focus is in the lysosomal storage diseases on improved therapies. And I think as you see the platform evolve here, you’ll see why we say improved.
So, usually I save this slide for the end, at a JP Morgan presentation. I wanted to begin this year because we do think this is such an important and transformational year for Amicus.
So a handful of key messages. First our Fabry Phase 3 monotherapy study is an ongoing Phase 3. As many of you saw back in December we unveiled the interim or stage one results, those were very encouraging and they were consistent with our years of Phase 2 experience in this disease. We also now have updated regulatory guidance from the FDA indicating that they will consider the entirety of the data from stage one to six month stage as well as stage 2 in the study and we think that’s particularly encouraging.
We also are advancing our Pompe ERT Co-Administration Repeat Dose Study, so we had the phase 2 data released just last Friday and that study the repeat dose, the next stage of development in Pompe will begin in 3Q 2013 this year. We also continue to advance the next generation ERT product, the Fabry co-formulated Chaperone ERT product, that advances to the clinic. We’re also announcing at this conference that we have in development a proprietary next generation ERT. And our financial strength, we begin the year with approximately $100 million on the balance sheet.
So, when we talk about the platform technology at Amicus there are really three key parts to that technology. The first is the use of pharmacological Chaperones as a monotherapy, designed specifically to target to bind to and stabilize a patient’s own enzyme to replace the need for enzyme replacement therapy in people with amenable genetic mutations. The second use of the technology is in co-administration. So, in people who don’t have amenable mutations to take this as a monotherapy, like about half the people living with Fabry, our drug can be used to potentially improve the characteristics and therapeutic outcome of existing enzyme replacement therapy, that is a Chaperone take in directly with the ERT product.
And then finally the third application of the technology is the development of next generation enzyme replacement therapies, they offer all the benefit of co-administered ERT and Chaperone products and with co-formulated products that is our own proprietary ERT and also has the additional benefit of stabilizing the protein in the infusion bag as well as in the patient.
So, one platform technology, three novel uses, which leads to our pipeline as you see, multiple programs in clinical development, Chaperone monotherapy programs, two phase 3 programs in Fabry, a late pre-clinical program with a pharmacological Chaperone in Parkinson’s disease and a co-administered series of products, we now have human data, phase 2 data in Fabry as well as in Pompe and those continue to advance. As well as a co-administered program we’re developing in Gouache disease.
And again the third application of the technology is Amicus’ entry into the biologic space scenario which many of us in the management team came from in our days at Genzyme and other companies, here we’re partnered with GSK and JCR, as we are in Fabry and our monotherapy and co-admin programs with GSK. JCR, Japanese biologics company, developing and now manufacturing for GSK and Amicus, a next generation ERT product. And Dr. Rashed I see from JCR here, so welcome. And the co-formulated products continue to advance I’ll have more to say in the presentation of their development timelines.
So, when we talk about investment highlights and the investment thesis for Amicus, we focus on four key foundations of our success in 2013. The first of these are products, and we are again developing these products, multiple phase 3 studies, phase 2 extension studies for the monotherapy and now multiple phase 2 studies with the co-administration of Chaperone and ERT. So, we’re developing products, generating clinical data. And it’s also a platform technology company.
Amicus was originally founded on the concept that you could use these small molecule Chaperones to be combined, I’m sorry, to be used in lieu of enzyme replacement therapy, where they could be taken to enhance the endogenous protein in people with amenable mutations. The use of that platform is really expanded and we’re now aggressively moving into the notion that – with the development, with the notion that we can combine these drugs directly with the ERTs, either as co-administered products or as next generation ERTs.
Another, strength is our partnerships, again, a great partnership with GSK rare diseases. GSK owns 19.9% of Amicus, in our Fabry programs there is a cost share element they pay 60% of the cost share. And to date GSK has invested in just over two years over $130 million in capital in Amicus in equity and in the cost share and the up-fronts related to that again, JCR an important partner as we develop that next generation biologic in Fabry.
And you may have seen in our press release with a strategic outlook that we put out this past Monday, we now have a relationship for contract manufacture of our own proprietary next generation ERT in Pompe disease and that’s with Laureate BioPharma in New Jersey.
And again our financial strength, yearend cash precisely $99.1 million as of the end of the year and again that gives us cash into at least the second half of 2014. And we believe we have multiple catalysts we’ll highlight throughout the next one to two years.
So, the rest of the presentation is divided in three different sections. It’s divided based on the use of the technology, first in the Chaperone monotherapy program and the data that we’ll show in the development plans now will be around the use of Migalastat as a monotherapy in Fabry disease.
So, Fabry disease, a lysosomal storage disease, it is a slowly progressing severe and fatal human genetic disease. It results in renal failure, cardiac failure and often times stroke in these patients. Traditional prevalence numbers are in the 5,000 to 10,000 range in the developed world. We actually think there is quite a few more patients than that. We think it’s one of the most significantly under-diagnosed human genetic diseases.
And again, it’s a disease characterized by the build-up of a specific lipid known as GL3, that is the fat or the lipid that builds up in the organs involved in Fabry disease and here you see a histology slide showing GL3, those dark inclusion bodies that are in the lysosomes of people with Fabry disease here in the kidney. As we look to the clinical development, and you’ll some in the clinical data here, this is a surrogate marker known to be likely to predict clinical benefit in people living with Fabry.
This is also a drug as a monotherapy, we’ve had significant experience with over the years. If you look at where we are today, as we sit here in this room there are a 102 people in the world who take Migalastat as a monotherapy, as their only treatment for Fabry disease. Many of those patients had previously been on enzyme replacement therapy, some had not been on any therapy, and this is the therapy that they entered into in one of various clinical studies.
We have now over 220 years of patient data, I’ll highlight one of our pieces of experience with that is the safety profile of this drug. We have never thankfully had a drug related serious adverse event in these years of study. And if you look at where we are today with the phase 3 study, the study 011 in Fabry disease, having completed stage 1 and stage 2, they were still blinded to the stage 2 data, 60-person study, 59 people who have completed that study, of those 57 have voluntarily elected to continue to Migalastat as their only treatment for Fabry disease.
And if you look at the development history, you can see an awful lot of work has gone into understanding this novel pharmacology and really there is new paradigm of treatment for Fabry disease so beginning with the Phase 1 safety studies, moving through years of dose ranging studies.
And with this new pharmacology, the two greatest challenges that we had to overcome were one, the dosing, and finally we realized after pre-clinical work and years of work in the clinic, that the way to optimize this drug was to deliver it at 150 milligrams every other day.
The second challenge that we had to overcome was in understanding precisely the genetic mutations that might respond to this medicine. There are over 500 known mutations that can lead to Fabry disease. We’ve characterized and built the constructs to every one of them in our lab, now that assay transferred to a GLP company, company with GLP capabilities. We now understand, we think very, very well and can predict with almost a 100% certainty the patients and the specific mutations who would respond to this medicine.
So the pharmacogentic element, the ability to predict patient response and who is amenable and non-amenable to this therapy is incredibly important. So, armed with those years of data, several years ago, we began the first of our phase 3 studies in late 2009. There is a lot of data that’s been generated, much of it presented in various scientific symposia, I just want to highlight in one slide, what we know that this drug can do.
Again, the purpose of Migalastat monotherapy is to target bind to and stabilize a person’s own enzyme, Chaperone it, allow it to be transported to the lysosome, where our drug disassociates and we’ve essentially chaperoned or rescued the patient’s own enzyme. Once we do that by delivering the drug every other day it becomes a lifelong therapy for this chronic severe disease. Again what we’re trying to show by a surrogate marker is the clearance of the GL3 lipid.
So, what this schematic represents is patient by patient in a small phase 2 study of eight patients in that study, five with known amenable mutations, three with non-amenable, what was the experience after more than a year of treatment. The blue lines represent baseline, the red lines is the biopsy point at various points, all just passed a year of treatment. And you can see in people with amenable mutations, significant response in reduction of the GL3 substrate. Again that’s the same substrate that was used for the conditional approval of Fabrazyme, the only approved ERT in the United States for the treatment of Fabry disease.
But also importantly in addition to the 78% median decrease over this period of time for people on treatment, for people with non-amenable mutations, it actually became an effective control and you can see 114% median increase, which tells us that the drug is not only working through the mechanism of action, it’s also working in the patients for whom it’s intended.
So, we designed this phase 3 study, it began again two years ago, 60-patient study. Half the patients randomized to Migalastat, half to Placebo, three biopsies at baseline, six months and 12 months.
We unveiled some data at the stage one interim analysis back on December 20, on the primary end point. And what we showed was that of the people on Migalastat, 41% achieved the primary end point for that six-month part of the study. And that was patients who had a 50% or greater reduction in GL3 in the kidney. That was very good news and we saw that was greater than the Placebo group, however the P value is disappointing because the Placebo response was much higher than expected.
We also however were able to release one other piece of the data at six-months and that was the secondary analysis of the primary end point. And here what we’re looking is over a continuous variable, looking at the overall level of GL3, so not just the pure responder analysis of yes, no, they hit that level of reduction at six months. But what was the overall magnitude and here you see a very clear separation, almost reaching statistical significance even in that six-month period.
So we think this data is very encouraging, it’s also very consistent with our years of experience in phase 2 studies, that at six months you can see a significant in this important biochemical marker. But we’re also hopeful going forward that we’ll continue to see the persistence and durability of this affect.
We’ve engaged in ongoing discussions with the FDA, one of the things I can update today is specific written feedback from the FDA that they will consider stage one or the six-month analysis to be the interim analysis of this study and stage 2, the 12-month data analysis for NDA submission. Importantly the FDA has also said that they will consider the entirety of the data in evaluating the safety and efficacy of Migalastat monotherapy and that no single end point will be determinative.
We think GL3 will continue to play an important part of how we evaluate the surrogate, by the surrogate marker, the efficacy of this disease so, some important things to look forward to. We have a world meeting, which is the world lysosomal disease symposium in February, we will be able to present the totality of the data at six months, beyond just the primary end point. We also will be able to present a number of secondary end points, other interpretations of the primary, and at that time I think it will become very, very clear why we had that unexpected Placebo response.
In the second quarter, we’ll get the data from the 12-month end point, and by the middle of this year, we expect to engage in discussions with FDA further discussions about US approval pathway for this important new medicine in Fabry. So we continue to be very bullish about this novel technology for patients with the minimal mutations.
One of the things we’re going to look at is a pre-specified in a statistical analysis plan, descriptive comparisons, we will have a larger, significantly larger dataset, at 12 months than we had at the stage 1 analysis. At six months patients who are Placebo crossed over to Migalastat, people who are on Migalastat for the first six months continued on Migalstat.
We’ll have the data to be able to compare the Placebo arm for the first six months to themselves as they crossed over, we’ll also then have 60-patient data at a six-month endpoint, looking – again comparing that to Placebo. And in addition, we’ll also have a full 12 months of data for at least 30 patients who began the study and continued. And again it was a one year study, all patients have completed one year of treatment, 59 of those patients who completed the study, of those 57 have elected to continue into that voluntary extension study.
So, we think that boards quite well. We also have a phase 2 study, our study 012. It is fully enrolled and ongoing, it is a clinical outcome, a year ago at JP Morgan, this was the study that kept me up at night. I worried about enrollment of this. How successfully could we convince patients and physicians to come off of an approved therapy for a fatal disease and replace that with an experimental medicine? We did that, we over-enrolled the study, we did it ahead of timeline, and that study continues to go quite well and again data expected in that study in the second half of 2014.
So, a number of different catalysts and inflexion points to look forward to, just on the Migalastat monotherapy, we have the world meeting. We have the additional top-line data for the 12-month end-point in 2Q. The FDA meeting, and then we’ll look forward to the results of the 012 study in 2014.
One last point on the Migalastat monotherapy, we’ve said that we believe about 30%, roughly a third of diagnosed Fabry patients have mutations that would make them amenable to this monotherapy. If you look at the new born screening studies, four of that have been published just in the last few years, they show a significantly higher level of Fabry prevalent and that’s really important in Fabry, because given that it’s an ex-linked disease, it’s not that you’re going to treat the infants in the disease because it’s ex-linked there is thought to be and it’s been published about three to five index patients per patient in a family. So, we think that boards quite well for the ability to identify and potentially treat people with this as a monotherapy.
So, the second use of the technology is the co-administration of the Chaperones with existing enzyme replacement therapies looking to improve the profiles of those ERTs. We think number of different issues with the existing ERTs, the fundamental problem with an enzyme replacement therapy is by putting a lysosomal enzyme in the blood, you’re taking a lysosome that all of us without disease make all-day, everyday within our cells. And the enzyme lives in the lysosome where the pH is about 5.0.
In the infusion, you’re putting it into the hostile environment of the blood about 7.4 pH. The most immunogenic thing present in a body is an unfolded aggregated protein in blood or among the most immunogenic. So when we think about the potential of this platform, this is what we think offers the greatest potential for patients and for shareholders of Amicus, that’s the ability going forward and for shareholders of Amicus, that’s the ability going forward to modify these proteins, existing therapies or the development of our own proteins to make potentially better therapeutics, potentially enhanced roots of administration and potentially with reduced levels of immunogenic.
So, a year ago at JP Morgan we presented data with the first four patients, patients on Fabrazyme, co-administered with our Chaperone Migalastat. And what we did here was quite straight forward, patients would come in for their ERT alone, we’d measure plasma activity and by the green bars here that you see, we’d measure how much ERT was taken up into skin as a measure of tissue uptake. They would come back generally two weeks later for their next infusion of ERT, and they would take our medicine just prior. What we saw with all patients was the response, 340% for Repligal, anywhere from 100% to 190% for Fabrazyme depending on the dose. And strong human proof of concept evidence that we can change the PK profile and also enhance the tissue uptake of the enzyme.
The data that we released last Friday in Pompe showed the same thing. Again, increasing the plasma activity of active enzyme, and what we saw with the highest dose cohort, was a more than doubling of the enzyme, the ERT product into muscle in Pompe patients. So, great proof of concept on two aspects, on plasma activity and on tissue uptake. But remember there is a third problem that we’re trying to solve for here and that’s the immunogencity of the protein.
It’s been known and published for some time that in Pompe specifically this is a significant problem. It for many patients is a matter of life of death overcoming these antibodies to the ERT. It’s been published that about 40% of the administered ERT in Pompe is captured by circulating antibodies and about half the people in Pompe develop infusion associated reactions. We’ve characterized this in an ExVivo study using healthy volunteer cells, looking at the immune response of lumizyme given alone. And then what you see is a marked reduction in – here it’s the T-cell responses or marker of the immunogenicity of the protein. We think this is good ExVivo proof of concept.
And so going forward, we intend to aggressively move forward with the development of AT2220 with the Chaperone co-administered with the existing Pompe ERT products. This afternoon at the conference we’re announcing that we have completed a new formulation of AT2220. In the early phase 2 studies it was given it is an oral dose, we’ve now developed it as an IV formulation, GMP manufacturing underway. And we expect to begin that study in Q3 of 2013. We see this is a study in adults and open label, short term study, looking at many of the endpoints we looked in the preliminary phase 2 study. Plasma activity, tissue uptake and importantly what impact we can have on patient’s immune response in the level of antibodies. So, this I think will be an increasingly important program for Amicus and for patients.
So, the final aspect of the technology that I’ll comment upon is the use of Chaperone’s directly co-formulated with our own proprietary enzyme replacement products. We announced last summer the extension of our collaboration with GSK and the partnership with their partner, JCR pharmaceuticals. We’ve characterized Fabrazyme and you can see this problem here graphically and an ExVivo assay over time in the pH of the blood the activity of Fabrazyme declines dramatically.
The 051 product which is the JCR enzyme, has very similar characteristics, almost a bio-similar to Fabrazyme. However, when co-formulated and manufactured with the Chaperone, you see it retains all of its activity, we keep it folded, we keep it stable. Significant amounts of pre-clinical data generated over almost two years now, again demonstrate that as compared to Fabrazyme, we see significant reductions of that GL3 substrate above and beyond the ERT alone. So, we think this has the potential for enormous benefit for people with Fabry. That is a very advanced program, already scaled to the 2000 leader scale. And we think it has the potential within about a year to enter the clinic.
We are also developing our own proprietary next generation ERT product in Pompe disease. This is an ERT that we’re developing with Amicus’ capacity and capabilities and together with our partner – contract partner at Laureate. We are combining it with AT2220, again we think it could increase the tissue exposure, tissue uptake, reduce the immune profile of the ERT. And while we’re making another ERT, we’re also looking at the basic protein itself, can we enhance the 906 phosphate content or the GAA protein in Pompe, looking at other ways in which we might de-immunize the protein.
One another really important piece of data that I’d like to share is this last bullet point. We know that by adding the Chaperone we could significantly stabilize these recombinant proteins. We also think that it offers the potential to keep these so stable that you might be able to deliver them subcutaneously, that could have enormous benefits for patient convenience but also we think potentially for therapeutic outcomes rather than a patient going to the hospital for once every other week infusion and spending every one cent of every 14 days of their life hooked up to an IV machine, we could much more closely mimic how all of us without disease. Potentially a needless zippy pen, would be able to deliver that in everyday, every other day whatever the format may be.
And here, we can actually show why we’re so excited. So if a picture tells a thousand words, I think this tells quite a bit. So, on the left, you see a control. This is myozyme after four weeks sitting at 37 degree Celsius. When it sits at four weeks with the chaperone you can see how clear it is.
Here is Myozyme alone, delivered in rats the PK study subcutaneously. And you see the significant difference in the levels of active GAA in the rats when you co-formulate with the Chaperone. Very exciting piece of data for us, something just presenting now, we’ll update it later in public presentations.
And when we look forward to 2013, we’ve got quite a bit ahead of us. So, Fabry monotherapy and a number of different catalysts moving forward. Pompe ERT combination, we’ll have some of that data again at the world meeting. We’ll also begin that next series of repeat dose studies in the third quarter of this year. Our Fabry chaperone co-administration additional data again in February.
And we continue to move forward with our combination programs with next generation ERTs. We think that this has the potential across the board, all three uses of this technology to really bring about the renaissance in the treatment of lysosomal storage diseases and we’re happy to be a part of it. Thank you.
[No Q&A session for this event]
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