Amicus Therapeutics, Inc. (NASDAQ:FOLD)
UBS Global Life Sciences Conference Call
September 20, 2012, 10:30 am ET
Bradley Campbell - Chief Business Officer
Good morning everyone. Welcome to the next session of the UBS 2012 Global Life Sciences Conference. It’s my pleasure to present the next speaker from Amicus Therapeutics, Mr. Bradley Campbell; the Chief Business Officer of Amicus Therapeutics. And I would just like to remind everyone that after this session, there will be a breakout session in the [Carnegie Room at the Campus level]. Thank you very much
Great; thank you [Terence]. Thanks to UBS for having us here this morning; welcome everybody. I’ll refer to you to our Safe Harbor provisions. I will be making certain forward-looking statements this morning.
So let me start by sharing with you how we position Amicus and why it's such an exciting value proposition for our shareholders. First and foremost, we have our small molecule, pharmacological chaperones which target and bind to misfolded and unstable proteins, has two fundamental uses. One as a monotherapy for patients with the appropriate genetic mutations where they can take our small molecules chaperones instead of their enzyme replacement therapy for the only treatment for their Fabry disease. And second, for patients who lack the appropriate genetic mutations, we can take our small molecules, combine them with enzyme replacement therapy and make that enzyme replacement therapy better.
Second, with our global clinical capabilities and capacities that puts us at the forefront of developing therapies for rare and orphan diseases, we have clinical sites in over 20 countries around the world. We have two ongoing Phase III registration studies for Fabry disease. We have two ongoing global Phase II studies in co-administration; one for Fabry and one from Pompe and I will talk about both of those later in the conversation. And then we also have a recently expanded deal with the GlaxoSmithKline rare diseases; discovers all uses of migalastat for Fabry disease as global co-development and cost sharing and now Amicus has U.S. rights to all uses of Fabry disease and GSK has ex-US rights.
So again, one technology with two novel applications, first for patients with appropriate genetic mutations that can take our small molecule competitive inhibitors that bind to stabilize and elevate the enzyme in a patient’s own mutated enzyme increasing its trafficking for lysosome with a small molecule can dissociate and the enzyme is free to turnover substrate.
For patients who lack the appropriate genetic mutations who have to stand their enzyme replacement therapy just as we can bind to and stabilize a patient’s own mutated enzyme, we can also bind to and stabilize exogenous recombinant protein increasing its activity in the blood, increasing the amount of active enzyme taking up in the key tissues of disease and reducing substrate over ERT alone.
We have now demonstrated this in seven different enzyme replacement therapies in preclinical animal models, three for Fabry disease, three for Pompe disease and one for Gaucher disease; so a very important extension of our technology.
This helps lead to a very robust product pipeline from a monotherapy perspective as I mentioned we have our two ongoing Phase III studies for Fabry disease Study 011 which is our U.S. registration study and Study 012 which is our ex-U.S. registration study. We also have ongoing preclinical work in Parkinson’s disease which takes advantage of our knowledge in Gaucher disease and uses a small molecule chaperone to target GCase to help reduce synuclein in preclinical anima models.
From a combination therapy perspective, as I mentioned we have our ongoing on Phase II co-administration study with migalastat combined with either Fabrazyme or Replagal. We also have our Study 010 which our Phase II co-administration study for our small molecule chaperone AT2220 co-administered with either Myozyme or Lumizyme. We've ongoing preclinical work looking at combination therapy for Gaucher disease using our small molecules AT2101 and AT3375 combined with ERT’s for Gaucher disease and we have a recently announce Fabry co-formulation study which I'll talk more about later in the conversion. This is in preclinical phase and its part of the rational for expanding our relationship with GSK. And then finally, we do have multiple ongoing studies in preclinical animal models for other LSD targets.
Now again, we recently expanded our collaboration with GSK. This is a collaboration that began back in November of 2010 under the leadership of Marc Dunoyer, who heads up the GSK rare diseases business unit. Originally it was focused on the migalastat for monotherapy and for co-administration, but after lot of the work that we did together looking at the possibilities around combination therapy we expanded the collaboration to include co-formulation as well.
Now Amicus will be responsible for commercializing these products in the US and GSK will be responsible for commercializing outside the US. In addition, GSK put another $18.5 million in equity into Amicus to raise their ownership stake back to 19.9%. We do continue to have global development cost sharing which is 25-75 this year and 40-60 in the remaining years of the collaboration. And finally, GSK is eligible for certain moderate approval and launch milestones for each of the Fabry programs. It’s a very important part of our value proposition and a key partner for us.
This is in part would lead us to our strong financial position. We announced at the end of second quarter that we had $95.8 million in cash, we do project that we’ll end the year in over $90 million in cash, which we think will fund us well beyond our 2013 operating plan. Importantly too, we worked hard in 2012 to strengthen our balance sheet.
This began earlier in the year when we had our secondary offering raised over $60 million continued with the additional $18.6 million that GSK put in as part of the extended collaboration and we also earned $3.5 million development milestone from GSK earlier this year for the last patient enrolled in our 011 Study. From an operating expense perspective, we do think we’ll stay within the range that we’ve given between $37 million and $43 million; which we think will come in at the upper end of that range and of course this is net of our anticipated Fabry cautionary.
Now let me talk in a little bit more detail about our Fabry monotherapy program. Again, we have two ongoing Phase III registration studies looking at migalastat as a monotherapy at 150 milligrams taken every other day for patients with the appropriate genetic mutations. Our Fabry Study 011 is our U.S. registration study; it’s a placebo controlled double blind study looking at a reduction in GL-3 as measured in interstitial capillaries; it is eligible for accelerated approval, our target enrollment was 60 patients although we over rolled the study to 67 patients.
We have already completed our first six month treatment period, the primary endpoint period. Those data are expected in the fourth quarter of this year after encouraging discussions with the FDA. Most patients have now moved into a second six month open-label treatment extension period and I will provide further detail and the status of those patients in a few minutes.
We also have our global registration Study 012. This will serve the story as the confirmatory study for our U.S. registration. In this study, patients will come in on either Fabrazyme or Replagal and/or randomized either stay on ERT or switch to migalastat is their only treatment for the Fabry disease. The target enrollment here is 50 patients; we are well under way towards enrollment here and we expect to announce full enrollment by the end of the year and the outcome measure for this study is in 18 month clinical endpoint looking Kidney function as measured by GFR.
So why are we still confident in the potential for success of migalastat monotherapy program? First and foremost, we have our ongoing Phase II experience. We have over a 150 patient years of experience to date with this drug; patients who have been on migalastat now is their only therapy for their Fabry disease for over five and even six years now when anyone of them could have switched back to enzyme replacement therapy we never had a single drug related SAE in this program.
We continue to see positive trends in improvement or stabilization of kidney function as measured by proteinuria or eGFR and we continue to see positive results in terms of reduction in GL-3 as measured in urine and in kidney biopsies. As it relates to 011 Study we had a very strict entry criteria; patients had to have an amendable genetic mutation to enter the study. They had to be naïve to ERT or washed out of ERT for over six months and they had to have urine GL-3 over four times the upper limit of normal, this is because in our Phase II experience urine GL-3 correlated well with interstitial capillary GL-3, so this helps us ensure that they have enough substrate at baseline to measure reduction overtime.
We have also improved the histological measure that we are using to look at that reduction in GL-3. This work was developed with Professor Laura Barisoni and was recently published in the Archive of Pathology. It’s a more sensitive objective digital measure to look at the reduction in GL-3 and vast improvement over the light microscopy method that was developed earlier for the Fabrazyme studies. And finally, we also know the progress of these patients moving through the studies. We already know that we’ve over enrolled the study. Originally, we are powered to enroll 60 patients with 10% drop out rate. We enrolled 67 patients only had a 6% drop out rate. So we have 63 patients who have already completed the primary treatment period, the first six months double-blind treatment period, all 63 of them elect to enroll into the second six months treatment period.
40 of those to-date have actually completed the full study and 38 of those 40 have now moved on to the open label extension where presumably they will stay until the drug is approved. So we continue to see fabry market as a robust and growing market especially after the resolution of the shortage of Fabrazyme and the way we see the distribution of the monotherapy opportunity into this marketplace as we think about 50% of the patients will have a (inaudible) to Migalastat as a monotherapy for their only treatment for their fabry disease.
This is based on our Pharmacogenetic work, our understanding of the distribution of patients between the two fabry registries and a growing understanding of our large undiagnosed population that’s born out in new born screening studies in Taiwan and Italy most recently in the United States. However, for the 50% of the patients who do not have amenable genetic mutation they will have to stay in their enzyme replacement therapy and we believe that the combination of our [shaft] run Migalastat with that enzyme replacement therapy will make their ERT better.
So with that let me transition over to our ERT chaperone combination technology platform. There is no question that enzyme replacement therapy has been an important first generation therapy for patients living with lysosomal storage disorders.
Patients have benefited from these therapies starting way back with invention of serozyme continuing through the most recent approvals today. However, infusing vast quantities of protein is a very unnatural act, so these lysosomal enzymes they are meant to live in a highly ascetic compartment of a lysosome. When you take these large quantities of proteins put them into the higher PH environment of the infusion bag and in the blood, they rapidly denature, they become unstable. This leads to significant instability in the blood and in the bag, it leads to immunogenicity which can impact both safety and efficacy as limitations on dosing and duration of infusion and we think that the combination therapy approach provides us with tools to address each of these.
In fact as I mentioned in seven of seven ERTs that we have looked at in pre-clinical animal models, we have shown that we can increase the stability and the activity of these ERTs in the blood.
We are going to increase the amount of active enzyme taken up in the key tissues and we can reduce substrate over ERT alone. And importantly this year we have demonstrated in two studies with patients from Pompe disease and Fabry disease then in fact we can do those first two steps increase the activity of the enzyme in blood and the increase the amount of active enzyme taken up in the key tissue.
So let me review with you that data. First of all, I will show you just why we think that this is such an important impact on these ERTs. It seems like nothing can stabilize these ERTs better than a small molecule competitive inhibitor bound at the active site.
This is a picture of co-crystal structure of the protein alpha GALE which is the cause of that rare disease with our small molecule Migalastat bound at the active site, in this stabilities what we believe lead to the benefits that we see from combination therapy.
So this is a brief overview of our two studies, our ongoing global studies with co-administration in both fabry and Pompe. We have studied 013 which is a drug-drug interaction study looking at two different ascending doses in the Migalastat combined with either Fabrazyme or Replagal.
We look at plasma PK and PD as measured by skin biopsy. We already released positive preliminary results at JP Morgan earlier this year from the first cohort a 150 milligrams plus Fabrazyme and importantly now we have actually completed all four cohorts all the patients have been enrolled in this study. We are in the process of analyzing all of the data and will show at Fall Scientific Congress this year. I’ll review the initial data that we showed earlier in the year in a minute.
As it relates to Pompe disease, we have our study 010 which the co-administration of small molecule chaperone AT2220 combined with Myozyme and Lumizyme again taking plasma PK in this case PD is measure by muscle biopsy which is a key tissue disease in Pompe disease.
Here too, we've already released positive preliminary results from the first two dose cohorts although we gave more detail recently at the SSIM Conference in Europe. I’ll show that detail in a moment. We've completed enrolling Cohort 3 the DSMB has given a green light to move into Cohort 4 which is enrolling now.
We'll have additional data at further Fall Scientific Congress this year and we'll have full data by the end of the year. This is a bit more detail on the study design. Again, two different doses of Migalastat, four different cohorts, 150 milligrams or 450 milligrams of Migalastat plus either Fabrazyme or Replagal.
Patients come in and get their normal ERT infusion; we take a baseline PK serial PK and skin biopsy. They come back in two weeks later for their ERT infusion expect just prior to getting ERT infuse, they take a single oral administration of Migalastat.
We take the PK samples, we take a skin biopsy and we compare the results. So these are the data that we showed earlier this year that demonstrated all seven patients from the first cohort that we can't in fact increase the activity of this enzyme in the plasma when co-administrated with Migalastat versus ERT alone.
On the left hand side, this is when patients come in and get their normal infusion of ERT as you would expect. Their enzyme activity increases. However, when they come back in two weeks later and get their administration of Migalastat plus in this case 0.5 milligram of Fabrazyme because these patients run of storage. You see two to four fold increase in enzyme activity over ERT alone.
For the patient on full dose of Fabrazyme, this is during the shortage for some patients around full doses of Fabrazyme again they come in, they get a higher increase in activity because they have a higher dose of Fabrazyme and when they get the co-administration of Migalastat plus the Fabrazyme, again you see a roughly two fold increase in enzyme activity in the blood over the ERT alone.
This translates well for the impact on skin, as a more variable measure and you will see differences in levels of activity but you can see a most patients they saw significant increase in the amount of active enzymes taken up in the key tissue over ERT alone.
So very existing results as it relates to fabry disease and again we look forward to showing the rest data at the end of this year. The Pompe study 010 co-administration studies are very similar to design study to the 013 study with fabry, the patients come in get their normal infusion of Myozyme and Lumizyme, we take base line PK samples as well as muscle biopsy in some cases, they come back in to get their ERT but they take a co-administration dose just prior to their ERT, take the same PK examples and muscle biopsies and compare the results.
Importantly here to, there are four increasing doses of AT2220. The first dose was actually only 50 milligrams it’s quite a low dose, it was just at the barely deductible level that we saw in pre-clinical animal models we weren’t entirely sure what we would see, when we look at those data.
And as you can see here, we are quite to pleased to see the effect in each patient in the 50 milligram cohort and the 100 milligrams chorot we saw an increase in enzyme activity after the co-administration of the chaperone plus ERT.
Again patients come in on the left hand panel. They get their ERTs, they see an increase in GAA activity. They come back and they get the co-administration of 50 milligrams of AT2220 and see a 20% to 60% increase in their enzyme activity over ERT alone.
Patients in the 100 milligram cohorts saw an even further increase here it ranges from 50% to 90%. In the next two dose cohorts which are 250 milligrams and 600 milligrams, we’d expect to see even more robust effects.
In terms of muscle biopsy, again slightly more variable. We didn’t see much of an impact at the 50 milligram dose level that’s the expected base in the work we did in the pre-clinical animal models, but at the 100 milligram dose, in three of the six patients we saw clear evidence of effect where we say 40% to 60% increase in the amount of active GAA taken up into muscle over ERT alone. So again we’ve essentially now replicated the first two steps that we saw in the animal models, stabilize the enzyme in blood, increases the activity in blood and increased amount of active enzymes taken up in the key issue. The next steps for both of these programs will be to move on to further clinical studies where we look to demonstrate either a clinical impact or reduction in GL3.
Another important part of the Pompe story though is immunogenicity. Remember that as these enzymes unfold in the blood, they cause a significant immune response. Most patients taking Myozyme and Lumizyme have a significant antibody response which can impact both safety and efficacy as active now standard of care for physicians who are treating infantile-onset Pompe patients to ablate these immune systems with Methotrexate or Rituxan in order for them to tolerarize Myozyme and Lumizyme.
The work we're doing here is sponsored by a grant from the Muscular Dystrophy Association. Essentially we’ve partnered with a group called (inaudible) based out of the UK that has a proprietary EpiScreen assay that looks at the T-cell response in vitro to various therapeutic protein.
The data that you see here are proteins like (inaudible), etcetera where they run them through their EpiScreen assay, see how immunogenic they are and compare them to what the results show in the literature and you can see (inaudible) for example on the upper right as very immunogenic where as [Zoller] on the bottom left is less so.
The first step of this work will be to show where Myozyme and Lumizyme fall in this output. We will then co-administer Myozyme and Lumizyme with AT2220 to see whether or not we can reduce that immune response in this T-cell assay. We'll also take samples from our 010 Study to see that whether or not Myozyme and Lumizyme show highly immunogenic responses in this T-cell assay from tissues from actual Pompe patients. And then finally, we’ll look at the co-administration of AT2220 plus those two ERTs to see whether or not we can produce that response. Results from this study will help us design further clinical studies to determine whether or not we can have an impact in the clinical setting and the immune response to Myozyme or Lumizyme when we we’re co-administering with our chaperone AT2220.
What we really see this as a continuum of innovation. We're moving from chaperone monotherapy for patients with addressable mutations. Chaperone co-administration therapy for patients who lack addressable mutations to co-formulation where we combine the chaperone earlier in the process in the infusion bag with currently marketed ERTs, moving all the way to chaperone plus proprietary next generation co-formulated ERT products.
And that was a key part of the expanded relationship with GSK. In 2009, GSK partnered with a Japanese biologics manufacturer called JCR. They’ve got over 20 years of experience, a very established company. In Japan, they got two marketed recombinant proteins today, HCH and EPO; five additional ones in development, including a next-generation ERT for Fabry disease, JR-051. And about 18 months ago, we started work and we saw the exciting results from our co-administration program.
We started work with these three organizations to see whether or not we could in fact have an improved impact on GL-3 reduction using the co-formulated products. These data are preliminary, but these are an example of some of the data that got us so excited about this opportunity and led to the expanded collaboration with GSK. What this shows you is a reduction in GL-3; 100% of this are GLA knock-out animals. So 100% would be in untreated animal. So on the far left inside, you can see the amount of GL-3 reduction with a single medium dose of JR-051 that corresponds roughly to a 1 mg per kg dose of Fabrazyme.
When we co-formally with Migalastat, though you see a significantly improved reduction in GLR3 over ERT alone. Interestingly, when we go to a high dose of JR-051, the results on GL3 are roughly similar to the co-formulated medium dose and when you go the high dose of JR-051 co-formulated with Migalastat, you can see reduction in GL3 to near (inaudible) levels which is something rarely been shown with ERT alone.
So very exciting data and one we continue to move forward, we hope to get into the clinics sometime in 2013. So I hope during the course of the presentation you have seen that we have continue to hit our major milestones over the course of the year.
For fabry, we have a number of exciting milestones coming up, we will have additional data from study 013 in Fall Scientific Congresses. Importantly, we will have our pivotal data from our US registration study 010 in Q4 of this year, and we plan to announce completion of enrollment by Q4 as well for study 012.
From a Pompe perspective, we have that pre-clinical immunogenicity work with the (inaudible) data. We have additional data from study 010 another Fall Scientific Congress and have full data from that study by the end of the year and then finally we will continue to progress our pre-clinical work in Parkinson’s and other programs.
So with that I thank for your attention and I look forward to taking your questions in the breakout.
[No Q&A session for this event]
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