Stephen Willey - Stifel Nicolaus
I’m Steven Willey, one of the biotech analysts here at Stifel and very glad to have with us today from Amicus Therapeutics, William Baird, the Chief Financial Officer. He is going to give us a presentation. We are going to have some Q&A at the end if time permits. Chip, thanks for coming.
William D. Baird, III
Yes, great. Okay. Thanks for having us and I would like to thank the conference organizers and everyone for inviting us to be here in Boston today. I will refer you to Safe Harbor provision. We are making forward-looking statements in today’s presentation.
So in Amicus Therapeutics, we’re focused on developing next generation medicines to treat a range of rare and orphan diseases with a particular focus on improved therapies for Lysosomal Storage Disorders. We show pictures of our patients here to illustrate for you and remind ourselves of our mission.
So on the right hand side you see a picture of a family with three generations, living with Fabry disease, which is a common occurrence in that indication. And on the left hand picture you see two siblings living with Pompe disease and while there are first generation approved therapies for these diseases, there are still a great deal of unmet medical need and I will tell you more about that today.
Our goal is to develop much better treatments for these patients and improve these patients’ lives. So from an investor perspective we have four pillars of strength. The first is our products in our pipeline we’re a product focused company. We have multiple clinical stage aspects as well as what we believe is a very promising preclinical pipeline. We have a very robust technology platform in our CHART technology. We think the Chart technology gives us the ability to make any ERT a better product and show you data why we believe that.
We have a great set of partnerships. Our largest partnership is collaboration with GSK. That’s the collaboration we entered into originally in 2010 and then expanded in 2012. Over the years GSK has made series of investments in Amicus such as now they’re now 19.9% owner in the company.
Financially they provide a great deal of support. Funding 60% of all development costs, of Migalastat, which is our chaperone for Fabry disease, our most advanced program. And commercially we retain the U.S commercial rights, while GSK is responsible for commercialization outside the U.S. So its -- they’re terrific partner for us and actually through the GSK partnership we also gain access to a collaboration with JCR. JCR is a Japanese by largest manufacturer; importantly they have a proprietary Fabry enzyme placement therapy. We are moving that Fabry enzyme replacement therapy coupled and co-formulated with our Chaperone into human clinical studies in the first half next year.
And finally we were pleased to announce just this week collaboration with Biogen Idec on our preclinical Parkinson's program. Long player in Parkinson's basin, we’re pleased to have them as collaborator. And finally the four pillar strength of course is balance sheet. Like (Indiscernible) biotech the balance sheet are important to manage and we’re in strong shape that way. We have $74 million of cash on hand at the end of the second quarter. That cash combined with the 6% cost share we get from GSK takes is well into the fourth quarter of ’14 based on the current trajectory.
So at Amicus we have a core technology, which is our pharmacological chaperone technology and we’ve been using in two distinct ways to transform the treatment of Lysosomal Storage Disorders. One approach is to use our chaperone as a monotherapy. So in this case the chaperone finds in patients own endogenous enzyme stabilizing that enzyme and trafficking it or chaperoning it to the lysosome where it’s been disassociates enables the enzyme to have its normal intended [catalytic] activity reducing substrate. That’s an approach that we’re currently utilizing at Phase 3 studies of monotherapy and Fabry disease.
And the bigger opportunity is the combination approach. So here we can use our pharmacologic chaperone in combination with exogenous or infused ERTs. In this case we deliver the chaperone alongside the ERT or even upstream co-formulated with that ERT, that has the same aspect as it does with the patients own endogenous enzyme stabilizes the ERT, improving availability in the plasma, improving uptick into tissue and achieving the same net result, which is lowered substrate and improved outcomes from patients.
So that’s the core pharmacological chaperone approach. And using that approach we built a very robust pipeline. I mean, we divided here into a couple of different types of products as I mentioned we’ve monotherapy approach for Fabry disease with Migalastat and we’re also using the same monotherapy approach in the deal that we just did with Biogen Idec.
A new shift to the combination approach, we have done Phase 2 proof-of-concept studies with our products as a co-administered therapy alongside commercially available ERTs. Here the Fabrazyme or Replagal in the case of Fabry or Lumizyme in the case of Pompe disease. Based on the proof-of-concept, we achieved there we’re rapidly moving for our own proprietary ERTs co-formulated with the chaperone. We think that can we intuit the best long-term outcome for patients and also from a commercial prospected keeps all of the economics for Amicus. So that’s the pipeline – it’s again frozen here.
Here we go. So that’s the summary of the pipeline and just to give you a little more background on the opportunity in enzyme replacement therapy and why we’re so excited about the combination approach. So back on enzyme replacement therapy its $3.5 billion market. It was pioneered by Genzyme with the introduction of Cerezyme little more than 20 years ago. And since that time has grown rapidly with multiple product introductions and it was the pioneer for the ultra-orphan model that is so popular in that space today. And these were important first generation therapies for patients.
That being said, these therapies suffer from a common set of problems. And those problems really come down to an issue of PH. So Lysosomal Storage Diseases and lysosomal enzymes typically are found in the acidic compartment of the lysosomal cell. That’s a place that has a PH of 5.0, so very acidic conditions.
When you take those enzymes and infuse them into the blood stream in a massive quantity and blood stream with a neutral PH of 7.3, the enzymes began to rapidly unfold the nature exposing inner epitopes and that began to aggregate. That leads to two negative outcomes. One is immune response, many of these enzymes have a black boxed label because of that immune response and two is that at least a poor tissue uptick, very little of the actual infused enzyme is making into the disease relevant tissues where its needed to reduce substrate.
So as you look at that $3.5 billion market, great first generation therapies, but severe limitations in terms of the overall efficacy of those products. We think our chaperone technology, the CHART technology, Chaperone Advanced Replacement Therapy is a generalizable solution to some of these problems. By binding to those infused enzymes, we can keep them stable in plasma; get more of the enzymes taken up into tissue where it can then have it intended activity.
And as I mentioned before we’ve shown it in a co-administered study in Phase 2. We are moving forward and a co-formulated study with our own proprietary ERTs and long-term this approach gives us the opportunity to look at even better delivery options for patients either short abrasion infusions or perhaps even ideas like subcutaneous delivery.
One of the places that we’ve explored the co-administration paradigms is in Pompe disease. So as a reminder Pompe disease is a severe and fatal nerve muscular disease. It's caused by a (indiscernible) in deficiency in lysosomal enzyme GAA. The only approved product out there is Myozyme, which is now Lumizyme and it’s about a $600 million market a year. To every other week infusion and one of the biggest challenges in addition to the low level of uptake into muscle cells is the amount of immunogenicity that has been served in its patients. In fact in infant onset patients the immunogenicity problem is so acute that doctors have taken to breaking the immune system with methotrexate and rituxan as the emerging standard of care to overcome that immune response.
So with that as a backdrop we did a Phase 2 study, we began at last year and finished it earlier this year where we asked can we improve the role of active enzyme in plasma and can we improve the amount of enzyme that could taken up into tissue when we co-administer the patient's normal ERT inflation alongside a chaperone. So are on the left panel you see ERT alone. This is a 24-hour area under the curves of total plasma concentration of the enzyme and then we looked at it again two weeks later ERT, given alongside a dose of 2220. And in all cases we’ve saw an increases in the amount of enzyme -- active enzyme in the plasma. So that’s step one. Then the question then is that lead to more enzyme getting taken up into disease relevant tissue and this case muscle and again (indiscernible) the answer here was yes, (indiscernible) in a dose dependent manner increases in the amount of active enzyme in the muscle, a very encouraging results. This should lead to greater reproductions in substrate level because it's a single dose experiment didn't have on the opportunity to fully explore that.
So very nice proof-of-concept in Pompe disease. The other thing that within evaluating a Pompe disease is this question of immunogenicity. So this is an Ex Vivo experiment here, but we looked at T-cell proliferation and asked when exposed to Lumizyme versus when exposed to Lumizyme plus 2220 our chaperone, do you see lower levels of T-cell proliferation? And the answer was clearly at this was something that we intend to explore in future clinical studies and if we were to see and really change that immune profile, that will be a huge step forward for patients with Pompe disease.
So let me shift gears to Fabry disease where we’ve done a similar co-administration experiment. But this is a reminder, Fabry disease is also Lysosomal Storage Disorder caused by mutations in GLA an (indiscernible) disease and patients typically die from renal failure, cardiac failure, strokes, so it’s a systemic disease. Current available treatments include Fabrazyme and Replagal and it’s about a $900 million worldwide market as of 2012.
Interestingly in the U.S. only Fabrazyme is approved and it's only conditionally approved. It was initially approved 10 years ago conditionally. It remains to be only the product available here in the States.
So these data should look similar. It's a similar set up as the Pompe Phase 2 experiment if you were looking to see when we co-administered the ERT alongside, Migalastat can we get more active enzyme available in the plasma and the answer was yes. 23 out of 23 patients showed increased levels of enzyme in the plasma. And then we asked does that lead to increased up tick into tissue and here skin is one of the disease relevant tissues in Fabry, and again we saw increases from roughly 100% to almost 300% in terms of the act of enzyme taken up into tissue. So this was very encouraging group of concept on Fabry co-administration.
Based on these results we then asked the question; can we improve the enzyme in a co-formulated paradigm? So here we’re taking our own proprietary enzyme called JR-051 which was designed to be a bio-similar to Fabrazyme. And you can see on the bottom left of this panel here that the PK curve JR-051 with Fabrazyme was very similar. But when you co-formulate JR-051 with Migalastat a profoundly effect to plasma PK characteristics of the product.
If you then look back on the right hand side in a mouse model, what can we do in terms of substrate reduction, and the grey bars are 051 alone and the blue bars are 051 with Migalastat. And with Migalastat you can see such a reduction in some cases that are approaching wild type levels. These are things that are never seen before with ERT. And these kinds of results are seen in clinical studies that’s going to be a major step forward in the treatment of Fabry disease. Because that’s a program that we’re finishing the IND-enabling tox and [CMC] work and should be ready for in clinical trial study in the first half of next year. So, in addition to co-formulated product on Fabry disease, we’re also exploring next-generation ERTs and co-formulated products in other Lysosomal Storage Disorders.
In Pompe disease we are developing our own proprietary Pompe (indiscernible) looking at ways to improve the GAA enzyme itself in terms of the glycosylation and the engineering out some of the immunogenetic epitopes. We’re also looking at putting that together with 2220 our chaperone and we think that should result in greater exposure, greater tissue uptake, lower levels immunogenicity and down the line offer approved dosing options for patients. And just like the co-formulated paradigm in Fabry, when you look at GAA alone versus GAA plus 2220 it's profoundly different in terms of the plasma PK profile, and it's profoundly better in terms of substrate reduction in the mouse model. So, again it's a similar pattern as we’ve seen in Fabry disease.
It also enables SubQ delivery. So by stabilizing the enzyme upstream in the formulation study and we can enable potentially other forms of delivery. On the left hand side you see, I’d like to say a picture is worth a thousand words. On the left is a saline solution, the middle vial is Myozyme, 28 days left alone and then you can see it had just aggregated and unfolded. 28 days of Myozyme plus 2220 and it looks like just the saline. So we’re able to stabilize the enzyme over a 28 day period. That enables ideas like SubQ delivery and we’ve actually tested SubQ in a mouse or rat model here and you can see profoundly better activity with the SubQ dosing versus Myozyme alone.
And finally we’re doing work in MPS-I we recently announced this. This is another Lysosomal Storage Disorder. It is -- there is Aldurazyme, it’s a marketed product here about 200 million in sales, but it does have a black-box warning to some of the same issues and challenges that are otherwise Lysosomal Storage Disorders. We’ve received grant funding from an enormous source to work on developing our own cell line here. And this is something that we’re very excited about from a preclinical perspective.
So finally that’s a lot on the combination approach and the chart platform, but we should remind you of where we stand with our most advanced program which is our Phase 3 development of Migalastat as a monotherapy. So as a reminder, we released results last year, six month results from a Phase 3 study and here it was a responder analysis looking at Interstitial Capillary GL-3 in the kidneys so the same endpoint that Fabrazyme was approved upon.
And we saw encouraging trends in the right direction favoring Migalastat over the Placebo. Although because of the small sample size, kind of number of patients who had low levels of baseline, we did not achieve statistical significance on this endpoint. I think the more relevant way to look at this is, looking at changes in the GL-3 levels, the levels of substrate of storage material. Looking at it more as a continuous variable, not shown here. So looking at the overall change in substrate Placebo patients on average went down about 6%. So basically unchanged.
Patients treated with Migalastat for six months went down about 41%. So P.09 we think an encouraging trend in the right direction. We do have 12 month data from the same study coming up at 12 months. The Placebo group will have crossed over and received treatment for six months. So we hope that their GL-3 levels will improve between months 6 and 12 and that Migalastat arm should show continued improvement and as I said we await results from that in the fourth quarter of this year.
Importantly the drug had an excellent safety profile. No apparent difference between Placebo and Migalastat and that’s an important point in a life long chronic therapy. Should note we have patients from our Phase 2 study that have been taking Migalastat as their only treatment for Fabry disease for more than seven years now. So, excellent long-term information in terms of the safety profile of this drug.
We have a second Phase 3 study that is fully enrolled and ongoing. It's an 18 month open-label study, a switch study of patients who are on ERT are randomized either to standard ERT or switched to Migalastat as their only treatment for Fabry disease. 60 patients enrolled in this study, we over enrolled it. And the clinical outcome, the primary endpoint is renal function were measured at iohexol GFR. We expect that data in the second half of ’14 and continue to be on track for that beat out.
We recently met with the FDA to talk about the regulatory and approval path. And the feedback from that meeting which was June which we press released was that they are looking for both information from study 011 and study 012 and that’s the data that we plan to bring to the FDA in the second half of next year to discuss the U.S. approval pathway.
So to summarize we have got a lot of very important upcoming milestones for Amicus. 12 month data on the monotherapy and repeat dose Pompe study set to start in the second half of this year. Beginning next year we will have the initiation of human clinical studies with Fabry and co-formulation study and initial results from that Pompe repeat those Phase 2. And then as we move into the second half of next year we should see the Phase 3 monotherapy results. We plan to meet with the FDA to discuss the U.S. approval pathway and we should start to see Phase 1 data on the Fabry co-formulation paradigm.
So as you can see, every set of milestones an important mission in improving the treatments and lives of patients. And I’m happy to take any questions in the time we have left.
Stephen Willey - Stifel Nicolaus
Go ahead and ask a question.. Do you have any thoughts I know BioMarin who’s running a Pompe study as well has proposed well it looks to be a bit of a novel primary efficacy endpoints that’s …
William D. Baird, III
In respiratory map.
Stephen Willey - Stifel Nicolaus
Yeah, Bitmap. I don’t think they’ve necessarily disclosed what level of agreement they have thus far. Well do you have any thoughts about that as an endpoint and whether or not you can -- that alone can demonstrate superiority or improve what Myozyme has with data perspective?
William D. Baird, III
Sure, I mean I think it's an interesting approach because if you look at the Myozyme data it was out to 78 weeks before they really saw a separation on six minute walk and that change may have been powered by a few super responders. So, I think when you, any time you’re talking about a clinical study that takes 78 weeks to sort of see the separation you start to wonder about sample size and what it's going to take to see it. So, I clearly -- respiratory function plays an important role. I think from a regulatory perspective it will be interesting to see what the FDA does with that. I haven't seen them be definitive on new endpoints that often [tasks] of thinking about innovation. So it may be a question of share, you can come in at the sponsors risk can become assure of the data but we’ll see what that regulatory feedback is. But certainly it's an innovative approach.
I think if it works that would be good for Amicus because down the line now there would be more than one potential endpoint and pathway to pursue as we think about Pompe. I do think there is more than one way to win in Pompe. I think for Amicus the immune profile, the immunogenicity is a big deal. It's commonly accepted among KOLs and advocates and patients in that category versus that the immunogenicity is a real problem and if you could, to master the show that you’ve approved that. That could be a clinical benefit in terms of how a patient feels conscious to survive. So the interest team has gone on primary and I think if they get regulatory buying we’d take that, that’s positive as we think about development.
Stephen Willey - Stifel Nicolaus
So as we think about moving forward in Pompe would be a goal than just kind of trying to establish some type of correlation between this reduction and T-cell proliferation you’re seeing in improved outcomes?
William D. Baird, III
Yeah, I mean I think it's already pretty clear that there is a relationship between antibody titers and long-term survival or (indiscernible) survival that’s already I think been established in some of the studies that we’re done by Genzyme. So I think they -- the interesting thing is how do you -- what's the best way to measure immunogenicity and can you see changes in immunogenicity in treatment experienced patients versus treatment naïve patients. Obviously and treatment naïve sets the greatest opportunity because if you can prevent them forever developing antibodies to begin with versus reducing someone who already has a high titer, that would be a big opportunity. So those are all the issues we’re thinking forward in terms of the clinical development plan.
Stephen Willey - Stifel Nicolaus
Okay. Great, sure thank you very much.
William D. Baird, III
Yeah. Thanks guys.
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