Matthew Harrison – UBS Securities LLC
Good morning everybody. next up, we have Laurence Reid from Alnylam Pharmaceuticals, and we’ll have a breakout later on after in Carnegie.
Thanks Mathew. Good morning. I’m Laurence Reid. I’m the Chief Business Officer, Alnylam. Thank you very much to UBS for the invitation to be here this morning to present to, and thank you for your interest in Alnylam. And so what I’ll do, as I’m going to talk to a little bit about where we see the state of our therapeutic platform and pipeline, and wrap up with our sort of thoughts on our financials and goals, and look forward to taking questions in the break-out session. I will be making some forward-looking statements as I go through the presentation obviously.
Alnylam is 10 years old. We’re a company committed to the development of novel, therapeutics that antagonized the natural pathway of RNA interference. And we really see this is as an opportunity to develop a whole new class of innovative medicines. RNA interference is a natural pathway, and that was discovered some 10 to 15 years ago, and our therapeutics aimed to harness and modulate that natural pathway.
Conceptually, we can attack any gene in the genome. and we believe that this creates really a unique opportunity to build a whole new class of medicines. The challenge since RNA interference is understood, several years ago has really been how do we develop and deliver chemicals in the body to disease sites that can actually have a beneficial effect in a patient.
We believe that that challenge with respect to the human liver has essentially been solved. And what I show here a data from the snapshots of data from our two platforms, essentially independent platforms both of which mediate the delivery of an siRNA molecule eye into the liver. These are actually animal data, but you’ll see data from human beings that looks essentially identical to the left-hand side of the slide.
The left-hand side is our proprietary lipid nanoparticle platform that we use for intravenous delivery of siRNA to the liver. And on the right-hand side is our subcutaneous delivery platform or so-called conjugate platform and this platform will be in the clinic at the beginning of next year. Our LNP platform on the left of the slide as you look at it underlies the clinical data in each of our leading programs that I’ll review later in the presentation.
So fundamentally, we feel that for the human liver, we’d really develop technologies to resolve this fundamental problem, enabling advancement of these medicines in human beings. The proof of this relies in three independent sets of human data that we’ve published over the last 18 months or so.
the top left of the slide just summarizes the overall amount of human data that we’ve generated delivering siRNAs with significant positive effects and generally very good tolerability into human beings. Top right is the proof of mechanism; this is a molecular assay demonstrating a specific molecular breakdown of an RNA in a human being. This is a biopsy sample, an RNA sample from a biopsy from a cancer patient in our ALN-VSP cancer trial, and you’re looking and RNA mediated cleavage of the VEGF messenger RNA.
Bottom left, proof of concept from our TTR amyloidosis program. this is data that was published earlier this summer, demonstrating knockdown of the serum levels of the TTR protein in a Phase I study. this is TTR protein, mutated TTR protein, is the pathological course of TTR Amyloidosis and this is direct ablation of the disease causing protein by an siRNA therapeutic.
And then bottom right is a data from our PCSK9 cardiovascular trials, this is our medicine ALN-PCS, and this is data showing correction of LDL levels, so it’s a clinically recognized end point now that we’re talking about in terms of response of human beings to ablation of that PCSK9 protein resulting in correction of LDL levels.
So overall, as we’ve understood our platform and how it functions pharmacologically both in animals, now more recently and importantly in human beings. We really laughed with what we believe is a very exciting and powerful profile of an RNAi therapeutic that what we believed, we’re going to see repeatedly in each of our therapeutics and this profile essentially is represented, but in response to a single dose of an IV administered siRNA therapeutic, we see a very rapid and potent knockdown of target.
so talking about a reduction of 80% to 90%, and you’ll see this data later in the presentation. It’s a very significant knockdown of the target that siRNA is addressing that’s rapid; the protein levels hit nadir, sometime around seven to ten days, after administration of the therapeutic. And that effect then is durable, but at last out around 30 days and more, it’s completely reversible, if we don’t come in with the second dose, the levels of protein will return to their natural levels. But the durability of the response we believe gives us the opportunity to dose these therapeutics, once every one to two months, potentially even longer as we continue to improve our technology.
Where we are from a strategic perspective with respect to our pipeline is summarized in our 5x15 strategy, which we’ve been talking about for almost two years now. This is really a strategy, where we aim to use siRNA for genetically defined diseases. And the goal is to have five products; I'm putting this strategy in clinical development by the end of 2015.
In the near-term we’re focused on the TTR and AT3 targets, and I’ll talk more about those. The product characteristics that each of these programs share are listed at the bottom of the slide, determine a genetically defined targets and pathways that leverage our existing platform, which means we're targeting proteins that are expressed in the human liver.
The disease of the mediate may be more removed from the liver meaning it maybe a metabolic disease or a disease of anemia, that’s mediated in the periphery, but the central expression of the gene is in the human liver, which is why we have a path antagonize it, and we look for programs more over what we can see very early biomarkers and you will see that direct readout of the molecular effect we're having, giving us the opportunity to move quickly through development.
I’m also looking for significant commercial opportunities. But the summary here is that we are focused on siRNA therapeutics and for treatment of genetically defined diseases. And the focus of our current investments is really around the TTR program for TTR Amyloidosis, and then secondly the 83 target for our hemophilia program.
So moving on to talk about the programs in a little more detail. My first program, the vanguard of this strategy is our program for TTR-mediated amyloidosis. This is a very important orphan disease, within around 50,000 patients world wide, who predominantly present with either a polyneuropathy referred to as FAP or cardiomyopathy referred to as FAC and through these roots and these effects, the disease is routinely fatal within 5 to 15 years.
Currently, the only standards of care involve either a liver transplant, which apart from being credibly debilitating from a quality of life perspective is also really only applicable to a subset of the patients. And then more recently, Pfizer has managed to get approved in Europe only, their drug Vyndaqel, which is a small molecule, has been approved in the EU for a little over a year and a half now and has not so far received approvability from the U.S. FDA.
So we see a significant opportunity here, the target, very well defined. They’re over 100 different mutations in this gene. the human TTR gene that cause a misfolding of the protein and results in a deposition of the protein and amyloid deposit particularly in nerve and heart tissue. You also get presence of wild-type protein accumulating and causing further deterioration of those tissues.
On our product ALN-TTR, which is in clinical development targets we believe very importantly both the mutant and wild-type forms of the protein. And our goal is to release a blatant expression of this misfolded protein, and remove its disease causing impact in these human beings. We’ve demonstrated positive clinical data with both our first and second generation technologies, and we’re in a Phase II with the program today aiming to initiate Phase III late next year.
We also have a another program, which we referred to as ALN-TTRsc for subcutaneous delivery and we’re aiming to file an IND for that at the end of this year. This is animal data from a humanized, human model of the disease in mice, and what you’re seeing through administration of, this is actually our first generation drug, ALN-TTR01, very significant regression of deposition of protein levels in a number of different issues, both the tissues of the gut and the nervous system. And on the right-hand side, the brand deposits in the control sample are actually the deposition of the mutant protein in these amyloid plaques being essentially completely reversed by chronic administration of ALN-TTR01.
So the thesis that really underlies what we’re doing here is that by reducing the expression of TTR, we’re removing the pathologic course of disease. That concept has been demonstrated in other forms of amyloidosis, data on the top right from a study and what’s called AL amyloidosis. We know that the liver transplant that I referred to, which actually has the ability to remove the TTR expressing tissue from a human body, causes a transit improvement in disease.
Stabilization of the mutant protein by tafamidis clearly has a clear, but weak positive benefit in human beings. And then lastly, the animal data that I show really validates that if you’re able to reverse expression of this mutant protein, but that will have a positive benefit.
We completed a Phase I study earlier this year; it was a 3:1 randomization. it was a single dose escalation study, IV administration obviously with a primary goal of safety and tolerability, but then secondly, looking at the PK, pharmacokinetic and pharmacodynamic impacts on TTR.
In terms of the safety profile, we were very pleased with the – essentially there were no serious adverse events that cause any pause for moving forward into Phase II. And the data in the terms of the pharmacological impact are summarized on this slide here. and what we’re really focusing on is, this is a single dose study at day zero of the study, and at the high doses of 0.15, 0.3, 0.5 mg/kg, which is the purple, light blue and dark blue lines you’re seeing, essentially the real human data supporting the cartoon that I showed you earlier on. So it is precipitous drop in TTR protein levels hitting a nadir at around seven to 10 days in this study and a prolonged impact that you’ll see concentrated on the next slide, but last out through greater than a month before we start to see return of the protein levels even to 50% of the starting level. the effect is completely specific, but the red line that just appeared actually is data from our PCSK9 file, we’re administering a different therapeutic and having no impact on TTR levels.
This is the quantification, I’m not going to go through this in detail, but the maximum amount of knockdown we’re seeing at the higher doses is essentially high-80% to low-90%, so very significant ablation of the pathologic causing protein and that at the doses that we think will be relevant to the longer-term development of the drug, 0.15 and above, we still have 50% to 70% knockdown even after a month after the administration of the dose.
We move forward into a Phase II study, which was started in May. This is a study now in patients being run in Europe, which is where the principal geographic foci of the disease are, it’s a two-cycle once every four week administration of the drug, again still continue to build out the safety and tolerability profile, but now looking at clinical activity, looking at circulating levels and the impact of repeat dosing to really begin to optimize the dose as we think about our registration study.
And then just lastly, this is the preclinical data package that will support our next generation subcutaneous technology. we see an opportunity for lifecycle management to have a second form of the drug. This is newer technology for Alnylam, that you are going to start to see influencing our pipeline more over the next one to two years, and this is not a subcutaneous administration of siRNA therapy, this is a primate study, and what you are seeing is that by, these studies are done by a small succession, daily succession of administration of the drug followed by a weekly administration once you get to a reduced steady-state.
The timeline to get to nadir is a little slower from the intravenous administration, but nevertheless once we're able to knock the gene down at very acceptable tolerable levels, we're seeing this sustained knockdown of the therapy. So, the advantage here over the longer term and for other programs in our pipeline is really the subcutaneous administration.
On the commercial angle of this product an orphan disease a very clear and significant unmet need, we believe that ALN-TTR can actually be a breakthrough therapy for the treatment of this disease, that has the potential to achieve significant disease regression based on dosing once every one to two months. The value of that proposition and the pricing that we followed from that really supported by a very clear pharmacoeconomic analysis and thinking, and we believe that it’s can be very rather straight forward to identify the provider basis given their concentration to administer the drug and to understand how to build this market, and this is part of our strategy, after building our commercial capability in our company, over the next several years particularly in the western world.
Moving on to our second priority program in our 5x15 strategy; this is our hemophilia program. Of this the hemophilia market is rather well understood market. Hemophilia have been well characterized genetic diseases for many years. There are two basic forms of hemophilia, hemophilia A and hemophilia B, and despite the advances in treating those patients with blood-borne factors over the last several years. There are still segments of that patient population that are not well managed particularly the circled inhibitor patients whereas significant subset of the population really become refractory to the administered blood clotting factor.
Those people still have an extremely poor quality of life, repeated bleeds, and hospitalizations during the course of the year, very significant financial and health management burden on the system and a very poor quality of life. The only therapy that really are able to, be useful in those patients and have significant drawbacks as we believe.
So we’ve been interested in the antithrombin protein. this is a liver expressed protein. it’s a genetically defined target who know that mutations in the AT protein are associated with increased thrombin generation, which is what you want to achieve to drive blood clotting in a hemophilia patient. And we know that there are genetic mutations in the part of the pathway in which AT acts particularly in factor V, which is one of its cofactors that when those mutations are co-inherited with hemophilia that they have a beneficial impact on those patients. This program is an R-to-D transition currently, and we’re aiming to file an IND in 2013.
This is our existing animal data package. This was reviewed at the World Federation of Hemophilia in July. and basically, showing that the pharmacology that we know start to see a) it begins to be sort of consistently predictable from our other preclinical studies. This importantly is a subcutaneously administered therapeutic. This is from our conjugate technology platform. next year, we’ll represent the first venture of this technology into human beings.
You see top-right, you see a very significant and sustained knockdown of the antithrombin protein and this is in rodents and that’s increasing thrombin generation in hemophilic mice models in the bottom left and bottom right.
We’re now moving on to the larger animal studies that are required to complete preclinical data package before moving into Phase I studies next year. In terms of the market, as I said, we think of this market in really sort of four quadrants. On the left-hand side, top-left, the inhibitor patients, people who are currently treated with the existing blood factors; bottom-left, the inhibitor patients who become recalcitrant to the administration of the regular blood factors.
And in particular, so we intend to start really with the inhibitor patients, the bottom patient populations of this slide where there is a very significant unmet need, and what we think our therapy can be particularly differentiated. But over time, we see an opportunity for a subcutaneously administered therapy perhaps on a weekly basis would represent a very significant improvement for the convenience, remember a lot of these patients are our children who are currently having to receive an IV administration of the drug up to three times per week. And therefore, this could be a very significant advance for this patient population, and a very significant and therefore competitive positioning in a very significant and an important market, which is what I just said essentially.
The problem of the market today, it is a $6 billion market, people are bringing new technologies on top of the existing protein therapies, but none of those are fundamentally able to address the inconvenience or the limitations on the poor quality of life that are associated with these products. So we see AT3 is having a very significant commercial opportunity, ALN-AT3, a fast path to approval in this inhibitor patient population, a very significant opportunity from a pharmacoeconomic perspective, and that there are also some opportunities then beyond that the inhibitor patients brought into the non-inhibitor patient population, also in certain rare bleeding disorders including genetic deficiencies in several of the blood factors, another genetic disorders such as (inaudible) disease.
The other 5x15 program, there are three other principal programs that we’ve nominated to-date, are ALN-PCS program against PCSK9 for hypercholesterolemia. Our refractory anemia program targeting to have side in pathway. And then on the right hand side, our hemoglobinopathies program, which targets the transmembrane protease 10 per 6 in which we have – we believe there are significant opportunities in the beta-thal and sickle cell disease areas.
Just quickly the data that we’ve released earlier this year, which is from our ALN-PCS Phase I for PCSK9 knockdown, this is of course, is one of the most exciting targets really in the industry and modern molecular medicine, and this drug, which we’ve been developing and putting to this Phase I study late last year, shows very significant ability in a single dose without other co-administration of other medicines including statins shows around 70% peak knockdown of the PCSK9 circulating protein levels. that’s the graph on the left hand side, I think it comes in with that, very significant reductions of up to 40% reductions of LDL levels and that’s the data on the right hand side.
We’re now looking to move this forward into a Phase II study, beginning to explore the synergy that we know will come once co-administrated with statins for these patients, and we’re doing that with a partner as we or we will be doing that with the partners we’ve announced.
So the 5x15 programs, they share all the facts that we sort of laid out upfront. we understand the gene target and its genetic basis for its role in disease. These are all liver expressed proteins; I'm with very significant validation. And then as we think about the program more completely in each case, they share very easily measured serum biomarkers that, in many cases are showing direct read out of modulation of the target of the therapy. We clear pass through both early development based on biomarkers and then advanced development, with excellent end points.
With three other programs that have been historically important path for our company and remain so; each of these has been advanced with partners. Our RSV program, which is part of the Cubist and Kyowa Hakko Kirin. Our liver cancer program, we call ALN-VSP, and over the summer we completed a partnership with Ascletis, and that company is going to develop the product in the China market, and over the next two years drive a trial in about cellular carcinoma, and we're going to about leverage that data back into the western world, and in the right hand side our Huntington’s program and which is partnered with Medtronic and the CHDI foundation.
This is the summary of our RSV data and which was published over the summer and then reviewed at Libyana Respiratory Meeting just at the beginning of September. This was a Phase IIb study, it was an international study run in both hemispheres, and the bottom line on the study was it very narrowly missed significant end points and some of the primary end point, but we're seeing very clear and clinically meaningful treatment effects, and as we've said, with an advance and have regulatory discussions now, in terms of what the best path forward with this program is, and we think we add, provide more clarity on that by the end of this year.
This is the pipeline in summary. the blue bars at the top part of the slide represent the leading programs in our 5x15 strategy. The two grey bars are our leading partnered programs. And again, this pipeline now, the advancement of this pipeline really underlies our evolution from a technology and platform company into a company with a bonafide product pipeline. And as I say with particular focus on the TTR program at the top of the slide, and the hemophilia program again advancing TTR02 into a registration trial late next year, and the AT3 hemophilia program into a Phase I study during the course of next year.
We continue to explore other applications of RNAi, and we’re very excited to announce at the end of August, a deal with Monsanto, where we’ve been able to license for a very significant upfront payment. I’m totaling almost $30 million, our complete technology platform into the agricultural world, we believe that’s a very – it brings a lot of non-diluted capital and is a complete leverage of our existing technology with modest effort or future effort on our part, beyond the significant investment that we already made to the platform of course.
Our investment in Regulus; we believe it continues on a very exciting path. Regulus is really the leading company in the microRNA world. We compounded this company together with Isis in 2008. we still own 45% of this; company has been very successful in developing partnerships with leading pharmaceutical companies and just recently filed the S1 for their effort too far from IPO over the next several months.
On the financial side, at the end of Q2, we’ve finished the quarter with $293 million in cash and our guidance is that, we’re getting this year north of $250 million. And in terms of goals, really as the years gone by, it has been a fantastic year. we announced the very successful and important TTRo2 clinical data, and likewise this PCSK9 program, and then the RSV clinical data, and really the upcoming events over the next three to fifteen months really the TTR program moving through its Phase II and into pivotal studies, the AT3 program moving into human beings were the key events in terms of driving value in the company.
Thank you very much for your interest.
[No Q&A session for this event]
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