Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY)
R&D Day Conference
July 11, 2013 8:30 am ET
Cynthia Clayton - Vice President of Investor Relations and Corporate Communications
John Maraganore - Chief Executive Officer
Barry Greene - President and Chief Operating Officer
Akshay Vaishnaw - Executive Vice President and Chief Medical Officer
Rachel Meyers - Vice President, Research and RLD
Jared Gollob - Vice President, Clinical Research
Philip Hawkins - Professor of Medicine, National Amyloidosis Centre, University College London Medical School
Craig Kessler - Professor of Medicine and Pathology, Lombardi Comprehensive Care Center, Georgetown University Medical Center
Robert Desnick - Dean for Genetics and Genomic Medicine and Professor and Chair Emeritus, Icahn School of Medicine at Mount Sinai in NYC
Marko Kozul - Leerink Swann
Shaukat Khan - Maxim Group
Michael King - Rodman & Renshaw, Inc.
Alethia Young - Deutsche Bank Securities Inc.
Good morning everybody. I think we will kick it off. We are here at the bottom of the hour. I'm Cynthia Clayton, Vice President of Investor Relations and Corporate Communications for Alnylam, and I’m glad to welcome you all here today for our R&D Day.
Before we begin, I just have a few housekeeping items, I’d just like to ask that you silence any devices, and I want to remind you that we will be making forward-looking statements throughout the course of this presentation, and so I encourage you to – give me just one moment – Marion the slides are not advancing -- here we go. I encourage you to refer to the Form 10-Q on file with the SEC.
So, we have a very full agenda for you today. In the first half of the morning, we will be hearing from – we will be focusing on our lead 5x15 program with a focus on TTR amyloidosis and hemophilia. In addition to presentations by Akshay Vaishnaw, our Chief Medical Officer; Jared Gollob, our Vice President of Clinical Research; and Rachel Meyers, our Vice President of Research and RNAi Lead Development, we will hear from two experts from their respective fields. Dr. Philip Hawkins, on TTR-mediated amyloidosis and Dr. Craig Kessler on hemophilia.
After these presentations, Barry Greene, our President and COO will moderate a Q&A session, and we will then take a brief break.
For the reminder of our time together, we will hear about acute intermittent porphyria from Dr. Robert Desnick; and Rachel will also walk you through the progress we are making in that program.
John Maraganore, our CEO will then share with you our thoughts about additional 5x15 programs and our path forward, and he will leave some additional time for Q&A.
In addition to the speakers that I have just mentioned, I also wanted to point out some other Alnylam representatives are here with us today, and they are going to stand as I call them out. Laurence Reid, our Chief Business Officer; Mike Mason, our VP of Finance; Oved Amitay, our Head of Commercial, and (inaudible) Scientific Lead in our Porphyria Program. And also in attendance is Makiko Yasuda, who is an Assistant Professor working with Dr. Desnick in Mount Sinai.
And then joining me from the Investor Relations and Corporate Communications team are Josh Brodsky and Maryellen Livingston. Please feel free to see any of us, if you need any assistance this morning.
And so just one final reminder, we will be – we ask that you hold your questions during the presentations because we do have the two Q&A sessions. And with that, I will turn it over to Akshay.
Good morning again to everybody in the room, everybody on the webcast, so it’s my pleasure to give you this update on our 5x15 strategy and the RNAi therapeutics platform that underlie Alnylam as a company. I think this is our fourth R&D Day Cynthia, and I think we as a team have never been more excited to share our updates and our progress in what is now a clinically validated platform with significant momentum and a pipeline that is truly very promising towards innovative therapeutics. So, with that, we will go to the first slide.
As most of you know, we are dedicated to the discovery and development of RNAi or RNA interference based therapeutics. With RNAi, we utilize small interfering RNAs or siRNAs to harness a natural, powerful, endogenous pathway that allows to catalytic and specific degradation of any given messenger RNA. And so, with the technology, we can therapeutically harness this approach to get any gene in the genome, and this gives us an unique opportunity to develop highly innovative medicines.
And as for those of you that have been following our story closely over the last couple of years, you know that with the recent proof-of-concept we had in the clinic, we have a truly clinically validated platform now. The progress that gave rise to that clinical validation is shown on this slide, and it’s essentially been our ability to solve delivery of RNAi therapeutics to the liver. On this slide, slide 8, you can see on the left hand side, an LNP-based approach towards delivery of siRNA to the liver. These lipid nanoparticles encapsulate siRNA, and in a dose-dependent fashion, allow knockdown of any given genes, in this case Transthyretin. You can see the knockdown is potent, and become virtually a glycoprotein at doses as low as 0.2 mg/kg.
Complementing this intravenous approach with the LNP based delivery is on the right a subcutaneous approach utilizing a GalNAc based conjugated siRNA approach. Here, the siRNA is tagged via linker with the sugar turned GalNAc to allow subcutaneous injection, and again powerful dose-dependent knockdown of any given target in the liver as you can see. With these two approaches, we think we can address any target in the liver and have a powerful way approach -- have a powerful way forward with our pipeline.
I spoke of the recent proof-of-concept, and this slide summarizes some of those data. On the top right, you can see the proof of mechanism that we established in our VSP or Liver Cancer Program, where we’ve repeated biopsies in patients, and we were able to show that treated patients had specific cleavage of the target in the liver as (inaudible).. The mechanism underlying this was definitively shown to the RNAi interfering space. We’ve moved on from that bottom left to show dose-dependent knockdown of Transthyretin, and as you can see in the human Phase I study, we got up to 94% knockdown with 0.5 mg/kg.
And finally, lastly we’re confident that with human clinical efficacy demonstrating powerful knockdown of LDL in our PCSK9 program with knockdown of more than 40% at 0.4 mg/kg. These observations represent a powerful validation of utility of RNAi in the clinic. We’ve now dosed over 625 individuals, and with reference to that hepatic approach, we have specifically dosed over 175 individuals with over 450 doses via intravenous LNP based formulations. Some of these patients have been taken out as far as two years of dosing, so we’re very encouraged by the tolerability of our drugs and the overall safety profile that we’ve seen to-date.
And what those proof-of-concepts have done have all – is that they’ve all found the (inaudible) in our R&D strategy, which we turn to the 5x15 strategy. And here, we’re developing RNAi therapeutics for genetically-defined diseases with a promise that we intend to have five key products in the clinic by 2015. The characteristics that these products will have is that in each case, there will be a genetically defined target and disease pairing; we’ll utilize the existing delivery platform, that the intravenous lipid nanoparticle-based technology or the subcutaneous conjugate-based technology, but in each case, because of the availability of circulated -- relevant circulating biomasses, we will establish proof-of-concept in our first-in-human study in Phase I; and that because of prudent choices in terms of the targets and diseases that we’re going after that we’ll have clear development path that allows to rapidly proceed to significant commercial opportunity.
And with that guiding strategy, we’ve begun to build this very substantial pipeline that we’re seeing on slide 11. In this pipeline, you can see the programs that are colored in dark blue where we’re utilizing the intravenous LNP, lipid nanoparticle platform, or in the light blue or aqua where we’re using the new validated subcutaneous conjugate platform. The lead programs at the top include, of course TTR-based program, the hemophilia program, and the porphyria; these are the full front of our pipeline, and we are going to be hearing a lot more about those later on.
And in the bottom half, you can see the deep and rich side of opportunities that we have beyond that, and I’m sure John will be turning his attention to these later on in the day to illustrate to you how far we can go with this technology approaching just liver targets alone.
But, the exciting thing about this is not just the richness and depth of this pipeline, but the momentum we’re building. And as you can see by the end of the year, which is going to be truly a multi-product company with drugs in all phases of development, the TTR02 program is on target to be in Phase III by the end of the year, the TTRsc program will be in Phase II, and hemophilia would have started its Phase I study.
And with that, I would now like to turn to the conjugate aspect of the platform. As I mentioned earlier that we began our clinical efforts with the intravenous lipid nanoparticle-based technology, that’s being highly successful, we have established a number of clear proof-of-concept. It is always our desire to develop a complementary approach that allowed subcutaneous delivery. And to do that, (inaudible) study the literature and realize that (inaudible) offers a wonderful opportunity to give positive delivery of subcutaneously delivering that by RNA.
And the observation that is key here is that the asialoglycoprotein receptor, , which is specifically expressed on the hepatocyte, shown on the right here, it is expressed in abundance on hepatocytes with over a million copies per cell, but it endogenously has the physiological capability of internalizing (inaudible) circulation, and then through an endocytic pathway release the siRNA’s into the cell for availability for the RISC complex for RNAi media to silence them.
(Inaudible) in specific fashion, and bottom left, that’s a lot of structure activity work, we define them an optimum approach towards a siRNA-GalNAc conjugate, and what you are seeing is a siRNA which is shown in the format of the duplex, then the linker joined to try and get into a GalNAc format. And in our hands, this is truly acting as a platform and allowing us to address multiple targets. And what we are seeing on slide 13 is the front end of our efforts with the siRNA GalNAc conjugate on how we have addressed three different targets.
On the top right, you can see dose dependent knockdown with Transthyretin; bottom right, dose-dependent knockdown in antithrombin; and our third therapeutic area of interest on bottom left, PCSK9. In each case, you see rapid and sustained knockdown. You can see, we can hold animals at whatever degree of knockdown we want, even degrees well beyond 90% reduction in circulating levels of [these proteins] (ph).
And finally, these initial efforts have really allowed us to understand the pharmacology of this approach, and it’s truly a powerful pharmacology. We can get over 80% suppression of any liver targets at doses between 0.5 and 5 mg/kg. These doses have been well tolerated in animals, generally with use of once a week dosing regimen to achieve those kinds of levels of knockdown. We continue to make improvements in these approaches since the doses are getting lower and lower. But regardless of that, provided we are below 2.5 mg/kg, we see injection volumes well below 1 mL per injection in the human context. And so, really this is going to be a platform as we move forward through the rest of the pipeline for us to use over and over again in a modular fashion to address many targets and diseases of the liver.
We have carried some of those knockdown basis through to the monkey, and slide 14 just illustrates dose dependent knockdown in the monkey, where you can see at doses between 2.5 mg/kg and 10 mg/kg, we can get over 90% knockdown. The two-weekly regimen holds animals well beyond 90% knockdown, and we get a very nice duration of effect, and the effect is fully [resourceful] (ph).
Of course, the data I will be showing you on the last few slides is just a small fraction of data that we have across many animal species across many targets. We have great confidence in this approach. We have studied the science of the GalNAc conjugate approach, and understood as you can see on this slide where we’re studying deep concentration for siRNAs required for knockdown utilizing the GalNAc approach, our concentration is around the 0.1 microgram per grams sufficient to get 50% or greater knockdown in the liver.
And this really is a powerful observation that complements what we’ve shown previously using lipid nanoparticle-based approaches. This demonstrates that the RNAi based, the messenger RNA targeting is extremely potent and working in the nanogram to gram range.
Now, many of you have been interested over time to compare our platform to the Anti-Sense oligonucleotide platform, and I think this slide gives us an option to discuss that.
Firstly, if we compare similar concentrations, if we compare a similar protein to the Anti-Sense oligonucleotide against the same target, the concentration required for 50% of greater knockdown in liver is of the order of 300 microgram per gram, but many log orders late from that which we require, exposure to that level of (inaudible) is surely going to lead to some issues potentially.
More importantly, our targeted delivery mechanism allowing targeting of our siRNA to the liver uniquely allows us to focus the drug on the most important organ where the targeting is expressed. In contrast, Anti-Sense oligonucleotides are much more broadly distributed, and once they accumulate in the liver at 300 microgram per gram, in the kidney they are about 1000 microgram per gram, and that of course is probably responsible for the proteinuria and other events that have been seen in the renal tract, for example the [Netromycin] (ph) program, which is an anti-sense oligonucleotide that was recently approved.
Both platforms have their pros and cons, but in terms of our platform, today we have seen excellent potency and we have seen excellent safety, with respect to antisense nuclear type platform I have outlined some of the issues there. What about our experience with safety so far; through the animal studies, we have demonstrated no evidence of inflammation either in small rodent species or in the non-human primate. We have done In Vitro and In Vivo studies y. At GLP, toxicology results have been very encouraging with the GalNAc conjugates to date at doses up to 300 mg/kg, up to 10 doses of the drug, there have been no in-life findings, no injection-site reactions, that's important, and no significant LFT changes.
In the monkey, which we believe to be the predictive species, we have demonstrated again no major in-life findings, no injection site reactions, and no clinical pathology or histopathology finding. And importantly, the no adverse event level was determined to be greater than the top dose in the study which is 300 mg/kg. What I am trying to say through this slide is that we have an extremely wide therapeutic index with this part of our platform, which is the go ahead part of the delivery platform supporting the rest of the pipeline.
And today, I am extremely excited to share with you our topline results from our first GalNAc conjugate that we have taken to the clinic, which is the ALN- TTRsc program. And in this preliminarily Phase I data, what I want to say is that we have demonstrated statistically significant knockdown of TTR as compared with placebo, p<0.01. We have seen very encouraging levels of knockdown with over 80% TTR knockdown in treated subjects, in fact it is entirely specific.
From a safety perspective, well, the team remains blinded in this double-blind randomized placebo control study. It is clear that the drug appears to be generally safe and well tolerated, and we don’t see any events that preclude further robust development of the GalNAc platform.
Importantly, and this really is a very important point we think, it confirms human translation of the GalNAc-siRNA conjugate approach as the way to utilize subcutaneous delivery of siRNA to the liver, and we will be extending this to the rest of the pipeline as shown and we will discuss.
The complete data from this study where dose escalation is still ongoing, we will be presenting at the Annual Scientific Meeting of the Heart Failure Society of America, September 22 onwards.
So in summary, Alnylam has developed a robust delivery platform to silence any gene in the hepatocypte. We have demonstrated multiple human POCs via our pipeline programs, and as of today, I think we can say truly that have done that via both the intravenous LNT-based approach and the subcutaneous GalNAc conjugate-based approach. These effects are rapid, dose dependent. They are potent, durable, and specific. The news that we have shared with you today, the top line data from the TTRsc GalNAc-siRNA program -- the conjugate program, shows that we have subcutaneous delivery with a very wide therapeutic index available to us now, and we intend to apply that approach to all our pipeline programs.
And finally, the perspectives that we have demonstrated recently in the clinic gives us great confidence in our pipeline 5x15 strategy to build great products of liver-targeted programs and address significant unmet need in a range of family disorders.
So with that, I would like to stop. Again, we are going to take questions later on, but I now want to invite Dr. Philip Hawkins to the podium to come and give a great view of our lead program in the pipeline, which is Transthyretin, and Philip is going to share with us his studies and his experiences with amyloidosis patients and the problems with amyloidosis. By way of introduction, Dr. Philip Hawkins trained from St. George’s Medical School in London. He followed that up with a PhD working with Dr. Mark Pepys, and on completion of his PhD in amyloidosis on 1989, he was appointed as Senior Lecturer at University of London, and it is (inaudible) to say that the studies that Mark and Philip conducted in the 1990’s have really opened up new vistas in understanding the pathogenesis and treatment of amyloidosis.
And in recognition of their works, in 1999, the National Health Service gave them a grant to establish The National Amyloidosis Center at the Royal Free Hospital in London where Philip is now Professor and head of that unit. And Philip’s commentary is a unique commentary, because he and Mark have collected the largest cohort of amyloidosis patients anywhere in the world, and the most probably recognized (inaudible) cohort, and I would like to hear thoughts on recent progress and understanding on amyloidosis. Thank you.
Thank you, Akshay.
The amyloid is the substance that causes the disease, and it's an abnormal extracellular protein deposit composed of amyloid fibrils, and these abnormal fibrils are fibers, we can stain them in tissue sections with the dye, Congo red which is characteristic staining and enables diagnosis of the disease histologically.
There are different fibrils and different types of amyloidosis, but all are derived by a similar protein misfolding mechanism and all have a similar final structure. This is the key to understanding the disease. The conversion of a globular normal soluble protein into this highly ordered aggregated fibril form, which builds up in the tissues and cause damage to the structure and function of those tissues.
These are some amyloid fibrils under the electron microscope in the extracellular space, clear amyloid is stained in Congo red in these renal glomerular in a form of hereditary renal amyloidosis using these typical staining patterns that we used to diagnose the disease and identify the type with clinical stains. The amyloidosis is a disease that is caused by the accumulation of amyloid deposit in various organs, in local types most systemic in effect, essentially many organs in the body. Systemic amyloidosis is usually fatal, we believe that it causes up to 1 in a 1000 or 1 in 1500 deaths in the western world with AL type being by far the most frequently diagnosed, and accounting for some 70% or so of our clinical workload.
Diagnosis is generally late, treatment is challenging, but there have been many major recent advances in understanding the pathogenesis, and in particular the amyloid precursor and amyloid [product] (ph) relationship in various different types. The amyloid deposits filled up in the extracellular space and are directly damaging by their physical presence. When there is no amyloid, there is no disease; whereas when amyloid deposits build up, the disease progresses and ultimately death occurs within just a few years. When the supply of amyloid precursor proteins in the blood can be reduced, as I will show you we have been able to achieve in the acquired AL and AA types, but may be gradual regression of the amyloid deposits in the organs, and this translates over a period of a year or two into major clinical benefits in terms of organ function and survival.
We and others are making great strides in early diagnosis and promoting amyloid awareness, and in the meantime maintaining organ function by whatever means one can remains a vital participation management. Hereditary Transthyretin Amyloidosis, often known as ATTR or just TTR amyloidosis, is a disease where the protein fibrils are derived from genetically abnormal mutant TTR protein, where it can be classified as the familial amyloid polyneuropathy, FAP type affecting peripheral nerves, autonomic nerves, as well as sometimes the heart, and then separately the familial amyloid cardiomyopathy type, FAC, in which the heart is the sole target organ.
There are 100 different mutations in TTR. The common is TTR Met30, it is most prevalent worldwide as the cause of FAP. It affects younger patients often under 40 years of age. It causes progressive peripheral and autonomic neuropathy and leads to death within about 10 years.
In the UK, the Ala60 mutation has most prevalence in British Caucasians and presents at an older age, typically about age 60 with autonomic neuropathy, cardiac involvement, and is a more aggressive disease leading to death often within just 5 to 10 years. FAP is associated with a variant of Transthyretin, TTR IIe122, which occurs in about 4% of black Africans, i.e., in about 1.5 million individuals in the U.S. We don’t know what proportion of these people with this variant develop the disease, but we think it is very much underdiagnosed, and this disease presents after about age 60 with cardiac failure and death within 3 to 5 years.
The clinical course of FAP can be broken up into three stages; it’s progressive disease where sensory and most of the nerves are damaged from the toes upward. Patients in Stage 1 remain ambulant; in Stage 2, they have to depend on assistance with walking sticks and so on and crutches et cetera for remaining ambulant; and in Stage 3, the patients are confined to wheelchair and then the bed. And this is very unpleasant, and the autonomic symptoms include weight loss, gastrointestinal failure, and essentially wasting away, low blood pressure, most of the patients raising their head from the pillow at the end of the disease.
This shows a description of the stages of FAP with the Met30 mutation for which there are four (inaudible), Sweden, Portugal, and Japan, each stage taking several years on average, although the disease has variants; some patients may die within just 5 to 10 years even with the Met30 variance.
The clinical course of FAP is that of progressive heart failure, with so called diastolic dysfunction in the early and middle stages of the disease. The heart continues to pump fairly normally, and for this reason, it is often missed on echocardiography. The symptoms are left and right-sided heart failure, fatigue, shortness of breath, poor exercise tolerance, fluid retention, enlargement of the liver, loss of appetite, loss of weight, and nausea. Some patients have major conduction abnormalities requiring pacemakers, et cetera. And patients are frequently hospitalized with cardiac decompensation in the later stages of the disease.
This is an amyloidotic heart showing – a normal heart is about 1 centimeter thick, but this you can see is about 2 centimeters thick, accumulates with amyloid in the extracellular space which makes the heart thick, and the syndrome of heart failure with well-preserved ejection fraction, this actually accounts for about 50% of cases of heart failure in all the patients, and what proportion of them may have amyloidosis remains to be determined.
Echocardiography, you can see, it shows the same kind of thing, a diffuse (inaudible) in heart groove, but this is also attributed incorrectly to left ventricular hypertrophy due to hypertension, et cetera. There is some way to go in improving diagnosis about the number of new imaging techniques, but I’m sure we will achieve this.
In terms of treatment, the proven method at the moment is to reduce the supply of the amyloid precursor proteins, and I will show you that. We have demonstrated that this is highly effective in thousands of patients with the acquired AA and AL types. There are a number of other ideas in development, none of them of yet have proven clinical benefit.
So, treatment at the moment of all kinds of amyloidosis is to reduce the supply of the serum concentration of the amyloid forming protein, which can be achieved in patients with AA amyloidosis by treating the inflammatory disease, which could drive to elevated levels of the precursor protein SAA. In AL amyloidosis, the commonest type, these patients have myeloma-like plasma cell dyscrasias, and chemotherapy can reduce the production of the monoclonal light chain protein, which forms the amyloid deposits.
In Transthyretin amyloid, we hope that a liver transplantation would be an effective treatment by removing the source of the genetically variant TTR, and given that almost all of the TTR is made in the liver. This is not proved to be the case for most patients. However. This is AA amyloidosis. These patients have got major deposits on FAP scintigraphy, and (inaudible) imaging method, amyloid in the liver and spleen with underlying rheumatoid arthritis was suppressed very effectively. The level of precursor protein SAA was suppressed to normal level or at least more than 90%, and there has been net regression of the amyloid in the liver and spleen over this two-year period.
So, amyloid deposits in the organs are naturally being cleared away, albeit at a very low rate. The best is about 50% of existing amyloid deposits can be cleared over a one-year period, while the amyloid precursor protein is depressed by 90% to 100%. Without treatment, the clearance of amyloid is very slow and almost always slower than the ongoing rate of new amyloid deposition.
Any degree of reduction in the supply of the precursor protein, the serum concentration of the amyloid fibril protein will – must slowdown progression of the disease. And in some patients with AA and AL, just a 50% reduction in precursor, reduction is enough to completely hold disease progression because of this ongoing slow clearance process.
In general, we now aim for 80% to 90% suppression of the AA and AL precursor protein, and that has a dramatic effect on survival and preservation or organ function in AA and AL types.
So, returning to FAP, how do we treat it now, probably just trying to treat the symptoms of neurologic pain, gastrointestinal symptoms associated with autonomic disease, and treat cardiac failure with simple diuretics.
Liver transplantation unfortunately has not provided the answer, expect in patients with one particular mutation, V30Met mutation, which doesn’t affect the heart. When these patients receive liver transplant in the early stages of their disease, the neuropathy can be halted and patients can certainly benefit from this approach.
But when there is cardiac involvement, normal Transthyretin after the liver transplant continues to build up all the templates of the genetically variant form, and liver transplantation to patients with most TTR mutations causing FAP have proved to be unsuccessful, and this is highlighted by the fact that of only six liver transplants from the UK for FAP during the past five years given that the V30 M mutation is incredibly rare in the UK, and most patients are simply too sick or because of cardiac involvement unsuited to this approach.
There has been a lot of interest in so called stabilizer drugs of Transthyretin, the hypothesis being that these will find the TTR in the blood and lock them in the normal confirmation and prevent TTR from misfolding and aggregating as amyloid fibrils. One drug, tafamidis, trade named Vyndaqel has been approved on the basis of a small study just in V30M patients who did not have cardiac disease. This has been approved in the EU, but not in the U.S. Evidence for efficacy was extremely borderline, and this drug has not been approved (inaudible) National Health Service in the UK, and so we are not using it.
There is a Phase III academic let trial of diflunisal, a non-steroidal anti-inflammatory drug which is – we are looking at repurposing this as a stabilizer given that there is something found to bond to TTR, and the results of that study should become available sometime within the next few months, so the management of amyloid cardiomyopathy is really the symptomatic release of congestive heart failure, some patients benefit from pacemakers, and cardiac defibrillators, but really we manage the mutation simply with diuretics and most heart failure drugs which are not very helpful, liver transplantation has no role in this, and most patients are too old to be considered for cardiac transplantation, but this can be successful in very selective cases.
There is a case history of a patient with FAP associated with the so-called Portuguese variant, the TTR Met30 variant that affects younger individuals and doesn’t affect the heart. This is a 36 year old Greek Cypriot women. She had a two-year history of painful peripheral neuropathy and some weakness in her feet. She had some autonomic symptoms that was very unpleasant, loss of bladder control. She was requiring self-catheterization. She didn’t have cardiac amyloid. She looked to be a suitable case for liver transplantation with early Met30 disease, perhaps had to wait two years to receive a liver before a suitable donor came up for her, and during that time of the course, her disease progressed. She lost weigh and developed further peripheral neuropathy and weakness.
However, she had stabilized quite well during the five years since surgery, she had put on weight, and there has been a hint of recovery of bladder control. But even in TTR Met30, we believe that maybe the possibility that normal (inaudible) TTR will continue to accumulate to some extent on the pre-existing genetically variant amyloid deposit.
This is a rather unique case history of a patient with familial amyloidotic cardiomyopathy, a 59-year-old Afro-Caribbean patient. He was unusually young, most patients beyond age 60 and most beyond age 65. He presented with congestive heart failure. He had a thick-walled heart on echocardiography that was initially thought to just represent hypertensive changes, which is common in the Afro-Caribbean population. He had preserved systolic function, but suspicion of amyloid was considered, and he underwent genetic testing which unusually showed that he was homozygous. He had two crosses of the TTR IIe 122 variant.
We don’t actually think that the homozygous have (inaudible) disease, but he has a strong genetic marker of the condition he was suspected to have. Amyloidosis was confirmed by biopsy, and because of his relatively young age, we are able to do a cardiac transplant for him, and he has done remarkably well and continues to do well 10 years later.
So, what about the prospects of treatment for this disease in general? Well, it’s a very serious, unpleasant disease with substantial unmet need. Maybe transplantation probably still has a role for patients with the TTR Met30 variant when they have early symptoms of neuropathy. This is not going to be right thing to do in patients with other mutations, and indeed we think it may actually lead to acceleration of the cardiac involvement somewhat paradoxically.
Stabilizing TTR in the blood shows some promise, though the study with– the pivotal study with tafamidis was rather disappointing showing a very borderline effect, and tafamidis has not so far been tested in a trial situation to show benefit in intensively autonomic disease, which is actually one of the major features, and certainly not, it hasn’t been tested in the respect of the product involvement. At the moment, management of familial amyloid cardiomyopathy is limited to supportive care and these patients die within just two to three to five years of diagnosis.
Our experience in thousands of patients with systemic AL and AA amyloidosis have provided a robust (inaudible) that reducing the supply of TTR in the blood with a highly effective treatments FAP and FAC, and I’m very excited to be involved with this project. My belief is that if we can suppress TTR production by 80% or more, this must lead to clinical benefits along with the drugs that are tolerated and are of course safe.
And at this point, I’ll hand over to Jared Gollob of Alnylam. Thank you.
Thank you, Professor Hawkins for that excellent presentation, and good morning everybody.
It’s my pleasure to be able to provide you with an update on the progress -- the exciting progress that we’ve been making in our TTR-mediated amyloidosis programs, which include ALN-TTR02, which is being developed for FAP and ALN-TTRsc, which is being developed for FAC.
As Doctor Professor Hawkins nicely outlined and reviewed in his presentation, both FAP and FAC are devastating and fatal diseases for which there are very, very few, very limited therapeutic options. For FAP, for example that Dr. Hawkins just went over, a smaller portion of early stage patients with the V30Met mutation are eligible to undergo liver transplantation or to receive tafamidis, both of these treatments having limitations in of themselves, so there remains a great unmet medical need for novel therapeutics that can really treat the full breadth of disease severity in FAP, and address all the different mutations that comprise FAP.
And to FAC, again we also saw that there are very limited therapeutic options really confined largely to supportive care symptoms. So there also exists a very high unmet need for the development of novel therapeutics for FAC. ALN-TTR02 is our intravenously administered lipid nanoparticle formulation of an siRNA directed against all mutant forms to TTR as well as against wild type TTR, and it’s important that it is directed against both mutant and wild type TTR because both of these form of the protein are responsible for amyloid deposition and disease pathogenesis.
This slide actually shows the important progress that we’ve made to date and also illustrates the important next stages in development of ALN-TTR02 that will occur over the rest of this year. It is important to point out that we have positive Phase I results in human volunteers that we’ve recorded last year. We now have positive Phase II results in ATTR patients that we just reported last month at the Peripheral Nerve Society Meeting. With regard to important upcoming events, we tend to present the final data for that Phase II study at the FAP symposium scheduled for this November in Brazil. We will be moving forward and opening our open-label Phase II extension study, which will start at the end of the third quarter of this year and that will include important clinical endpoints, and most importantly, we will be moving forward with the start of our Phase III pivotal study by the end of this year.
We are now on slide 42, and this particular slide shows the key clinical activity data that was our proof-of-concept from our Phase I healthy volunteers study that we reported out last year. You can see on this particular graph that at ALN-TTR doses of greater than or equal to 0.15 mg/kg, we see substantial knockdown of serum TTR protein. Following a single dose of drug, you see the typical profile that we also see in non-human primates where we see rapid robust endurable suppression of serum TTR with suppression durable past 28 days after that single dose.
At the highest dose level, at 0.3 mg/kg, we had an average knockdown at nadir of approximately 87%, and at the highest dose of 0.5 mg/kg knockdown of 94%. Within the study, in addition to proof-of-concept for TTR lowering, it is also very important that we demonstrated the RNAi mechanism of action In Vivo that we confirmed by using a 5'RACE analysis on circulating mRNA in the three subjects that were treated at 0.3 mg/kg dose level.
And already with those encouraging positive proof-of-concept data from the Phase I healthy volunteer study that let us to then proceed on to a Phase II open-label, multi-dose dose escalation study in actual FAP patients. And the relationship that we’ve established with key investigators in this field over the past three to four years really enabled us to perform this study in FAP patients in multiple different geographic locations.
The design of the study was presented last month at the PNS Annual Meeting in France and consisted of nine cohorts with three subjects each. The primary objective of the study was to evaluate safety and tolerability of multiple doses of ALN-TTR02 with patients receiving two doses of drug. Secondary objectives were to assess preliminary clinical activity which included measurements of serum levels of TTR, retinol binding protein, and vitamin A.
So, the status of the study has now completed enrollment and dosing for the first 6 cohorts. We’ve also analyzed those data, and I’ll be presenting those on the subsequent slides. We’ve also dosed our patients on cohorts 7 and 8, and are in the process of now dosing the (inaudible) patients on the last cohort, which is cohort number 9.
Here, we are showing the baseline characteristics for the 19 subjects treated on the first 6 cohorts on the clinical trial, and what I’ll point out here is that the demographics are typical for this sort of population that we will treat in the Phase II study, importantly we were able to evaluate multiple different TTR genotypes, the most common was the Val30Met, which happens to be the most common mutation worldwide, and it’s present in endemic regions such as Portugal and Sweden. In addition, I want to point out that at the majority of patients treated so far have also been on concurrent tetramer stabilizer treatment with either tafamidis or with diflunisal.
The key clinical activity data coming from the Phase II study are now shown in this slide, which is slide 45. Just to orient you on the X-axis, we’re now going out to 120 days, and on the Y-axis, we’re looking at the Percent Mean Serum TTR knockdowns relative to baseline for each of these dose groups, and here we have got a very clear dose response, so you can appreciate that a 0.05 mg/kg, that is when we first see substantial TTR suppression, but it was really at the 0.3 mg/kg dose level that we saw the greatest degree of TTR protein suppression using either in every four-week regimen shown by the turquoise triangle or in every three-week regimen shown by the red triangle.
We saw a result that was very consistent with what we saw in our Phase I healthy volunteer study and what we’ve seen in our non-human primate pharmacology studies , which is with the first dose, we see rapid, robust, and durable knockdown of TTR with a nadir of greater than 80% at around 14 days after that first dose. We then see relatively little recovery prior to the next dose which was given either four weeks later or three weeks after the first dose, and after that second dose we again see suppression of TTR with nadir levels of greater than 80% followed by gradual slow recovery.
I’d point out that for the 0.3 mg/kg group treated every three weeks and we have data now going out to 36 days, we have additional data points beyond that that are in the process of being collected and are pending, and as we anticipated with the shorter dosing with every three week dosing, we’re able to see more sustained suppression of greater than 80% with the q.3 week regimen compared to the q.4 week regimens.
The table set on this slide summarizes those data that I just showed from the graph on the previous slide. I mean, here we’re looking at maximum TTR knockdowns and also the average TTR knockdown, the nadir following either dose one or dose two, and we’re looking at it for all the doses, but I would ask you to focus your attention on the bottom two rows which are the 0.3 mg/kg doses dosed either every four weeks or every three weeks.
And you can see that with regard to the average TTR knockdown at nadir, we see 83% reduction at nadir for both the q.4 week and q.3 week dose groups with the 0.3 mg/kg dose after dose one, and we see approximately 85% to 87% knockdown of TTR after the second dose. If you look at maximum TTR knockdown for any individual subject, you can see that the greatest knockdown we’re seeing for one of the subjects on the three weeks q.3 week dosing regimen was we saw close to 93% reduction of TTR.
I’d also point out that you can see that between dose 1 and dose 2, we actually see an increase in the degree of TTR knockdowns with consecutive doses, and this is dose consistent with what we also saw in the non-human primate. We’ve done multi dosing of up to 7 doses in non-human primates with similar dose levels and similar dosing regimen, and we see that with each consecutive dose, we actually see more and more TTR suppression at nadir. And so, we expect to see this continued increase in the nadir with continued dosing as well beyond two doses in humans.
Because we performed this Phase II study in FAP patients, this gave us the unique opportunity to examine the effect of ALN-TTR02 on both the mutant form of the protein as well as on the wild type form of the protein.
(Inaudible) method in the V30Met patients that were treated at the highest dose level at 0.3 mg/kg. And you’ll see on the left-hand graph that we saw a very strong one-to-one concordance between knockdown of TTR wild type protein and knockdown of the V30Met mutant proteins. One the right panel, you can see a graph which looks now like a kinetic suppression of both the mutant and wild type protein after the first dose and after the second dose in patients receiving 0.3 mg/kg every four weeks, and you can appreciate that these curves are essentially superimposable showing the exact same effect on the kinetics of suppression whether it be the V30Met mutant proteins or the wild type protein.
In reality, we expected this results because we know that our siRNA is directed against the 3’ translated region of the messenger RNA for TTR, so we should be effective against all different mutant forms as well as wild types, and we’ve actually performed some In Vitro studies that have further shown that the siRNA is active against all different mutations with TTR.
This figure also illustrates an important point with regard to the potential of this approach for treating FAP as opposed to liver transplantation. As Professor Hawkins mentioned, with liver transplantation, you’re only getting rid of the mutant protein, but the wild type protein remains and is able to continue deposition into organs like the heart. Here, we’re able to reduce to a large extent both mutant and wild type proteins, so our expectations are that clinical benefit with this approach should go beyond that which is seen in liver transplantation.
With regard to safety and tolerability, we’ve been very encouraged by the safety profile that has emerged both in the Phase I single-dose healthy volunteer study and that has emerged so far from the Phase II study – multi-dose study in FAP patients. We presented the safety data emerging from the Phase II study at the PNS Meeting last month, and we saw that it was generally safe and well tolerated when given as two doses either every three or every four weeks apart. Importantly, all of the adverse events -- and there were few adverse events that were associated with drug administration. They were either mild or moderate in severity. We had a very low incidence of infusion-related reactions. We had only one patient who developed a mild infusion reaction at the top dose that was treated easily just by slowing the rate of the infusion. Importantly, we saw no laboratory abnormalities either after the first dose or the second dose in these patients including no change in liver function test, no alterations in renal function, and no change in hematologic parameter.
In terms of the next step for the Phase II study, we are in the process of completing accruals to the remaining cohorts, which will then be followed by data analysis. We plan to present the final Phase II data at this International Symposium on FAP in Brazil in the early part of November. Now for FAP patients who were dosed on the Phase II trial, they’re all eligible to roll over on to our Phase II open-label extension study, and patients are actually -- they’re eagerly awaiting the opening of this Phase II open-label extension study, which will be initiated by the end of the third quarter, because this gives them the opportunity now to receive up to two years of continuous dosing at 0.3 mg/kg dose either every three or every four weeks with the final dosing schedule and pre-medication regimen to be based on the complete Phase II data.
Importantly, in addition to being able to monitor safety with chronic multi-dosing on this study, this open-label extension study will also include clinical endpoints including many of the same clinical endpoints that are planned for our Phase III study, and these will be evaluated every six months. So, this study will give us the unique opportunity to have a [lead out] (ph) clinical efficacy while the study is ongoing in parallel with our Phase III study. The study objective that’s shown here as well, safety and tolerability of long-term dosing is certainly one of the main objectives, but the key secondary objectives relate to these clinical endpoints looking at the effects on serum TTR levels, looking at the effects of drug on neurologic impairments using a neurologic impairment score, also looking at quality of life, and looking at the patient’s nutritional status through their body mass index.
So again, we’re very excited about this open-label extension study as our patients and we plan to begin this by the end of the third quarter, and we anticipate the majority of patients on the Phase II study rolling over on to the Phase II open-label extension study. And of course all of these efforts in Phase I and Phase II are ultimately geared toward getting us to the important pivotal Phase III study designed to demonstrate safety and efficacy to enable global registration and approval as a single study and importantly to support the product and value proposition. We are in the process of having ongoing discussions with regulators with regard to the details of this Phase III trial where we can provide some color at this point on some of the key features of that Phase III trial. This will be a randomized double-blind, placebo-controlled global study. It will be 2:1 randomization of active drug to placebo. We expect to enroll anywhere from 150 to 200 patients with FAP on the study, and dosing will be at 0.3 mg/kg every three or every four weeks.
The primary endpoint will be a change in a composite neurologic impairment score, we call that the Neurologic Impairment Score or NIS at 12 to 18 months. The final decision on the duration of the primary endpoints will be pending further regulatory discussions. And there will also the key secondary endpoints such as the effect of (inaudible) TTR levels, the effect on quality of life, on level of visibility, on motor function, and on body mass index, again which is a measure of nutritional status. And really, these assessments are aimed at providing the pharmaco-economic framework supporting the value propositions here for competitive pricing based on showing the clinical benefit of treatment with ALN-TTR02, and as this is a drug that can truly transform the lives of patients with this devastating disease.
Turning to ALN TTRsc which is our GalNAc-siRNA conjugate also directed against mutants as well as wild type TTR for the development of FAC. The GalNAc conjugate enables subcutaneous delivery, and also enables a wide therapeutic index that Akshay reviewed in this presentation. We’ve completed the GLP tox studies, and importantly within the GLP tox studies, we have noticed very little in the way of any organ toxicity, really this means nothing of any concern , and in particular, we’ve not seen any renal toxicity and we’ve seen relatively little accumulation of drug in the kidney, and this is important especially for FAC patients, because these patients with heart failure often have renal insufficiency due both to their heart failure and to diuretic treatment that’s used in these patients.
So, it is very important that any drug that is going to be used in this population needs to be very safe from a renal standpoint, so we’re very encouraged from the GLP tox studies that we have seen that sort of safety so far. Akshay already shared the positive top-line study results from the Phase I healthy volunteer study that is ongoing. In terms of next steps for the program, we’ve planned to complete the Phase I study and show those complete results at the Annual Scientific Meeting of the Heart Failure Society of America in late September, and based on these positive results that we’ve now seen in Phase I, we plan on moving forward with our Pilot Phase II study in FAC patients that will start in the latter part of this year, and then ultimately our goal of course is to start Phase III in 2014.
We’re now in slide 53, and this slide provides more detail around the design of the ALN-TTRsc Phase I study, because this is a randomized double-blind placebo controlled single and multi-dose dose-escalation study in up to 40 healthy volunteer subjects. We have four dose levels in the SAD, the single-ascending dose portion ranging from 1.25 to 10 mg/kg, and three dose levels in the multiple-ascending dose portions with doses ranging from 2.5 to 10 mg/kg. The dosing regimens for multi-dose consists of the daily doses times 5 followed by five more weekly doses. The primary objective of this study is safety and tolerability, secondary objectives are assessment of clinical activity as measured by serum TTR levels.
And in terms of the status of the study, we have now completed dosing of the SAD cohort, the MAD dosing is ongoing. Akshay reviewed the very exciting positive top-line results. The fact that we are seeing statistically significant TTR knockdown, the fact that we are seeing greater than 80% TTR knockdown in treated subjects, that treatment has been generally safe and well tolerated to-date, and we’re obviously very pleased that this now really confirms the human translation of the GalNAc-siRNA conjugate platform, and as I mentioned previously, we will present complete data at the HFSA Meeting in September.
And again, based on the positive results that we’re seeing in this Phase I healthy volunteer study, we’re now moving forward with our plan for the Pilot Phase II study in FAC. The study design is shown on the slide. This will be an open-label study in patients with FAC. We anticipate accruing approximately 12 patients with the dose and regimen to be based on our final Phase I results. The primary objective will be safety and tolerability of multiple doses of drug in this particular patient population and secondary objectives will include assessment of clinical activity including looking at the impact of the drug on serum TTR levels and looking at select measures of cardiac function, and again we plan to start that particular study in Q4.
Finally, I would like to summarize both of these programs with regard to ALN-TTR02. Robust and durable knockdown of TTR has now been demonstrated in patients using our multi-dose regimen. Importantly, we saw a similar activity against mutant and wild-type TTR, and we are seeing so far a favorable safety profile. The open-label Phase II extension Study is slated to start at the end of Q3, where we’ll evaluate the safety of long-term dosing, and importantly as I mentioned, this will include key clinical endpoints that will reflect what will be in Phase III. And importantly, the Phase III study in FAP will start by the end of this year, and we plan on having a single study to support approval.
For ALN-TTRsc, we now have positive top-line data from our Phase I trial in healthy volunteers, which now provides human proof-of-concept for this GalNAc-siRNA delivery approach. Our pilot Phase II trial in FAC is scheduled to start in Q4, and we will then proceed with a Phase III trial in 2014. So, with that I’ll close and thank you for your attention, and I’ll go ahead now and introduce our next speaker who will be talking on Hemophilia. Our next speaker is Dr. Craig Kessler. Dr. Kessler is a Professor of Medicine and Pathology at the Lombardi Comprehensive Care Center at Georgetown University Medical Center. In addition, Dr. Kessler is Director of the Division of Coagulation, Director of Cellular and Therapeutic Apheresis, and Director of the Hemophilia and Thrombophilia Comprehensive Treatment Center. So, with that, I’ll introduce Dr. Kessler.
Thank you very much Jared. It’s a pleasure to be here this morning to introduce to you the hereditary and acquired bleeding disorders in the family of hemophiliacs. These are my disclosures. What I would like to do over the next 20 minutes is go over some of the genetics of the hereditary bleeding disorders. I would like to provide a rationale to you for different approaches to the treatment of the bleeding complications associated with hemophilia and probably most important what I would like to do is to point out some of the unmet needs that we as physicians have currently for the treatment of these bleeding disorders.
As you know, this is a very exciting time to be treating patients with hemophilia, because over the next several years, there are going to be any number of new molecules that will be introduced into the clinical arena, and although you may think that the introduction of these new molecules provides an ultimate cure and an unburdening of the disease complications on the population of individuals with bleeding disorders, I’m going to try to point out to you where are these gaps, and treatment convenience, and the concept of how these new molecules don’t really cure the disease, and even if you just feel the idea that the ultimate cure of the disease, which has been advertised as being gene therapy, in no way actually cures the disease.
And so, there is – there are many unmet needs right now in spite of the hype and the hope that these other new molecules are going to be bringing to the investment community and also to the treatment community. So, there is nothing more (inaudible) than to discuss the coagulation cascade to a group of individuals early in the morning. So, what I’m going to try to do is to just provide the concept of coagulation. So, essentially the blood contains - the plasma of the blood contains a series of proteins, which are inactive as they are circulating in the plasma, and then they become activated. They can become activated by injury to the blood vessel. They can become activated by activation of platelets. They can be activated by disease such as cancer and catastrophic pregnancy complications etc.
So, essentially we think traditionally the coagulation occurs in a system whereby you can trigger coagulation within the blood vessel that is called the intrinsic pathway as you see on the left, and the extrinsic pathway is a series of proteins, which are triggered by damage to tissues outside of the blood vessel. Essentially though they actually do interact with each other and the ultimate goal of coagulation is to produce a protein called thrombin that you see down at the bottom of the slide. The thrombin is a pivotal enzyme, which cleaves fibrinogen to form a blood clot.
Now, as you can see on the left hand side and on the right hand side, there are any number of proteins that have roman numerals. These roman numerals identify the various types of proteins in the order that they were actually discovered by scientists in the laboratory. And you can see that there are 13 coagulation clotting factors that have been identified thus far. In actuality, there are only 10, because scientist found that three of these were actually similar to the others that have been already discovered.
But on the left hand side, you can see that there are two pivotal proteins that we are going to be talking about this morning, and that is Factor VIII and also Factor IX. These are the two proteins that are missing in Hemophilia A and Hemophilia B respectively. And essentially, there are any number of examples of this natural experiment of deficiencies in all of these clotting factors. So, you can take a look at any of these clotting factors and find individuals who have inherited or developed the abnormalities of bleeding associated with deficiencies in any of these clotting factors, but Factor VIII and Factor IX are the two most common.
Now, you also see over here in the blue boxes a series of what I call modulators of coagulation. So, when you have these clotting factor proteins, their job is to promote the development of blood clots that will always promote blood clots in our body. And if we didn’t have modulators to dampen down the (inaudible) and the promotion of blood clotting, we will be walking around as total body clots. If you cut yourself shaving, you would turn out to be a total body clot because this mechanism of coagulation will be triggered.
So, we have a system of modulators of coagulation, and you can see that these include Protein S and Protein C, antithrombin III in the center of this diagram, and TFPI, which is Tissue Factor Pathway Inhibitor. Now, individuals who are born with deficiencies in these modulators, and when they have a substantial reduction in the concentration of these modulators, they walk around developing blood clots, and so you have a sort of a ying and a yang here. You have the promotion of clotting. You have the modulation of clotting. And so, over the next few minutes, I’m going to discuss with you how we can take advantage of stimulating some of the modulators or dampening down the modulators to enhance coagulation when you have deficiencies in the promoters of coagulation.
So, discussing Hemophilia A and B, Hemophilia A is deficiency of Factor VIII. It is the most common inherited bleeding disorder, and yet as you can see in actuality that statement has to be modulated in a certain perspective, because in actuality Von Willebrand's disease is the most common inherited bleeding disorder and may also serve as a clinical model for the use of some of the modulators of the coagulation system that we are going to be discussing later on this morning. But when you take a look at the specific gene and what we know about gene defects, right now Hemophilia A and Hemophilia B are the best understood, and we know much more about the phenotype, that is how the bleeding occurs and also the genotype what happens to the gene that produces these various bleeding disorders.
So, Hemophilia A occurs in one out of 5,000 male births. This is what we call an X-linked or sex-linked recessive bleeding disorder. Factor IX is also an X-linked recessive bleeding disorder, and it’s much less common than as Hemophilia A. So, essentially even though in the United States we only have 400 new births that occur in the United States who are hemophiliacs, the essence is that this is a well-defined disease in a well-defined population, which is an extremely expensive set of diseases to care for.
So around the world, we believe that there are many more cases of Hemophilia A and B. We have been able to identify over 40,000 cases of Hemophilia A and 10,000 cases of Hemophilia B, and the worldwide statistics are indicative that worldwide there are probably over 120,000 Hemophilia A and B patients, and one of the complications that occurs with this disease is that individuals when they are replaced with these proteins that they are missing as a way of trying to treat their bleeding or to prevent their bleeding complications, they develop inhibitors, they develop antibodies to the proteins that they are missing in their own system.
So, essentially because of the genetic repertoire and the immunologic repertoire, these individuals by replacing them with the proteins that they are missing, their immune systems recognize the replacement normal protein as being foreign and they develop inhibitors, which neutralize the activity of the replacement factor so that you can use those clotting factor concentrates to be able to stop or to prevent bleeding, and this is a major complication, and I’ll show you what the problems are with this in a minute.
Now in developing nations we do not really know how many patients there are with this bleeding disorder. These are underreported. They are under diagnosed because of the laboratory facilities and lack there are in these other countries and we know that hemophilia does not have any estimate predisposition so that we should have many, many more patients around the world than what we have identified in Europe and in the United States.
I might add that currently only 15% to 20% of all hemophilia patients in the world receive adequate treatment. So, we have a vast market and a vast need for other ways of treating these diseases in a very economically sensible manner. And also I might add that it’s going to be very important to have delivery systems that make sense for developing countries because these hemophilia patients are treated with intravenous infusions of the clotting factors that they are missing.
They have to treat themselves frequently and it doesn’t make sense to have intravenous medications in developing countries, where you don’t have a supply of needles, you don’t have a medical system that can provide intravenous infusions, the patients are not sophisticated enough to give themselves intravenous medications and so that is another unmet need.
In addition to the Hemophilia A&B population, there are also these other rare bleeding disorders at young or the other roman numerals on the coagulation pathway can be inherited as a deficiency and so there are any number of other natural models of coagulation deficiencies for which modulation of coagulation will be useful. So, we divide hemophilia into severities. We call them severe, moderate and mild. The severe patients bleed spontaneously without trauma. The individuals with moderate and mild both usually bleed unless they have some trauma.
On the other hand, what we are talking about with gene therapy is not to cure hemophilia but is to make a severe patient into a moderate or mild individual so that they don’t have spontaneous bleeding but it does not protect them from bleeding when they are traumatized or when they go to surgery. So, the idea here then is to be able when we treat patients to give them clotting factor levels to replace their clotting factor levels to a level where they are phenotypes, they are bleeding phenotype changes. And hemophilia 60% of all the bleeds occur in the joints and/or 30% in other areas 10% occurring in areas that you don’t want to have bleeds in because it causes death like the brain and others.
And then in fact, if you take a look at the death rates in these bleeding populations even though we have all of these clotting factors available in the United States, the hemophilia A and B, currently the major cause of death still remains catastrophic bleeds in these patients.
So, we are changing the landscape with all of these new drugs and yet bleeding is still the biggest area of morbidity and mortality. And inhibitors are a major issue because you cannot use the traditional drugs to reserve bleeding when the inhibitors occur in as you can see on this slide, you have on the upper left hand panel, this individual as self-tissue bleed. And this is very important because this is an acquired antibody to hemophilia protein.
So but not only can you bleed because you are inherit and then develop an alloantibody for these clotting factors, but you can have a normal coagulation mechanism and all of a sudden develop an auto-antibody for these clotting factors and that is another major gap in the treatment of bleeding disorders because none of these products currently work.
You can also see the joint damage, so essentially right now what we do to care for these patients as we replace the clotting factors. And typically these patients treat themselves two to three, four times a week and then they treat themselves prophylactically, if they know they are going to be involved in activities that would stimulate a trauma and bleeding complications. But if they develop inhibitors then all that you are off.
There is now a move in the U.S. and in Europe particularly to try to develop a prophylaxis regimen so that you are treating yourself whether or not you bleed, so that you can prevent any bleeding complications from occurring, this is called primary prophylaxis, the aim of this is to prevent any damage to the joints and to prevent any bleeds versus the on-demand theory of treatment where you just treat when you begin to bleed or treat in advance of a time that you know you are going to bleed.
The number of joint bleeds as you can see on this table, has substantially reduced with the primary prophylaxis and yet only 50% of American Children are receiving this way of treatment. And you can see on this graph that those individuals who are receiving prophylaxis regimens versus episodic regimens have a much lesser degree of bleeding complications. And yet when you have an inhibitor all of these rules are broken. The treatment is much more expensive. The death rate is much more expensive. The number of bleeds are much more plentiful. These patients die, these patients have major complications and it’s very difficult to treat them and we have a list of various type of products but they are not all perfect.
So in this case of a nine-month old male child, who has a family history of hemophilia A, of the patient the baby was born with suction delivery, in vacuum delivery, you can see on his head that he actually developed a major bleed by virtue of the delivery process. So this is a disease that has manifested at birth. And in fact the first medicine of hemophilia in all history is in the Talmud where it’s been described, the individuals undergoing circumcision were bleeding and if a family knows that they were two children in the same family that have circumcision and bled that other males do not have to undergo circumcision.
Okay. So this child develops an inhibitor, the baby develops an alloantibody, he was what we say a new immune tolerized that means that he was placed on clotting factor every day in order to try to desensitize the immune system and eventually this was successful. This is what I would call the $1.5 million approach to the treatment of these patients and it’s successful and these patients need to be on prophylaxis two to three times a week thereafter for the rest of their lives in order to prevent that inhibitor from recurring.
This is a menu of the product that we have available, I can tell you that for inhibitor patients none of these products works. Well, for everybody but I want to bring out one concept and that is that the downstream result of the use of these products is that it produces a hypercoagulable state in these individuals in order to stop their bleeding, this is going to be very important when we discuss the antithrombin 3 program.
This is a total financial burden of the inhibitors and you can see that patients on the prophylaxis appear to have a lower cost overall than patients’ on-demand. But the reason for that is that this table and primary prophylaxis is only used in children. And treatment is weight based. So we don’t have the adults represented for the cost over here. So when these young children develop into adolescence and adults, this cause the primary care is going to shoot up dramatically.
And of course, you can see on the left-hand side the cost of inhibitor patients’ treatment is much greater than the non-inhibitor patients. In the U.S., we have treatments after networks to try to take care of patients and if you can direct these patients into the hemophilia treatment center network, you actually have a reduction in the morbidity, mortality and cost.
So what are these strategies for the treatment of hemophilia? Well, we are now looking at reengineered proteins which extends separating half-life, but still patients are going to have to be treating themselves two to three times a week, alternate routes of administration have not been successful up to now, there is a need to diminish the immunogenicity and the inhibitor formation related to these newer drugs. We don’t know what the inhibitor rate is going to be on these new medications, gene therapy is not a cure for the disease, but is a new way of changing phenotype and in the expensive way of that find specific antibodies to try to stimulate the activation of foreign factors are being developed and then rebalancing approaches such as antithrombin 3 program that you will hear about in a few minutes are also going to be used.
So looking at this rebalancing, I just want to go back to the coagulation cascade. Essentially, I told you that we have the series of modulators of coagulation. So if you blank out and increase the deficiency of these modulators you actually make these individuals hypercoagulable, but we know from the studies that you will be seeing in a few minutes that you can modulate how you damp down the activity of these modulators.
So you can take a bleeder damp down the inhibitor and theoretically allow these individuals to be able to clot even though they are deficient in some of the coagulation proteins and we have an experiment in nature that you can see on the right-hand top column over here where there are some hemophilia patients who have been born also with the deficiencies and antithrombin 3 and then phenotype is essentially normal. They have severe hemophilia A, but the deficiency of the antithrombin molecule does not produce clots in these individuals, it changes their phenotype to almost normal non-coagulopathic phenotype.
So that you will see in the next few minutes then wrapping up, so we have unmet needs in the care of bleeding patients. Besides hemophilia A and B, we have also a series of other coagulation disorders that modulating the modulators of coagulation we can actually change phenotype from bleeding to normal on a theoretic basis. This is extremely provocative to think that we can now modulate in a very ordered fashion antithrombin 3 and thereby changing individual who is bleeding into a normal coagulopathic individual.
So, I want to thank you very much for your time and I hope I have been able to introduce you to some difficult concepts and some promises for the future. Thank you very much.
Thank you, Dr. Kessler. And good morning.
What I’m going to do today is give you a little bit of insight into – from the preclinical data that we have in our ALN-AT3 program and I’m also going to share with you some of our initial thoughts on what a clinical development plan looks like for these hemophilia patients.
So, of course I don’t need to go into this in any detail because Dr. Kessler just did a wonderful job with that. But I just want to emphasize the point that we recognize that there is a high unmet need for additional and novel therapies. And we anticipate that ALN-AT3 drug candidate will have a really significant impact on the life of patients who currently aren’t being effectively managed by the therapy sets. And Dr. Kessler illustrated for you.
And again, we just saw this coagulate cascade, I don’t really need to introduce it anymore, but I really want to emphasize one point that you just heard from Dr. Kessler and that is that we really became excited about this strategy by some human genetics that Dr. Kessler just pointed out and that is to say in that sub-set of hemophilia patients and co-inherent prothrombotic mutation. We see a much milder course of disease and so that’s really the basis of our strategy. We are going to decrease antithrombins, up-regulate thrombin generation. And as a consequence convert the severe hemophilia patients into a much more mild phenotype.
How we are going to do that? I’m sure it’s no surprise for you to know that we are going to harness our incredible GalNAc targeting strategy. So we’ve designed ALN-AT3, which is a siRNA conjugated to GalNAc and it takes advantage of that receptor meditated through hepatocyte specific uptake mechanism to deliver these siRNA molecules.
And what you can see on the right-hand side is a graph that shows in wild type mice the ability of low doses delivered subcutaneously on a weekly basis significantly down-regulate antithrombin in a consistent fashion. Importantly really this is the fundamental basis of our therapeutic hypothesis hinges on the idea that thrombin generation is correlated with disease severity. And that has really illustrated nicely on the graph here from the published literature and if you just focus your attention on the graph on the right what you can see is the curve for what normal thrombin generation looks like in a well type patient. And what you can see is that there is sequentially decreasing levels of thrombin generation correlated with the severity of disease.
So if you look at those patients that have the most severe phenotype, you can see the lowest levels of thrombin generation and of course the goal then is to convert those patients at a very low levels of thrombin generation to a more mild phenotype by upregulating thrombin. And we anticipate doing that through the down modulation – through the knockdown of AT3.
And some evidence that really suggest that this hypothesis – is a valid hypothesis comes from these data in – from human – from plasma of hemophilia patients and I will ask you just to focus on the graph on the left which is a hemophilia A plasma, the data sustained on the graph on the right-hand you see the D plasma and what you can see is that, if you look at the black curve, you can see what a normal thrombin generation curve looks like in normal individual.
And then you can see in the lowest graph which is in sort of a grey you can see the state of affairs for the severe hemophilia patients in which those practically no thrombin generation. And importantly what you can see here in this – actually both thrombin is that as you decrease the levels of antithrombin sequentially you up-regulate the thrombin generation. And that’s exactly what we intend to do with our targeting strategy.
We have just shown you, but that’s been effective in the next in vivo setting in plasma, but what about in vivo? And so in these experiments, we have done in collaboration with (inaudible), where we asked the question in an in vivo setting in a model hemophilia in this case hemophilia B mice, can we introduce ALN-AT3 down modulate the target and have an impact on thrombin generation.
So if you focus on the graph on the left, first what you can see is, the hemophilia state, which you see significantly decreased levels of thrombin generation in these hemophilia B mice. And then what you can see is that in a dose dependent fashion as we knock down antithrombin, we can see a normalization of thrombin generation.
If you move over to the right-hand side of the curve what you can see is the dependence of AT knock down on that normalization and if you focus all the way to the right, you can see that at a 100% knock down of AT3 we can completely normalize thrombin generation and importantly in fact we don’t over shoot. And so that suggest to us in this mouse model we can knock down AT3 and have a significant impact on thrombin generation. And of course the next question that we ask is okay, so what about bleeding?
And we turn to another model of hemophilia in fact the microvessel laser injury model to ask a question about whether knockdown of AT3 could have an impact on bleeding. What I’m going to show you in a minute are two movies. The movie on the left is from a hemophilia B mouse, its untreated that’s otherwise untreated. And the movie on the right is going to be a hemophilia mouse that’s treated with a single high dose of our GalNAc conjugated AT3 module in which we got a 100% knock down of antithrombin.
And I’m going to ask you to watch and pay close attention to the movie on the right and what you will see there is in red the accumulation of platelets and in green the deposition of fiber. And ultimately we can form a stable clot in these animals by completely knocking down AT3. Give you a minute to appreciate that. In fact, it’s so nice I’m just going to show to you one more time. You can really, really appreciate that. So again, you watch that film on the right and you can see those platelets come in, you can see that fiber indicative and you can see that stable clot. Beautiful.
And importantly, we can actually use the same model and now in hemophilia A mouse, we can quantify that effect that impact on bleeding. And that’s shown here by looking at deposition of platelets as well as deposition of fiber and you can see again, if you focus on the black curve what you can see is, what the wild type state looks like the amount of platelets and fiber maybe deposited. And if you look at those grey curves on the bottom of flat line curves, at the bottom you can see the state of affairs for the severe hemophilia, in fact where there is no evidence of platelets accumulation or fiber accumulation.
And importantly again, in a dose-dependent fashion as we increase the levels of knockdown of anti-thrombin, we can see a restoration and improvement in hemostasis. And again, the way we think about this is we can covert these purple guys who are the severe hemophilia to a more mild phenotype by improving overall hemostasis.
As I think you have come to appreciate from everything that Jared and Akshay have said to you we recognize that the non-human primate is really the most important model for us to appreciate the translation, the ultimate translation into humans. So, it was really important for us to get some data in this large animal model.
I’m going to take a couple of minutes to take you through these data because there is a couple of really key points here. So, if you focus first on just the red curves, what you can see is that doses as low as 1.5 mg/kg delivers subcutaneously, weekly give you almost a 100% knockdown of antithrombin. That knockdown is sustained after you stop dosing and it’s sustained for over a month. And then you can see this slow and steady recovery over a couple of months and you recover exactly back to baseline. It’s a beautiful result.
If you now focus your attention on the dark blue diamond what you can see there are doses as low as 0.5 mg/kg, given weekly subcutaneously in a non-human primate, you can see about 90% silencing. It’s really low doses again, once you stop dosing you see a sustained effect that starts to recover.
And interestingly in this experiment we ask the question, can we actually in these same animals can we reset the level of silencing by changing the dose with antithrombin. And so what we did in those animals in the dark blue diamonds is, we decreased the dose by four-fold. And we went from 0.5 mg/kg to 0.125 mg/kg and we asked if we do that as a regular subcutaneous dose, can we maintain a stable new level of target modulation. And the answer is of course yes and we can achieve about 55 or so percent knockdown which is stable and consistent as long as we continue the dosing of this drug.
And this data really set us up to do two important things. First, it sets up for some of the remarks I’m going to make a little bit later when we talk about our thoughts in clinical development plans but it also importantly allows us to evaluate this drug in a large animal model of disease. And that’s a model of hemophilia A inhibitors in non-human primate.
The way this model works using an antibody against factor VIII, you induced a hemophilic state by completely obliterating factor VIII. And then we ask the question, with two different doses of antithrombin that give us two different levels of knockdown, can we see an impact on thrombin generation in this non-human primate model. And to what I’m showing you from the next slide, if you focus on the left-hand side, first, you can see we were able to induce hemophilia and that’s evidenced by the fact that in all of these animals and all of these dosing groups we were able to show complete obliteration of factor VIII and levels of factor that are less than 1%, which is reminiscent of exactly the state of affairs, so with inhibitors patients who have developed antibodies and principally have no factor.
And now as you look at the right-hand side of this panel what you can see again, first to the model sets up and if you compare those purple bars to the first sailing blue bar, you can see a significant decrease in thrombin generation that’s associated with inducing a severe hemophilic state and importantly as you look at that dose response of ALN-AT3, you can see this increasing knockdown, you can see a complete normalization of thrombin generation in these animals.
So again, the way think about this, and if you remember that those ex-vivo primates I showed you a little bit earlier, we are converting these hemophilia A severe hemophiliacs, not in primate into a much more mild phenotype. And these are really was very, very exciting data for us and really collectively suggested to a specialist drug behaving exactly as we expected, it would robustly knockdown the target that would lead to thrombin up-regulation and that would have an impact on disease end point.
Of course, I’m sure you were asking yourself so that’s great so you’ve got this beautifully potent compound, but we of course need to make sure that we have the appropriate safety profile for this drug. And I’m pleased to report that this drug is behaving again exactly as you would expect. Those with respect to potency as well as with respect to its toxicity and that’s illustrated on this slide in which you can see if you look at the left-hand graph you can see what happens as you give aggregated doses in the context of a wild type mouse.
And you can see that’s extremely toxic as you would expect if you up regulate this clot and cascade and you get a series of procoagulant effects that you would anticipate. But really importantly if you look at the right-hand side of the graph and you see in hemophilia mice and you can give doses of 100mg/kg weekly subcutaneously and it’s extremely well tolerated and I really suggest that we have a therapeutic index that exceeds a 100 fold for this drug. In fact, we have given dozes that had 500 mg/kg at a single dose. And we have seen that extremely well tolerated. So that suggestion have an incredibly (inaudible) and safe drug in the setting of hemophilia.
And that combined with the beautiful data that we heard about from our subcu program in TTR, really makes us enthusiastic about moving it directly into the clinic. And this is an illustration of how we are thinking about our Phase I design which starts with a single sending dose study and healthy volunteers and which importantly, of course, we are looking for safety NPK. And we can get some early read outs on (TED-PD) by measuring antithrombin levels in each healthy volunteers, and will dose these patients up to about 40% knockdown of antithrombin. And when we successfully see that level of knockdown, we can then move directly into a multi-sending dose study in patients with moderate-to-severe hemophilia in which of course we will again with the safety NPK and look at those PD end points for antithrombin.
But again, importantly we can get our first clinical end point by looking at improvements in thrombin generation and these will then set us up to look at further development. And these are just some ideas which are really were highlighted by Dr. Kessler which suggest us that there is a variety of path forward to get to NDA, for example in severe hemophilia A patients by using on-demand prophylaxis where there is obviously frequently in these patients as well as a significant requirement of factors. And we would imagine in a relatively small trial of probably less than 200 patients, we produce ALN-AT3 and monitor frequency of bleeds as well as requirement for factor.
And alternatively and again you heard about this from Dr. Kessler, there is a population of inhibitor patients who obviously are serious – they have serious unmet needs. And in those patients we imagine doing even smaller trial in which perhaps about 50 patients. And we again be monitoring bleeding frequency and show a decrease in the number of bleeds in these patients as a consequence of delivery of ALN-AT3. And of course again as Dr. Kessler mentioned we recognized that there is other opportunities in the rare bleeding disorder patients and we are staring to really understand that better.
So finally in summary, I hope you appreciate that we are incredibly enthusiastic about this program and ALN-AT3 as a subcu delivery strategy for retrieving the hemophilia patients and as I think you appreciate these hemophilia patients including inhibitor patients can really be significantly helped by this strategy. I’ve shown you that weekly subcu dosing leads to robust and specific knockdown of antithrombin in both mice and non-human primate and I also demonstrated proof points and proof of concept in a couple of different models. Importantly I’ve shown you increases in thrombin generation in hemophilia, mouse model, I’ve shown you hemostatic plug formation in that laser entry model and I’ve also shown you thrombin generation in a non-human primate inhibitor model of hemophilia. I hope I convinced you that we have an enormous therapeutic index in hemophilia patients and we are very aggressively moving forward in this plan to initiate a Phase I study later this year and of course I’ve already articulated our further plans for development of this drug. And with that I’m going to turn it over to Barry for Q&A.
Thanks, Rachel and if anybody interested Rachel will be showing her videos again at break, so stay tuned for that. We’ve got this Q&A, we’ve got microphones coming around; before that I would like to thank all of our speakers for a wonderful job this morning. It’s likely that I’ll repeat your question for the benefit of those listening in via webcast. So Marko?
Marko Kozul - Leerink Swann
So, good morning and congrats on your progress and the release this morning as well. So couple of questions, first a clarification then a question for Dr. Hawkins and a follow-up as well. I think you said you would measure clinical endpoints every six months in the open label expansion. Can you clarify that?
Unidentified Company Speaker
Yes, Marko is asking about the open label expansion study which we plan on initiating following the successful completion of the Phase II. Jared, do you want to take that?
Yes, so our plan is to really look at the key endpoints, secondary endpoints, these clinical endpoints every six months while patients are being dosed on studies so that will give a chance to look at things like neurologic impairment, quality of life, nutritional status by using these measures and looking at that on an every six month basis while these patients are dosed for two years on the expansion study.
Marko Kozul - Leerink Swann
Great. And then a question for Dr. Hawkins given your experience of treating TTR patients and experience with TTR02, do you have an early predictions on how long it will take for TTR knockdown substantially translate into clinical benefit as measured in the open label expansion?
Unidentified Company Speaker
Well as soon as TTR production is knocked down, amyloid formation will be inhibited pro rata. So, within a week with TTR serum concentration having fallen by 80% that will be 80% less new amyloid formation that is what we believe. And therefore some benefits will be in terms of the pathogenesis will be fairly immediate, I mean, you know there are several possibilities knocking down TTR by 80% perhaps that worse will reduce progression of the disease by that amount, so patients might live not for five or 10 years but for 30 or 40 years knocked down by 80% maybe enough to change the balance of amyloid deposition versus it’s natural clearance.
So that's an 80% knockdown we will see gradual regression of amyloid over the next one to two years, I mean what we don't know is the power of regeneration of amyloidosis nerves or heart. So you know we may simply see halting of disease or slowing of progression or gradual recovery and it would seem that from liver transplantation in TTR Met30, there is some potential for recovery of autonomic and peripheral never function albeit we don’t see that in every patient and it may be quite slow.
Unidentified Company Speaker
As you heard from the discussion that Jared had that our belief is that in the Phase III study is that somewhere between 150 and 200 patients measuring the neuropathy indicators for the NIS scores in 12 to 18 months provides proof of clinical benefit and clearly the longer we treat patients up chronically the more we hope that the disease not only stabilize but progresses. Importantly for these patients as (inaudible) highlighted this, it’s important that these patients stay ambulatory so they stay out of their wheelchairs, out of their beds and be prolonged life.
Unidentified Company Speaker
And so the follow-up question is on the last point. Can you talk about the type of patients who are Phase III TTR02 study that you consider enrolling in terms of mutational status after they are reached?
Unidentified Company Speaker
Yes, so Marko was asking about the potential inclusion criteria in the Phase III study, do you want to take that Jared?
Sure, yes I think we want to be able to use this drug in a real world setting and not just for patients with very early disease or just with the 30Met mutation which is really what tafamidis is approved for, but really to extend the benefit we hope of this treatment to a broad spectrum of disease severity and really across all different mutations. So, I think as we are thinking about the eligibility criteria for this study we are thinking of being more inclusive than exclusive and really trying to include patients with both Stage 1 and Stage 2 disease and really look at the entire broad spectrum, include the broad spectrum of different TTR genotypes that you see in FAP.
Unidentified Company Speaker
Great. Thank you. Question up.
(inaudible) here: Few questions sorry, one, I have the math study still ongoing but just curious on your initial follow up and Dosing Frequency with the Subcu and kind of that what gauge needle you might think about that, just putting that in context for us? And the second one for Dr. Hawkins, -- just want to talk a little more about how we find these back patients, in this really kind of block –(inaudible) improve them and how you kind of figure out how like once you have a therapy perhaps will they - how do you get these people to be diagnosed?
Unidentified Company Speaker
And so the first question from (Alicia) is about TTR subcu question is about frequency of dosing and how we imagine the subcu injection working and the second question is about how we bring patients in for the treatment that Dr. Hawkins can answer. Jared, do you want to take the first one?
Yes in terms of the subcutaneous injection that we use a small gauge needle which really results in very little discomfort for the patients when they are receiving the injections. And as I showed our current dosing schedule is to give five daily doses for the first week and then weekly dosing thereafter. So, we anticipate bringing that same sort of regimen into our more advanced trials for Phase II and Phase III, but really patients will for the vast majority of the time that they are receiving the drug will be giving themselves essentially one injection once a week or [chronically].
Unidentified Company Speaker
And Philip if you want to talk about, the question was around with the therapy like this how would you imagine reaching out to patients and bringing patients into a new therapeutic approach?
Well, I mean, I don't think there would be any difficulty in patients who are diagnosed with the disease (inaudible) treatment, I mean terrific disease that you’ve seen, I’m not sure what your question is I mean are you asking how we are getting to identify undiagnosed patients.
Yes to some degree, it seems like the FAC status can be a little tricky to find instead of the basal mutation and if you don't have therapies available like how do you find them I mean generally seems like a late stage they present with heart failure, but you know how do you kind of step in front of that and then you are talking a little about the imaging, the new imaging technique, kind of elaborate on that in general?
Unidentified Company Speaker
Yes, well, let’s break this down into FAP and FAC. So FAP most patients have got and also some have dominant family history, they will have, they will know about other members of that family with neurological, progressive neurological disease, many of whom have been misdiagnosed in previous generation. I think neurologists see patients with peripheral neuropathy, there are almost no treatable causes of neuropathy and I think as soon as a treatment out there you know genetic testing for FAP will become far more sort and we are beginning to see that amongst some neurologists who have got awareness of the disease. I think FAC, so these patients with the (inaudible) 1 to 2 mutation they present with cardiac failure beyond about age 60, I mean that has been a difficult disease to diagnose as the genetic marker in black Africa are in-patients, but of course there are people with wild type normal PCR who present the same, with the same syndrome who don't have a genetic marker. And I think there has been potentially very large under diagnosis for late onset transthyretin amyloid cardiomyopathy because the most, that most patients have been getting investigation wise so far is echocardiography which simply shows a thick-walled heart that is pumping well but not relaxing and this often or generally mistaken for hypertensive left ventricular hypertrophy.
But the thing that is changing diagnosis is firstly cardiac MRI which is - which shows a very characteristic pattern of abnormalities in cardiac amyloidosis. And the vast majority of patients who have been diagnosed with FAC or wild-type TTR amyloid cardiomyopathy during the past year or two has been on the basis of cardiac MRI. So cardiac MRI will show the presence, will throw up the diagnosis of cardiac amyloid. We and others are also working on a nuclear medicine imaging method using a bone scan tracer that is essentially no longer used called DPD technician, technician DPD which the reasons we don't understand localizes amazingly sensibly and fairly specifically to cardiac TTR amyloid deposits and indeed I think that method which is cheap every single hospital in the country has a gamma camera, I think we will see re-purposing of this DPD tracer as almost a screening test to pull out cardiac TTR amyloid and we are about to perform a kind of screening study to look at that.
Unidentified Company Speaker
Thank you. The other thing I would add and we’ve seen this with other diseases is clearly when there is a safe and effective and far more economically appropriate treatment, there are tremendous incentives to improve diagnosis and get diagnosis out much more broadly and that’s our intention here. Are there questions?
Hi, thank you. I have a couple of questions. First one is what do you think the consequences are increasing normal TTR and have you had any advent thyroid abnormalities or...
Unidentified Company Speaker
Yes, well the question is what are the consequences, the target consequences of TTR knockdown and not only were decreasing the mutinous we explained but also wild-type. Jared, do you want to take that?
So we know that the normal function of TTR in humans is primarily to bind retinol binding protein which transports Vitamin A. In humans its role in transporting thyroxine is actually very minor, most thyroxine is transported by thyroxine binding globule in humans and we have actually seen in knockout mice that completely lack TTR that they do not have thyroid abnormalities and they do not develop severe Vitamin A deficiency because there are other methods for transporting and taking up Vitamin A aside from those that depends on retinol binding protein. So our expectation is that reduction of wild-type TTR will be very well tolerated in humans and we’ve also seen in our non-human primate, GLP toxicology study where we had dosed animals for nine months and suppressed TTR to a level, the grade of 90% and that we don't see any thyroid abnormalities in those animals and we don't see any evidence for Vitamin A deficiency.
So, the other question what I had is trickier. What is the kinetics of aggregation if amyloid and kind of the finding at GLP amyloid with this tissue and how does that vary by mutation side, how confident are you that, that is going to wash away, how does it wash away and I need just the whole story of how that work?
Unidentified Company Speaker
So the question is about the kinetics of I guess the mis-folding and the aggregation of the deposition of TTR and how it works. Philip, do you want to address that?
Yes I think we are studying this quite a lot at the moment and there are certain TTR variants that aggregates much more readily in the amyloid fold than in others. But one thing is certain if you haven't got a soluble normal transparency and precursor you can’t make amyloid. And amyloid is an incredibly stable fold, its gradual clearance that I’ve been talking about is not through unfolding it, actually mediated the things by macrophages. So for some reason the body just doesn’t really identify amyloid deposits as being abnormal in the same way as after breaking a bone or having a bleed in muscle, there is abnormal tissue there and the body does recognize that macrophages come in and gobble it up and clear it away. So, the human body just seems to be very ineffective at recognizing the amyloid fibrillar protein as something that's abnormal and needs to be shifted. But there are the clearance does exist and we believe that is through macrophages through a complement-mediated mechanism which just seems to be very inefficient.
Unidentified Company Speaker
Thank you. Are there questions? I can see that fall back.
Good morning. Can you hear me?
Unidentified Company Speaker
Will you please discuss your pharmacoeconomic study plans, design for both TTR and AT3 and what pricing and reimbursement strategies might look like?
Unidentified Company Speaker
Yes, the question is how we think about pharmacoeconomics for the TTR program and the hemophilia program. Jared highlighted in the Phase III maybe he want to comment that we are actively studying key parameters that will help the pharmacoeconomics. Jared, do you want to take that?
Yes, I think that it’s very important that we include assessments that really show how the drug effects, how patient's feel and function and with that in mind we had chosen assessment that in addition to the primary composite neurologic endpoint that we’ve talked about, secondary assessments are also very important looking at quality of life, looking at level of disability, looking at motor function, looking at nutritional status. These are also all deemed very important by regulated it’s very important to the patients themselves and that and these form the basis for the pharmacoeconomic approach to really showing that changes in the degree of neurologic impairment that we achieve with TTR lowering really translated to clinical benefit for the patients that can really transform their life.
Unidentified Company Speaker
Yes just to give you some view into our thought prop process. We spent time not only with the key opinion leaders across these various issues but also payers and providers to understand what in their mind and we plan on studying the parameters that are important so our global value (inaudible) at submission then we show the kind of benefit we’re going to provide at the patients and I said this before but in the case of TTR when these patients are no longer able to care for themselves when they waste and then clearly move on to death that the cost of healthcare system is extreme.
If we can delay that and turn this into a chronic treatment prolonged life for long time on a wheel chair the economic benefits would be pretty clear. If you think about liver transplant which works in small population depending on where you are in the world, we are talking about $150 to $300,000 for the first year and then $50 to $100,000 thereafter. The one approved drug in Europe tafamidis in some countries is priced at about €150 to €200,000, but clearly given the marginal efficacy some other countries like the UK made the decision that, that is not an economic proposition that they want to reimburse. So we are cognizant of all that. On the hemophilia side, again it's very early to talk about specific design but we’ll have criteria in our pivotal design that help us present the value proposition and clearly some of these inhibitor patients are million dollar outpatients. That gives us a very broad pricing window to come within that we can demonstrate economic benefit compared to providers in healthcare system.
Alright, maybe, maybe Dr. Craig Kessler you might want to comment on just some of the cost of managing these patients just to provide some context in terms of the hemophilia setting?
I think that the way I envision the antithrombin modulation I look at this as being more of a prophylaxis treatment than treatment for an acute bleed. So if you can change the phenotypic character of all of your severe patients, you actually end up saving considerable amount of money downstream. If you have joint disease for instance that impacts the ability of the individual to be employed and impact his productivity and quite truthfully the treatment of those individuals is extremely high not only because of product replacement needs, but also for ancillary medical needs. So, if you can present the bleeds upfront then that makes a big difference. Remember hemophilia is a bleeding disorder that occurs at birth. Can you imagine being a parent and trying to perform an intravenous injection of a squirming infant when that infant begins to bleed? So the idea that you can provide a different delivery technique which is not currently available with any of the other treatments also adds to the quality of life and will make this kind of therapy much more likely to be adapted and adopted in the developing countries.
Unidentified Company Speaker
Thank you. We have time for one more question before we head out to break. Okay. So we’re going to start the program in about 15 minutes, so please be back at 10:45. Thank you.
If I could ask our speakers to come back up that would be great. Thank you. So thank you. Thanks everybody for coming back. We appreciate it. I hope you all enjoyed your break.
Now, it’s my pleasure to introduce Dr. Robert Desnick, who is at Mount Sinai as Professor of Pediatrics and Genetics and Chief of the division of Medicines and Molecular Genetics. And he is the first Chairman of the Department of Genetics and Genomic Sciences. I think very importantly is to understand Dr. Desnick's background. He really is passionate about finding new drugs for his patients with genetic disorders. He was one of the pioneers in the whole creation of treatment for Fabry’s disease was actually a leader in bringing Fabrazyme to the market.
He has been studying porphyria for 20 years as lab synthesized over five of the heme gene. And he has been very active with the porphyria patients and I think you’ll see the level of enthusiasm and excitement he has in bringing new approaches for porphyria to his patients. So with that, I would like to turn over to Bob.
Thank you very much, Barry. My pleasure to speak with you today. You may know me from LSDs and we’ve developed the treatment for Fabrazyme with Genzyme and we’ve developed now in process of Niemann-Pick therapeutic trials. We started Amicus Therapeutics. So, I had a little bit of background here but what you didn’t know is for the last 40 years, I’d been working on porphyrias as well. And what I’d like to do with you today is to introduce you to the acute porphyrias and in particular talk about their life threatening acute attacks, their liver - primary liver pathogenesis, their estimated prevalence and their unmet therapeutic needs.
So, let me just bring you to the pathway now. Like Dr. Kessler, I’m not going to point out all the little tricks in the pathways and all the steps and so forth. But let me just point out that in the pathway, there are eight enzymes that takes succinyl-coA to heme. And what’s very important that you recognize is that the first enzyme in the pathway ALA-Synthase, ALA-Synthase 1 in the liver, it is under regulation and control of the final product heme; heme controls how much expression, how much miRNA of ALA-Synthase is made. So, this is very key and it’s the target of our therapy for the acute porphyrias.
And the other two points that you should notice are the ALA-Synthase produces ALA and the next enzyme in the pathway produces PBG. And we’re going to focus on those two porphyrin precursors because they are critical to following the effectiveness of knocking down ALAS-1.
So, let me just also point out that in the pathway, there are four acute porphyrias that are shown in yellow. And these porphyrias, three of them are autosomal dominance, acute intermittent porphyria being the most common, hereditary copro and variegate being less common. Each one is a dominant disease. So, you get linear vertical transmission of the disease which is very important because in families you identify one patient, you know the risk of members.
And there is also a very rare autosomal recessive porphyria called ALA Dehydratase deficient porphyria or ADP. That’s a recessive, very rare, dozen patients known.
In all these porphyrias there are common clinical manifestations and that is the life threatening acute neurologic attacks. And there is also which is not fully appreciated but the patients know that there is a neuropathic pain, a chronic neuropathic pain that they have and also a progressive neuropathy. And we’re going to tie that in from studies in the mouse model about how important that might be with controlling the ALA-Synthase.
Now, how are these diseases diagnosed? Well, they are not easy to diagnose because when they have acute attack doctors sometimes don't do the right thing, we got to educate them. They just have to measure the urinary ALA and PBG, it’s simple, not the porphyrins but urinary ALA and PBG. And we can diagnose all patients simply by gene mutation analysis.
Now, what goes on in acute neurologic attacks? First of all, they start after puberty. They are an autonomic neuropathy. The key symptom is the abdominal pain that leads to nausea, vomiting, et cetera. They also have a peripheral neuropathy, which we are going to talk about a little bit, weakness leading to severe attacks, paralysis. They also have mental involvement and the precipitating factors are anything that consumes heme. Heme is depleted in the liver, hepatocyte, turns up ALA-Synthase, to produce ALA and PBG, these are neuro-toxic. And that’s the simple fundamental pathology of the disease.
So, what are heme consuming drugs, all the P450 inducers? They’re heme eating. You induce P450s, they consume heme, [inaudible] [ph] intake. These patients will have an acute attack. And also in woman, the hormonal changes particularly during the luteal phase of menstruation, it can cause an attack and many of these are repeated, who have recurrent monthly attacks. Now, biochemical diagnosis as I pointed out, urinary - elevated urinary ALA or plasma ALA and PBG.
So, let’s turn to the most common acute intermittent porphyria. It’s the most common acute hepatic porphyria. And what you should know right off the bat is many of the gene carriers or heterozygous are asymptomatic unless they have one of these precipitating events. And then they will have an acute attack. And we don’t know what the incidence of the chronic neuropathic pain that they may have, that’s something that has to be further delineated and we’ll talk about that at the moment. We do know there are about 10% to 20% of the AIP heterozygotes are symptomatic and there are three categories of these acute neurologic attacks. There are those patients who have chronic attacks and the porphyria group has sort of defined that as more than four attacks a year and these are both men and women. They can be as frequent as weekly to monthly. And women who – they have these monthly attacks during the luteal phase of their menstrual cycle. There is also the sporadic attacks and these are less than four per year, they occur in men and women and they usually occur with one of the triggering agents, lot of unsafe drugs that they may take that to treat their other symptoms and that will trigger attack.
Then there is a third group which we want to pay a lot of attention to because these are the persistent high ALA and PBG excreters. These are men and women who have high ALA and PBG levels and they may develop the neuropathic pain and the progressive neuropathy, I’m going to tie that in with the mouse model in a moment. So one of the symptoms of an attack, well they have kind of a prodrome and the prodrome will start with maybe some what they call brain fog, they get a little confused, they get fatigued, they have insomnia, and then bingo!, excruciating abdominal pain will hit. They are in the emergency room shortly and they’ll have vomiting, constipation, muscle weakness, tachycardia, mental symptoms, hypertension, hyponatremia. And if untreated they can and severe, they can have convulsions and ultimately [lumbar] [ph] paralysis which has led to death in those patients years ago before there was any treatment.
Now this is a case that I want to show you in fact I’m going to see her tomorrow in clinic, this is a 30 year-old female, she is a lawyer, she is very well educated and has a job that accommodates her, but in 2012 she had 20 attacks, she had 32 days of the current therapy Hematin IV.
In the first three months of the year she had four attacks and seven days of IV Hematin. Tomorrow I will catch up and know what’s happened since. She has a local center that treats her, she is – comes to us for her management, I’ve now got to her on weekly Hematin which has been fairly decent in controlling her attacks, this is going to lead to iron overload. And that’s problem with this disease and it’s one of the reasons that this therapy is problematic. I should point out that the mechanism so let’s understand the liver pathogenesis, about 15% of heme is made in the liver, the other 85% is made in the erythron for hemoglobin. Now I want to call your attention to HMBS. These cylinders that you see here are the amounts of the enzymes, the relative amount of the enzymes in heme biosynthesis so all eight enzymes are shown here. Notice HMBS it’s a thinnest cylinder next to ALAS-1.
Also notice that CPO and the PPOX those are the next smallest cylinders and those are the enzymes for variegate porphyria and hereditary copro-porphyria. So it’s the limits that when they reduce 50% set you up, but if you take a drug or you have your menstrual cycle or whatever you deplete your heme, you turn on your ALAS-1, it up-regulates, makes more RNA and as you are percolating ALA and PBG through the enzymes the small cylinders really are rate limiting and cause a backup of ALA and PBG. So if you look here in normal individuals the ALAS, the glycine and succinyl coA the ALAS and percolating through the pathway to heme, there is a normal hepatic heme regulating heme with feedback repression. This is homeostasis. However in patients who have a 50% reduction of HMB-synthase the enzyme deficient in AIP they are depleted in heme and they end up turning on the ALAS-1 and then you get a large amount of the neurotoxic ALA and PBG and that’s accumulating causing the acute attacks.
And we now know that you can have an increase of the ALA and PBG in clinically latent patients in other words asymptomatic patients but they may have an increase in ALA and PBG not like those who are clinically manifest during an acute attack but it’s – I want to call your attention to that because what we’ve learned from the AIP mouse is that these mice at baseline without inducing the attack which you’re going to hear about in a few minutes because we can use them as a model for target for our ALAS-1 knockdown but these mice have a 1.5 and greater than three-fold ALA and PBG respectively just as they are sitting in the cage. And what they do is they develop a progressive axonal degeneration and this is most likely what’s going on in the patients and in fact in the old literature where they biopsy quadriceps and other muscle and nerves they were able to show that indeed you do see this degeneration and this is probably the cause of these chronic neuropathy, progressive neuropathy that these patients have. This hasn’t been put together only recently and recognized that this is a constant ongoing problem that these patients have and maybe the high excreters and this hasn’t been well studied but we think that most of the high excreters are now the ones who are also having not acute attacks but the chronic pain and progressive neuropathy that takes them into the pain clinics and so forth.
Now what’s the estimated prevalence of AIP for instance, the most common? Well in Sweden we know it’s highly prevalent, it’s more than 1 in 10,000, but these estimates that I’m showing you patients per 100,000 they are really estimates, we don’t really have a proper study, there is no newborn screening, they don’t know what the incidence is. The American Porphyria Foundation which is the only patient advocacy group in the U.S., they have over 4,400 patients registered with “acute porphyria”. Now the ones where they really know which type they have 1,284 with AIP, HCP they have over 360 and VP 160, for a total of over 1,800 known patients, so that’s important, these are documented, and usually to be known you have had an acute attack so you haven’t really on probably other members in the family will all be at risk.
And now I just want to show you we’ve run a diagnostic lab or we do gene analysis so we are just doing gene analysis. And if you look at our results for the last three and a half years we’ve diagnosed new patients over 230 in the U.S. and we are not the only ones who do gene analysis in the U.S. So this is just an indication of the new patients that are out there; this is real data. Let me turn to current and experimental therapies.
Heme replacement, orthotopic liver transplantation kind of heroic, enzyme replacement therapy and I’m only going to say one thing, it was tried, it didn’t work. So it was a whole effort to do that, but just didn’t work so that’s out. And we’ll talk about gene therapy and sort of like Dr. Kessler pointed out we’re all hyped up about the hope of gene therapy but I think we should realize that there are some challenges here in terms of trying to affect a long-term therapeutic benefit.
So let me just talk about what the current therapy is now. Patient has an acute attack, they are admitted to the hospital, we withdraw all the common precipitants, all those things that might have triggered it, but we end up giving them opiates and some patients are on a lot of pain medicine and chlorpromazine to take care of the abdominal symptoms and then we start IV glucose and then in the old days we use to think IV glucose was great because we were waiting for the Hematin to come because usually the hospitals don’t stop that and it takes 24 hours and if that happens on the weekend you’re in deep into an attack by the time you get the hematin ordered. And then you begin the infusions, now these are IV infusions and we know we should start as soon as possible, you end up giving about 4 mg/kg a day for four days and if the PBG doesn’t come down you’re carrying it on for longer time and more severe attack as long as the symptoms persist. And what the hematin does is it knocks down hepatic ALAS because you’re providing more here so it’s turning down the regulation of ALAS.
And now we all agree that IV glucose, don’t start, you start right away with hematin as soon as you can because that’s more effective. Now hematin has been in use for over 30 years it was the first orphan drug. You can see that it’s a reasonable therapy however it’s troublesome because it causes [probitis] [ph], it causes coagulopathy. You usually have to mix it with albumin for it to be stable, it has to come up from the pharmacy in the first 30 minutes of its mix or it loses it stability, its effectiveness. And there have been a lot of reported side effects that it’s the only drug out there and those patients are absolutely dependent on it that’s the unmet need.
They have to go to the hospital to get it so they have to get the admission of multiple days. And also for prophylactic use the FDA has never really - they’ve never approved the use of hematin and that is a crucial unmet need for reoccurring - patients who are having reoccurring attacks.
Now in UK they’ve done a number of liver transplants and this pointed out the pathogenesis of AIP and the acute porphyrias because if they successfully transplanted a unaffected liver they cured the patient, so to speak, now you have the liver transplant and as you can see on the right the ALA and PBG after the transplant came down in 24 hours, these people have not had reoccurring attacks and the domino transplant where they took the patients liver and put it into a patient who wouldn’t normally get a liver but needed one they ended up with the biochemical and critical features of AIP, they have acute attacks.
Of course the challenge is that there is a high frequency of arterial vessel thrombosis, there’s really limited availability of organs and of course with liver transplantation you still have the high mortality and morbidity of the transplant.
Now there are – there is a group that’s working on gene therapy and I can tell you that Dr. Yasuda and I have – we are the first to publish on gene therapy in the AIP mouse. The Spanish group did it after us as you can see from the papers here are and based on the experience in the mouse they’ve gone forward with a [Unicor] [ph] develop a AAV Phase I clinical trial. Now gene therapy first of all is disease specific and if we can treat ALAS-1 directly we can treat all the acute porphyrias, so that’s a benefit.
There are safety concerns, for instance a lot of us have powerful virus antibodies so we’re not even considered as candidates because already we have the antibodies that are problematic for introducing the AAV gene therapy and then there have been some immune responses for the captive in the patients. So this is true in hemophilia as Dr. Kessler would point out and others where they’ve attempted to do this. And once they’ve develop antibodies you can’t re-administer so if you think you can deliver to the liver and you don’t get enough AMU you deliver again, you can’t do it. So also it’s expensive there is only one approved gene therapy in the world today approved by EMA, it cost €1.6 million, €1.3 million upfront and that’s before you even you know that it’s really going to work.
So this would really be limited to patients who have select chronic patients whereas if we have something like sub-Q ALAS-1 siRNA we would have a safe and effective way that we could prophylactically prevent and treat perhaps the progress of neuropathy. So if you want to talk about the ideal next generation therapy it’s got to be convenient; we talked about this is Pan-ethnic, worldwide, it has to have an excellent safety profile and it’s got to have a faster, longer lasting effect for the acute treatment of attacks to minimize the hospitalization; it’d be nice if they could do it at home. And of course we wanted to be not only for the acute attack but we wanted for prophylaxis and for these people who are having reoccurring attacks.
Just two [inaudible] I’m the PI of an NIH funded rare diseases clinical research network program; we brought together in a porphyry consortium the top six experts in the U.S. in fact all six experts in the U.S. and we do clinical trials together and I think this would be a great asset and we’ve already been talking with Alnylam, with the consortium, they’re all eager to recruit patients to clinical trials in the future and they’re all excited about this therapy.
So in conclusion AIP, acute hepatic porphyrias worldwide, attacks, they can be spontaneous or recurrent, they’re life threatening, they have poor quality of life, long hospital stays and they also have this [high] compressive neuropathic pain; the key, the site of pathology is the ALAS-1 and targeting that in the liver has been validated, liver transplant and hematin document the liver pathogenesis, they also point out that these are unmet needs because they’re not of the therapeutic [trace] [ph] and therefore if we had a better safety profile, faster acting and effective prophylaxis we will have a better drug. Thank you.
Thanks Desnick. And good morning again. No movies this time but again this time I am going to take you through some of our pre-clinical data in our porphyria program and I’m also going to give you a little bit of a hint as to how we’re thinking about clinical development for this disease which Dr. Desnick just introduced us to. And so of course I’m really not going to say anything about this because Dr. Desnick did a great job here but I really am going to emphasize the fact that there is a significant unmet need and we recognize that there are patients who are suffering and for whom the heme therapy really is inadequate and it’s that notion that really makes us excited about the idea of developing an siRNA that can target ALAS-1 and really have an impact and change the lives of these patients and of course that’s our goal.
So I’m going to spend a minute here on this slide because it really reflects our therapeutic hypothesis. So if we focus on the top first it’s the schematic representation of how we view this acute attack setting in which you initiate an attack with a significant up regulation of this messenger RNA for ALAS-1 which is sustained and then as the attacks subside you see a decrease in those levels of up regulation and con-commitment with that up regulation of the message as Dr. Desnick illustrated you see an up regulation of these metabolites, these toxic metabolites ALA and PBG which are [inaudible] in a disease. And what we imagine is that we could introduce a siRNA targeting ALAS-1 and very acutely knock down this levels of this message and again reduce the levels very quickly of these metabolites. And we expect, with respect to the clinic, to have an indications of an improvement in the clinical symptoms for these patients and this represents how we think about the treatment setting for the disease as Dr. Desnick pointed out we really want to have a therapy that’s both for treatment and prophylaxis.
So if you focus on the bottom of the slide you can see how we’re thinking about prophylaxis. And on the left hand side of that slide what you can see is how we schematically represents this recurrent attack state in which you get sequential and systematic up regulation and down regulation of this messenger RNA as well as those metabolites. And the goal in this kind of therapy is the prophylaxis, that is chronically suppressed this target messenger RNA or ALAS-1 and as a result of that chronic suppression we’ve blunt any up regulations of metabolites and with respect to the clinic we anticipate that we can reduce the number and the severity of attacks. I’m going to come back and talk about this again when I talk to you about our thoughts on the clinical development path.
And so how do we go about really getting some evidence that this proof-of-concept for this idea that’s targeting ALAS within siRNA will have an impact in disease, and we turn to rodent models and Dr. Desnick already pointed out a mouse model, a knockout mouse model that he’s been using and in collaboration with Dr. Desnick and Makiko we have really explored this mouse model and used an siRNA in an LNP formulation as a way to get the very earliest proof-of-concept for this whole strategy.
There is also a second model which is a rat model in which we can induce porphyria by using siRNAs to target the enzyme PBG deaminase and in so targeting as a consequence of introduction of these phenobarbital we can get up-regulation in these metabolites and again see the porphyria stage and we’ve used that rat model at Alnylam to develop our GalNAc conjugates and I'm going to show you some data in both of these models right now.
And so if we first turn our attention again to the mouse model which we – and these experiments are all done as I said in collaboration with Dr. Desnick’s lab, what you can see in the prophylactic setting, so that is we introduced our siRNA and again this is – these are proof-of-concept experiments and these are one mg per kg doses of an siRNA in an LNP and then we introduced phenobarbital, we up-regulate the system, we up-regulate both the message and those metabolites and we look at the impacts on the graph in the bottom. So if you focus on the left first, what you can see is the expected up-regulation of the target, ALAS, the messenger RNA in the liver and now we can see if you move over to the – and of course upon siRNA treatment you can see a complete blunting of that up-regulation in those two animals.
If you move over to the right and now you look at metabolites both ALA and PBG again you can see the expected up-regulation of those metabolites as a function of inducing the pathway. And then again with this single prophylactic treatment of our siRNA you can see a complete suppression of that up-regulation of the metabolite. And so that’s in the prophylactic setting.
If we now turn to the treatment setting and we ask the same question now you already induced the pathway by introducing phenobarbital and now you ask after inducing the pathway you introduce our ALAS siRNA, can you still have an impact on these metabolites. And what you can see here is for both PBG and ALA as early as 8 hours after the introduction of that siRNA you completely decrease those levels – those up—regulated levels of metabolites and again over time you can see this – the continued separation of those curves as you see that siRNA continuing to suppress ALAS and suppress those metabolites, which will continue to increase in the treated – in the animals that are untreated with our siRNA. And so, we have shown now that in both prophylaxis and treatment, we can have an effect and we would ask the question, how does this compare with the standard of care, which is as Dr. Desnick illustrated IV dosing with heme.
And so in this experiment, we are doing now a comparative study in the treatment paradigm comparing our siRNA treatment as a single IV injection to the standard of care, which is - which is heme and again you up-regulate the pathway by introducing Phenobarbital. You introduce the siRNA and again, what you can see is very quickly with the siRNA treatment you can substantially decrease the level of these metabolites.
And what I’ll point out if you look at those purple boxes is that this heme therapy in this mouse model really has a very, very modest effect. And so this really gives us a sense that this targeting strategy, which is quite novel and directly targets these causal enzymes that starts - that flows through this pathway if we can directly target it with siRNA we can have a significant impact on these toxic metabolites and presume we have significant impact on disease.
Again I’m sure at this point you are not surprised at all when I tell you that of course the drug that we are going to move into the clinic is going to be a GalNAc conjugate and so we are very actively working on the development of an siRNA conjugated to GalNAc that specifically targets ALAS-1 and we are currently in lead optimization. We are applying different chemistries and using in-vitro and in-vivo screens to get at that test molecule.
But in the meantime, we have developed a GalNAc conjugate, which we call our prototype molecule so it’s not a development candidate but it’s a molecule that we can use to evaluate the GalNAc targeting strategies in the context of AIP in a rat model. And of course, I’m going to show you a couple of experiments with that prototype of the GalNAc conjugate. So, again, I’m just going to remind you this is schematic up in the top left, which shows you on slide 128 that you first introduce an siRNA, to PBG deaminase you then deliver our siRNA that targets - GalNAc conjugated siRNA sub-cutaneously that target ALAS-1 and then you up-regulate the pathway again with phenobarbital and you measure the metabolites in the urine and you measure the message in the liver, and as exactly as expected and as I’ve shown you for the previous model, you can see on the bottom left that you can significantly up-regulate the message as you would expect when you induce the system and then you can blunt that up-regulation in a dose-dependent fashion with the introduction of our GalNAc conjugated RNA. And similarly if you move over to the right you can see those toxic metabolites PBG and ALA you can also up-regulate them when you induce the system and again you can significantly blunt that up-regulation in a dose-dependent fashion as you knock down ALAS-1.
Importantly, in another prophylactic study again with this prototype molecule again same induction model what you can see is that very quickly in fact at the earliest time-point we measured which in this experiment is 24 hours you can see a complete blunting of the up-regulation of those metabolites as a function of a single dose of our GalNAc conjugated siRNA delivered subcutaneously. And so these data collectively say to us that we can actually modulate this pathway, we can design an siRNA as we’d expect, we can deliver it either IV or subcutaneously, we can have a very profound effect on the messenger RNA and the subsequent significant effect on those metabolites and we imagine that this is really going to be a good readout for the impact that we’re going to have on the disease in these patients.
And so with that and of course again I’ll remind you based on our enthusiasm which comes out of the positive clinical data that we shared with you this morning about this subcu platform of course we’re excited to think about how we’re going to rapidly advance this program into clinical development. And so I'm – I’ll share with you our early shots which are illustrated here on slide 130. And it start with the Phase I study in the patient population that Dr. Desnick introduced you to and these are patients who are what we call the high excreters; so these are patients that really are asymptomatic but in fact they had elevated levels of these metabolites and what that allows us to do is that it allows us to introduce our subcutaneous ALAS-specific siRNA and monitoring these patients of course in addition to safety in PK we can get an early readout of pharmacodynamic by looking at the modulation levels for these metabolites in these patients who are otherwise relatively normal. And that really set us up to do a Phase II, III study in AIP patients.
And again we imagine this will be quite a small study probably less than 50 patients in which as I described to you we have these patients who get these recurring attacks. And so what we imagined doing is bringing those patients in, studying them, understand the chronicity of those attacks and the levels of metabolites that are associated with those attacks. And then we treat them prophylactically with our siRNA chronically and then we measure with respect to the clinical endpoint we measure the reduction in the frequency as well as the severity of those attacks. And we think we can very rapidly get to a very nice endpoint in the study.
And so with that I'm going to wrap up and say once again that I remain quite enthusiastic about this program, this ALN-AS1 program for the treatment of acute intermittent porphyria. I’ve shown you some proof-of-concepts in a couple of different animal models, rodent model of disease in which we can robustly knock down the target, we can a have a impact on those metabolites and as I just described to you we’re currently working very hard to generate our clinical candidate and we’re on track to nominate that clinical candidate later in this year. We’ve got a plan to file our IND next year and as I –just went through we’ve got some really nice thoughts but a very rapid clinical development path that will get us to proof-of-concept very early in Phase I and then give us some real clinical endpoints in a relatively small Phase II, III trial.
And so with that I think I'm going to turn it over to John.
Thank you Rachel. So I have the challenge of being the last presenter after some fantastic presentations which is always a challenge, but I just want to reiterate what Akshay said at the way beginning and I think you’ve heard at a number of these different presentations of just how excited we are here in terms of the progress that we made at Alnylam. I remember the first analyst day we had many years ago where the company was really just focusing on the promise of our RNA interference and I think what you can see now is that with the advances that we’ve made on the achieving delivery to hepatocytes and the focus that we’ve generated on this Alnylam 5x15 strategy is that we’re really building a great product company and a company that we think in advance some very important and innovative medicines to patients and obviously reward our shareholders in the process of doing that.
So, I have the task of reminding you that the three programs that you heard earlier is not the only thing we’re doing. And just to highlight briefly some of the other efforts that we have going on in the company that really are part of this broader genetic disease strategy that we’re really very excited about at Alnylam and I'm going to go through the programs that are outlined here one focused on hypercholesterolemia our program in complement that we’re quite excited about a program in thalassemia and other iron-overload disorders and then our program on alpha-1 antitrypsin deficiency.
So let me start with PCSK9, and then complement and with PCSK9 obviously I’ll -- I don’t think that target needs any introduction to this audience, it is clearly one of the most compelling targets of molecular medicine today, gain-of-function human mutations associated with hypercholesterolemia, loss-of-function or no human mutations that are associated with improved cardiovascular outcomes in subjects, fantastic science and a fantastic target and we have shown with our RNAi therapeutic using our lipid nanoparticle approach the ability of achieving a robust and significant knockdown of PCSK9 as well as reductions of up to 50% in LDL cholesterol and a Phase I study that we reported early in 2012.
But I think what’s exciting about where we’re going is obviously in the context of this new GalNAc platform. And these are data that we haven’t shown before with our current lead molecules for PCSK9 this is now a subcu delivered small interfering RNA targeting PCSK9 and what you can see is the ability here at dose of one milligram per kilogram deliverable and less than one ml per subcutaneous injection the ability of getting very robust knockdown of PCSK9, these are in non-human primates, and then also achieving significant lowering of LDL cholesterol and this in the absence of concomitant statin therapy.
So our goal for this effort which is partnered with The Medicines Company is to really use this GalNAc conjugate approach to have an sRNA targeting PCSK9 that is going to be competitive in the landscape of the antibodies that are being developed targeting PCSK9 as well, and what is a very substantial commercial and market opportunity.
The next program I want to highlight is a more recently disclosed program at Alnylam focusing on complement. And I'm incredibly excited about this approach because this is not just a genetically validated target namely C5, but it’s actually a clinically validated target because of the data and result that have been generated using eculizumab in clinical studies across a broad range of indications such as PNH, aHUS, amongst others as well.
And what we’ve been able to show here with our GalNAc conjugate approach, so now we have a subcu drug in the setting of C5 mediated - complement-mediated disease, we’ve been able to show 90% knockdown of C5 as well as 90% decrease of hemolytic activity in rats. And that 90% number is quite important because the very nice work that was done and published in the New England Journal by (inaudible) and Et al show clearly that an over 80% decrease of hemolytic activity in patients with PNH was associated with clinical benefit. So this knockdown level is incredibly encouraging as we think about human translation of this approach that we intend to take forward.
And clearly one approach with this drug is the standalone therapy where we would administer this drug and obviously introduce that in the setting of complement-mediated diseases, but the other approach is that this approach by depleting C5 would drastically reduce the dose levels that would be required for eculizumab administration. So one approach is really a standalone therapy but another approach that could be explored here is obviously a strategy that would be useful for sparing the need for frequent intravenous infusions of a drug like eculizumab.
The other two programs that I’ll just comment on in this slide are shown here, our program targeting Tmprss6 for iron-overload disorders that was a very nice review article in the June 13 article – issue of the New England Journal on our results, preclinical results from this program clearly opportunities in thalassemia intermedia but also in other iron-overload diseases. And then finally a program that we’re quite excited about targeting alpha-1 antitrypsin as you know alpha-1 antitrypsin is a loss-of-function mutation as it relates to the lung pathology but it’s actually a gain-of-function mutation as it relates to our liver pathology that exists in these patients and our focus in this program is to knock down the mutant Z allele of alpha-1 antitrypsin as a way of reducing the liver injury that ultimately leads to cirrhosis in patients with alpha-1 antitrypsin deficiency, and that program is also advancing at Alnylam.
So let me just now focus on the path forward and I think clearly what you’ve heard today is a product strategy that is linked to a technical ability at Alnylam of achieving robust knockdown of target genes in the liver and this product strategy is one focusing on genetic of an orphan diseases that we think can build significant value for our company and help us build a great company for the future.
But there is something behind that strategy that I think and I hope is painfully obvious to all of you here today which is number one, we’re focusing in every single case on liver-expressed target genes. Why are we doing that? Because we get great knockdown of genes in the liver, okay. The other point here is that we’re focusing on genes that had been validated in human genetics they are either human gain-of-function mutations or loss-of-function mutations that validate the approach that we’re taking. So what does that do? It takes the biological and clinical risk of what we’re doing asymptotically down to zero as or as close to zero as you can get in drug development. So we’re trying to raise the likelihood that our drugs will work by focusing on these genetically-defined targets. So that’s the first point.
The second point if this has not been clear to you already is that in every single case and every single program that we will take forward we will only take it forward if there is a biomarker in Phase I clinical studies that we can readout, whether it’s TTR levels, whether it’s antithrombin levels or thrombin generation levels, whether it’s levels of ALA and PBG and high excreter AIP patients or whether it’s hemolytic activity levels where we knockdown C5 in patients we could read this out in our first clinical studies. But what does that do for you? Well it increases your likelihood that you’ll get to the right dose quickly. The number one killer of drugs in drug development is pharmacology, getting the dosing wrong, okay. But if we can actually get the dosing right very early in clinical development plus also de-risk the approach that we’re taking, it’s enormously powerful from the standpoint of advancing medicines to patients.
And then finally, and there is no free lunch here, but at the end of the day we want to focus on indications where there is a definable clinical path, where the numbers of patients that we have to fill in our ISS and our ISE of our NDAs is sort of measured in the hundreds of patients as opposed to the thousands or the tens of thousands of patients. And where our approach could be useful in larger populations we’ll partner them, but where our approach can be used in focused population where we can also commercialize our products we’re going to keep those products.
So let’s now reflect on the next several years going forward and, and clearly we’ve given you guidance on our pipeline for 2013 I’ll come back to that in just a minute. Obviously as we think about 2014 we’re going to be well into our Phase III trial with TTR02, we’ll be initiating our Phase III trial with our TTR subcu program in cardiomyopathy. But then reflecting on the next few years I think what’s exciting about where Alnylam is, is that we will be introducing programs into Phase III in our hemophilia program, we will be doing the same in our porphyria effort and in both of those two programs as you can fully appreciate the numbers of patients that are needed for these Phase III trials are relatively small compared to traditional drug development standards. And then with our C5 effort we intend also to move that forward into a Phase I toward the end of next year early ’15 into a Phase II, III trial leading to an approval and we know how quickly drug development in the case of C5 inhibition has taken in other cases.
So we’re excited about where this is going, we’re excited about the trajectory and also our level of confidence that we can actually pull this off based on the data that we’ve generated to date.
Again as I said before, it’s really important as we think about value creation at Alnylam to understand that the clear and undeniable path for building great companies is to ultimately control your drug development efforts, number one, and number two, to retain significant market rights and it is Alnylam’s clear intention for certainly the vast majority of programs that we have in our pipelines to retain North America, South American rights, European rights, others parts of the world and at least for the time being to strategically consider partnering in Japan and Asia as a way of generating some additional leverage and additional funding for our overall efforts, but this is our commercial strategy, we’re building our team to support that, Oved Amitay came from Genzyme, understands the orphan space incredibly well and we will be expanding our capabilities obviously in the future.
So let me now talk quickly with goals, it’s been an exciting first half of the year, it’s going to be an exciting second half of the year as well, a number of important milestones that have been already been discussed, the open label study for TTR2, the Phase III start. We are on track with TTR02; our subcu TTR program will be starting a Phase II in late 2013. The antithrombin program for hemophilia which I’m very excited about, IND filing middle of the year, Phase I start by the end of the year, and then development candidates for both our porphyria program and our complement program by end of the year.
And I think it’s also useful for all of you to understand how news flow might emerge over the next period of time and what’s interesting here with the exception of August which is a time where people might want to take a break or so, in every other month of the year September, October, November, December, we are going to be showing data from a number of these programs and highlighting obviously the important progress that we are continuing to make on advancing RNAi therapeutics to patients.
So with those comments, I really want to thank you for your interest and your attention and we are now going to open it up for additional Q&A. Barry?
Thanks John. And we are committed to getting out of here by noon and I know there is another R&D Day [Unclear] that some of you might go to. But before I go to Q&A, please join me in thanking and applauding the speakers for today. It was really wonderful. Questions?
Marko Kozul - Leerink Swann
Hi, thanks. Just a quick one for Dr. Desnick. If you have AS 1 improved as well as (inaudible) how do you think they’d be used in the clinic?
The question is how do you think AS1 will be used in the clinic?
So, I’m hoping that there is subcu therapy in the future and that proves to be very effective. I think that it will provide the opportunity for those patients who are having acute attack to be effectively treated and rapidly treated, decrease hospital time et cetera. I’m thinking that for many of the patients who are high excreters and developing the chronic neuropathy, the progressive neuropathy that we won’t like to be able to show that perhaps, you know, therapy with those patients whether it’s every two weeks or four weeks or whatever might avoid that. And we have the opportunity to study that in the mouse model to show that we could avoid that and I think - and prevent the chronic [Unclear] degeneration that they have. And if that proves to be effective I think this could be a very effective drug in terms of treating that patient population.
Well, it certainly looks like you have a lot on your plate with liver. But, is there any possibility of using the technology with non-liver areas of disease?
The question is clearly we have demonstrated effective deliverables IV and subcu to hepatocytes and the question, John, maybe you want to take, is, are we exploring delivery of extra hepatically?
So, Walter, it’s a great question. And absolutely, there is no question that over time that there will be approaches that we go beyond the liver with RNAi. But, you know, for the near term, I don’t care. Because we got so much to do and so and there is something wonderful and reproducible and modular, okay, about what we are doing. And so as long as we are hitting on these great genetic validated targets in the liver and being able to generate a pipeline of other important innovative medicines. That can keep us very busy for the foreseeable future. But clearly, we have done work and have looked at other extra hepatic sites of delivery. And there are data that we generated an animal studies, I don’t view them as being ready for prime time, vis-à-vis, clinical development. But, we are – we have got our hand very full as it stands right now.
Understand. Will it make any sense to do spin out?
You want to repeat that John?
Yeah, the question is would it make any sense to do a spin out. I mean I think at the end of the day those can be distracting, those can be difficult to do in a way that really preserves the value for shareholders. And so we are not really contemplating that right now.
Mike, is that you?
Michael King - Rodman & Renshaw, Inc.
Yes, it is me. Thanks for taking the question. There is one major topic that you guys haven't discussed and that's all these call options that you have got with, Takeda, Novartis, Monsanto, et cetera. And I am just wondering if, well two things, one, any speculation about when we might get some visibility because those have been, they have been gestating for a while, and then second is GalNAc perhaps accelerate the possibility of seeing something come out of those collaborations?
Yes, so the question, I will ask John to comment. I might have some further comments, is we have clearly been very successful in multiple partnerships, and the question is, will we see progress from our partners and might that progress accelerate with human data we have seen with GalNAc.
Yes, Mike, I think obviously let’s put Monsanto in a different bucket because it's an ag field. And I think they are actually making great progress, I should say at Monsanto with RNAi based technologies, in fact you know, they are in advanced stages of product advancement from a field standpoint with what they are doing. But as it relates to the therapeutics side of the shop, clearly those partnerships are ongoing, in many cases Novartis has the 31 target programs, they have a very robust effort. They were aware off. I’m hopeful there that they will begin to advance things that we can start seeing as outsiders in terms of the pipeline.
Takeda also has maintained a very robust effort now, clearly there has been changes within Takeda recently as it relates to their overall R&D and we will see how that plays out for them.
But you know, I think in general the pharma companies have been slower to advance these type of medicines, it’s not surprising, we have seen that with biologics as well. And I think obviously the success that we were having and certainly there is a lot of attention and interest with the GalNAc delivery approach I think that's going to help those companies advance as well.
But for us, Mike, those are great call option as you referred to them but for us building value for the company is all on our pipeline and we are advancing on those.
Michael King - Rodman & Renshaw, Inc.
Any other question?
Shaukat Khan - Maxim Group
Hi, John, this is Shaukat from Maxim Group. I have a question with the thing on partnerships, so for PCS with MedCo, are you going, would you be waiting for GalNAc to come up to speed or would you advance with the LNP platform that you already had Phase I data with and also for VSP, where are we with VSP?
Yes. So a little bit more color on where we are with PCSK9 program partnered with The Medicines Company and our liver cancer program ALN VSP which is partnered in China with Ascletis. John, you want to take it?
I will just quickly comment on those. I mean, so for PCSK9 with The Medicines Company, they are very excited about the GalNAc technology, they are very excited about subcu delivery, clearly the antibody space, given the competitive landscape there is important to play in my view. And I think they share this view with the subcu drug.
All the antibodies by the way are not created equal, okay, Amgen’s drug is 6 ml injection, subcu injection. We have heard that Roche is no longer progressing with their program because it is not competitive; Pfizer is limited to IV Infusion at this point in time. So having a subcu drug in the space that can block synthesis of PCSK9 to be very compelling. And we are excited about and so is The Medicines Company.
Now on the liver cancer VSP program that is partnered in China with a company called Ascletis. We are not going to do any more work on it. We are going to wait to see what they generate hepatocellular carcinoma Phase II that they are committed to running. If those data look good, we can decide to advance that program ourselves or we can decide to partner that globally.
We as a company have decided to focus on genetic disease as where we want to go; cancer is a tougher development path not sure we would ourselves want to go down that path. But we can certainly partner that program for the rest of world rights that have not been granted to Ascletis.
Shaukat Khan - Maxim Group
Alethia Young - Deutsche Bank Securities Inc.
Just on your big picture question, are you [inaudible] with the 5x15, [inaudible] more than five. But are you guys at a critical mass right now or should we expect over the next 12 months for announcements of program or are we kind of there?
So the question is, I think John put up the that slide that showed possibly 5 or 6 Phase IIIs in the next few years and clearly commercial after that. Is that it or there’s more to come, John?
I’m not sure that was the tone of the question, but there is a lot more to come. We know there is a huge amount – I mean first of all if you had to target any tissue in the body for developing new medicine, the liver is about as good as it gets. And there is a range of different amyloidotic diseases where targeting other genes in the liver could be quite interesting to us. There is a range of other complement diseases; there is a range of different coagulation factors; iron homeostasis, infection in the liver as well, so there is a broad range of different targets that we can go after where there is very exciting and sufficient levels of validation.
As a company we are very right sized. We are relatively a small company about 140 employees. We are very right sized in our R&D organization, I am sorry, our research organization because we have got the ability of generating more clinical candidates out of that engine as it currently is staffed for the foreseeable future. And there will be growth there but it will relatively be smaller growth there. Where the more significant growth is occurring right now in the company is in Dr. Vaishnaw’s organization and the development because indeed as we start ramping up with these Phase III trials, Alethia, we are going to be obviously expanding and need to expand the clinical footprint; it’s already a very robust organization and staffed with some great people. But we will be adding some people in that dimension.
We also manufacture GNP at Alnylam so we make our TRR02 program and so there is some growth in our manufacturing organization and our quality organization as well. And let’s not forget about Oved and his beginnings of an organization within Alnylam, we’ll obviously be growing on the commercial side as well. So, but we are doing all these very thoughtfully and methodically and we are very focused on being efficient in the use of our capital – in the capital that you entrust us with to build value.
Thanks John, Mike.
Michael King - Rodman & Renshaw, Inc.
Just maybe further to that, but I’m just being curious how you think about TMP strategically because it seems to hit all your desired criteria about an ideal product for Alnylam to retain for its own account as opposed to partners. So what's the – could you just maybe speak specifically about that program, why you are not retaining it and instead preferred to partner?
So question is, there on TMP, how we are thinking about moving it forward or partnering it?
Yes. So, Mike, we agree with you. So, we may well advance our program on our own and the same thing with alpha-1 antitrypsin deficiency. And again think geographically about how we partner that program in ex-US. As you know for thalassemia there is a huge proportion of patients that are in the Southeast Asia, quarter of that would be benefited in our view by having a partner there. But for other parts of the world and also other iron overload diseases we may in fact want to retain full value for that program.
There is a question that came in from people listening on the web and that was, what’s our confidence around the biology with porphyria and knocking ALS down and its effect on toxic intermediaries, Bob, you want to talk to that?
Sorry, I didn't hear the question?
What our confidence around the biology of knocking ALS down and its effect on the cause of the disease and toxic intermediaries?
I think the effect on the patient population will be dramatic and to be able to take patients who have chronic pain, recurring attacks, they have terrible quality of life. If we can effectively do this with the subcu this is going to change their whole -- the whole face of this disease. So I think I’m very encouraged by what's going forward and the other colleagues of mine who are in the porphyria consortium are enthusiastic about it as well.
They realized that we have an unmet need here. The current therapies really are not - are rate limiting, I mean, you know in terms of the hematin infusions and the hospitalizations and all the other problems that they have associated with hematin and just being able to get it to places small hospitals in the country they wait and they have progressive pain and progressive symptomology.
I think having subcu particularly if it turns out that the chronic - the neuropathic pain and chronic progressive neuropathy can be treated by let's say two weekly subcu, it got to be something spectacular for these patients. Take them out of all the drugs that they are using now, all the opiates et cetera. I don't consider liver transplantation an approach to this disease, they are just – it’s just not going to happen.
Let me just add one small point to what Dr. Desnick said and that is in addition to our own pharmacology data which strongly supports the idea that down modulating the target has an impact on these toxic metabolites there is also data in the literature that suggest that delivering heme also has that same impact on ALS. And so to the extent that heme works at all, we believe that it is in fact working through that same mechanism of regulating ALS. And so that gives us some comfort and the idea that this direct targeting strategy of modulating ALS really will have an impact on [Unclear].
Thank you. Any final questions before we wrap it up? Again, I like to thank the speakers today, phenomenal day. Thank you for your time and attention. And I hope that that everybody has been able to help you understand the enthusiasm, the confidence that we have in turning RNAi into an entirely new class of innovative drugs. Thank you for your time.
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