Alnylam's CEO Presents at 31st Annual J.P. Morgan Healthcare Conference (Transcript)

Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY)

31st Annual J.P. Morgan Healthcare Conference Transcript

January 9, 2013 11:00 AM ET


John Maraganore - Chief Executive Officer

Barry Greene - President and COO

Akshay Vaishnaw - Chief Medical Officer


Geoff Meacham - J.P. Morgan

Geoff Meacham - J.P. Morgan

Good morning. And welcome to day three of the 31st Annual J.P. Morgan Healthcare Conference. My name is Geoff Meacham. I’m the Biotechnology Analyst here at J.P. Morgan. It’s a pleasure to introduce Alnylam Pharmaceuticals and speaking on behalf of Alnylam is CEO, John Maraganore. John.

John Maraganore

Thanks Geoff and thanks for having us here again this year. It’s always a terrific conference for us. Joining me today on the stage are Barry Greene, our President and Chief Operating Officer and Akshay Vaishnaw, our Chief Medical Officer.

2012 was really an amazing year for Alnylam because it was a year that we showed beyond any doubt that RNA Interference works in man. When we think about 2013, we think it’s going to be a huge year for the company. It’s going to be a year that we advance our programs into Phase III clinical trials, bringing our products closer to patients through the trial process and ultimately to the market.

As a reminder, I’ll be making forward-looking statements during my presentation. I think all of you know that RNA Interference is an important transformative discovery in biology that’s already been very impactful in biomedical research. Our focus at Alynlam since day one has been on harnessing this natural pathway to develop a whole new class of innovative medicines call RNAi therapeutics. And today, we can say that this platform for new medicines is clinically validated.

Indeed as we look at some of the progress that we have made at Alnylam over the last 12 to 24 months and more specifically over the last six to 12 months, we are very excited about the clinical proof points that have been established for this technology and for this field.

We have a growing safety database of human exposure, hundreds of patients that have been treated in clinical studies, as well as patients that have gone out in therapy for over two years. We have molecular data showing proof of mechanism.

But I think most importantly and data that we presented and generated last year were the data in our TTR program where we showed up to 94% knockdown of the disease causing protein and then in our PCSK9 program where we showed up to 50% decrease in LDL cholesterol, unambiguous proof points at RNAi works in men.

So with those data in hand, we continue to execute on our product strategy that we call Alnylam 5x15. This is a strategy to advance five programs into clinical studies by the end of 2015 including in advanced stages of development. And this includes our focus in the near-term on our transthyretin amyloidosis program or hemophilia program, and our program that we disclosed for the first time earlier this week focused on porphyria an ultra-orphan opportunity.

And all of these clinical opportunities and our 5x15 strategy have common themes and the themes include genetically defined targets in diseases where there are significant unmet need and opportunity in our Phase I clinical studies to show knockdown of the disease target, so that we can unambiguously and early demonstrate that our drugs are working and effectively doing what they are supposed to do. And then ultimately and finally, a clear and definable path for development of these programs in advanced stages to get regulatory approval and then to advance to the market.

Now in addition to our 5x15 strategy we also want to be very clear on our commercial strategy as a company and that strategy is that Alnylam will advance on its own, our products, products in TTR, products in hemophilia and in porphyria, and commercialize those products on our room in North America, South America, Europe and other parts of the world.

At the same time to gain leverage in our efforts we will partner programs in Japan and Asia. But very importantly our goal is to keep our core 5x15 programs for Alnylam so that we retain the value of these opportunities as we bring them to the market and to patients.

So let’s go into some of these programs in a little bit more detail and I’ll start with my transthyretin amyloidosis program. This is an autosomal dominant inherited disease that afflicts about 50,000 patients worldwide. There are two predominant clinical manifestations of this disease, one is a polyneuropathy known as FAP and the other is a cardiomyopathy refer to as FAC.

But uniformly this is a progressive debilitating disease that of course ultimately leads to death. The current treatments in this indication are severely limited and there is significant need for new medicines.

The approach the disease is caused by mutations in transthyretin, protein that expressed in the liver and there over a hundred such mutations in the transthyretin protein. And when this protein is mutated it has a propensity to miss-fold and then deposits in a number of tissues, including tissues in the gut, nerve, nervous system and also in the heart. And the deposition of these so-called amyloid deposits in the tissues causes cell damage and ultimately tissue pathology that leads the clinical disease.

The approach that we’re taking at Alnylam is to knockdown both wild-type and mutant TTR because there are genetic data confirming that the objective here should be to block both the wild-type protein and mutant protein.

And I think very importantly there is a clearer and well-established relationship of TTR knockdown with clinical outcomes. This is true in the settings of other systemic amyloidotic diseases, but it’s also true in the setting of TTR amyloidosis, for example the experience with liver transplantation where removing the mutant TTR in the setting of liver transplantation can result in disease stabilization of patients and there are other lines of evidence confirming that TTR knockdown removing that toxic protein can result in clinical benefit.

So the lead effort in this indication is ALN-TTR02. This is an intravenously delivered RNAi therapeutic with orphan drug status in the U.S. and Europe is currently in a Phase II clinical study that will report data in middle of 2013. We’ll open up a Phase II extension study from related to this study in the middle of this year. And then I think very importantly and very excitingly for our company is a fact that we will be starting our Phase III clinical study of ALN-TTR02 in FAP patients by the end of this year.

We were very pleased last year to report the Phase I data in our TTR02 program and they are shown here on this slide. What you can see is that a single dose of drug given to normal human volunteers resulted in dose-dependent knockdown of the transthyretin protein that we can measure in serum samples from these patients -- from these subjects.

And what you can see is that there is a rapid onset of action within days we start seeing decreases of TTR protein level that we reach nadir levels of knockdown at about day 10 and that the effect of that single dose administration is durable and last for weeks after that single administration. These data are very impactful and clearly showed the power of this approach in knocking down this disease causing protein.

We also look at safety and tolerability of the study and we were very pleased to see an equal incidence of any reported adverse events between patients receiving -- subjects receiving placebo or drug.

The only adverse event that we believe is related to drug is a mild infusion reaction that occurred in the patient that was simply modified or monitor -- managed by extending the infusion period for that subject so the subject did continue with therapy, so beautiful results on safety.

So with those data in hand last year we initiated a Phase II study of ALN-TTR02 in patients with FAP. And this is an open-label, multi-center, multi-dose, dose-escalation study where such patients are getting two doses of drug once monthly -- with a once monthly frequency.

And of course, the primary objective here is to confirm safety and tolerability but we are also again looking at clinical activity, looking at the knockdown of serum TTR levels and in this case we’ll be able to look at the knockdown of both wild-type protein but also mutant protein.

Now we have a pretty good idea of what these results will look like and I want to share with you some data from an ongoing six dose non-human primate study where we are giving once monthly intravenous infusions of TTR02 in non-human primate setting and we’re looking here at the results of two doses 0.15 mg per kg and 0.3 mg per kg.

And what you can see is that each dose of drug results in a decrease in levels of TTR reaching nadir levels at the same exact time about 10 days after each dose, okay. And you can also see a cumulative decrease in the nadir levels down to as high as 92% after the third dose has been administered.

So these data clearly show what we will expect from our TTR02 Phase II study that we’ll report in the middle of this year and the reason we have that confidence is that when we plot our human data from the data that we generated last year with non-human primate data. There is a remarkable concordance of the pharmacology of this drug between humans and non-human primates.

And those are data from a prior non-human primate experiment and when we add our latest non-human primate data onto that plot again, we see this remarkable concordance of pharmacology between humans and non-human primates. So we have a predictive ability with this technology based on our non-human primate results. So we’ll look forward to seeing those data in the middle of 2013.

Moving on to our second effort in ATTR, we have a subcutaneously delivered RNAi therapeutic that we’re going to be advancing into the cardiomyopathy indication. We just filed our CTA for this program to start our Phase I study. We will have data from that Phase I study in middle 2013. We will start a pilot Phase II study of TTRsc in the FAC indication by the end of the year and if all goes well we expect to start our Phase III in this program in 2014.

We have quite a bit of preclinical data from this program that I’ll just share with you briefly. These are some data in non-human primates looking at once weekly subcutaneous injection of our drug in the non-human primates setting.

As you can see we get dose-dependent knockdown of TTR, again the disease causing protein and we get a very durable effect after we discontinue drug, it takes weeks for the drug, for the TTR levels to come back to normal.

We’ve also done studies in a disease model of ATTR. This is a mouse model that is transgenic expressing the mutant protein -- mutant human protein in which you can see in the left-hand side is the wonderful ability of achieving knockdown of the disease causing protein in this model.

But then very importantly on the right-hand side you can see the impact of knockdown on tissue deposition of these amyloids and so if you look on the panels top to bottom on the left under this heading control. These are control treated animals and you can see the brown staining related to TTR deposition and then the animals on the right and the tissue sections on the right relate to those animals that have received drug, clearance of the TTR deposits, confirming again that if we shutdown TTR production in the liver we get clearance of these amyloid depositions in the tissue.

When we think about the commercial opportunity for this program, we think it’s quite exciting. We have a transformative approach that really can provide a breakthrough therapy for patients that have a progressive fatal disease.

We have medicines that appear to have very profound pharmacologic effects that should ultimately relate into important clinical outcomes. We believe we have the potential of halting disease progression with our drugs and possibly even having reversal of existing disease in patients.

This is an opportunity where there’s significant need for medicines to improve the overall cost of the management of these patients, so there is pharmacoeconomics support for value based pricing, a very active patient base here and an opportunity for Alnylam to commercialize our products in these indication as our initial commercial setting.

We are very pleased this past October to form an alliance in Japan and Asia and Pacific countries, again consistent with our commercial strategy with Genzyme, the leading company in advancing -- one of the leading company in advancing innovative medicines in orphan diseases.

Again Alnylam is maintaining all rights in Europe, North America, South America and the rest of world. And very importantly we believe this alliance with Genzyme will help us bring these products to patients faster and to these markets sooner.

Let me now turn to our hemophilia and rare bleeding disorder program. This is an opportunity at Alnylam for addressing the significant unmet needs that exist in a broad range of different bleeding disorders, including those defined by hemophilia and the opportunities that that really define the highest unmet need here including inhibitor patients.

These are patients that have antibodies against their factor VIII or against their factor IX. These are patients that cannot receive prophylaxis. They have to suffer through and have bleeds every year and then get treated further for their bleeds, which obviously is a very poor quality of life and obviously at a cost that’s quite significant.

It also includes patients with other rare bleeding disorders defined by congenital deficiencies and other blood coagulation factors, of which of the 14,000 or so patients that exist worldwide, there are thousand of them that have such severe disease that they require routine prophylaxis.

Now, the approach that we’re taking at Alnylam in this setting really comes down to an understanding of the blood coagulation cascade. And if you allow me the ability of giving you an analogy, think of the clotting cascade as a car where the objective of this car is to make more thrombin, all right. And in this system, there are accelerators and there are brakes, okay. The accelerators are things like factor VIII and factor IX. And when things like factor VIII and factor IX are missing in this system, you don’t have the acceleration that’s needed to make enough thrombin, okay.

So the approach that we’re taking at Alnylam is to basically shut down the brake, all right, to allow the endogenous system to make enough thrombin by turning off the brake and allowing thrombin generation to occur. And by allowing thrombin generation to occur, we can establish hemostasis in these patients. In fact, that experiment has been done genetically. There are patients that have hemophilia that have happened to co-inherit thrombophilic mutations and those patients have a much milder clinical phenotype as compared to other hemophilia patients.

Now our drug in this program is ALN-AT3. It’s a subcutaneously administered RNAi therapeutic that targets antithrombin. We’ve shown in a number of preclinical studies the ability of achieving dose-dependent knockdown of antithrombin. We can achieve a consistent knockdown effect by giving weekly subcu doses as shown on the upper right hand side of the slide. But I think most importantly on the bottom of the slide, you see the impact of turning off the brake in the system.

So on the lower right hand side of the slide, as we look at the mouse model of hemophilia, these are mice that have no factor IX in this case. You can see that as compared to wild type controls, mice with hemophilia have lower levels of thrombin generation. They can make thrombin to establish that fibrin clot. But if we treat these mice with ALN-AT3 subcutaneously and we let off the break, we can normalize thrombin generation, essentially restoring these levels back to normal.

Now, we’ve taken all this work that we’ve done in on rodents and now have extended this into non-human primates with data we presented at ASH. And ALN-AT3 in this case shows beautiful pharmacology subcu dosing leading to knockdown, 80%, 90% knockdown of antithrombin levels in non-human primates.

And as we look at the impact of that knockdown on thrombin generation, you can see a beautiful relationship of knockdown level on the X-axis to increase thrombin generation on the Y-axis rights, all right and a very predictable amount of thrombin generation, consistent with computer models that define the coagulation cascade.

Now with this program, we will be filing our IND in mid 2013 and then we’ll be going on to start our Phase I study by the end of the year and report clinical data in 2014. But when we think about the commercial potential here, we think we have a very significant opportunity for a new therapeutic strategy for the management of bleeding disorders, including hemophilia and other rare bleeding disorders.

And I think an important feature of the program that should not go unmentioned is the subcu dosing elements of this. Because all drugs today for the management of bleeding disorders are given by intravenous infusion. So we have an opportunity with subcu dosing of significantly changing the management of these patients and providing them an alternative to something that they don’t have today.

So finally, on our core efforts within Alnylam, I want to highlight a new program that we’ve introduced an ultra-orphan opportunity focused on acute intermittent porphyria. This is a disease that is genetically defined by loss of function mutations in an enzyme that’s involved in heme biosynthesis. There are about 5000 patients that have severe life-threatening attacks every year and there are about 500 patients in the U.S. and Europe that have recurrent attacks.

These recurrent attacks typically occur in women in association with menses because during menstruation there’s a demand on heme biosynthesis. And the demand on heme biosynthesis results in the generation of toxic intermediates by virtue of this mutation that then causes these severe attacks.

So we have an opportunity here of really providing a prophylactic option for these patients. And without getting into the details of the heme biosynthetic pathway, I just want to highlight some key points, which is when you have a loss of function mutation in the enzyme PBG deaminase and you accumulate these toxic precursors called ALA and PBG that’s what defines the disease. Okay.

So what are we doing with RNAi, we’re targeting an enzyme upstream of that mutation an enzyme called ALA-synthase or ALAS1. And we can knockdown that gene in the liver and therefore block the overproduction of these toxic precursors that cause the disease.

So very exciting approach, very exciting program in an ultra-orphan setting, we’re going to present data from this study from this program in middle 2013. We will have a development candidate in hand by the end of the year and we plan on filing our IND in this effort in 2014. And the development of this program will go very fast from Phase I into Phase III clinical studies.

Now, in addition to those efforts, we also have other programs in a 5x15 effort. These include a program targeting PCSK9 for the treatment of severe hypercholesterolemia, a program targeting a gene called Tmprss6 for the treatment of hemoglobinopathies and a program targeting alpha-1 antitrypsin for the treatment of liver disease associated with alpha-1 antitrypsin deficiency.

These are very exciting programs but we’re going to partner these programs for further advancement partnering PCSK9 for advancement into Phase II and targeting -- partnering our TMP and alpha-1 antitrypsin programs for advancement into Phase I. We were very pleased last year to present the clinical data from our PCSK9 program where we show that a single dose of drug, our drug ALN-PCS, which is administered by intravenous infusion results in dose-dependent knockdown of PCSK9.

We also showed that a single dose of drug results in the absence of any statin coadministration of these patient results in up to a 50% decrease of LDL cholesterol, so very impressive pharmacologic data. We’ve also generated a subcu version of this drug and were hopeful that we will partner this program for further advancement into Phase II.

So I want to come back to the overall theme of our 5x15 effort and just highlight something which I think is very important. These programs have a lot of common features, okay. They are all targeting genes that are expressed in the liver. Why are we doing that because we got great delivery of RNAi therapeutics to liver. They are also targeting genes that have been validated in human genetics.

So the overall confidence that by silencing these genes that we can result in clinical outcomes that were interested in is actually quite high in these programs. The other features I want to highlight are illustrated in this slide. And if you go to the third column, I’ll highlight the fact that in every one of these programs, there is a Phase I biomarker that we can read out in our initial clinical studies to give us confidence that we are knocking down the target in establishing the right clinical pharmacology.

And then if you go to the last column on the slide and you look at the types of clinical endpoints that are needed for the ultimate advancement of these products to the market, you can see that there’s a definable path for how these programs get to the market.

So the 5x15 strategy really is an intersection of where RNAi therapeutics have shown wonderful efficacy with targets that are clinically validated and therefore have less clinical risk with opportunities that are very significant for the advancement of important new medicines, okay, and with clinical paths that are definable.

So with some underdevelopment pipeline, today Alnylam has four programs in clinical development in the coming weeks. We’ll be adding TTR subcu and having our fifth program in clinical development and by the end of the year, this will be up to six.

In addition to our 5x15 programs, we also have some legacy programs, our RSV program that is partnered with Cubist as well as our liver cancer program that is partnered with Ascletis. And those programs will continue we hope with those partner-based efforts.

So then in closing, let me just wrap up with our financials and our 2013 goals. We are going to end 2012 with about $225 million in cash and will provide our financial guidance in the next few weeks when we do our annual year-end call.

And then turning to our goals as I said before 2012 was an amazing year for Alnylam. 2013 is going to be a huge year for Alnylam because we’re going at the Phase III. With our TTR02 program, we’ll have Phase II data in mid-2013 and the Phase III start in our FAP study, we’ll start by the end of the year.

In our TTR subcu program starting that study in the weeks to come and then Phase I data in middle of the year with the start of a Phase II study in cardiomyopathy patients by the end of the year leading to a Phase III cardiomyopathy study in 2014, our hemophilia antithrombin program, IND filing middle of 2013, Phase I start by end of the year, clinical data in 2014, our porphyria program data, preclinical data middle of the year, development candidate by the end of the year and then IND filing in 2014, okay.

And now in addition to those pipeline goals, we also aim to form partnerships around programs that we will partner for further advancement. This includes for example our PCSK9 program, a Phase II ready program as well as other programs in our pipeline. And we’ll also support the efforts of our partners that are advancing other clinical assets at Alnylam including our RSV program as well as our liver cancer VSP program.

So with those comments, I’d like to thank you for your attention. We have a breakout at the Yorkshire room. I’m happy to take your questions at that time. This is going to be a very exciting year for Alnylam and look forward to updating you throughout the year. Thank you very much.

Question-and-Answer Session

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