Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY)
Barclays Global Healthcare Conference Call
March 12, 2013 10:15 am ET
Barry Greene - President & COO
I'm Barry Greene, the President and Chief Operating Officer of Alnylam Pharmaceuticals. And I'll be making some forward-looking statements.
So, I'm thrilled to be here today to provide an update on the amazing progress that Alnylam is making in creating an entirely new class of drugs, based upon RNA interference, RNAi therapeutics. This is now an opportunity to literally challenge any gene in the genome involved in the cause or pathway of disease. And at this point, given the work we've done over the last couple years, we have a clinically validated platform.
In fact, if you think about number of trials we've run, literally over the last two years, we've matched a significant amount of human safety, and PK we've dosed over 575 subjects and patients, over a 100 have been dosed systemically, over 325 doses administered. And in the context of our liver cancer program, we've had multiple patients out over a year and patients out over two years of dosing.
In general, RNAi therapeutics thus far are well-tolerated and we are demonstrating pharmacologically relevant human tissue levels also. So we're getting enough drug to the site of disease, to silence a disease causing gene. We've demonstrated mechanistically that in fact what's happening is being mediated by RNAi. We've done that through a PCR technique called 5'RACE. We've shown in the context of our TTR program clear human proof-of-concept with significant protein suppression and the context of our cholesterol program by targeting PCSK9, we've seen a reduction in LDL, so human clinical efficacy.
Now, given all of the translation we've seen here, our strategy is focused on developing a pipeline of innovative medicines that we call Alnylam 5x15. This is RNAi for genetically defined diseases as core to our strategy and our commitment here is it has five key products in clinical development through 2015, with a near-term focus on TTR-mediated amyloidosis, hemophilia, and our porphyria programs.
Now, very importantly each of the 5x15 programs have characteristics that we think make it strategically ideal for drug development. Our first and foremost we're pursuing diseases of significant unmet need and our approach to those diseases are by knocking down a genetically defined target. If we got the biology right, then we've significantly derisk the clinical efficacy.
We're using our existing delivery platform of each of these programs either IV or SubQ. Each of these programs has a distinct opportunity of giving us Phase I proof-of-concept. We've got clear and rapid development outreach of this program and based upon these significant unmet needs and the kind of impact we believe we can have on the disease, we believe each of these has a significant commercial opportunity.
Now, our commercial strategy, given the high unmet need and the fact that these diseases have a concentrated market access and strong patient efficacy, is to retain ATTR hemophilia, and porphyria, on our own, and commercialize North and South America, Europe, and other territories, while selectively partnering Japan and other Asian markets as we've done with the TTR program.
Now, let me start with Transthyretin-Mediated Amyloidosis or ATTR. This is a significant orphan disease. There is about 50,000 patients worldwide. Its clinical pathology hits in the really the prime of people's lives, 40s, 50s, 60s, with two predominant forms of TTR, a FAP or polyneuropathy and FAC or cardiomyopathy. These patients die within 5 to 15 years of clinical onset and unfortunately have significant comorbidities along the way, peripheral sensorimotor neuropathy, autonomic neuropathy and as I mentioned cardiomyopathy as well as wasting. The unmet need here remains significant. There's liver transplant viable for very small subsection of FAP patients. Pfizer approved the drug tafamidis in Europe, not yet approved in the United States. The unmet need to stop or and reverse disease remains very significant.
Now, TTR is caused by 1 of about a 100 mutations. It's autosomally dominant. It misfolds and it forms amyloid deposits in nerves, heart, gut, and other tissues. Now unfortunately and we know this through liver transplant, wild type continues to accumulate amyloid plaques. So therefore we're knocking down all forms of TTR, wild type of mutation.
Now, we've got significant confidence that Transthyretin knockdown are below kind of an area under the curve of 50%, 60% will translate to clinical outcome. We know with other systemic amyloid diseases that with around a 50% reduction of the insulting protein you see disease improvement or stabilization.
We know as I mentioned with liver transplant when you're eliminating the mutant TTR following liver transplant in the right patient selection early stage-1 polyneuropathy patients that we do see disease improvement and stabilization, and then later on we know that the mutant form of the protein is removed from peripheral tissue.
As I mentioned, tafamidis approved in Europe, which is a TTR stabilizer, show disease stabilization using a neuropathy score of the lower limb and we have animal model data with a transgenic mouse model showing that we've complete amyloid regression when we knock TTR down. I'll show some of those data.
So, let me start with ALN-TTR02. This is our approach to pursue polyneuropathy. This is an IV delivery. We've orphan drug status in the U.S. and Europe. We've seen positive clinical results in a Phase I study. We're planning on presenting data midyear on our ongoing Phase II study. With that Phase II study being complete, our plan is to initiate and open-label Phase II extension study midyear and our goal is to be in Phase III in FAP at the end of 2013, end of this year.
Now, the Phase I data that we presented last year were quite dramatic. We showed in randomized, placebo-controlled, single-blind, single-dose escalation study in healthy volunteers, up to 94% TTR knockdown at nadir and a 77% knockdown sustained as you can see out through about a month. The RNAi mechanism was confirmed by using that 5'RACE analysis and you can see that we've knockdown a dose dependent traction at doses as low as 0.15 mg/kg.
Now, when we presented these data we also shared our safety and tolerability, you see drug and placebo about the same with the exception of one infusion reaction, which we anticipate based upon the lipid part of delivery. We're very safe and well tolerated profile no real difference between drug levels or drug and placebo. So this is the kind of profile that we hope to also have in our Phase II study. The Phase II is an open-label multi-centre, multi-dose escalation study around 20 FAP patients that will receive two doses. The primary objective safety and tolerability, and as we can with the circulating biomarker measure TTR levels both wild-type and mutant. The study was initiated mid last year, and as I mentioned already we're planning having data mid-2013, and then in open-label excessive study starting midyear.
Now, we presented the data last year we commented that we would run a non-human primate study. So the first three doses of that non-human primates are represented here. You can see that through each of the doses you see a significant TTR knockdown that sustained through that 28 day level and then upon re-administration in these non-human primates you see subsequent reduction, slightly better reduction in fact at second and third doses. Now, this is significant because as we've demonstrated previously our non-human primate at a mean procured level is predictive of what we've seen in human. So these are the kind of data at two doses that we're hope for seeing in our Phase II study.
Now, let me turn to ALN-TTRsc or SubQ. This is our approach to go after the FAC opportunity about 40,000 of these patients worldwide. This utilizes our subcutaneous delivery. We completed the GLP tox studies confirming a very broad therapeutic index. We saw a no liver enzyme elevation, no injection site reactions. Our plan is to start Phase I very shortly and to present mid this year. We're also this year going to start a pilot Phase II study with a goal of being in a cardiomyopathy Phase III study in 2014.
Now, with our programs we've also amassed a significant amount of data mouse, rat and non-human primate, the non-human primate data are represented here, you can see that with our SubQ administration of ALN-TTRsc we've robust and sustained TTR suppression. Around 80% suppression at doses as low as 2.5 mg/kg, our nadir knockdown here at about day 14, and then sustained suppression with once a week SubQ, recovery to baseline levels happen over 40 days from last dose. So this is a kind of profile that we're hoping to see in our single and multi dose Phase I study.
Now, I mentioned the Transgenic Mouse Model. This is a model that uses the V30M mutation, which is a polyneuropathy form. These animals are grown for about nine months and the TTR, which is synthesized liver then starts to accumulate in peripheral terbs. In this case CNS, nerve, stomach, and colon, and you can see that with three months of dosing we've complete regression of the TTR deposits in peripheral tissue. So this is exactly what we're trying to do in people.
Commercially, as I mentioned upfront, we see the amyloidosis opportunity as a very robust commercial opportunity. It's an orphan disease with significant unmet need. We've got very attractive profiles of both TTR-02 and TTR SubQ. Value based orphan pricing is supported by pharmacoeconomics, delay or reducing liver transplant, reducing comorbodities and hospitalization, is a concentrated provider base, and active patient community, and then beyond the opportunities I described, expansion into pre-symptomatic patients or systematic senile TTR amyloidosis, which is driven by wild-type TTR, so very robust commercial opportunity for TTR-02 and TTRsc.
As I mentioned upfront, we partnered this program in Asia with arguably one of the best orphan companies in the world Genzyme. They have what we call the JPAC. They call the JPAC for development. With a very attractive mid-teens to mid-20 royalties and thus far they've been a fantastic partner.
Now, let me turn to hemophilia and rare bleeding disorders. I think we all appreciate that hemophilia continues to represent a significant unmet need. Hemophilias as male dominated, recessive monogenic bleeding disorders. Hemophilia A is due to the loss of function with Factor VIII. Hemophilia B is driven by the loss of function of Factor IX. About a third of the most severe hemophilia patients developed inhibitor antibodies. These are patients that replacement factor no longer becomes viable, because the antibody rejects them. These patients represent one of the biggest unmet need. They've over 6 bleeds per year, over 5 in-hospital days per year, about $3000 per year on average cost and significant unmet need. We also have about a 1000 rare bleeding disorder patients represented by factors II, V, VII, X, XI.
Additionally, there are severe on-demand patients that we can look at as well here. Sort of the fast task to market opportunity. What we're doing is targeting Antithrombin or AT-3, a genetically defined target, which defines a key natural anticoagulant pathway. It inactivates Factor Xa and thrombin and attenuates thrombin generation. Now importantly human antithrombin deficiency is associated with increased thrombin generation and we also know that coinheritance of other thrombophilic traits, and hemophilia represent a milder disease phenotype. So, what we're doing is we're really taking the break off, allowing thrombin generation to be made, so that we can produce Fibrinogen and Fibrin therefore forming stopping to bleeds. It's a very novel different approach to hemophilia that that does not involve a replacement factor. And importantly, we can pursue this with a subcutaneous administration, which also very unique in the world of hemophilia. As you know, almost all drugs are administered once, twice, or three times a week even with IV infusion.
Now, thus far, we've generated some attractive pre-clinical data. ALN-AT3 SubQ administration results in potent and durable antithrombin knockdown. We've seen potent activities in animal models are lower than 0.75 mg/kg. You can see in the upper left that it works in a dose dependent fashion. A message protein in activity, we see that the profile that I've described now many times where sustained dosing remains balancing. The work we've done with collaborators in Hemophilia-B Mice return thrombin generation to normal and we graft that on the right side normalization of thrombin generation in Mice. So again that's what we're trying to do with thrombin generation in people.
In non-human primates, we also saw a very attractive profile at doses as low as 0.5 mg/kg with weekly dosing. And on the right side because the coagulation pathway is so well described, there are good in silico, our computer models that predict percent antithrombin knockdown with fold key chains that's represented by red wine. And we confirm the in silico model in Vevo and non-human primates, which you can see with the Blue Diamond. So, we're very good predictive model now to move into people.
As with our other opportunities we believe that the significant potential for new therapeutic approach here. I mentioned is, it's a differentiate product with SubQ dosing that could literally completely change the landscape for rebalancing the coagulation system. We think there is a fast path to approval by pursuing inhibitor patients or rare bleeding disorders. Given the kind of expences these patients undergo, there is value supported by pharmacoeconomics. There is a well organized patient advocacy group. And again, we see significant opportunity for global expansion.
The third program that we've committed driving forward on our own is a program for Acute Intermittent Porphyria or AIP. This is an ultra rare orphan disease caused by the loss of function mutation in PBG deaminase, a key step in the heme synthesis pathway. There's about 5000 patients and these are patients that are known and identified about 5000 patients with annual attacks in U.S. and Europe, and about 500 patients most of whom are women driven by menses monthly who undergo recurrent attacks, so these women are literally hospitalized every month. These patients are present with acute or recurrent attacks and when they present, they're hospitalized with severe abdominal pain, peripheral and autonomic neuropathy and neuropsychiatric symptoms.
The treatment options right now are limited when they come in and are appropriately diagnosed, they're given glucose and then heme replacement is ordered and then given IV for 4 to 10 days. There is no prophylactic treatment for these patients.
Now, the heme synthesis pathway in the liver is very well described. ALAS-1 is a key rate limiting enzyme in the heme synthesis pathway. So when PBG deaminase is deficient, it results in up regulation of ALAS-1. The up regulation of ALAS-1 causing accumulation of toxic precursors of ALA and PBG. So by silencing ALAS-1, we prevent the toxic in the mirrors from being made in the first place thereby stopping these attacks.
Right now we've seen efficacy in pre-clinical animal models. We plan to presenting those data at the Porphyria Congress in May of this year. Our goal is to have a lead development candidate in 2013 and to be in the clinic next year.
Additionally other 5x15 programs are cholesterol program, which we recently partnered with The Medicines Company. This is a program targeting PCSK9 for the reduction of LDL-C or bad cholesterol. There is about half a million patients with severe hypercholesterolemia that still represented a very large unmet need.
We have a hemoglobinopathies program targeting TMPRSS6. We've seen efficacy in preclinical animal model showing disease modifying effects in a beta cell ischemia a model, this is a program that we intend on partnering to move into Phase I.
And then another program A80 deficiency associated with liver disease, so alpha-1 antitrypsin deficiency is associated with emphysema, also is associated with liver sclerosis so by knocking down alpha-1 antitrypsin, we have an opportunity of stabilizing or reversing the liver sclerosis. This is also a program that we intend on partnering to move into Phase I.
On the PCSK9 program we presented data last year, a very robust knockdown of PCSK9 as well as a reduction in LDL, I talked about that upfront. Not represented on slides, but we also have a subcutaneous form of PCSK9, and we and The Medicines Company plan on moving to Phase II with either the IV or SubQ form of ALN-PCS.
The Medicines Company deal includes both these programs. We received $25 million upfront, up to $180 million of milestone payments, scale double-digit royalties and a phenomenal partner in The Medicines Company to lead and fund development from Phase II through commercialization. They are very committed and enthusiastic about this program.
So I hope that I will be able to share with you is all of our 5x15 program, the genetically defined target expressed in hepatocytes with good genetic validation, a clear unmet need, a very clear Phase I proof-of-concepts seeing knockdown for the drug effects that we’re looking for in Phase I clearly de-risks the rest of the process and for each of these programs we've what we believe are good development approvable endpoints.
Giving us a very attractive profile again the TTR, hemophilia, and porphyria programs we intend on taking forward and commercializing on our own. The other programs are either partnered or will be partnered to move them forward. That’s how we’re managing the portfolio.
Let me wrap up with the financials and then a review of our goals. We last reported financials Q4 with $226 million of cash that exclude the net proceeds from the January falling off and that brought in $174 million. So, the guidance is to end 2013 with over $320 million in cash. What we said when we did the January offering is that the current balance sheet we had in $174 million with sufficient balance sheet to drive both TTR programs through Phase III, drive the hemophilia program into Phase III and drive the porphyria program to human proof concept. So, very attractive profile for us then to move to next leg of commercialization.
From a goals perspective ALN TTR-2 our plan is to have data mid-year, have our extension starting mid-year to launch the Phase III FAP study late this year and importantly to have data from the extensive study in 2014. These data certainly will serve as significantly derisking for the Phase III study.
The TTR SubQ program goal is to start to Phase I soon. We’ll have data mid 2013; we’ll start our pilot Phase II later this year and the goal is 2014 to start a Phase III FAC Study. The hemophilia program, our goal is to file an IND mid this year, to start our Phase I this year and to have data and these are patient data to present in 2014.
And then, finally, the ALN AS1, the porphyria program, pre-clinical proof concept this year, our lead development candidate later this year with the goal being clinic in 2014.
We formed great partnerships with Genzyme last year, The Medicines Company this year. The goal is to form partnerships with ALN-TMP and ALN-ATT start to Phase I, support partner efforts with our other programs ALN-RCO1 and ALN-VSP. And as I mentioned, to end this year the very robust balance sheet that gives us a clear runway to drive these programs through Phase III.
So, I hope I have been able to convey the energy and enthusiasm that I and all of us at Alnylam have created an entirely new class of innovative medicines. Thank you for your attention.
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