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Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY)

Deutsche Bank 2012 dbAccess BioFEST

December 3, 2012, 07:50 a.m. ET

Executive

Barry Greene - President and COO

Analyst

Robyn Karnauskas - Deutsche Bank

Robyn Karnauskas - Deutsche Bank

Hey everybody good morning. So, we just want to kick it off. We are happy to have you here Alnylam. I’m Robyn Karnauskas, on the Deutsche Bank Biotech research team here. I’m happy to have here today Alnylam Pharmaceuticals with Barry Greene, COO. And with that maybe we will just kind of start it off. Can you give us an overview, your 5x15 program kind of the key priorities and the timelines on that program and features that you find less emphasis?

Barry Greene

Sure. Thanks for having us. Thanks Robyn, I’d like to thank the organizers of Deutsche Bank for having us here as well. I’m Barry Greene, President and Chief Operating Officer of Alnylam. And it's a pleasure to be here and give you guys an update.

Before I get into 5x15, let me just as a sense of background. Alnylam was founded on the breakthrough science of RNA interference, which is a process in all of ourselves naturally found genes and we are harnessing that natural biology process to silencing disease-causing genes. As you can appreciate because of RNAi we have an opportunity to go after any gene or the genome that is in the causal pathway of disease.

5x15 is really created with the concept in mind that where we can deliver our sRNA which is a molecule that meets RNAi (inaudible). So if we think about silencing genes we are pursuing genes that are expressed in liver hepatocytes that cause disease. 5x15 is strategy to develop innovative management that silencing disease-causing genes and specifically each of the 5x15 program is caused by a genetically defined G target for serious disease and our commitment is to have five programs in clinical trials by 2015. The most advanced program and will cover this more is targeting transthyretin-mediated amyloidosis or TTR gene. It's an orphan disease about 50,000 patients world-wide.

Second program is anti-thrombin or AT3 for the treatment of hemophilia. We also have a hypercholesterolemia program targeting PCSK9. An anemia program targeting the hepcidin pathway and a program targeting (inaudible) for things like the (inaudible).

Robyn Karnauskas - Deutsche Bank

Can just talk about let’s go into like little bit more about, how you can possibly leverage beyond even the 5x15 like, different opportunities this technology like, how does you expand the invitations?

Barry Greene

We are showing that if there is a gene that causes the disease virtually any tissue we can found that, we think our best opportunity to develop near-term clinical and then commercial opportunities is for targets expressed in liver hepatocytes. So, our focus right now from a clinical development and commercial perspective is really liver hepatocytes. We have demonstrated expect the ability to found genes in lung and CNS and other tissues as well. But our focus right now really is 5x15.

Robyn Karnauskas - Deutsche Bank

Okay. Great. So, maybe just we will start end of the TTR program and talk about how many people have this orphan disease globally and it's mix between the two invitations [SAP and SNC].

Barry Greene

Again, ATTR or transthyretin-mediated amyloidosis is a misfolded disorder, it's caused by transthyretin gene which misfolds and causes this gene to form amyloids and those amyloids are deposited in peripheral tissue, nerve, heart and gut. There is two predominant forms of ATTR, FAP or polyneuropathy or FAC cardiomyopathy is about 10,000 FAP patients world-wide and they are endemic in certain areas like Portugal, Sweden, UK, France, United States, Japan, Brazil are big areas. And then cardiomyopathy FAC which again is endemic in certain areas. It's a horrific disease after diagnosis stale in 5 to 15 years. And because the misfolded protein gathers and expressed in a variety of tissues as I mentioned heart, peripheral tissue also gut unfortunately there is horrific co-morbidity, there is pain, people are wheel chair bound, they often can’t ingest food they waste because of the gut deposits. Right now there is a very limited option for these patients and a very small set of SAP FAC patients liver transplant is used so the liver that is manufacturing the misfolded protein is removed and healthy liver is put in. That helps in early stage FAP unfortunately the wild type which continues to get to boost that healthy liver will exacerbate deposits in certain tissues like the heart for example. So, we really won’t use in a small subset of that patient. Another drug by Pfizer (inaudible) was recently approved in Europe not approved in United States we have to run, we got complete response in United States and that’s because it was a small trial that did not hit its primary endpoint and while it worked it should moderate efficacy. So, it really is an area where it's an orphan disease really in need for therapeutic that help stop (inaudible) disease.

Robyn Karnauskas - Deutsche Bank

And so maybe you can talk a little bit more about how your therapy in comparison sort of injection dose sometimes a few methods of dosing it?

Barry Greene

Yes, we have ALN-TTR 2, it uses our second-generation lipid nanoparticle delivery, that’s the delivery that we showed works exquisitely well in our Phase 1 TTR 2 study. A variety of doses between 0.15 milligram per kilogram to 0.5 milligram per kilogram. We had 70 to 94% knockdown of the TTR gene and 7 to 10 days it lasted out 1 to 6 week at 50%. And what we are trying to do with this disease is we are trying to knock that TTR protein down below 50% and kind of keep it by 50%. With systemic amyloidotic diseases it's been well established that you can keep the insulting protein at expression level under 50% that you have an opportunity of stopping or reversing the disease. So, ALN-TTR 2 is once a month IV injection knocks the gene down and keep the genes down with muscle expressions below 50%. We demonstrated that in Phase 1, we are running a Phase 2 trial, right now with some multi-dose Phase 2 trial two doses where we intent to show, what we showed in Phase 1 but knocked down two months in a row with a very good safety and tolerability profile. We have a Phase 3 that we guided it will start in 2013. We also have because it's an orphan disease and there is a variety of patients. We also subcutaneous form of TTR that uses our GalNAc-conjugate which you can imagine might lead to about once a week subcutaneous injection. Also hopefully with that same kind of knockdown. Median 7 to 10 days and suppression CTR below 50% continuously.

Robyn Karnauskas - Deutsche Bank

So, what are the timelines on these subcutaneous ones?

Barry Greene

Yes, so the subcu will have an IND filed later this year with clinical data on our Phase 1 next year.

Robyn Karnauskas - Deutsche Bank

Seem like there is like a real lead even for a subcutaneous, it seems like it would have a fair amount of (inaudible) even from just the single injection.

Barry Greene

We think the IV injection certainly help is orphan disease for sure. Once a month IV injection for patients who have seen their physician on a monthly and have an aggressive and failed disease certainly is not dosing regimen. We do think given orphan nature of the disease and the IV of that once we acquire a patient, we want to be able to help that patient for their lifetime frankly and that’s where subcutaneous will expand and potentially go after other remediated diseases.

Robyn Karnauskas - Deutsche Bank

Okay, can get you a broader reach from technology.

Barry Greene

Yes much broader.

Robyn Karnauskas - Deutsche Bank

And that’s basically probably going to play out in Phase 2 maybe in 2014.

Barry Greene

We haven’t given any formal guidance, the formal for IND filed later this year with a Phase 1 next year and then we will go from there.

Robyn Karnauskas - Deutsche Bank

So, maybe we talk about you are going after the FAP right now, can you go after the cardio side of it or kind of how do you expand it.

Barry Greene

If you think about what’s known right now is about 50,000 patients across FAP and FAC, and our intent is to treat that entire population. There are also because this is an (inaudible) dominant disease and heritable, they are also family members that are pre-symptomatic that we could expand into and then there is another population that is being better understood now that cause the cardiomyopathy which is systemic familial amyloidotic doses caused by the wild type expression also cause the cardiomyopathy and there is many, many more of those patients. SO, our strategy to pursue that entire patient orient, to start where the clinical outcomes are most understood and that’s in the FAC population. One of the things that (inaudible) is very well for us is it use a neuropathy endpoint called (inaudible) neuropathy indicator system of the lower limb. And they showed that they could slow the progress of the disease and that’s what probably got the drug approved in Europe. The United States and the advisory panel confirm that the end point was a clinically meaningful endpoint, daily get approved because they miss that endpoint in a small what the U.S. FDA call uncontrolled or not well controlled trial. So, our status here is to pursue FAC as sort of the fast path to market, very clear known outcome and whether we use this to which is a lower limb score (inaudible) in the process of determining. And then post or in parallel to FAP you can pursue the cardiomyopathy indications where the endpoints are now being established but a little bit less clear.

Robyn Karnauskas - Deutsche Bank

You have kind of going on how what endpoints might be clinically meaningful there.

Barry Greene

There is cardiac imaging endpoints that are being pursued and then the field looking at some biomarkers right now. So, in a year or so, when we initiate an FAC trial we think the endpoints are lot better understood.

Robyn Karnauskas - Deutsche Bank

And so basically the population is like maybe 10, 15% FAC and the rest is FAP, is that correct?

Barry Greene

That’s right. Right now what’s known is well 20% of the population of FAC is the FAP population the rest is FAC.

Robyn Karnauskas - Deutsche Bank

Okay. And so just basically going back to like you are identifying the patients, so can you just walk us through kind of how many patients out really identified in the population as it easily figured out by doctors or what the opportunity was that in the program?

Barry Greene

ATTR is classic orphan disease where the thought leaders believe that the population is actually much broader than the 50,000. The 50,000 are the ones that cross all the investigators databases if you will, they believe that they have identified. So, most of those patients are out there and identified and that’s because they both FAP and FAC because of limitation are fall in endemic areas with specific mutations. So, there is actually pockets of families in Portugal, Pakistan and Sweden, and Brazil, United States areas where it's endemic and they are centers and doses centers and specific trend. The opportunity expand the numbers and certainly there the opportunity to identify mutation is getting less expensive every year as we can diagnose and scan in gnome. So, we think diagnosis we will expand the opportunity. And then certainly education with Pfizer out there promoting (inaudible) and raising awareness not only along whole line of doses community but among cardiologist, gastroenterologist, because of the gut, neurologist that the fact these is caused by (inaudible). We think we will expand that patient population, it will stay in FAP and FAC however.

Robyn Karnauskas - Deutsche Bank

So, what’s the doc feedback being so far and like can you describe the doc community for those population, like how many are there, world-wide?

Barry Greene

In the ATTR area, there is a couple handful of global thought leaders that really are listened to and drive immune therapies. They tend to be from the areas of endemic patient, so they are in Portugal, they are in Japan, Brazil. There was an Alnylam Doses Meeting in May and all 20 of them we had in a room and they were enthusiastic about the opportunity of balancing the TTR gene and keeping it worth 50%. Because in their mind what we are doing with the drug is a chemical liver transplant if you will, instead of an actual liver transplant we are keeping the TTR genes suppressed. The advantage of a drug like ours targeting both mute and wild side is we are suppressing both and what we have known from liver transplant is the manufacturer of wild type, it can exasperate the disease because wild side will continue deposit with these amyloids. So, they are incredibly enthusiastic in recruiting our Phase 2 and are anxious to get the Phase 3 up and running in 2013.

Robyn Karnauskas - Deutsche Bank

So, maybe if you can we will wrap up TTR, if you can walk through again the timeline, so all the program. You have a lot going on in TTR over the next year and a half.

Barry Greene

TTR is incredibly exciting, so we will tart our Phase 3 in 2013 near the end of 2013. We will get clear guidance on the size of the trial at specific endpoint, it's likely to be one of this neuropathy endpoints that I talked about measured out 12 to 18 months. That’s about the right timeframe to see a separation between placebo and drug group. And we will give further guidance once that trial started. With the subcu and we will have data on our Phase 2 mid next year for the TTR for ALN-TTR 2. For ALN-TTR subcu IND this year, Phase 1 next year and then we will provide guidance thereafter.

Robyn Karnauskas - Deutsche Bank

Okay, great. Well, maybe we will move onto hemophilia, so maybe you can kind of talk about how you leverage your technology with kind of what’s going on in the [passive] world.

Barry Greene

Yes, I think we all appreciate that hemophilia remains a challenging leading disorder and well factors exists for AMD and in fact longer lasting factors exist as demonstrated by Biogenetics recent file which is of great manifestation. There is still is a significant unmet need in hemophilia place. There is a group of patient that develop inhibitor antibodies called inhibitor patients where factor no longer works. And what we are doing with ALN 83 is we are targeting (inaudible). And we have demonstrated in hemophilia animal models already that we can sign 83 and cause thrombin generation back to normal, we showed that with collaborators in hemophilia. So, our program is a once a week subcutaneous injection. So, kind of one stick a week if you will, subcutaneous injection. That can be used in conjunction with factors which are given three times a week and maybe now twice or once a week in certain patients or some certain patients are replacement for factor. So, we are excited to have guide that our IND will be filed next year with trial starting next year.

Robyn Karnauskas - Deutsche Bank

And so can you walk us through exactly the population that you plan on targeting within the hemophilia like inhibitor population.

Barry Greene

We are still in the process of clearly delineating what the clinical development plans beyond the Phase 1 looks like. Clearly, we need to get into hemophilia patients in Phase 1 growth shows steady thrombin generation across multiple doses or steady knockdown of thrombin with resulting thrombin generation with kind of once a week subcu dosing. And we will define the clinical developing stand clearly thereafter. We see the areas of biggest unmet need in the inhibitor patient population unmet with (inaudible) and then a number of other bleeding disorders that call upon to the rare bleeding disorder category, where there are no viable factors or easy to obtain factors on the market to our patients. And then after showing inhibitor and their bleeding disorders we can move into other AMD population than kind of back to kids. So, the way we are thinking about it is clinical development plan that gives us sort of faster path to market in a most significant unmet need population and expansion virtually in the any of these patients thereafter.

Robyn Karnauskas - Deutsche Bank

And with this program are you planning on partnering or are you going out alone?

Barry Greene

We should have mentioned with and I did with our TTR program, so the TTR program we did a partnership with Genzyme. It was a partnership that’s called JPAC, Japan and the Asia Pacific region, great partnership clearly Genzyme is the world leader given innovative medicine to an orphan indication. We are incredibly impressed with their Japanese team and their merger with Sanofi went incredibly well in the Asian given the bigger footprint. So, that partnership we got 22.5 million of [fund] we have about 50 million in milestone and the most valuable aspect of the partnership is the royalties. We believe in the products it's a backend loaded deal that gives us mid-teens to mid-20s level. So, upper sales levels in that area we have almost, it's almost like a profit sharing in terms of royalties with Genzyme. So, you asked about affiliate program, as TTR moves forward ad it's successful and we employed capabilities globally in Europe all of North America, South America, it will make most sense for hemophilia if a partnership works with something like Genzyme our partnership. It's unlikely we partner it more broadly than that unless business changes in some way in the future. We certainly have a strong balance sheet that allows to drive TTR to successful Phase 3 in hemophilia improved concept. So, we don't need a partnership to judge the program forward.

Robyn Karnauskas - Deutsche Bank

PCSK9 and what you have seen there I mean I was interesting the first initial data we (inaudible) can you walk us through like how you find developing the drug or partnering it.

Barry Greene

We employed our second generation license and product delivery to target PCS, that’s a hot target particularly among the antibody world. And it's hot target because it's been shown in long longitude genetic studies that low expresses a PCSK9 have a consistently significant lower instance to cardiac event and high expresses are reverse. So, our strategy as we do with RNAi is silence PCSK9. Now potential advantage with our RNAi is that we really human genetics where silencing PCSK9 both outside and inside the cell and we showed in a Phase 1 study with people with high cholesterol who are otherwise healthy at a variety of doses a significant knockdown of PCSK9 and a statistically significant lowering of LDL or bad cholesterol. So, very compelling data with a single dose IV injection.

Robyn Karnauskas - Deutsche Bank

So a combination of antibody and neurotechnology it would be in play?

Barry Greene

Yes for certain patients who really have uncontrolled bad cholesterol and have ridiculous levels of LDL to 300 and 400 that risk of cardiac event any day, the combination is certainly play out. And we also think that our program both the LMP and the subcu has a single agent might be beneficial as well. At the end of the day it will have to be shown in broader population as we are learning from anti-bodies, it looks like outcomes trials outside of (inaudible).

Robyn Karnauskas - Deutsche Bank

So, what’s been the feedback so far with some of the file initial compensations you has a lot of interest in the big pharma space or it's kind of the technology.

Barry Greene

Given the risk we have gone with RNAi and the data we have across PCS, TTR and some of the earlier data, our liver cancer program, patients out over year in fact one women with cancer that resulted in a complete response after two years of therapy, really derisk chronic treatment for the (inaudible). So, we have got great feedback across RNAi and with PCSK9 specifically. We think it's a partnership is out there, there is certainly a very competitive space and with a significant clinical trials going on with (inaudible) other we and partner have to navigate patients population. But we feel good about the opportunity to partner with program.

Robyn Karnauskas - Deutsche Bank

So, what’s the most common question that you are asked and then also unappreciated about your business model going forward and the value that’s in your thought right now.

Barry Greene

Yes, I guess we covered the most common questions, what’s the focus and we like this focus has really turned from tell me about RNAi and will RNAi work. I think the world is event with those who are paying attention. So, this event that RNAi is going to produce product, an important product innovative medicines. We really derisk that with the chronic treatment in VSP and with second generation programs as we have seen with TTR and AT3. So, the question is tell me why TTR is going to be a drug, tell me why hemophilia will be a drug, what’s the treatment look like, what’s the competitive landscape look like and have we gone through that today. I think in terms of the thing is not fully appreciated, it's this significant attention to ALN-TTR2 and the subcu program, and as we talk about our Phase 3 we will be starting in 2013. The hemophilia program is something that a lot of attention does not yet being paid to. And that’s the program either in combination with factors or the single agent later in clinical development really can impact on these inhibitor patients and other rare bleeding disorders, and really presents a significant opportunity to our Alnylam and a significant upside for us.

Robyn Karnauskas - Deutsche Bank

You will have a very exciting 2013 going forward. I really appreciate that.

Barry Greene

Thanks Robyn.

Question-and-Answer Session

[Question-and-answer session not available]

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