Alnylam Pharmaceuticals Inc (ALNY) 2012 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Fourth Quarter 2012 Earnings Conference Call. (Operator Instructions) As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference for Alnylam. You may begin.

Good afternoon. I'm Cynthia Clayton, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Executive Officer; Barry Greene, President and Chief Operating Officer; Akshay Vaishnaw, Executive Vice President and Chief Medical Officer; and Mike Mason, Vice President of Finance and Treasurer.

For those of you participating via conference call, the slides that we have made available via webcast can also be accessed by going to the Investors page of our website at www.alnylam.com.

During today's call, as outlined in slide 2, John will provide some introductory remarks and provide general context. Akshay will summarize the clinical progress with our Alnylam 5x15 and partner program; Mike will review our financials and guidance; and Barry will provide a brief summary of our business highlights and goals before opening the call for your questions.

Before we begin, and as you can see on slide 3, I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements. I will now turn the call over to John.

Thanks, Cynthia. Welcome, and thanks, everyone, for joining us this afternoon. By all accounts, 2012 was a remarkable year of clinical and business achievement for Alnylam as we lead the development of RNAi therapeutics. Over the last year there were two notable clinical accomplishments that give us tremendous confidence in the continued advancement of our science. Specifically, data from our ALN-TTR02 program demonstrated an up to 94% knockdown of a disease-causing protein, and data from our PCSK9 program showed an up to a 50% decrease in LDL cholesterol. These data serve as unambiguous proof points that RNAi works in man.

In the recent period, we continued to execute on our pipeline efforts by enrolling patients in our Phase 2 trial for TTR02, and filing and obtaining approval for a CTA to initiate a Phase 1 study with ALN-TTRsc, a subcutaneously administered RNAi therapeutic for the treatment of ATTR, the first subcutaneous RNAi therapeutic to ever go into clinical studies.

We also advanced our ALN-AT3 program for hemophilia and rare bleeding disorders with non-human primate data presented at ASH. And we have advanced a new program, ALN-AS1, for the treatment of acute intermittent porphyria, an ultra rare orphan disease.

In aggregate, it has been a tremendously productive and exciting period for the Company. We are executing on a clear product development and commercialization path that we call Alnylam 5x15, where we are advancing RNAi therapeutics toward genetically defined targets for diseases with high unmet need, and where we intend to directly commercialize certain core programs in this effort in major parts of the world.

Our science is working and we have demonstrated robust RNAi effects in man. And we are supporting our business with new alliances with outstanding partners that will work with us in advancing RNAi therapeutics to patients while we also retain key product rights to build maximal value for our shareholders. The year ahead is where we advance programs into late-stage development and toward the market.

So, with those introductory comments, I'll now turn the call over to Akshay for a more detailed review of our clinical activities, our pipeline, and our scientific progress. Akshay?

Akshay Vaishnawˆ Thanks, John, and hello, everyone. As John mentioned, we have had an extremely rewarding and productive year on the clinical front with our Alnylam 5x15 product development and commercialization strategy.

As all of you are aware, ALN-TTR02 is our flagship program that is aimed at the treatment of TTR-mediated amyloidosis, or ATTR. ATTR is a devastating hereditary and fatal disease caused by mutations in the TTR gene. As an orphan disease, ATTR afflicts approximately 50,000 people worldwide and is associated with significant morbidity and a mean life expectancy of just 5 to 15 years from symptom onset.

It is clear that new therapies are needed for the treatment of ATTR, and we believe that our mechanism of action silencing of the disease-causing TTR gene leading to knockdown of the circulating TTR protein, has the potential to generate a profound therapeutic impact.

In mid-2012, we reported positive clinical data from our Phase 1 trial with ALN-TTR02, an intravenously delivered RNAi therapeutic. Results from this study, as shown on slide 8, showed that a single dose of ALN-TTR02 resulted in rapid dose-dependent, durable and specific knockdown of serum TTR levels. The overall results were highly statistically significant with a p-value of less than 0.00001.

Even at doses as low as 0.15 milligram per kilogram, substantial serum TTR suppression was achieved, where a mean 82% reduction was observed at nadir. This was extended at the next dose cohort of 0.3 milligram per kilogram, where we showed an 87% mean TTR knockdown, and then at 0.5 milligram per kilogram, where we showed a 94% level of TTR knockdown.

ALN-TTR02 exhibited a rapid onset of action and a durable response, and we believe this profile supports a once-a-month [or so] dosing regimen going forward, a very compelling profile for a breakthrough therapy in this clinical setting.

ALN-TTR02 was found to be generally safe and well tolerated in this study, consistent with our broader clinical experience of RNAi therapeutics using IV delivery, where we have treated over 100 patients or subjects now, with over 325 doses of drug delivered and for duration of over two years in certain subjects.

In mid-2012, we also initiated a Phase 2 trial with ALN-TTR02. This is an open label, multi-center, multi-dose, dose-escalation trial designed to enroll approximately 20 ATTR subjects. Subjects are being enrolled into cohorts of increasing doses. The primary objectives of the study are to evaluate the safety and tolerability of multiple doses of ALN-TTR02, and to measure clinical activity based on serial measurement of circulating serum TTR levels.

The study is over 50% enrolled, and we expect to report results from this trial in mid-2013, at which time we also plan to enroll patients in an open label extension study. Assuming positive results from this Phase 2 trial, we plan to start a Phase 3 trial for ALN-TTR02 in ATTR patients with polyneuropathy by the end of 2013.

We are also advancing ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR. In this case, our focus will be on the ATTR patients with cardiomyopathy as their primary clinical manifestation.

In late 2012, we filed a clinical trial application, which I am pleased to now report has been accepted by the UK regulatory authority. We expect to begin enrolling in this trial in the coming weeks, and the clinical trial is designed as a randomized, double-blind, placebo-controlled, single-and multi-dose, dose escalation study enrolling up to 40 healthy volunteer subjects.

The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. The secondary objective includes assessment of clinical activity of the drug as measured by serum TTR levels. We expect to report data [media] and upon completion of this trial, start a Phase 2 clinical study of ALN-TTRsc in ATTR patients with cardiomyopathy by the end of 2013. Looking ahead and assuming positive results, we expect to start a pivotal trial for ALN-TTRsc in ATTR cardiomyopathy patients in 2014.

I will now turn to another important program in Alnylam 5x15 initiative, namely, ALN-AT3, an RNAi therapeutic targeting antithrombin for the treatment of hemophilia and rare bleeding disorders. Our preclinical findings to date for this program show that subcutaneous administration of ALN-AT3 results in potent dose dependent and durable silencing of antithrombin in preclinical models, and that antithrombin reduction can normalize thrombin generation in an animal model of hemophilia, establishing proof of concept for this program.

At ASH this past December, we reported on nonhuman primate data for this program, sharing potent knockdown of antithrombin and increases in thrombin generation. We are very excited about the potential for ALN-AT3 in hemophilia and other rare bleeding disorders, and believe these new data support a once-a-week or twice-a-month subcutaneous dosing paradigm, which can be a game-changer for hemophilia patients. This includes hemophilia patients with inhibitors that represent the area of highest unmet need, as well as patients with rare bleeding disorders that have a severe bleeding phenotype.

We have initiated our GLP toxicology studies for this program and expect to file an IND for ALN-AT3 in mid-2013, leading to the start of a Phase 1 trial in late 2013.

Beyond our TTR and AT3 programs, we were pleased earlier this year to designate ALN-AS1 as a new program in our Alnylam 5x15 product strategy. ALN-AS1 is an RNAi therapeutic targeting a aminolevulinate synthase 1, or ALAS-1, for the treatment of acute intermittent porphyria.

ALAP is an ultra rare genetic disease caused by loss of function mutations in porphobilinogen deaminase, or PBGD, an enzyme in the heme biosynthetic pathway. Loss of function mutations in PBGD can result in accumulation of toxic heme precursors. Patients with AIP suffer from acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations. Also, there is an approximately 15% mortality rate. Approximately 5,000 patients in the US and Europe suffer AIP attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks.

Turning to slide 14, ALN-AS1 is a GalNAc conjugated siRNA targeting ALAS-1, a liver-expressed, rate-limiting enzyme upstream of PBGD in the heme biosynthetic pathway. Inhibition of ALAS-1 is known to reduce the accumulation of heme precursors that cause the clinical manifestations of AIP. We are very excited about this new 5x15 program and believe that it has the potential to help patients who currently have very limited options.

We plan to present preclinical data for this program in mid-2013, and expect to identify final development candidate by late 2013, to advance into the clinic in 2014.

Finally, we also made progress in some of our earlier stage 5x15 efforts this year, including ALN-TMP and ALN-AAT. We are pleased with our progress to date with these programs and we plan to [pilot] both of these programs before advancing to a Phase 1 trial. Clearly, we have made tremendous progress with our Alnylam 5x15 programs, and we look forward to continuing to share data and updates from these programs with you in the coming months.

With our recently completed PCSK9 alliance, we will also be sharing more routine updates on these programs as well. And with that, I'd like to now turn the call over to Mike for review of our financials. Mike?

Thanks, Akshay, and good afternoon, everyone. I will be referring to slide 16. We continue to maintain a strong financial profile, ending 2012 with $226.2 million in cash, cash equivalents and fixed income marketable securities. We also improved our cash position in Q1 as a result of a public offering of common stock that we completed in January, generating net proceeds of $174 million, as well as a $25 million upfront payment from our recent Medicines Company Alliance.

With respect to guidance for 2013, we believe we will finish the year with greater than $320 million in cash. This financial profile provides us with a strong balance sheet to build our business mainly through execution on our Alnylam 5x15 product strategy.

Our GAAP revenues for the fourth quarter of 2012 were $8.5 million as compared to $20.5 million in the prior year period. For the full year in 2012, we recognized $66.7 million of GAAP revenue as compared to $82.8 million for the prior year period. As you know, we continue to record the amortization of upfront payments from the strategic alliances we have formed, which account for a significant and recurring portion of our quarterly GAAP revenues.

Regarding the $22.5 million upfront payment from our Q4 Genzyme alliance, we will be fully deferring revenue recognition and not record any GAAP revenues for the time being with this Alliance.

GAAP revenues are expected to decrease significantly during 2013 as compared to 2012, due to the completion of amortization of Roche deferred revenue. This decrease will be partially offset by the expected recognition of our remaining deferred revenue balance of $9.7 million related to our Cubist collaboration, which ended in Q1 '13 after Cubist elected not to opt into further developed ALN-RSV01.

Moving to expenses, R&D expenses were $21.7 million in the fourth quarter of 2012 as compared to $23.4 million in the prior year period. For the full year of 2012, R&D expenses were $86.6 million as compared to $99.3 million for the prior year period. R&D expenses in 2012 decreased as compared to the prior year primarily as a result of lower clinical trial and manufacturing expenses related to our ALN-RSV, ALN-TCS and ALN-VSP programs, partially offset by additional expenses related to the advancement of our ALN-TTR program. Looking ahead, R&D expenses are expected to remain consistent in 2013 when compared to 2012.

G&A expenses were $10.2 million in the fourth quarter of 2012 as compared to $10.7 million for the prior year period. For the full year of 2012, G&A expenses were $44.6 million compared to $38.3 million for the prior year. The increase in G&A expenses as compared to the prior year period is primarily due to higher consulting and professional services expenses related to business activities, primarily legal activities. G&A expenses are expected to decrease significantly during 2013 compared to 2012, due to a lower consulting and professional services expenses, primarily legal activities.

Also included in operating expenses and contributing to the higher net loss for Q4 and full year 2012 is a $65 million charge in connection with the restructuring of our license agreement with Tekmira.

In Q4, Regulus completed an initial public offering and a concurrent private placement. As a result, our percentage ownership in Regulus decreased from approximately 44% to 17%, which resulted in a gain of $16.1 million in other income. Beginning in the fourth quarter, we now account for our investment in Regulus at fair value by adjusting the value to reflect fluctuations in Regulus stock price each reporting period. Our investment in Regulus was valued at approximately $38.7 million at December 31, 2012. In addition, a tax benefit of $10.6 million associated with the increase in value of our investment in Regulus was reported in Q4. This concludes the financial highlights, and I'll now turn the call over to Barry. Barry?

Thanks, Mike. As you've heard this afternoon, we're demonstrating with human clinical data that the RNAi pathway can be harnessed to create high impact, innovative medicines for patients in need of new therapeutic approaches. In addition to the substantial advancements with our pipeline, we have also made tremendous progress in our business development efforts for new collaborations with Genzyme, Monsanto, Ascletis, and most recently, the Medicines Company. These new collaborations have resulted in over $75 million in realized cash payments.

Now, turning to slide 18. In the fourth quarter we formed a strategic alliance with Genzyme to advance our TTR amyloidosis program in Japan and the broader Asian-Pacific region. Genzyme, the industry innovator and leader in bringing orphan drugs to patients in need, will leverage its proven regulatory and commercial capabilities in the Japanese and broader Asian market to advance Alnylam TTR program, which includes both ALN-TTR02 and ALN-TTRsc. Very importantly, Alnylam maintains all other rights consistent with our plans to develop and directly commercialize this potential breakthrough medicine in North and South America, Europe and rest of world.

Under the terms of the agreement, Genzyme has made an upfront cash payment of $22.5 million to Alnylam. In addition, Alnylam is eligible to [receive] certain success-based development milestone totaling $50 million. Furthermore, Genzyme will make tiered royalty payments to Alnylam that are expected to yield an effective rate in the mid-teens to mid-twenties on sales of ALN-TTR in the territories covered by Genzyme. The royalties in this agreement represent a very attractive way for Alnylam to participate in the success of the product in Japan and other Asian countries.

We are very excited to form this alliance with Genzyme, and it's already off to a great start. We are convinced that as a result of this new alliance, ALN-TTR will get to patients in Japan and other Asian-Pacific countries sooner, and that our drug will reach those markets much faster.

Also with our Alnylam 5x15 strategy and as the detail on slide 19, earlier this week we were very pleased to announce that we formed an exclusive global strategic alliance with the Medicines Company to develop and commercialize RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. As you are all aware, cardiovascular disease and in particular coronary artery disease leading to heart attacks remains the leading cause of mortality worldwide. With elevated LDL cholesterol, a major modifiable risk factor.

Now, the key regulator of the LDL receptor, liver expressed PCSK9 is one of the most important and best validated new targets in molecular medicine for the treatment of hypercholesterolemia. We and the Medicines Company intend to collaborate on the continued advancement of ALN-PCS program which includes ALN-PCS02, the IV-administered RNAi therapeutic, which has completed a Phase 1 trial, and ALN-PCSsc, a subcutaneously administered RNAi therapeutic currently in preclinical development.

While funded by the Medicines Company, Alnylam will continue to lead the program for an estimated one to two years to complete certain preclinical and Phase 1 clinical studies. The Medicines Company will then lead and fund development from Phase 2 forward and commercialize the ALN-PCS program, if successful.

Under the terms of the agreement, the Medicines Company will make an upfront cash payment of $25 million to Alnylam. Alnylam will also receive potential development and commercial milestone payments of up to $180 million. Alnylam will be eligible to receive scale double-digit royalties on global product sales of ALN-PCS products.

Overall, the Medicines Company and Alnylam share the objective to get this drug to patients as quickly as possible. We believe an RNAi therapeutic approach could have important advantages as compared to monoclonal antibodies. And if we prove this out in clinical studies, we'll have an opportunity to have the best-in-class drugs in a dynamic, rapidly changing and very large market. We believe this alliance is ideally structured to enable to the realization of that potential opportunity by leveraging our organization's respective strengths. To say the least, a successful outcome here will result in significant value for both parties.

Now, beyond our 5x15 programs, Alnylam has a few legacy programs that are currently partnered. This includes our RSV program partnered with Kyowa Hakko in Japan, a liver cancer program with Ascletis, and our Huntington's program with Medtronic and CHDI.

We announced today that Cubist has elected not to opt in to further development of ALN-RSV01, and the parties have agreed to end the collaboration. As you may recall, we reported Phase 2b data last year from a study of ALN-RSV01 in RSV infected lung transplant patients. The study narrowly missed its primary endpoint but showed encouraging evidence of clinical activity.

Last year, we met with US and European regulatory authorities to discuss the results of the Phase 2b study, and to obtain guidance on potential paths forward for a Phase 3 study design. Based on these discussions, we obtained preliminary guidance on the design of a Phase 3 study that we believe could lead to approval of ALN-RSV01.

Cubist has been a great partner with Alnylam on this effort but has chosen to focus its resources on the many programs in their own pipeline, including three programs in Phase 3 trials. At the same time, Alnylam will remain focused on our 5x15 programs. So, our plans with the RSV program are to find a new partner for the program's advancement into Phase 3. Accordingly, we will update you on this program if and when we identify a new partner.

In closing, as Mike mentioned, we continue to maintain a solid balance sheet and are poised to execute on our goals. Turning to slide 21, we regard our ALN-TTR program -- with respect to that, we expect to present our Phase 2 data with ALN-TTR02 in mid 2013 and begin open label extension study at around the same time. We also plan to begin a Phase 3 pivotal trial in polyneuropathy patients with ALN-TTR02 this year.

On ALN-TTRsc, we plan to begin enrolling subjects in our Phase 1 trial in the next few weeks with data in the middle of the year. And we then expect to do a Phase 2 study in cardiomyopathy patients with ALN-TTRsc in late 2013, leading to the start of a Phase 3 trial in cardiomyopathy patients in 2014.

In our ALN-AT3 program for hemophilia, we intend to file an IND in mid 2013 with a Phase 1 start later this year. And with our ALN-AS1 program for the treatment of AIP, as Akshay described, we plan to present preclinical data in mid-2013, and expect to identify a final development candidate late this year to advance into the clinic in 2014.

Turning to the business side, we'll seek additional partnerships on other Alnylam 5x15 programs while retaining significant rights in major markets of the world for our core programs. Following our successful financing earlier this year, we plan to end the year with greater than $320 in cash.

In summary, we are executing on our goal of driving innovative RNAi therapeutics to patients in need. Alnylam 5x15 defines an exciting path forward for advancing our pipeline, which we believe, in addition to helping patients significantly, will lead to real value creation. We look forward to reporting on our continued progress with you in the coming months. And with that, I'd like to turn the call back over to the operator for your questions. Kate, we'll take questions now. Thank you.

(Operator Instructions) Our first question comes from the line of Ted Tenthoff with Piper Jaffray. Your line is open.

Can you guys hear me okay?

Yes. Yes. Hi, Ted.

Hey, how are you, and congrats on the great success after a really exciting start. Question on ALN-TTRsc, and I want to get a sense on where that program is and really why this is the drug that you're looking to take forward into familial cardiomyopathy? Are there differences specifically between the formulation? I mean, obviously, while ALN-TTR is synthesized in the liver, so is there something that's different between the drugs, or is -- why is it that this is the one that you want to take forward into the larger TTR patient population?

Great question, Ted, and let me start it and Akshay and Barry can chime in as well. You know, we're very committed to developing therapies for ATTR patients and obviously have been involved in this community with these patients for the last, almost three and a half years now, between our TTR01 program and now TTR02, and this new (inaudible) key program. So, we have a very strong commitment to this patient community and to advancing important high impact medicines, and making a difference in these patients' lives.

As part of that overall effort, obviously, TTR02 has shown beautiful data last year. We're now in our Phase 2 study with that. We're looking forward to having data that we report middle of the year with that program and advancing that program into a Phase 3 trial. As you know, Ted, that drug is given by intravenous infusion. It shows a very significant knockdown effect on TTR, which is a pathogenic protein. But at the same time, we have also been interested in developing a subcu version of the drug that would for many patients potentially be preferable than an IV infusion type approach.

And with the advances that we made in our GalNAc conjugate platform, so this is now a chemically-modified, small interfering RNA without any formulation, it's a simple formulation that can be administered subcutaneously, we think we have an opportunity for a new program that would be complementing our IV drug to go after -- to approach the needs of these patients. And that our focus from a developmental standpoint is to really focus on the cardiomyopathy indication with TTRsc, while we're focusing on the polyneuropathy patient population with our IV administered TTR02.

So, you asked at the front part of your question, where is the drug at. Well, great news -- we filed our IND equivalent in the UK late last year. We've just received approval to start our Phase 1 study that's about to start in the next few weeks, and we'll have data from that Phase 1 study in the middle of the year. And those data, I think, are going to be quite important. Not only will they show the knockdown of the disease-causing protein with a subcu delivered RNAi therapeutic, but that same delivery technology is also being used in our hemophilia program, and also in our porphyria program, and potentially in our PCSK9 program. And so that validating event will be quite significant for the broader pipeline activities that Alnylam is undertaking.

So, that is some context and some perspective. Akshay, I don't know if you wanted to -- I was a little bit long-winded there, but anything to add to what I just said?

Akshay Vaishnawˆ You were perfect. You made many important points, John, I agree.

Yes, good. Does that answer your question?

Very helpful, I appreciate it.

Yes.

Our next question comes from the line of Marko Kozul with Leerink Swann. Your line is open.

Hey, good afternoon, and congrats on a terrific 2012.

Thanks, Marko.

I also have a TTRsc FAC question. I was hoping that maybe you could talk a little bit about the literature and what it shows, as well as clinical data, what does it suggest regarding the rationale for why TTRsc should work in the cardiomyopathy patients?

Great. I'm going to have Akshay answer that.

Akshay Vaishnawˆ Hi, Marko. So, familial amyloidotic cardiomyopathy is mediated by both mutant and wild-type TTR. And as John was describing, we have a wonderful opportunity with TTRsc, a subcutaneous, self-administered conjugate, to attack both forms of the protein that cause infiltration of the heart muscle and lead to arrhythmias and heart failure. Now, the form of the disease that is best known, the FAC, is caused by mutations typically in the US. One of the common mutations is valine ti solution mutation at position 122, V122I it's called. And that's very common in the African American population. Sadly, about 4% of African Americans have V122I, and many of them will go on to develop TTR cardiomyopathy in relation to that.

Many of the other mutations, there are about 100 TTR mutations described, can also mediate cardiomyopathy in (inaudible). Another, for example, is this T60A mutation. And so the disease will come on a little bit later than FAP, which tends to come on in the 40s. Cardiomyopathy will tend to come on in late 50s and 60s, but once it comes on with the heart failure and arrhythmia, sadly, mortality is high, and patients will die generally within a two- to four-year period after diagnosis and onset. So, a very serious and devastating disease, and we think that reducing the burden of TTR will have a very significant impact in this disease, as it has done in other amyloidotic cardiomyopathies, where amyloid proteins are deposited in the heart.

Now, there is a second form of TTR cardiomyopathy that is important, and that is mediated by wild-type TTR, so-called senile systemic amyloidosis. And, of course, our drug TTRsc will also be offered to them, because we can reduce wild-type TTR. That is increasingly being recognized in patients starting in their mid-60s onwards, and it too is associated with heart failure and arrhythmias, and it too is also fatal and patients die within a five-year period or so. So, we have a very expansive opportunity here and we hope to really confirm very significant clinical benefit for these patients.

Does that answer your question, Marko?

It does. And if you don't mind, just a quick follow-up. Congrats on obtaining clearance to initiate the Phase 1 TTRsc trial. Can you talk a little bit about your enrollment expectations for the 40 patients you have planned? And then how long would these patients receive exposure to the candidate? Thanks.

Akshay Vaishnawˆ So, Marko, it is exciting. You're absolutely right, we're going to be taking off very shortly with this study, which will encompass both single ascending and multi-ascending dose aspects. The study will be in healthy volunteers, so we expect it to go obviously relatively quickly and smoothly. And if you follow our progress last year with our PCS and TTR02 studies in healthy volunteers, that gives you something of an idea of the time frame in which we're operating in. And our goal is to get some data out by midyear or so this year.

Yes. It will go quickly, Marko.

All right. Thanks for taking the questions.

Our next question comes from the line of Geoff Meacham with JPMorgan. Your line is open.

Hey, guys. This is Anupam in for Geoff. Just a quick question on TTR02 Phase 3, which you guys are going to start at the year end. When you say you start the trial at year end, does that mean you're going to start the sort of activation or are you going to have actual patients enrolled starting by year end? And just talk a little bit about enrollment timelines for that trial.

Sure, Anupam. When we give guidance that we'll start the trial, that means that we've dosed the patient, so that is what we're guiding for the end of the year. And Akshay, you want to comment a little bit about enrollment expectations?

Akshay Vaishnawˆ Yes. The sample size, obviously it's a Phase 3 study, so it will be consistent with that. The tafamidis study that was conducted by FoldRx, and tafamidis then went on to Pfizer, circa 125 patient study, took several years to accrue. We're going to be in that ballpark of 100 to 200 patients, and I think we'll be able to give much more detailed guidance of the accrual period obviously as we get closer and start enrolling.

Great. Thanks for taking our question.

(Operator Instructions) Our next question comes from the line of Alan Carr with Needham & Company. Your line is open.

Hi, guys. It's actually Mark on for Alan. I wanted to -- well, first off, I'm wishing you good luck. I read on the Weather Channel that beginning (inaudible) of all time or something, so be safe.

Yes, that usually means it's going to be a little dusting.

I don't know, they seemed to be calling for Armageddon by you guys, so please be safe over the next 24 to 36 hours. I had a question on, sort of a bigger picture question on nominating programs going forward in the 5x15 strategy. Are you guys expecting one a year going forward? After this, it seems like it's sort of the track we've been on, and we're just wondering if that was the sort of thing we could expect going forward next year?

You know, that's a great question and I'm glad you're asking it. We've got a number of programs that you don't even hear about that are advancing in our research group that always represent opportunities for us to consider putting it into a development cycle or not. And we're excited about the potential. I mean, given our confidence around delivering sRNAs to hepatocytes and knocking down hepatocyte express disease genes, and given the incredible disease burden of human disease that is mediated by liver expressed target genes, we have a lot we can do. And we have a lot that we can consider doing, and evaluate that on a very active basis.

Now, we are going to stay very focused on TTR, AT3 and our prophyria program at least in the near term, because we think those are the programs that we can allocate significant resources to enable advancement for late-stage clinicals, and then into the market, where we're going to control significant portions of the commercialization of those products. And what that does mean is that for some of these earlier efforts that we have, some of them will choose to advance with partners, but some of them we're just going to hold onto for a while and make them part of Alnylam's next wave beyond porphyria, if you will.

And so it is a strategy, it's an active strategy, a portfolio management. It's an active strategy of identifying opportunities that we think create the greatest amount of impact for patients and value for shareholders. Near term focus on the three that I just mentioned, but lots of opportunities beyond that. And having demonstrated with such confidence the ability of achieving target gene knockdown in the liver and doing that increasingly and more reproducibly even with our subcu platform has opened up a lot of opportunities for us that we can execute on in the years to come.

So, no guidance on adding one a year, per se, to development, but there is certainly a lot that we can do. But we're also staying very focused on our lead programs at this point.

Let me just add a little context to that. I obviously agree with everything John said. Two things -- one is that we committed from the very beginning that we want to be a multiple product company, and clearly that's what we're doing. We think there will be more than three that we'll end up with.

And secondly, very importantly, as we have articulated, our business model we think for maximal value creation is to commercialize on our own in North and South America, Europe and other countries, and we'll portfolio manager on that. Because the most important thing is that the TTR program gets the patients, the hemophilia program gets the patients as rapidly as possible. So, as John said, our focus really is getting these products out to patients in the market as quickly as we can.

So, would you say that product to market comes before next candidate?

I think product to market absolutely comes before next candidate. It doesn't mean that next candidates won't potentially emerge in the meantime, but we've got a very sharp focus on getting our products to market. That is mission No. 1 in this company.

Great. Well, thanks very much, guys. Have a good weekend.

Our final question comes from the line of Steve Byrne with Bank of America. Your line is open.

Hi. Can you elaborate on your confidence level in your 50,000 worldwide patient estimate with TTR? And can you comment on whether there are any geographic trends on a per capita basis that favor the prevalence in one region over another?

Yes, that's a great question, Steve. Akshay, you want to handle that?

Akshay Vaishnawˆ Yes. So, in terms of that 50,000 number, one way to approach it is that about 10,000 represent the FAP population, the polyneuropathy population. There is a geographic concentration of those patients around Portugal, Sweden, Japan, Brazil, and the United States. And more recently, as the disease has become even better known, we are identifying large pockets of patients in several European countries, including France, Italy and Germany, Spain, etc., and, of course, this means there are clinical sites there as well to study with.

The FAP number has been complemented by a much larger number for the cardiomyopathy FAC, which is at least 40,000. We think that's a very conservative estimate in part because FAC is heavily driven by this V122I African American mutation we spoke of earlier. And V122I is present in 4% of the African American population, so that's really a much larger number. And even if we assume lack of full penetrance, you know, 40,000 is really a very conservative estimate. That is not accounting for other forms of FAC associated with other minor mutations, like T60A, etc.

And what we're not really accounting for even in the 50,000 number is recently emergence around data suggesting that senile systemic amyloidosis, that's the cardiomyopathy with wild-type TTR is really a very significant burden in older patients. And the experts, if you speak with the cardiologists who are interested in this field believe the numbers there will eclipse anything to do with FAP and FAC. So, that's kind of how we get to this 50,000, which we believe is a conservative estimate for ATTR.

And, Steve, you know, certainly Pfizer's estimated or commented number for the FAP population is similar to our number, and certainly key opinion leaders that we work with agree with the numbers that we have. So, we think that these are reasonable estimates. Obviously, there is no exactness around these type of numbers, but they are obviously very well supported in the literature.

And was Japan an area of particular interest for Genzyme, or was that negotiation really limited by your interest in holding the rest of the world to yourself?

Well, actually both, Steve. You know, we certainly in our negotiations with Genzyme made it very clear that we want to build a Genzyme also, and we want to keep significant parts of the world to commercialize TTR. And so that was important as part of that discussion and they understood it and appreciated and agreed with what that represented. But they are also quite excited about the opportunity in Japan.

You know, the disease is endemic in Japan, and there's without a question, they are the strongest company in advancing and developing and commercializing orphan medicines in Japan. Stronger than any of the nationals in Japan as well. And so they really represent a very powerful partner for us in the setting of our TTR program.

We've had a number of meetings with them since the partnership was formed. We couldn't be more pleased with our colleagues over there in terms of the quality of the people that we're working with and their commitment to helping us get this product into that market and to those patients as fast as possible. So, we are poised to do great things with them in those markets.

Akshay Vaishnawˆ And just to add to that, Japan, of course -- Genzyme is, of course, very knowledgeable about Asia Pacific that we're partnered with them in, and with them we've started identifying pockets of patients, significant numbers of patients in additional Asian countries beyond Japan, including Korea, Taiwan, and other places. So, it's really going to be terrific to work with them in that part of the world.

Okay, very helpful. And just, lastly, your agreement with Monsanto, I was curious, is that strictly an IP license agreement or do you think you will be actively involved in developing some plant-based gene blockers?

Well, it is a license and collaboration agreement, so there is a collaborative aspect of that relationship that is ongoing. But, Steve, we're not proposing or planning ourselves on developing products in the ag market, but we will certainly work with them around specific projects, or are working with them around specific projects where we're using aspects of our technology to enhance their commercial advancement. I mean, they are very active in this field. They're an impressive company, to say the least, and they clearly see the opportunity with RNAi as a natural approach for generating some products in the ag space that could be very important [for our] products.

Very good. Thank you.

Great. Thank you. So -- yes, go ahead, Operator.

My apologies. That concludes our question-and-answer session for today's call. I'd like to turn the call back over to Alnylam for closing remarks.

Great. Thanks, everyone. Obviously, we continue to be very excited about where we're going and obviously, as part of that, advancing our RNAi therapeutics to patients. We're really pleased with the progress we've made in our clinical and business sides of the shop, and we very much look forward to sharing results with you this year. We believe it will be a very exciting year for the Company. Thank you very much and goodnight.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone have a great day.