Aug 8, 2013
Executives
Cynthia Clayton – Vice President-Investor Relations and Corporate Communications John Maraganore – Chief Executive Officer Jared Gollob – Vice President-Clinical Research Michael Mason – Vice President-Finance and Treasurer Barry Greene – President and Chief Operating Officer Laurence Reid – Senior Vice President and Chief Business Officer
Analysts
Alan Carr – Needham & Company Marko K. Kozul – Leerink Swann LLC Edward A.
Tenthoff – Piper Jaffray, Inc. Mike G.
King – JMP Securities LLC Alethia Young – UBS
Operator
Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss the Second Quarter 2013 Financial Results.
There will be a question-and-answer session to follow. Please be advised that this call is being taped at the Company's request.
I’d now like to turn the call over to the Company.
Cynthia Clayton
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; Jared Gollob, Vice President of Clinical Research; and Mike Mason, Vice President of Finance and Treasurer; Laurence Reid, our Chief Business Officer is also here and available for Q&A.
Akshay Vaishnaw, our Chief Medical Officer could not be with us today due to a well earned vacation. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investors page of our website www.alnylam.com.
During today's call, as outlined in Slide 2, John will provide some introductory remarks and provide general context; Jarold will summarize the clinical progress with our Alnylam 5x15 incentive program; Mike will review our financials and guidance; and Barry will provide a brief review of our upcoming 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 containing 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.
John Maraganore
Thank you, Cynthia. Welcome, and thanks to everyone for joining us this afternoon.
The second quarter and the recent period has been a very exciting time for Alnylam. As we execute on our Alnylam 5x15 product development and commercialization strategy, where we are advancing RNAi therapeutics through genetically defined targets for diseases with high unmet need.
Notably, this has been a very data rich period. We’ve reported positive clinical results for two of our 5x15 programs and positive pre-clinical data for three other 5x15 programs.
First, we’ve reported positive clinical results from our Phase II trial with ALN-TTR02, where we showed an up to 93% knockdown of circulating wild-type and mutant TTR in patients with ATTR disease, and we showed sustained pharmacodynamic effects across the two doses administered. [All accounts] this is a very impressive level of TTR knockdown, that clearly exceeds the reported levels achieved with other gene silencing drugs.
In addition, we reported positive top line results from our Phase I clinical study of ALN-TTRsc, a subcutaneously administered RNAi therapeutic targeting TTR for the treatment of ATTR, with over 80% knockdown of serum TTR and an encouraging safety profile. Importantly, we believe these clinical results for the ALN-TTRsc established human translation for RNAi therapeutics employing our GalNAc-siRNA conjugate delivery platform, with implications for the entirety of our Alnylam 5x15 pre-clinical pipeline, which employs a clinically validated subcutaneous delivery approach.
Since subQ delivery and a wide therapeutic index greatly broadens the opportunities for RNAi therapeutics, we view these results as a game changer for Alnylam. In deed, we see our proprietary GalNAc conjugate platform as the fast forward for execution on our Alnylam 5x15 pipeline and believe that it now represents the best in class approach for knockdown of liver-expressed disease genes across the industry.
In addition to these positive clinical data, we were also pleased to report promising preclinical results, including key proof-of-concept data from three other Alnylam 5x15 programs, including our ALN-AT3 hemophilia program or ALN-AS1 porphyria program and our new Alnylam 5x15 program, namely ALN-CC5, which is an RNAi therapeutic targeting complement component C5 for the treatment of complement mediated diseases. With these recent advances, we believe that we are building a compelling opportunity for shareholder value creation with a modular and reproducible approach for development and ultimately commercialization of innovative medicines for genetically defined diseases.
This modular and reproducible approach, for genetically defined diseases is something which we believe is actually unmatched in the entire biopharmaceutical industry and should position Alnylam as the leading company in the genetic disease space for the future. I’ll now turn the call over to Jared for a more detailed review of our clinical activities, our pipeline and our scientific progress.
Jared?
Jared Gollob
Thanks John and hello every one. As John mentioned, we’ve had an extremely exciting and productive period on the clinical front with our Alnylam 5x15 product strategy and we are very encouraged by the growing clinical activity and safety data from these programs.
I will start with an update on our ALN-TTR02 program. As most of you are aware, ALN-TTR02 is our lead 5x15 program and is aimed at the treatments of TTR-mediated amyloidosis doses or ATTR.
ATTR is a devastating often fatal hereditary orphan disease caused by mutations in the TTR gene affecting approximately 50,000 people worldwide. There are two clinical presentations at ATTR.
These include familial amyloidotic polyneuropathy or FAP which affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy or FAC which affects at least 40,000 worldwide. Of course, many patients also show evidence of mixed nerve and heart involvement.
New therapies are clearly 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 pathogenic TTR protein as the potential to generate a profound therapeutic impact. In the second quarter we reported positive Phase II data for ALN-TTR02.
As shown on slide 8, these interim results show that multiple doses of ALN-TTR02 led to robust knockdown of serum TTR protein levels of up to 93%. These results were highly statistically significant with a p-value of less than 0.001.
Knockdown of TTR was found to be rapid, dose-dependent, and durable, with similar activity observed toward both wild-type and mutant protein. The knockdown effect at the top dose of 0.3 milligram per kilogram was sustained across the two doses given either once every four weeks or once every three weeks.
In addition, ALN-TTR02 was found to be generally safe and well tolerated in this study. We’re just about done with enrollment in this study with about 30 ATTR patients and we plan to present the final data from this Phase II study at the upcoming International Symposium on Familial Amyloidotic Polyneuropathy to be held in Rio de Janeiro, Brazil in November.
In the coming weeks we will be initiating an open-label extension study of ALN-TTR02 for patients treated in our Phase II study. This study will include a number of clinical endpoint measurements including Neuropathy Impairment Score or NIS with initial data to be presented in 2014.
Moreover, we remain on track to start a Phase III pivotal trial for ALN-TTR02 in FAP patients by the end of 2013. We are also advancing ALN-TTRsc, a subcutaneously delivered RNAi therapeutic for the treatment of ATTR.
We began enrollment in our Phase I trail with ALN-TTRsc earlier in the year. This trail was 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 was to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives included assessment of clinical activity of the drug as measured by serum TTR levels.
As you can see on slide 11, at our R&D Day last month we announced positive top line results from this ongoing trial. Specifically we reported robust knockdown of serum TTR of greater than 80% in healthy volunteer subjects.
These results were very much in line with results previously reported in non-human primate. We also reported that ALN-TTRsc was found to be generally safe and well tolerated.
Of course as in any clinical study there are adverse events that are reported, but we believe that all of our findings to-date at all dose levels are fully supportive of program advancement. We very much look forward to presentation of data from the Phase I trial at the HFSA meeting in September.
We also look forward to the start of a Phase II study of ALN-TTRsc and FAC patients by the end of this year, and assuming positive results start of a pivotal Phase III trial for this subcutaneously administered RNAi therapeutic in 2014. Also, as John mentioned earlier, these results have important implications for the entirety of our preclinical Alnylam 5x15 pipeline.
Since all of these programs utilize the GalNAc-siRNA conjugate approach employed in TTRsc and our Phase I results provide clinical validation for this exciting delivery approach. In this recent period we also presented new preclinical data with our ALN-AT3 program for the treatment of hemophilia and rare bleeding disorders.
We’ve use this as a very exciting and innovative program since antithrombin knockdown can rebalance the coagulation cascade in patients with hemophilia and other rare bleeding disorders, resulting in enhanced thrombin generation and improved hemostasis. Further, as a subcutaneously administered medicine, ALN-AT3 can provide patients with a new approach for prophylaxis in a clinical setting where all other drugs are administered by frequent intravenous infusions, usually two to three times per week and where in the case of hemophilia inhibitor patients there are simply no prophylactic therapies available.
At the recent International Society on Thrombosis and Haemostasis meeting and as described on Slide 14, we presented new pre-clinical results demonstrating that ALN-AT3 can normalize thrombin generation and improve haemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate hemophilia inhibitor model. These results are important since thrombin generation is a validated biomarker that has closely correlated with disease severity in patients with hemophilia.
In addition, the Company presented results of tolerability studies that support a broad therapeutic index for ALN-AT3 in the hemophilia setting. We are currently completing a number of IND-enabling pre-clinical and CMC study.
As we announced today, these activities have resulted in a one quarter shift in our program timeline and we now expect to file an IND for ALN-AT3 in the fourth quarter of 2013 and so initiate a Phase I clinical trial in early 2014. Beyond our TTR and AT3 programs, we have also made progress with additional Alnylam 5x15 programs including ALN-AS1 for the treatment of porphyria, ALN-CC5 for the treatment of complement-mediated disease and ALN-PCSsc for the treatment of hypercholesterolemia among others.
ALN-AS1, is an RNAi therapeutic targeting aminolevulinate synthase-1 or ALAS-1 for the treatment of porphyria or AIP. AIP is an ultra rare genetic disease caused by loss of function mutations in porphobilinogen deaminase or PBGD, an enzyme in the heme biosynthesis pathway.
Loss of function mutations in PBGD can result in accumulation of toxic heme precursors. ALN-AS1 is a GalNAc conjugated siRNA targeting ALAS-1, a liver expressed rate limiting enzyme upstream of PBGD in the heme biosynthesis pathway.
In addition, ALAS-1 is known to reduce the accumulation of heme precursors, that cause the clinical manifestations of AIP. New pre-clinical data in rodent models of AIP were presented at the International Congress of Porphyrins and Porphyrias held in May.
As you can see on Slide 16, these results demonstrated that RNAi therapeutic is targeting ALAS-1, can completely block the abnormal production of toxic intermediates of the heme biosynthesis pathway that cause the symptoms and disease pathology of AIP. These results support the advancement of RNAi therapeutics of a promising strategy for the prevention and or treatment of the acute attacks in patients with AIP.
We are on tract to designate a GalNAc-siRNA development candidate in late 2013 and plan to file an IND in 2014. Also in the quarter we designated ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5, for the treatment of complement-mediated diseases, as a new Almylam 5x15 program.
The complement system play the central role in immunity as a protective mechanism for host defense, but its dysregulation results in life-threatening complications in a broad range of human diseases including paroxysmal nocturnal hemoglobinuria or PNH, atypical hemolytic-uremic syndrome or aHUS, and neuromyelitis optica, amongst others. C5, which is predominantly expressed in liver cells, is a genetically and clinically validated target.
Loss-of-function human mutations are associated with an attenuated immune response against certain infections, and intravenous anti-C5 monoclonal antibody therapy has demonstrated clinical activity and the tolerability in a number of complement-mediated diseases. A subcutaneously administered RNAi therapeutic that silences C5 represents a novel approach to the treatment of complement-mediated diseases.
We presented pre-clinical data from this program at the International Conference on Complement Therapeutics in June demonstrating potent, dose-dependent, and durable RNAi-mediated knockdown of serum C5 and inhibition of complement-mediated hemolytic activity of approximately 90%. We are in final stages of optimization of the current GalNAc-siRNA conjugate lead molecule and expect to nominate our ALN-CC5 development candidate in late 2013.
And at our recent R&D Day, we also presented an update from our ALN-PCS program showing pre-clinical results with a PCSK9 targeted GalNAc-siRNA conjugate, ALN-PCSsc which enables subcutaneous dose administration. Specifically, as shown on slide 18, in non-human primate studies performed in the absence of concomitant statin therapy, ALN-PCSsc showed greater than 80% knockdown of plasma PCSK9 with greater than 50% reductions in LDL-c.
Our ALN-PCS program is partnered with The Medicines Company and we look forward to advancing this program into the clinic. Clearly, we continue to make 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 weeks and months.
And with that, I'd like to now turn the call over to Mike for a review of our financials. Mike?
Michael Mason
Thanks, Jared and good afternoon everyone. I will be referring to Slide 20.
Alnylam continues to maintain a very solid balance sheet ending the second quarter with $379.5 million in cash, cash equivalents and marketable securities. Our GAAP revenues for the second quarter of 2013 were $8.7 million as compared to $20.9 million in the second quarter of 2012.
Revenues this quarter included $5.5 million related to our collaboration with Takeda, $1.4 million related to our collaboration with Monsanto, and $1.8 million related to our collaboration with The Medicines Company, research reagent licenses, and other sources. Revenues were lower than the prior year period due to the completion of amortization of gross overhead deferred revenue during 2012.
For the remainder of 2013, we expect net GAAP revenues from research collaborators to remain consistent with the amount recorded in the second quarter. Moving to expenses, R&D expenses were $24.2 million in the second quarter of 2013 as compared to $21.7 million in the prior year period.
This increase was due primarily to higher clinical trial and manufacturing expenses related to our ALN-TTR02 and ALN-TTRsc programs. In addition, external services expenses increased, due primarily to higher pre-clinical expenses for our ALN-TTR and ALN-AT3 programs.
Partially offsetting these increases were license fees due to certain entities related to our delivery and platform technologies that were expensed in 2012. Looking ahead, we expect R&D expenses to increase moderately for the second half of 2013 as the positive results from our ALN-TTRsc program give us confidence to increase our investment in our pre-clinical Alnylam 5x15 pipeline since all of these programs utilize the GalNAc-siRNA conjugate approach employed in our ALN-TTRsc program.
G&A expenses were $5.8 million in the second quarter of 2013 as compared to $11.2 million in the second quarter of 2012. The decrease in G&A expenses for the second quarter of 2013 as compared to the prior year period was due primarily to a decrease in consulting and professional services related to business and legal activities.
Alnylam expects G&A expenses will remain consistent for the second half of 2013. With respect to guidance for 2013, we believe we will finish the year with greater than $320 million cash which provides us with a strong balance sheet to execute on our business plan and advance our RNAi therapeutics through clinical trials and towards the market.
This concludes the financial highlights and I will now turn the call over to Barry.
Barry Greene
Thanks Mike and hello everyone. As you've heard this afternoon, we are demonstrating with human clinical data that the RNAi pathway can be harnessed to create high impact innovative medicines.
Certainly the first half of 2013 has been a very exciting period. By all accounts, we expect the second half of the year to be every bit of data rich as important and as we see on slide 22.
With regard to our TTR program, we expect to present complete data from our Phase II trail, ALN-TTR02 at the International Symposium on FAP in Rio de Janeiro, Brazil of November. This data will include full TTR knockdown data for about 30 ATTR patients, and will also include important safety data on reduced and simplified pre-medication regimen.
For patients enrollment in the Phase II study we aim to begin an open-label extension study in the coming weeks. This study will include clinical end-point data that will begin to readout in 2014.
Finally, we plan to initiate a Phase III pivotal trial for ALN-TTR02 in polyneuropathy patients by the end of this year. This will be an exciting transition for Alnylam, as the company entered the final stages of clinical development with our lead program.
I’ll turning to ALN-TTRsc, we plan to present data from our Phase I trial at the Heart Failure Society of America conference in Orlando, this September. This clinical study is the first we reported using our GalNAc-siRNA conjugate platform with clear implications for the entirety of the Alnylam 5x15 preclinical pipeline, as John and Jared already commended.
As we communicated, we expect to start Phase II study in cardiomyopathy patients with ALN-TTRsc in late 2013, with the goal of initiating a Phase III trial from 2014. In our ALN-AT3 program we’ve really made tremendous progress on this highly innovative approach to treat hemophilia, and are shifting our program standing by a quarter, with an IND goal in the fourth quarter of this year and a Phase I start early 2014.
With our ALN-AS1 program for the treatment of porphyria, we expect to identify the final development candidate of the program by late 2013 and to advance into the clinic in 2014. We also plan to nominate all these candidates for an ALN-CC5 program by the end of this year.
For ALN-CC5, we will provide clinical timing guidance at the beginning of next year, but it certainly can expect us to move this program forward expeditiously. As Mike said, we plan to end the year with greater than $320 million in cash.
In summary, I think it’s very clear that we’re executing on our goal of driving innovative RNAi therapeutics for patients in need and creating a highly valuable enterprise. Finally, and turning to slide 23, while May, June, July were very dearest months for Alnylam, we expect a continued rich period of data readouts through the end of the year.
Indeed we expect new data’s to be presented at a number of scientific and clinical meetings in September, October, November and December, which will continue to highlight our progress with Alnylam 5x15 product strategy, we integrate into business and patients for the treatment of genetically defined diseases. With that I’d like to turn the call back over to the operator for your questions.
Charlet, will take questions now.
Operator
(Operator Instructions) Our first question comes from the line of Alan Carr from Needham & Company. Your line is open and you may proceed.
Alan Carr – Needham & Company
Hi, thanks for taking my questions.
John Maraganore
Hi Alan.
Alan Carr – Needham & Company
.
John Maraganore
Sure. Those are two great questions.
Let me address the C5 question and then I will have Jared Gollob to address the TTR02 Phase III trial question. So with C5, we are really excited about the program.
We have current lead molecule, which shows very impressive knockdown of C5 in rodents where literally as we speak in non-human primate studies, we have a molecule that we think will be optimized a little bit further before we declare it as a development candidate, but we will enable weekly subcu dosing, with knockdown levels of serum C5 that are over 90% with resulting decreases in hemolytic activity to similar extents, and this is the type of knockdown of hemolytic activity that per the experience of eculizumab in PNH were associated with clinical benefit. So, clearly this type of performance with subcu administered drug could be a very compelling product in a very broad range of different complement-mediated diseases including PNH amongst others.
So we are excited about the program. As Barry said, we are going to move this forward pretty expeditiously and we’ll give formal guidance on when will be in the clinic at the beginning of next year as we give our annual goals and guidance at one of the investor conferences, but we are very excited about where that’s going.
So let me turn to TTR02 and Jared, do you want to comment a little bit on the trial design and where we are at this point.
Jared Gollob
Sure. So for the Phase III study, our plan is to initiate Phase III by the end of this year, and as we outlined at R&D Day with regard to the study design, the plan for this it will be randomized, double-blind, placebo-controlled global study with two-to-one randomization of active drug ALN-TTR02 to placebo, we anticipate enrolling anywhere from 150 to 200 patients, dosing at 0.3 milligram per kilogram every three or four weeks.
The primary endpoint for this study will be a change in a composite neurologic impairment score, that we call NIS, either 12 to 18 months, the final determination of the length of primary endpoint is still being discussed, and there will also be key secondary endpoints that we’ll look at TTR levels, quality of life, level of disability, motor function assessments as well as nutritional status. So we’re on track for initiating that study at the end of year and essentially that’s the high level design that we plan to move forward for the Phase III trial.
John Maraganore
I will just add, you had that question about timing and obviously once we get into the accrual of the study we’ll have better visibly on that, but we estimate anywhere from 2.5 to 3.5 years following the start of the study to opening up the envelope and having the result. That’s the general time period to do this type of study.
And we have a lot of experience enrolling patients in the ATTR community. Obviously we’ve just completed or just about completed this Phase II study.
We have an experience before that with TTR01 which is a predecessor to TTR02. So we have a very good sense of this community, the physicians, the KOLs, the accrual ability of this type of study, and we feel pretty optimistic about that type of timeframe.
So we are finalizing the protocol literally as we speak with regulatory authorities. We’ve got some very good input, the type of design that we outlined in R&D Day is certainly holding up with regulatory input and scrutiny, and we look forward to starting the study and giving people the details on the design when we finally nail it down.
Alan Carr – Needham & Company
So you’re still waiting for the outcome of that two dose Phase II study in terms of you had like a few extra cohorts there at the end there to explore pre-dosing regimen and that sort of thing. I guess you’re still waiting for the outcome of that and, well from that trial to get a better handle on whether three weeks or four weeks and what sort of regimen you are going to put in place before dosing the drug?
Barry Greene
John Maraganore
The real key is we want to communicate the final phase III design, the one we’ve locked in with regulators globally and with investigators and that’s happening the rest of this year.
Alan Carr – Needham & Company
Okay, great. Thanks very much.
Operator
Thank you. And our next question comes from the line of Marko Kozul from Leerink Swann.
Your line is open and you may proceed.
Marko K. Kozul – Leerink Swann LLC
Hey, good afternoon.
John Maraganore
Hey, Marko. How are you?
Marko K. Kozul – Leerink Swann LLC
Pretty well. Thanks.
John, because your platform is modular and reproducible, I wanted to ask about your potential future plans to advance compounds for other complement-mediated diseases that might target factor B or C3 where Solaris is ineffective?
John Maraganore
Yeah, it’s a great question. We’re very interested in that.
Obviously there is quite a bit of data that shows that there is extravascular hemolysis associated with the remains and patients with PNH notwithstanding administration of eculizumab and clearly targeting other targets within the complement pathway would be very logical and we have ongoing research activities targeting multiple of those targets. It turns out that the entirety of the complement pathway is expressed in liver and so we have an approach that as I said first and you said first and you said afterwards, modular and reproducible that we can leverage and we are doing that.
Marko K. Kozul – Leerink Swann LLC
Appreciate that. And just a quick one on ALN-AT3.
Do you have any emerging preference, the way you might start the actual Phase II clinical development program in hemophilia patients, would this be maybe first in severe hemophilia A, on-demand prophylaxis kind of a study or maybe [hem A, B] inhibitor patients or rare bleeding disorders, how do you think about prioritizing the progress there? Thanks.
John Maraganore
It’s still an evolving discussion. Obviously, we have the potential for going after all of those segments that you just mentioned, and it’s very possible, Marko, as we look at this program that we can go quickly into a Phase III type trial in inhibitor patients and then do additional studies in on-demand hemophilia, severe hemophilia A patients for example, as well as segments of the rare bleeding disorder population like factor V deficiency or factor X deficiency and multiple studies maybe initiated simultaneously after the Phase I is completed.
So, I think there is an opportunity for going broad with the program, and obviously advancing it into these, all of these areas of unmet need. We remain very excited about the inhibitor population in particularly because of the significant unmet need in that population and feel that that’s where this drug can have a huge impact in the management of those patients.
Jared, anything else to add to that?
Jared Gollob
No, no. I think that covers it, John.
John Maraganore
Yeah.
Marko K. Kozul – Leerink Swann LLC
Terrific. Thanks for taking the questions.
John Maraganore
Thanks Marko.
Operator
Thank you. And our next question comes from the line of Ted Tenthoff from Piper Jaffray.
Your line is open and you may proceed.
Edward A. Tenthoff – Piper Jaffray, Inc.
Great. Thank you very much.
John Maraganore
Hi, Chad.
Edward A. Tenthoff – Piper Jaffray, Inc.
Hey. How are you guys?
Congrats on all the fantastic progress, it's been a really exciting year. So maybe something, a little bit sort of off the beat and pass.
Obviously the focus has been on the therapeutics side, but can you give us an update on some of the other partnerships you've done such as the ag deal with Monsanto, I believe, the vaccine deal, the protein production deals. I now the focus has been more on the human therapeutics, but what’s been going on that side of business?
John Maraganore
Yeah, Laurence, do you want to comment a little bit on some of these?
Laurence Reid
Sure. So let’s start with the Ag deal, just to refresh peoples mind, that a year ago now, I don’t know quite we executed on licensing, exquisite agricultural license with Monsanto and a big part of the early months of that have really been enabling my colleagues in St.
Louis with various aspects of the RNAi technology. That’s been going very well.
There is a milestone associated with that successful type transfer and we expect to have news on progress against that between now and the end of this year. But it’s been – it’s a platform license that cost that deal.
We are not currently actively involved in any plant work in collaboration with them, or that might happen in the future, but the – we planned the alliance which will enable the Monsanto team with all aspects of or with certain aspects of the RNAi platform particularly over the fundamental chemistry and RNAi design technology that we’ve developed over many years here and that’s being actively deployed by the Monsanto teams. That was at Monsanto…
Unidentified Company Representative
The Biotherapeutics, on the GSK collaboration is still progressing and I think we’ll probably have news on that between now and the end of the year. That collaboration is now sort of late in the second year.
We’ve been working with GSK as people recall exclusively on increasing the yield of flu vaccines through application of RNAi in cell culture and that program has been progressing. Nothing specific to enhance there, I think we will probably have more announcements of that in the not too distant future.
And then the third piece, the Alnylam Biotherapeutics platform more for use around production of protein therapeutics and protein products, in cell culture, we have quite an active collaboration which we’ve not talked about publicly or publically announced. I think but it’s a proof-of-concept, collaboration with a major pharmaceutical company and that’s progressing very well.
We are hoping to move some of that technology into deployment in certain of that product production system. So I think in summary, I think each of those areas in different business fashions have been progressing.
As you can always tie them in there is sort of the high level priorities for us to occupy a major piece of our bandwidth which is really focused on the hemotherapeutic, but they are all going along, I would say quite nicely in the background.
Edward A. Tenthoff – Piper Jaffray, Inc.
That’s a great update. And then I guess some of our metrics – one other one switching gears.
I guess it’s always been dangerous to declare mission accomplished, but you guys have been investing heavily and I think really starting to bear fruit on the whole delivery side of thing, the GalNAc and subQ programs are evidence of that. What else has been going on, on the delivery side, are there conjugation technologies that you are looking beyond that, are there target specifics things you’re considering for different indications beyond liver.
Maybe you can give us just a kind of high level update on that?
John Maraganore
Yeah, that’s a great question Ted. Let me try to address it.
I think and we said that there is a little bit at our R&D date. We are so flush with opportunities in liver right now, that we are I think appropriately and wisely focusing or capital on those opportunities.
And the goal is to really generate a pretty Rich pipeline of programs that target genetically defined targets in liver. With the technology that we created, we believe that the current GalNAc-siRNA conjugate platform is extremely validated.
We feel very good about the data, we are going to commit to that in a big way. We are committing that in a big way and we’ll continue to execute on that pipeline.
And we see it very much the pipeline of the future, for what we’re doing at Alnylam with liver-expressed target genes. Obviously we still always make optimization around these type of things over time and we have an research activity that’s focused on that.
And I’d say in a very low level, Ted, we continue to keep our eyes and ears open for extra hepatic delivery, but for the foreseeable future the liver is such a rich source of target genes for executing on our pipeline strategies that its hard for me to imagine, why we would want to do something outside of the liver at least over the next decade or so. And so we’re pretty happy with where we are.
We are building a tremendously exciting pipeline, and it’s hard to imagine why we would want to get distracted with another place to go, at least in the near-term.
Edward A. Tenthoff – Piper Jaffray, Inc.
Well, it’s definitely been successful. And I guess just I am sorry monopolize, but you’d done – I mean we’ve seen the Medtronic collaboration for example in neuro and so would there be opportunities to pursue extra-hepatic programs with partners, or is that something that’s still on the table and something it’s so…
John Maraganore
Absolutely. We’re not actively shopping that opportunity because we don’t obviously that that type of approach would end up resulting in a milestone royalty type value opportunity for the most part Ted, which is I think you appreciate quite well.
It’s not really a value creating strategy for at least where Alnylam is, at this point in time. So for us it’s really about developing pipeline assets that we can ultimately take to the market.
We will partner in Japan and Asia for the foreseeable future, but retaining product value for Alnylam as far as we’re concerned, I think you agree with this, the best value creation strategy fro the company.
Edward A. Tenthoff – Piper Jaffray, Inc.
Yeah, well it’s been working. So great, quarter guys keep it up and we’ll talk to you soon.
John Maraganore
Bye Jeff, thank you.
Operator
Thank you. And our next question comes from the line of David Friedman from Morgan Stanley.
Your line is open and you may proceed.
Unidentified Analyst
Hi, this is (inaudible) calling in for Dave. Thanks for taking the question.
John Maraganore
Hi, how are you?
Unidentified Analyst
Good. I was wondering if you could talk a little about the types of clinical endpoints.
You may look at in FAC. And also could you discuss how the EU FAC market compares with the U.S.
FAC markets?
John Maraganore
Absolutely. Jared, do you want to cover both of those.
Jared Gollob
Sure…
John Maraganore
And then maybe Berry you can helps us with the markets out of it,
Jared Gollob
So in terms of clinical endpoints, there are a variety of different heart failure endpoints that we are looking into and considering for the eventual pivotal study. We obviously have made a decision as to what exactly will be say, primary and secondary endpoints in a Ppivotal Phase III study, but some of the end points that we are looking into and that have been commonly considered with the heart failure space include things such as cardiovascular hospitalizations, mortality, and functional tests such as a six minute walk test, there are other exercise sorts of functional tests that have also used as endpoints, they are even cardiac biomarkers that could be use as endpoints such as a biomarker called BMT and an other one called troponin, and there are also quality of life, questionnaire is in quality of life questionnaire that’s specific for cardiomyopathy something called the Kansas City Cardiomyopathy Questionnaire.
So these are some of the endpoints that we would be considering as we look further ahead towards a pivotal Phase III trial. There are also endpoints that are radiographic such as echocardiographic endpoints looking at heart wall thickness systolic function, diastolic function et cetera.
So, there are number of different parameters that we can look at these clinical trials and I think as we move forward in our thinking around Phase II, and Phase III, and we’ll get a better idea as to which of these endpoints will be most appropriate this population that we plan to target for our pivotal study. In terms of your second question with regards to FAC in Europe and in the U.S.
the FAC population can consist of a variety of different mutation, probably in the most common mutation associated with FAC, is V122I mutation that is actually founded in approximately 4% of African-Americans, and it’s likely that a significant number of those who actually carry that mutation eventually develop a cardiomyopathy and FAC. So in the United States, it’s estimated there could be as many as 30,000 to 40,000 cases of V122I FAC and there could be additional cases, there likely be additional cases of FAC also in the United Kingdom, for example whether is an Afro-Caribbean, it also had V122I, so estimated that world wide there could be at least 40,000 cases of FAC both in the U.S.
and in Europe as well as in Asia too, so in Japan there are also cases with FAC, but with regard to the most common mutation, the V122I, we will be looking predominantly at the U.S. and at Europe and there is another mutation called T60A, which is also found in the United Kingdom and Ireland as well as in the U.S.
Unidentified Analyst
Great, thank you.
John Maraganore
Thank you.
Operator
Thank you. (Operator Instructions) Our next question comes from the line of Mike King from JMP Securities.
Your line is open and you may proceed.
Mike G. King – JMP Securities LLC
Good afternoon guys, thanks for taking my question. Can you hear me, okay?
Barry Greene
Yeah, sure can Mike.
Mike G. King – JMP Securities LLC
Couple of questions, one for Barry on AT3, I don’t know if you can elaborate on what additional pre-clinical preparations you need to make in order to enable the IND there, but. Can we just get a sense that maybe kind of things you’re thinking may have to do?
John Maraganore
Yeah. Hey Mike, this is John.
Just for quickly, so we are just ramping up some studies on it. As you know from the ISTH presentation, it’s doing incredibly robust data package, I mean this is a really, really innovative target in hemophilia, and we’ve done an amazing amount of work, which has been really exciting and very encouraging and so you saw a big chunk of that at ISTH and there is obviously quite a bit more.
We are just ramping it all up together, it’s obviously there is a bit of a shift in our timelines from our perspective, we are going to submit this IND, and we are gong to be starting that Phase I, but things have shifted just a little bit. It’s also time where right now we are in the midst of starting our pivotal study with TTR02, we are in the midst of starting our open label study with TTR02, we’re in the midst of starting our Phase II study with TTRsc.
And so, our development organization is sort of quite hexed. So, a shift in timing is something which is going to be needed here for ALN-AT3, but we’re very excited about the program and look forward to getting this thing into the clinic.
Mike G. King – JMP Securities LLC
Okay. So it sounds to me like you’re not generating any additional data.
You are just bandwidth constrained and it’s just going to take time to put the reports together that are required to enable the IND. Is that a fair statement?
John Maraganore
Yeah. There is no new data we need.
It’s a matter of, again as you know, as is our practice, we want to make sure that we’re highly aligned on what the Phase I looks like, what the package looks like before we submit our CTA and we want to be very clear with what we think the timing will be.
Mike G. King – JMP Securities LLC
Okay. All right.
Fair enough. If I could just move on to C5.
Some feedback that we’ve heard from clients is that the eculizumab, Alexion believes that there is production of complement beyond the liver, and that significantly more than 90% of complement needs to be, complement production needs to blocked in order to have the therapeutic effect that eculizumab has. I just wonder if you might comment on that, and give us your perspective.
John Maraganore
Yeah, absolutely. Well, the supposed role of local complement has never been clinically validated in any way they perform and in point of fact certainly for many of the complement-mediated diseases like PNH there is no reasons to image that there is a local role for complement.
So for the vast majority of patients even if local complement were involved, it would have been involved or be relevant in things like aHUS or PNH. With regard to the level of knockdown of C5, the helm it all papers in The New England Journal that were published in 2004 and 2006 are the definitive papers on that issue and in those papers they validated that greater than 80% inhibition of hemolytic activity as being clinically relevant in PNH and those are very clear cut data that people should take a look at.
But even if a greater level of knockdown is needed, there is a therapeutic approach with our drug where our drug is used as foundational therapy as a subcu drug for patients with PNH or aHUS and that eculizumab is used in a provisional manner, because without a doubt, Mike, by depleting C5 from the circulation, you wouldn’t need as much eculizumab intravenously to be given. And so, you can imagine if 99.99% were needed, which I don’t believe is the case, you’d be able to see a product profile which is different where the drug is actually a staring approach to eculizumab.
Does that make sense?
Mike G. King – JMP Securities LLC
Yeah. John, that’s very helpful.
I’ll see if we can pull those papers. And then one final question, which is, wanted to see if you could comment about, we had a call last week with a KOL in for the FAC space and one, just a hypothetical concern that he had was whether or not there would be any potential for long-term talks by constant innovation of the manufacturer of transthyretin because it does transport important proceeds and the likes, so I’m just wondering if there is any common angular side from whether or not in a longer term there might be some consequences to continued blockage of TTR.
John Maraganore
Yes, I’ll let Jared answer that, we’ve done a lot of diligence on this issue, so Jared you want to give?
Jared Gollob
Sure, it’s an important question. I think there is abundant evidence that one can lower TTR substantially and really not resulted any complexity, probably most compelling experiences then with the TTR knockdown mouse.
So that mouse potentially has no TTR and the phenotype is relatively benign. So even though TTR plays fairly minor role in transporting thyroid hormones, and a somewhat larger role in transporting vitamin A in the mouse loss of TTR does not result in deficiency of thyroid hormones.
Hormones within various tissues and these mice do not become (inaudible) deficiency, and that is because there are other mechanisms for binding and transporting thyroid hormones, but most notably thyroxine binding globulin. And for vitamin A there are redundant pathways for binding and transporting vitamin A to tissues.
We’ve actually in non-human primates we’ve been able to knockdown TTR for greater than 90% for nine months, and have not seen any toxicity related to that sort of knockdown, which again is consistent with the site that when the lower TTR by 90% or more, and not see any source of ill effects. So I think we are confident from those sorts of human data as well as animal data that TTR knockdown will be well-tolerated chronically.
John Maraganore
There also Mike, and Jared had elaborated there are a number of other human mutations in retinal binding protein that result in cannulated Vitamin A, and you should comment on that.
Jared Gollob
Yeah exactly, so there are rare individuals who have a mutation in the retinal binding protein gene which results in essentially absence of retinol-binding protein expression. So these individuals obviously have very circulating, little over the circulating Vitamin A, but again because there are redundant mechanisms for getting vitamin A from the diet, transport it to various tissues including the eyes, these individuals do not develop symptoms of severe vitamin A deficiency and again that’s consistent with what we’ve seen in the animal models, most notably the TTR knockout mouse.
And so I think it really looks at the loss of TTR, lowering of TTR, will not result in any kind of side effects either to thyroid hormone, homeostasis or vitamin A homeostasis. Did that help Mike?
Mike G. King – JMP Securities LLC
Yeah, it does. One just quick follow-up on then I’ll jump back and that is are TTR knockout mice embryonically viable?
John Maraganore
Yeah, completely.
Mike G. King – JMP Securities LLC
They are?
John Maraganore
They are essentially (inaudible). Yeah.
Mike G. King – JMP Securities LLC
Perfect. All right, perfect.
Thanks, guys.
John Maraganore
Thank you.
Operator
Thank you. And our final question comes from the line of Alethia Young from UBS.
Your line is open and you may proceed.
John Maraganore
Hi.
Barry Greene
Hi, Alethia. How are you?
Alethia Young – UBS
Hi, there. I guess I moved to UBS over that Michael.
John Maraganore
Well, that was quick.
Alethia Young – UBS
Yeah, that was quick. Congrats on the game changing data and just one, I just want you to kind of help us understand kind of the pre-clinical confidential things you’ve seen in hemophilia program and how you think it might play out in human and kind of just like help us – I know that you guys have had a lot of correlation between what you’ve seen pre-clinically and what you have seen in the clinic.
So any color on that will be really helpful?
John Maraganore
Yeah, let me address that directly. So obviously it’s a very interesting program.
We’re resetting the coagulation cascade in the context of hemophilia and I think the data we showed at ISTH that are to meet most exciting were the data in this non-human primate inhibitor model where in the primate that has a – where factor VIII has been completely removed by administering an antibody to factor VIII. So it’s sort of like an inhibitor patient.
We were able to administer ALN-AT3 and show a complete normalization of thrombin generation in those animals. And the reason that’s important is in the clinic, in hemophilia patients it’s known that patients with severe phenotype, severe bleeding phenotypes have very low thrombin generation as compared to patients with mild bleeding phenotypes that have higher thrombin generation levels.
And so the type of results we have in the non-human primate is like taking the severe hemophilia patient and converting them into a milder or ideally normal type of phenotype. And so those type of data are very compelling and very strong and give us great confidence.
It’s hard for me to imagine that we won’t be able to show that type of restoration of thrombin generation in patients in our Phase 1 study. I mean, those type of data will happen after the study gets started into next year, but I think those data are quite clear and then obviously in the Phase 3 study we’ll then relate that correction thrombin generation to the expected reduction in bleeding frequency and bleeding severity, which based on the existing data in hemophilia patients should correlate very closely.
So we’re excited about those data, obviously it’s a very compelling approach and of course we’re also confident by the fact that there are human experiments that have been done in patients of hemophilia that have co-inherited things like antithrombin deficiency that also show a very mild clinical phenotype compared to other hemophilia patients. So the genetic data that are there also strengthen everything that we’ve been able to show pharmacologically.
So pretty compelling program and one that we think will be a real value driver and a real opportunity for these patients who are looking especially the inhibitor patients who are looking for treatment options compared to what they have today.
Alethia Young – UBS
Also then just a quick follow-up or another – what should we expect of the subQ data in September, is there anything in particular beyond the dose that we should be looking for or that you’re interested in?
John Maraganore
I will let Jared comment in a minute, but at a high level, obviously you will look at the kinetics of knockdown, you look at the extent of knockdown, the duration of knockdown, these are all the types of relevant things we will see with our subQ platform, obviously safety tolerability is always important as well, so I think you will get a very complete picture for how this platform performs with TTR and then obviously those data and how well they correlate to non-human primate will then provide people the guide with what they should expect with AT3, what they should expect with C5 and other programs in our pipeline. I mean Jared anything else to add with that?
Jared Gollob
No, I think that’s helpful, John
Alethia Young – UBS
Great, thanks.
John Maraganore
Good. Okay.
Well, thanks everyone. Obviously we’ve had a very exciting quarter and a very exciting recent period.
I think as Barry said earlier, without a doubt, we have a lot more data to share in September, in October, in November, and December. So, stay tuned and we look forward to updating you in our third quarter if not in between.
Thank you very much and have a good rest of the day. Bye.
Operator
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.