Alnylam Pharmaceuticals Inc (ALNY) 2015 Q2 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss the second quarter 2015 financial results. There will be a question and answer session to follow. Please be advised this call is being taped at the Company's request. I would like to turn the call over to the Company.

Good afternoon everyone. I am Josh Brodsky, Senior Manager of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, our Chief Executive Officer, Barry Greene, President and Chief Operating Officer, Akshay Vaishnaw, Executive VicePresident of R&D and Chief Medical Officer, and Mike Mason, Vice President of Finance and Treasurer. In addition, DA Gros, our new Senior VP and Chief Business Officer is in the room, and available for Q&A.

For those of you participating via conference call, the slides we've 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 on slide two, John will provide some introductory remarks and provide general context for some of our recent progress and achievements. Akshay will summarize recent clinical progress, Mike will review our financials and guidance, and then Barry will provide a brief summary of recent business highlights and goals for 2015 and beyond, before we even the call for your questions. 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, and 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. With that, I will now turn the call over to John.

Thanks Josh. Thanks everyone for joining us this afternoon. During the second quarter of 2015 and recent period. we made excellent progress as we continued to execute on the Alnylam 2020 strategy, and advance RNAi therapeutics to patients and to the market. Before Akshay goes into our recent pipeline progress in more detail, I would like to provide some context on our second quarter and recent achievements, in addition to upcoming milestones. First, we now have seven RNAi therapeutic programs in active clinical development, including two in Phase 3, and by the end of 2015 we plan to have eight programs in clinical development across our three strategic therapy areas or STArs.

A major recent highlight was the emergence of new clinical data that continued to highlight what we believe to be the promising potential for RNAi therapeutics. In this regard, we reported in April on very encouraging 12 month clinical data from our Phase 2 open-label extension, or OLE study with patisiran. Specifically, we believe the results that we reported are consistent with our therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression, in patients with TTR polyneuropathy. With our hemophilia program, we were very pleased in June to report interim data from our ongoing Phase 1 trial, showing what we believe to be continued evidence that ALN-AT3 can rebalance hemostasis through normalization of trauma generation in people with severe hemophilia. We believe these clinical data with both patisiran and ALN-AT3 continue to strengthen the bridge that connects RNAi mediated target J knockdown with clinical outcomes, a critically important theme for Alnylam going forward, as we continue to advance in late stage development and toward commercialization.

We also reported positive initial data from our Phase 1/2 study with ALN-CC5 in June, where we showed robust knockdown of serum C5, and we saw initial evidence for reductions in complement activity, including inhibition of serum hemolytic activity. ALN-CC5 clearly works in man, and with this study now well into its multidose phase, we fully expect to achieve our target level of serum hemolytic activity inhibition with this agent. Of course, we are now also engaged in a rather large and broad based drug development effort across our seven clinical programs. We are noting today some adverse events, specifically injection site reactions, or ISRs, that have led to study discontinuation in three patients in our revusiran Phase 2 OLE study. Nevertheless, and very importantly, our overall experience continues to support what we believe to be a very encouraging tolerability profile for RNAi therapeutics, across hundreds of human volunteers, and patients that are currently enrolled, and currently being dosed in ongoing studies.

A second important point that I would like to make is that we are now entering a very data-rich back half of the year, where we expect to present important clinical data from six distinct clinical programs. For starters, later this month we will be sharing data from our ALN-PCSsc Phase 1 trial. If we can achieve once monthly subcutaneous efficacy, we believe we will have a very competitive profile versus anti-PCSK9 monoclonal antibodies. And then for every additional month of durability we achieve thereafter, this will provide us with even a stronger competitive profile.

Indeed, it is important to remember that the antiPCSK9 monoclonals act by mopping up the PCSK9 in plasma, and that their optimal effects require twice monthly dosing. And then we announced today that we are going to share initial Phase 1 data for our ALN-AS1 porphyria program in mid-September. This is way ahead of our previous guidance for data in early 2016. There is enormous unmet need for new medicines in porphyria, and our investigational RNAi therapeutic has the potential to block the production of toxic chem synthesis intermediates that mediate life threatening attacks in these patients.

Now beyond these two important data readouts in August and mid-September, we will have more clinical data in October, in November, and in December, from our two TTR programs ALN-AT3 and ALN-CC5, amongst other program updates. We very much look forward to sharing all of these results during this very dynamic and data rich back half of the year. Now finally, I would like to emphasize the very unique opportunity Alnylam is creating for patients and shareholders. With our GalNAc conjugate platform, especially our second generation ESC approach, and our focus on genetically validated liver expressed disease genes, we built a reproducible and modular platform that has been matched with what we believe to be a compelling and differentiated product strategy for continued value creation.

Indeed we are positioned to continue to deliver three or more new programs into the clinic every year, with multiple new Phase 3 trial starts expected over the next 12to 24 months. In conclusion, we believe that we are now at a very exciting stage of bringing our innovative medicines closer to patients, and to the market as we execute on our Alnylam 2020 strategy, and build what we believe will emerge as a top tier biotech company. With those introductory comments, I would like to now turn the call over to Akshay to review our pipeline progress. Akshay.

Thanks John. Good afternoon everybody. As John said, we have continued to make great progress with our pipeline of investigational RNAi therapeutics. Let me begin with our programs our genetic medicine STAr, and start with our RNAi therapeutics in development for the treatment of TTR mediated amyloidosis, or ATTR amyloidosis, for which we have two clinical stage product candidates. Patisiran is our lead program, and aimed at the treatment of AATR amyloidosis patients with familial amyloidotic polyneuropathy, or FAP. Patisiran is in a Phase 3 trial called APOLLO. We now have over 40 sites in over 15 countries open. Revusiran is our most advanced subcutaneously administered RNAi therapeutic in the clinic today. It is focused on the treatment of ATTR amyloidosis patients, with familial amyloidotic cardiomyopathy, or FAC. This product candidate is also in a Phase 3 trial called ENDEAVOUR. Now during the second quarter, we presented interim 12 month results of AN from our ongoing Phase 2 early study of patisiran in patients with FAP. At 12 months, we showed a mean 2.5 point decrease in the modified neuropathy impairment score, mNIS+7 in 20 patients with mNIS+7data available for the current analysis.

And to put this into perspective this decrease in neuropathy progression compares quite favorably with the 13 to 18 point increase in mNIS+7 at 12 months, that can be estimated from historical data sets in untreated FAP patients with similar baseline characteristics. Our caveat that our results stem from an open label study in a small number of patients, but we are nevertheless encouraged to see what we believe to be evidence for a possible halting of neuropathy progression after the first 12 months of treatment. These data are also encouraging with regard to our APOLLO Phase 3 study, since the primary endpoint of this study is the same measure we evaluating in the Phase 2 OLE namely the mNIS+7 neuropathy score. From a safety perspective, patisiran was also found to be generally well tolerated in this study, after 17 months of treatment with no drug related serious adverse events to date. Of course the key moving forward, is to see how these results mature. We announced today that we plan on presenting complete 12 month data from all 27 patients at the NA meeting in September.

We then plan to show the next transfer of data, including 18 months of MNS+7 results in late 2015, likely at the European TTI amyloidosis meeting being held in early November. In addition, we plan on discussing these results with regulatory authorities in the US and EU, as they relate to potential considerations for an interim analysis for efficacy in our APOLLO Phase 3 study, and will accordingly update you, if and when appropriate.

Turning to APOLLO, the trial continues to enroll FAP patients, and is proceeding well. As a reminder, APOLLO is a randomized double-blind placebo-controlled study, designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP, and if successful the study would support marketing authorization for patisiran in countries around the world. We continue to be very pleased with the pace of APOLLO enrollment, which has been increasing since the presentation of our six and the 12 month early results. We expect that if positive, APOLLO will enable an NDA submission in the 2017 time frame. We are also excited to report recently that we have initiated dosing in our APOLLO early trial, which provides patients who participate in our APOLLO Phase 3 trial, with the opportunity to receive patisiran on an ongoing basis for up to two years, or until the drug is commercially available on the market.

With that let's now turn to Revusiran. As a reminder, we are currently conducting a Phase 2 early study in which TTR cardiomyopathy patients who participated in a Phase 2 trial, who are eligible to rollover into the early study and receive revusiran on an ongoing basis, similar to what we are doing for patisiran. The early study will evaluate the safety and tolerability of long-term dosing with Revusiran for up to two years, and will also measure effects of treatment toward a number of clinical endpoints, including mortality, hospitalization, and 6-minute walk distance, in addition to cardiac biomarkers. Revusiran is a first generation GalNAc-conjugate, requiring weekly subcutaneous dosing, and injection site reactions are a known side effect for all GalNAc type therapeutics. We are reporting today that three patients in the Revusiran Phase 2 early study have discontinued from the trial due to injection site reactions, including some associated with a more diffuse rash. The drug remains otherwise generally well tolerated in the broader revusiran Phase 2 early study population, and we plan on reporting the initial six month clinical data from about 15 patients who have reached the time point in late 2015, at either the European ATTR meeting, or at AHA, both in November.

Revusiran is also in a Phase 3 trial called ENDEAVOUR which is being conducted in patients with FAC and enrollment is ongoing. This is a randomized double-blind placebo-controlled study, where we are looking at two co-primary endpoints measured at 18 months. One being the change in six minute walk distance between drug and placebo, and the other being reduction in serum TTR between drug and placebo. It is still relatively early in the study's initiation, and we will provide more guidance on the study timeline as enrollment continues. Finally, in our TTR program we are pleased to announce today that we are advancing a development candidate for a second generation ESC GalNAc SRNa targeting TTR.

Based on the emerging profile of this candidate, we expect it to support a once monthly and possibly once quarterly subcutaneous dose regimen. While we have not previously disclosed this program, it is fairly mature in development, and we plan to share further details and guidance on this program at the OTS meeting in October. I would like to now move on to discuss our latest progress with ALN-AT3, an RNAi therapeutic targeting antithrombin in development for the treatment of hemophilia and rare bleeding disorders.

We view this as a very exciting and innovative program since antithrombin knockdown has the potential to rebalance hemostasis through normalization of thrombin generation, which could lead to a possible disease modifying effect, providing what may amount to a functional cure in hemophilia patients. Our ALN-AT3 program is gaining increasing recognition as a potentially transformative approach for hemophilia, and the New England Journal of Medicine acknowledged that program in a clinical implications of basic research article in an issue just last month.

At the ISDH conference in June, we were pleased to present positive interim results from our ongoing Phase 1 trial. Specifically subcutaneous administration of ALN-AT3 resulted in potent dose dependent and statistically significant knockdown of plasma antithrombin of up to 86%. AT knockdown was found to be highly durable with the effects lasting over two months after the last dose. AT knockdown was also associated with statistically significant increases in thrombin generation, of up to a mean of 350%. We also performed an exploratory post tox analysis of the frequency of onstudy bleeding events in all hemophilia patients in Part B of the study, in which AT knockdown was segmented into turtiles. In summary, this exploratory data analysis appeared to show an AT knockdown dependent reduction in bleeding frequency. We are very encouraged by these new interim results, since ABR is the endpoint we intend to use in Phase 3. Also shown on the slide is a case report of one of the patients in this study. You can see that with three weekly doses of ALN-AT3, this patient's AT levels were knocked down by up to 86%. He also showed significant increases in thrombin generation levels, that were temporarily matched with his AT knockdown. In addition during the time in which the patient's AT was reduced and thrombin generation increased, the patient remained bleed-free for a period of 114 days. Which compares very favorably to self-reported ABR of 22 bleeds per annum prior to entering the ALN-AT3 study. The results illustrated by this patient exemplify our therapeutic hypothesis, that by knocking down antithrombin, ALN-AT3 has the potential to normalize thrombin generation, and achieve a rebalancing of hemostasis in patients with severe hemophilia.

Moreover ALN-AT3 was generally well tolerated in all patients in this study, through the data cutoff date, with no clinically significant increases in levels of D-Dimer a marker of biologic clot formation. Now based on these encouraging results, we plan to advance ALN-AT3 directly to a Phase 3 study, which we plan to initiate in mid-2016. In the meantime, we have transitioned to the next part of Phase 1 study in which we are exploring a monthly subcutaneous dosing regimen, and we expect to present initial data from these monthly dose cohorts in late 2015, likely at ASH in early December pending abstract acceptance.

Now let's turn to recent progress with ALN-CC5, a subcutaneously administered and investigational RNAi therapeutic, targeting complement component C5 for the treatment of complement mediated diseases. At EHA or EHI in June, we presented positive initial data from our ongoing Phase 1/2 clinical trial. Specifically single doses of ALN-CC5 in healthy volunteers resulted in potent dose dependent and durable C5 knockdown of up to 96%. The observed durability potentially supports a once monthly subcutaneous dosing regimen. We also observed initial evidence for potentially clinically meaningful reduction in complement activity with an up to 92% inhibition of complement active by ELISA, and up to 61% inhibition of serum hemolytic activity. Importantly, ALN-CC5 was generally well tolerated through the data cutoff date.

In summary, AL-CC5 is clearly clinically active, and shows excellent translation from our preclinical results in nonhuman primates. We he now have transitioned to the multidose phase of the study, in which study volunteers are receiving weekly doses of ALN-CC5. We fully expect that these multidose administrations of ALN-CC5 will result in yet more robust effects on complemented inhibition, including an over 80% inhibition of serum hemolysis, just like we see in primates. We plan to present initial multidose data in late 2015, also likely at ASH in early December, pending abstract acceptance. We also still expect to initiate dosing in PNH patients by the end of this year.

Also during this quarter we progressed with ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting ALS1 for the treatment of hypathic porphyrias, including acute intermittent porphyria, otherwise known as AIP. We recently began dosing in our Phase 1 trial with ALN-AS1, this trial is being conducted initially in AIP patients who are asymptomatic high excreters, or ASHE patients, and then we can plan to transition to symptomatic AIP patients, who experience recurrent porphyria attacks. ASHE patients have elevated levels of ALA and PBG, two heme sensitive intermediates that cause the life threatening attacks that occur in AIP patients. Our interest is to see whether ALN-AS1 an RNAi mediated knockdown of ALS1 can reduce the levels of ALA and PBG in these patients, thereby generating important human proof of concept for our therapeutic hypothesis.

We are announcing today that we plan to present initial data from this Phase 1 trial at the International Congress of Porphyrins and Porphyrias, or ICPP, in mid-September. We have also been actively enrolling AIP patients with the recurrent porphyria attacks, into our explore natural history study, where we are learning about the severe of porphyria attacks, and the enormous burden of disease for patients, and we also plan to share these initial data from the prospective natural history study at the ICPP meeting in September. Finally, from our genetic medicine style, we have been advancing ALN-AT an RNAi therapeutic in development for the treatment of alpha-1 antitrypsin deficiency associated liver disease. Patients with this disease present with liver cirrhosis of varying degrees due to a mutation in the alpha-1 antitrypsin gene, with the misfolding of the mutant ZAIT protein. Alpha 1 liver disease can lead to parasital carcinoma. And the only treatment option currently available is a liver transplant. We have recently initiated our Phase 1/2 study, and plan to present the initial data from the study in early 2016.

I will now turn to a review of progress from our Cardio-Metabolic disease pipeline. Of course our leading program in this STAr is the ALN-PCSsc which targets PCSK9, and is in development for the treatment of hypercholesterolemia. Our Phase 1 study is being performed in normal healthy volunteers with elevated baseline LDL cholesterol, and we announced today that we have completed enrollment in this study. Subjects are randomized three to one drug to placebo, and received either single or multiple doses of drug. We will present initial clinical results from this Phase 1 trial at the ASC conference on August 30, that will include data on safety and tolerability of single and multiple subcutaneous doses of ALN-PCSsc in about 70 subjects, and data on the drug's effects on PCSK9 levels and on LDL cholesterol. We plan to present all data that are available as of the data cutoff date, including initial multidose results. Also worth noting that we can evaluate the potential for quarterly dosing, based on a single ascending dose data, since we followed these subjects for well over 90 days. Recall that ALN-PCSsc is partnered with The Medicines Company, who will lead clinical development of the program from Phase 2 onwards, and commercialization if successful. Also in our Cardio-Metabolic STAr, we continue to advance a number of additional programs, including our assets on ALN-AC3 an investigational RNAi therapeutic targeting APOCIII. We are very excited about this program, which like PCSK9 targets an exquisitely well validated human disease target in cardiovascular disease.

Finally we are also making strong progress in our Hepatic Infectious Disease STAr, and are on track to file our CTA for ALN-HPV in late 2015. We continue to be excited by ALN-HPV, as we believe that it has the potential to emerge as the Best in Class RNAi therapeutic in the field, with potential for a subcutaneous once monthly dosing profile, and a wide therapeutic window. In summary, we are making excellent progress on the RNAi therapeutics pipeline across all three STArs. It is certainly has been an especially exciting and productive time for all of us, as we continue to lead the translation of the science of RNAi towards the development of innovative medicines. I will turn the call over to Mike for a review of financials.

Thanks Akshay. I will be referring to slide 24, for a discussion of second quarter 2015 financial results. This quarter we maintained a solid balance sheet with $1.4 billion in cash, cash equivalents, and marketable secures. Our GAAP revenue for the second quarter of 2015 were $8.7 million, as compared to $7.3 million in the second quarter of 2014. GAAP revenues this quarter included $3.4 million from the alliance with Takeda, $2.6 million related to our alliance with The Medicines Company, $2.6 million from our alliance with Genzyme, and $0.1 million from research reagent licenses and other sources.

Moving to expenses, R&D expenses were $67 million in the second quarter of 2015, as compared to $44.7 million in the prior year period. This increase was due primarily to additional expenses associated with the significant advancement of a number of our clinical and preclinical programs. In addition, compensation, noncash stock-based compensation and related expenses increased during the second quarter of 2015, as compared to the second quarter of 2014, due primarily at the a significant increase in head count during the period, as we continue to advance our growing development pipeline.

We expect that R&D expenses will continue to increase in 2015, as we continue to expand and our pipeline across our three STArs. However, as of the first quarter of 2015, a significant portion of the expenses on our patisiran and Revusiran programs are being shared with Genzyme, pursuant to the terms of our license agreement. G&A expenses were $14.6 million in the second quarter of 2015, as compared to $11.5 million in the second quarter of 2014. This increase was due primarily to an increase in consulting and professional services, related to an increase in general business activities. For the remainder of 2015, we expect that G&A expenses will increase slightly in comparison to the first half of 2015.

The non-GAAP net loss for the second quarter of 2015 was $71.8 million, as compared to a non-GAAP net loss of $48 million for the same period in the previous year. The non-GAAP net loss for the second quarter of 2014 excludes the $3.9 million reduction to in-process R&D expense for the purchase of the Sirna RNAi assets from Merck. The GAAP net loss for the second quarter of 2015 was $71.8 million, as compared to a GAAP net loss of $44.1 million for the same period in the previous year. Regarding our equity investment in Regulus, the fair market value of our investment in Regulus as of June 30, 2015 was $64.6 million, as compared to $94.6 million as of December 31, 2014. With respect to guidance for 2015, we remain on track to finish the year with greater than $1.2 billion in cash, which we believe will continue to provide us with a strong balance sheet to execute on the Alnylam 2020 strategy. I will now turn the call over to Barry.

Thanks, Mike. As you heard from both John and Akshay, we have had a tremendously productive second quarter and recent period, as we continue to build the industry's leading pipeline of RNAi therapeutics, and advance our innovative investigational medicines to patients into the market. Now let's turn to our 2015 goals and guidance. As John mentioned, this will continue to be a very data rich period in the coming months. With regard to our patisiran program, we are on plan and continue to enroll patients in the Phase 3 APOLLO study. As mentioned, we currently have over 40 active sites in over 15 countries. As we previously guided, assuming a positive study, we expect that APOLLO will enable a possible NDA submission in the 2017 time frame. We also continue dosing patients in our patisiran Phase 2 OLE study, and plan to present additional data, including full 12 month data at ANA in September, and additional 18 month mNIS+7 data in the European TTR amyloidosis meeting in early November in Paris.

Now with Revusiran, we are currently enrolling FAC patients in our Phase 3 ENDEAVOR study, was are also dosing patients in a Phase 2 open label extension study, and we plan to present additional Revusiran data from that study in November, either at the European TTR amyloidosis meeting, or at AHA, pending abstract acceptance. Now moving to ALN-AT3, we are continuing to roll additional dose cohorts in the ongoing Phase 1 trial, including people with hemophilia receiving a monthly subcutaneous dose regimen. As Akshay mentioned, we plan to share additional data from this trial in late 2015. Likely at ASH in early December again, pending abstract acceptance. Also in late 2015, we plan to initiate dosing in the Phase 1 OLE study with ALN-AT3, in which people with hemophilia enrolled in the Phase 1 study can enroll in the OLE study, and receive ALN-AT3 on an ongoing basis for an extended period.

Turning to ALN-CC5, we continue dosing healthy volunteers in the multidose phase of our Phase 1/2 study, and plan to present initial data from these cohorts, as well as longer follow-up from the single dose cohorts in late 2015, also likely at ASH, pending abstract acceptance. In addition our plan is still to continue to enroll TNH patients in Part 2 of the study by the end of the year. With ALN-AS1 we announced today that we expect to present initial data from our Phase 1 trial at ICPT meeting September 15 ahead of schedule. ALN-AS1 has the potential to be a promising therapy for patients with hepatic porphyrias, and this upcoming presentation should be of great interest to the patient community and the clinicians and caregivers, who manage this devastating disease.

With ALN-AAT, the Phase 1/2 trial is now ongoing, we expect to present initial clinical data from the trial in early 2016. With our ALN GO1 program for the treatment of Primary Hyperoxaluria Type 1, we expect to select a development candidate in mid-2015, with an IND expected in 2016. We plan to present preclinical data from this program in an oral presentation at the European Society of Pediatric Nephrology, or ESPN Conference on September 5.

Turning to our Cardio-Metabolic STAr, with ALN-PCS we have completed enrollment in our Phase 1 study, and plan to present initial data in the trial at the ESD meeting on August 30. As John noted, we believe that achievement of an efficacious monthly subcutaneous profile will be highly competitive, as compared to anti-PCSK9 monochronal antibodies. And every month of additional durability is expected to provide yet further differentiation in this field. Now within our hepatic infectious disease STAr, we are continuing preclinical studies with ALN-HPV in support of a CTA filing, which we expect to happen later this year. ALN-HPV will mark our eighth pipeline program to enter clinical development. And wrapping up as Mike said, we remain on track to end the year with greater than $1.2 billion in cash. We want to remind everyone about our online RNAi round table series that we have been hosting. As we announced in our press release today, we have now filled out the rest of schedule with five remaining RNAi round tables to be held later in August and September, the details of which are shown here on slide 27. I invite you to attend. In summary, we are now poised for a very data rich back half of 2015. We very much look forward to sharing more updates from our pipeline in the coming weeks and months. At this point I would like to turn the call back to Josh. Josh.

Thanks a lot, Barry. Operator, we will now open the call up for questions. And as a reminder to those dialed in, we would like to ask you to limit your questions to two each.

(Operator Instructions). Our first question from Anupam Rama with JPMorgan.

Hi, guys. Thanks so much for taking the question. I know you announced a development candidate today for targeting TTR, that could support once monthly or even quarterly dosing. I'm wondering if you could help put into context the improvement in potential dosing frequency into the context of the medical unmet need in FAP and FAC that you are seeing? Thanks.

It as great question and before I turn it over to Akshay to answer the question fully, I will just say that we are very excited about this development candidate. It has been in the works for quite some time, and we will share a lot of specific data on this at the OTS meeting in October, which is being held in Europe some place this year. Netherlands. Let me now turn it over to Akshay to address the second part of your question.

We are very committed and have been for some time to the TTR space and range of disease, FAP and FAC and SSA, and we are developing a range of options and we have intravenous patisiran, we also have subcutaneous approaches. TTR SCR2, our announcement today looks to us based on everything we understand about these ESC SRNa conjugates that we are building now, to be far and away the most potent and best conjugate we have built in association with the program, and it looks at least based on animal work, like it could readily be a once monthly or once quarterly injection at low doses, and I think ultimately a product like that is going to be very important in the management of these patients as we look across the spectrum of TTR diseases, and we will feather that in, and create that as an option for patients, at the entire sort of program is developed. But we are pretty excited and confident based on our understanding of the ESC platform, that this is going to be a very important low dose infrequent option for patients.

Awesome. Thanks for taking our question.

Thanks Anupam.

Our next question comes from Ritu Baral with Cowen.

Hi, guys. Thanks for taking the question.

Thanks Ritu.

Could we get a little more detail on the FAC injection site reactions that you mentioned? Could you characterize the diffuse rash a little better, and where along the treatment duration did the really problematic reactions emerge, since it was in the open-label?

Sure. Akshay.

Sure. Ritu, we described three patients today that had discontinuations, and of the three, two had diffuse rash. By diffuse rash, I mean is the rash being somewhere beyond the injection site, and with respect to where they were in terms of the duration of the exposure, I think all of the patients are out into many months of exposure, they are all at slightly varying stages, and these patients weren't necessarily the most advanced in terms of the expense of exposure. In fact, there are other patients who have been dosed longer and are doing just fine. I don't think there is any evidence that this is some exposure based event.

So there was no associated anaphylactoid reactions, or did they have reactions that got worse and worse? Or was it sort of--?

No, none that were reported. And in fact, there were no sort of anaphylactic reaction or reactions that got worse and worse.

My second question is on the porphyria data. Given it is so early that, was that just a function of enrollment, or were you seeing a biological effect or biochemical effect earlier than you had expected?

Let me answer that. I mean obviously we have to wait just a few weeks here before we talk about the specific effects, and any data regarding that. We, of course, are able to look at these patients. We have had good enrollment in this study. The study is being performed in Sweden. The site there is extremely poised. They have done studies in these ASHE patients before, and so we have been very pleased the enrollment. That has helped considerably, but let's wait until the mid-September meeting in Germany, and we'll have an opportunity of sharing those specific data with you.

Got it. Fair enough. I had to try. Thanks guys.

Thanks Ritu.

Our next question comes from Robyn Karnauskas with Deutsche Bank.

Hi, guys. This is [Ale] on for Robyn. Thanks for taking the questions.

How are you?

Good, how are you?

Great.

So my first question is on PCSK9. At this upcoming readout will we get a good feel if quarterly dosing is possible? And secondly, how do you think the recent approvals and labels affect your market opportunity?

So I will answer the first part, and then maybe Barry can answer the second part. Obviously in the study we are going to report all of the data we have got. IT is about 70 subjects worth of data. These are subjects that had elevated LDL cholesterol at baseline, in the multidose phase of the study we also explored on statins and off statins, and we've been able to follow subjects beyond 90 days, from the single dose phase of the study. So to the extent that the pharmacology supports quarterly dosing, we will be able to infer that very clearly from the quarterly dose, from the subjects that get single doses that are followed for considerable long periods of time. I think we will certainly be able to address the profile of the drug at this upcoming presentation, and let's just wait for the presentation before we get into any further detail. Barry, want to talk with about the recent approval and label.

Absolutely.

Or thoughts on that?

Absolutely. And just to emphasize the point we made earlier, it is a first in class synthesis inhibitor with a once monthly or less frequent subcutaneous opportunity, we think is incredibly competitive. From the regulatory path perspective, setting up the commercial opportunity, we find tremendous synergy between our belief set and has now been proved out in Europe and the US, which is that on LDL lowering, as long as the cardiovascular outcome study is up and running, a drug with can be approved. We find that rewarding as well at the label that was granted so far, and the pricing is consistent with our belief set. That $10,000 to $15,000 per year price set, so they are defining the market that the first in class RNAi synthesis inhibitor can come behind, and I think have a big impact on the market that being defined by the PCSK9 antibodies.

Great thanks. And just a quick follow-up on Hemophilia. Can you characterize the PK or just context as to what doses we might start to move into the thresholds of over and greater than 66% knockdown?

I think what you are asking what doses will get us to the consistent over 66% knockdown?

Yes, yes.

The first dose cohort monthly is using the equivalent of 75 micrograms per kilogram times three monthly, in other words 225 micrograms per kilogram monthly, and we are going to be very likely exploring dose escalation as well beyond that dose, and again we will have a considerable number of additional subjects 9 to potentially 12 patients worth of data at ASH, again pending abstract acceptance. There will be a lot of information there, and we are very encouraged by the program. We thought the data at ISTH were very exciting. And we believe that we will continue to show the important approach that this can present for hemophilia patients.

Great. Thanks, guys.

Great. Thank you.

The next question from Geoff Meacham with Barclays.

Actually Mike in for Jeff. With respect to the ALN-CC5 program you mentioned beginning dosing in PNH by year end 2015. Remind us what endpoints you will be looking at there, and sort of how you are thinking of the bar to sort of move that program forward? Thanks.

Let me have Akshay answer that.

First and foremost we want to understand safety in that population. Beyond that, PNH patients with the validation of C5 as a target offer a range of other very important biochemical and other endpoints. LDH is a very important marker for clinical efficacy, and just as Eculizumab has shown, we hope to show reductions in LDH, and underlying that the basis for that reduction in LDH. Reductions in hemolysis, which will associated with reductions in C5, so we also aim to show substantial reductions in C5 levels, just as we have begun to show in the Phase 1 study in healthy volunteers, associated with significant suppression of serum hemolysis. Those are some of the key data sets. I think that they set us up hopefully to show clear validation of ALN-CC5 for PNH, accelerating us into Phase 3.

And just add to Akshay's comments, Mike, that at ASH, at the upcoming ASH meeting, we would expect to have the results of our single dose, complete single dose results combined with multidose results, and our expectation is very much that we will see a very complete inhibition of serum hemolytic activity, just as we see in the nonhuman primates. That is something that we will present in December. And then by starting our first PNH patients by the end of the year, we would expect to see these type of LDH data that are very derisking and important, probably sometime in 2016. But that is how you can expect the news flow to go on that program at this point.

Okay. Great. Thanks, guys.

Thank you.

The next question from Terence Flynn with Goldman Sachs.

This is Cameron filling in for Terence. Thanks for taking our question.

Hi, how are you?

Doing great, thanks. Just a follow-up on the rash in the press release, can you give us any more details on the severity of the rash, and how these patients were treated? Were they biopsied? And if so can you tell us what the findings were? And finally, were these the three patients part of the initial cohort of six patients that had a rash, or are they different patients? Thanks.

Akshay, do you want to handle that?

Yes, so in terms of severity the two patients with the diffuse rash. One was mild and one was deemed to be severe. Neither were serious adverse events, so not of the magnitude that would require hospitalization or anything. It all resolved spontaneously, and so really required no specific treatment that I need to describe, and in terms of the investigation of biopsy, or such, of course we are bringing you all of the clinical data as we have it today. We are doing everything to understand these events, and at the later disclosure in the year, when we will announce the six month data on the study, we will have many more details and we will share at that time.

The next question comes from Alan Carr with Needham & Company.

Thanks for taking my questions.

Hi.

Hi. Coming back to the rash, anything you are running a Phase 3 also. Can you comment on what you are seeing from a safety perspective there around the rash, and discontinuation rate? And then also with the AS1 program moving along here, do you have any estimates of when that might move into registration trials? Would that be a little sooner than you expected? Thanks.

Sure, Alan. Akshay, do you want to handle both those questions?

Sure, yes. With respect to the Revusiran and rashes in Phase 3 ENDEAVOR study, of course we started that study towards the end of last year. It is proceeding nicely, more details to follow. With the respect to the safety itself, it is a randomized double-blind placebo-controlled study, so I'm sure Alan, you are not surprised to hear me say that I can't really speak to the safety. But suffice it to say that the overall conduct of the study is fine, and ongoing, and we are excited to continue with it.

With respect to the AS1, as we announced today we are excited to present the initial data on the study, and we will be looking at very important biochemical markers, such as LNPPG, which is the mediator that is believed to off acute intermittent porphyria, and as that data set develops through this year and early part of next year, I think we will want to give guidance with the additional understanding of the impact of those effect in actual recurrent attack patients, which we intend to enroll in that study, we will be able to give guidance later this year early part of next year, on the plan as to the pivotal. But suffice it to say that we are obviously excited that we are slightly ahead of schedule, with are presenting the data that we intend to present.

I will just add to that, Alan, that obviously the Phase 1 study, the porphyria study is going to go into recurrent attack patients as sort of Part C of that study, and then once we demonstrate in an open label fashion encouraging data there in addition to potential effects on these biochemical markers, really the plan would be to go right to a Phase 2/3 or pivotal study, of course pending discussions with regulators. I think it will move quickly as a program, and of course, the other aspect of this program is the enormous unmet need for new therapies here. I think it will be of great interest for people to see how we have been able to quantify the disease burden in porphyria in this EXPLORE prospective natural history study, because these are subjects that have a very, very poor quality of life for sure. So you will see more of that in mid-September.

Great. Thanks for taking my questions.

Thanks, Alan.

Our next question cops from Mike King with JMP Securities.

Good afternoon.

Hi, Mike.

Thanks for taking my questions. I just wanted to, I don't want to harp on this incidence of rash, but I did want to come back to Akshay, because I'm not sure he answered the previous question, regarding the denominator of patients, so this was three out of how many at the time that were in the Revusiran OLE?

Akshay can comment as well. The answer there is of the patients that went into OLE, 25 patients went into the OLE.

Sorry. I think the question asked about six patients.

There are not six patients. 25 patients went into the OLE.

It is no three out of six, it is three out of 25?

Yes.

That is a lot different. And then I'm just curious remind us again about, you characterized the new TTR inhibitor as a second gen chemistry, but I thought technically Revusiran was second gen chemistry. Perhaps you could just illuminate for us what the difference between Revusiran would be relative to the new TTR inhibitor?

Akshay, want to handle that?

Sure. Revusiran is the first conjugate we built, Mike, and that was the first clinic, and the first to show that the GalNAc conjugate siRNAs could be very effectively delivered to these sites. It being the first generation, naturally the potency and the dose required is higher from what we have seen with subsequent use of chemistries with the second generation, that we call ESC GalNAcs. In fact, the entire pipeline beyond patisiran and Revusiran, all of these other amazing programs that we are now exploring, hemophilia, C5, porphyria, et cetera, these are all based on second generation chemistry PCS, et cetera. One of the learnings from that, and I think we have reported data both for AT3 and C5 is the substantially greater potency associated with the second generation, and durability which leads to us make these statements. Q monthly, Q quarterly dosing at lower doses, with all of the those programs and the second generation ESC GalNAc. And of course with that as you reduce exposure, or exposure related adverse events would also go down, so overall it is a very exciting package I think that the ESC--

Right. So if I can sort of paraphrase from your comments, Akshay, the Revusiran is different than every construct that comes behind it, correct?

That is exactly right, yes.

That's correct, Mike.

Great. Super. I want to shift can quickly to patisiran, to ask you I know John we had spoken recently a couple of weeks ago about your taking a look after 100 patients had been on patisiran for 18 months. But I'm also, I'm asking is there a possibility of either a shorter interval or lesser number of patients now, that you would be comfortable talking about, as far as when the next analysis occurs, or is that number still fixed?

Yes, no, Mike I think what we have discussed is what the potential is for an interim analysis for efficacy with the APOLLO study, and where we are on that, is we are going to have discussions with FDA and EMA to explore that. What I think I commented to you is that it would be reasonable to consider something like half of the study population at the 18 month endpoint, as a type of way of doing that type of analysis, which would take you into sometime next year for when that would take place. If and when we reach agreement with the regulatory authorities on this, we will come back and provide guidance. There are other reasons to not do it, right. There are other reasons to say, let's not take a hit on our power, and just complete up the study. We will have to, we will get back to you on that when we have clarity with regulators on the path forward. But what I was referring to is really a logical way to think about doing an IEA, would be at sort of the mid-mark from an accrual standpoint at the 18 month endpoint.

Great. Thanks for the clarification.

Great. Thanks, Mike.

Our next question comes from Ted Tenthoff of Piper Jaffray.

Great, thanks. Can you hear me okay?

Yes. Hi, Ted.

Thanks so much for the thorough update. A lot of questions answered. Just a quick one, if I may on Hepatitis B. Obviously a very dynamic market. So really where do you sort of see the role of RNAi is fitting into the Hepatitis B therapy? And remind me if you would, sort of what the construct, or what ALN-HPV actually is? Are there multiple sequences within that?

Yes. Let's address the first question, and then the second question. So in terms of where this fits in, I mean we believe and the community believes and agrees with us, that an agent that can substantially knockdown surface antigen, has the potential of changing the dynamic of how HPV is managed. Surface antigen is known to be tolerogenic, it is one of the mechanisms whereby HPV can elude immune detection. Clearly having an agent like an RNAi therapeutic that can substantially knockdown, and significant multilog knockdown of surface antigen is something that we think we can achieve with ALN-HPV. I often refer to the Regulus data with RG-101 as an interesting data point, they are using our GalNAc technology. Look at how impressive they have seen antiviral effects towards HCP, and we think that is the type of knockdown of surface antigen that we can achieve with our drug. So that is really the key part of where it fits in. We always see it as being used on top of nukes. It would be illogical not to add it on top of nukes, and as a result of that, using a single sRNA, is something which will be fully able to be done without any emergence or resistance, because there is no active replication of the virus. So we will be able to shutdown surface antigen levels very effectively on top of nucleoside analogs, and therefore not have active replications of the virus. And it is a single sRNA.

I was going to also add, John, that we talked about the fact that ALN-HPV hits all four transcripts.

That's right.

Okay, got you. And then if I may just sort of sneak in a real follow-up there. Seems like HPV is sort of outside of this orphan concept. I mean certainly a large or a liver focused disease, but outside of the orphan concept, so where would you guys I mean, is this something you would take further yourselves? Something you would ultimately partner? Maybe a little bit early to kind of figure that out, but what are kind of your long-term strategy here with ALN-HPV?

Ted, it is a great question. As you know, we are developing and broadening our efforts beyond just genetic medicines with our Cardio-Metabolic Disease STAr as well as our Hepatic Infectious Disease STAr. These are all areas we think our GalNAc platform, and our ability to target any liver expressed disease gene, makes sense for us as a Company to go toward. Specifically with HPV and partnering, we will certainly have a global partner there for ex-US and ex-Europe, but we plan on maintaining our US and European rights for that program, because that is a commercial footprint that we plan on building as an organization. We are not a Company that is going to license away substantial product rights. We want to retain that value for our shareholders, and we think it is ultimately the best way to build value as a Company. So HPV will stay in our hands, at least in our territories, but we will probably for Asia and other parts of the world, find partners to help us advance that program.

Great. That is super helpful. Thanks, guys.

Great. Thank you.

The next question interest Michael Schmidt with Leerink.

Good afternoon. Thanks for taking my questions.

Hi, Michael.

Hey. Sorry to harp on this, but one more on the rash. My question there is or for were these one-off events, or did they occur repeatedly in the same patients, and what might a logic explanation be, and the other question is on PCSK9 I know The Medicines Company is talking over Phase 2 development, but I was wondering what Phase 2 plans might look like in terms of magnitude and extent and timing?

I think on the second one first if I may. And then I will hand over to Akshay. We will give more guidance on that in the coming weeks, right. As we present data there will be additional guidance in terms of plans going forward. So please stay tuned on that one, Michael. But then Akshay, do you want to handle the first question?

Recap the first question were they recurrent was the question?

Recurrent or one-off events, and what might sort of the mechanistic explanation be?

In terms of mechanism, I think we will accept that subcutaneous therapeutics regardless of class are associated at some discrete level with injection site reactions, even with Revusiran in the Phase 2 study, we reported some injection site reactions which in some subjects were recurrent. So no surprise there for us. And indeed, in these three individuals, some of them were recurrent. The diffuse rash that I described wasn't a recurrent diffuse rash as such. And that is how we have got the clinical understanding at the moment. With respect to the pathophysiology I think somebody else asked about if we got biopsies, we are trying to understand all of this right now, and later in the year when we present the six month data, we will present all of the laboratory analyses that we are doing, to try and characterize this further. But the clinical understanding is as I have described it today and in the press release.

And I would just add, Michael, that this is related to other oligo nucleotide therapies as well. Drisapersen has an over 70% incidence of injection site reactions. Mipomersen has equally great level of injection site reactions. We are not seeing that high of an incidence in our study. And so this is really oligo nucleotide type things. It also happens with other classes of drugs, it happens with protein therapeutics, emberal, others, so it is part of drug development, and obviously something which we want to be transparent about, and that is why we are reporting it. The full data will come out when we present our data in November with the six month update from Revusiran. The good news is that patients, the vast majority of the patients are tolerating the drug well, and continue on study.

Understood. Great. Thank you.

Thank you.

I'm not showing any questions at this time. I would like to turn the conference back over to our host.

Okay. Thank you everybody, appreciate the time today. As I said earlier this is going to be a very data rich period in the back half of the year, and we can't wait to share all of the data with you. Thank you, bye bye.

Ladies and gentlemen, this does concludes today's presentation. You may now disconnect. And have a wonderful day.