Alnylam Pharmaceuticals (ALNY) John M. Maraganore on Q2 2016 Results - Earnings Call Transcript

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Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY) Q2 2016 Earnings Call August 4, 2016 4:30 PM ET

Executives

Christine Regan Lindenboom - VP-Investor Relations & Corporate Communications

John M. Maraganore - Chief Executive Officer & Director

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Michael Mason - Vice President of Finance and Treasurer, Alnylam Pharmaceuticals, Inc.

Barry E. Greene - President & Chief Operating Officer

Analysts

Ritu Baral - Cowen & Co. LLC

Gena Wang - Jefferies LLC

David N. Lebowitz - Morgan Stanley & Co. LLC

Alan Carr - Needham & Co. LLC

Eliana Merle - Credit Suisse Securities (NYSE:USA) LLC (Broker)

Anupam Rama - JPMorgan Securities LLC

Mike G. King - JMP Securities LLC

Madhu Kumar - Chardan Capital Markets LLC

Ted A. Tenthoff - Piper Jaffray & Co. (Broker)

Operator

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to Discuss Second Quarter 2016 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 would now like to turn the call over to the company.

Christine Regan Lindenboom - VP-Investor Relations & Corporate Communications

Good afternoon. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Executive Officer; Barry Greene, President and Chief Operating Officer; Akshay Vaishnaw, Executive Vice President of R&D and Chief Medical Officer; and Mike Mason, Vice President of Finance and Treasurer. In addition, DA Gros, Senior Vice President and Chief Business Officer, is in the room and available for Q&A.

For those of you participating via conference call, the webcast slides can also be accessed by going to the investor page of our website, www.alnylam.com. During today's call, as outlined in slide two, John will provide some introductory remarks and provide some general context; Akshay will then summarize recent clinical progress; Mike will review our financials and Barry will provide a brief summary of our 2016 goals and beyond before opening the call to your question.

Before we begin, I would like to remind you that this call contains remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as well as results of various important factors, including those discussed in our most recently 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 on any subsequent date. We specifically disclaim any obligation to update such statements except as maybe required by law.

With that, I would like to turn the call over to John.

John M. Maraganore - Chief Executive Officer & Director

Thanks, Christine, and thank you, everyone, for joining us on this beautiful afternoon. The second quarter and recent period were once again marked by important progress as we advanced RNAi therapeutics through clinical trials and toward the market. Akshay will go into our recent pipeline progress in more detail. But I would first like to provide some overall context.

First, these are certainly exciting times at Alnylam, as we continue to execute on our Alnylam 2020 strategy. As a reminder, Alnylam 2020 is our goal to build a multi-product commercial stage company with a deep and sustainable clinical pipeline by the end of 2020, achieving a profile that has rarely been achieved in our industry and that is comparable to a top five biotech.

To that end, we are at an important stage of growth in the company where we're expanding the needed capabilities in our R&D organization, growing our manufacturing and quality efforts and seeding the beginnings of our commercial teams in both the U.S. and European Union.

Second, I'd like to provide some context on key quarter two and recent period clinical data readouts across our pipeline. With both patisiran and fitusiran, we achieved what we believe to be important positive results. Specifically, we reported 24-month data from our Phase 2 open label study showing that patisiran continues to be generally well tolerated and has the potential to halt or possibly even improve the neuropathy progression in patients with hATTR.

More recently with our fitusiran program in hemophilia and rare bleeding disorders, we were very pleased to report interim Phase 1 data just last week at the World Federation of Hemophilia meeting and showing a median estimated ABR of 0 in patients with hemophilia A or B without inhibitors along with encouraging initial data in patients with inhibitors, and importantly, an encouraging safety profile with no related SAEs and no thromboembolic events through the data cutoff date. These new data sets with patisiran and fitusiran highlight what we believe to be the transformative potential for RNAi therapeutics.

We also reported clinical data from our revusiran program in hATTR cardiomyopathy patients, where we believe results are slightly too early to interpret as they relate to clinical endpoints in hATTR cardiomyopathy. We continue to believe that we'll need to await results from our controlled studies, namely from ENDEAVOUR as well as the cardiac subgroup in APOLLO to truly assess the effect of TTR knockdown on clinical outcomes in the setting of hATTR cardiomyopathy.

And then, we reported our initial PNH patient data with ALN-CC5 at EHA. These data have driven a shift in our ALN-CC5 strategy, where we're planning to execute on this change in a Phase 1/Phase 2 study in eculizumab inadequate responder patients later this year.

In some, we believe that our Q2 and recent clinical data readouts have been highly informative for the advancement of these important clinical programs, and we're very encouraged by the potential for all of these programs to make a difference in patients' lives.

Finally, over the second quarter period, Alnylam achieved a new milestone of having 10 programs in clinical development and having now enrolled over 1,000 cumulative patients in our clinical studies. In addition to the four programs I mentioned earlier, these 10 investigational clinical programs include many promising programs across our three strategic therapeutic areas, or STArs.

Furthermore, our partners at The Medicines Company completed enrollment in the ORION-1 Phase 2 trial of ALN-PCSsc during the second quarter, and this 501-patient study represents the largest single trial for an investigational RNAi therapeutic ever conducted. So, in addition to our Q2 and recent clinical results, we're also very pleased with the excellent progress our team is making on drug discovery, R&D filings, clinical trial starts and patient enrollment, the operational nuts and bolts of drug development.

Importantly, because of this high quality execution, the back half of 2016 is now poised to include data readouts from almost all of these programs, in addition to more data from fitusiran and ALN-CC5. With all of these clinical data readouts in the coming months, we believe it will be a highly informative period throughout the rest of the year, and we really can't wait to share our results as they mature.

With those introductory comments, I'd like to now turn the call over to Akshay to review our pipeline progress in more detail. Akshay?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Thanks, John, and good afternoon, everyone. We've indeed continued to make great progress with our pipeline of investigational RNAi therapeutics. I'll begin with the programs in our Genetic Medicines STAr and start with our RNAi therapeutics for the treatment of TTR amyloidosis or ATTR amyloidosis.

As you know, we have multiple product candidates in this area. Let's start with patisiran, our most advanced effort, which we're developing for the treatment of hereditary ATTR amyloidosis with polyneuropathy, or hATTR-PN. At the ISA meeting last month, we reported initial 24-month data from our open-label extension, or OLE, study.

These results continue to provide evidence that patisiran administration has the potential to halt or improve neuropathy progression in patients with hATTR-PN. Specifically, as shown on slide seven, our new data showed a mean 6.7% decrease in mNIS+7 at 24 months in the 24 patients with data available from this current analysis.

We believe this is a very encouraging result and compares very favorably to an expected mean increase in mNIS+7 of 26 points to 30 points at 24 months, estimated from analyses of historical data sets in untreated hATTR-PN patients with similar baseline characteristics. Furthermore, 71% of patients had either an improvement or no change in their mNIS+7 at 24 months. The maximal individual improvement in mNIS+7 observed was a decrease of 35 points. We continue to be very encouraged by the generally favorable safety profile we've seen with patisiran with treatment out to 25 months.

SAEs were reported in six patients and all were reported as unrelated to study drug. The majority of reported adverse events were mild to moderate.

At the ISA meeting last month, we also reported on the baseline demographics with patients enrolled in APOLLO. As shown in this slide, the 225-patient Phase 3 study represents a truly global patient population with over 55 unique TTR mutations and enrollment at 44 sites in 19 countries.

Of note, 54% of patients entered the study with cardiac involvement at baseline. Since APOLLO includes a number of secondary and exploratory endpoints regarding cardiac measures, we'll certainly be interested in seeing how patisiran performs here as compared with placebo, and this may inform further discussions with the regulators.

In summary, we're very pleased with the progress on our patisiran program. Our results support the therapeutic hypothesis that TTR knockdown with patisiran has the potential to halt or even improve neuropathy progression. We believe these results bode well for our APOLLO Phase 3 trial, which is fully enrolled and where we expect to report top-line results in just a little over a year from now.

Assuming positive data from APOLLO, we expect to file our first regulatory applications for approval in late 2017.

Let's now turn to revusiran, our most advanced subcutaneously administered RNAi therapeutic in the clinic today, focused on the treatment of ATTR amyloidosis patients with cardiomyopathy or hATTR-CM. As a reminder, revusiran employs our first-generation standard template chemistry, or STC, GalNAc-conjugate technology.

As John alluded to earlier, the patients comprising our Phase 2 OLE study population are relatively advanced in their disease course with a mean time from diagnosis to first dose of 35 months. hATTR-CM is a terrible disease that is generally fatal within a few years of diagnosis, not unlike cancer. So, our Phase 2 OLE patients comprise a rather advanced study population. And to put this in context, the mean time from diagnosis to first dose is approximately one year for the first 139 patients enrolled in our ENDEAVOUR Phase 3 trial.

Regarding clinical activity, revusiran achieved robust and sustained TTR knockdown over 18 months, with an up to 98% maximum and 88% mean maximum knockdown of TTR.

In terms of 6-minute walk distance, we were pleased to see that the majority of evaluable hATTR-CM patients, five out of nine to be precise, exhibited generally stable 6-minute walk distance results. In terms of safety, 14 patients in the revusiran OLE presented with serious adverse events. One SAE was deemed possibly related to study drug, a case of lactic acidosis in a patient with many other complicating factors.

There were a total of seven deaths, all of which were unrelated to study drug. The majority of AEs were mild to moderate in severity and included injection site reactions in 12 patients. Importantly, beyond the three cases reported on at the ECATTR conference last November, there were no further discontinuations due to ISRs.

In summary with revusiran, we continue to believe that we'll need to await results from controlled studies, namely from ENDEAVOUR, as well as from cardiac subgroup analyses in APOLLO to evaluate the effect of TTR knockdown on clinical outcomes in hATTR-CM.

Also, we recently guided that the enrollment in ENDEAVOUR is proceeding well. Indeed, we now expect to complete enrollment by the end of the summer putting us in a position to present initial top-line data in early 2018.

And finally, within our ATTR amyloidosis portfolio, we initiated a Phase 1 trial for ALN-TTRsc02, an ESC-GalNAc-siRNA conjugate targeting TTR. Based on the preclinical profile of this candidate as well as the emerging clinical profiles of other ESC-GalNAc conjugates in our pipeline, we believe that ALN-TTRsc02 has the potential to support a low volume once-quarterly subcutaneous dose regimen.

Beyond our ATTR programs, another exciting milestone in the recent period was the presentation of interim Phase 1 results with fitusiran or ALN-AT3 which we're developing for the treatment of hemophilia and rare bleeding disorders. Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis, thereby preventing bleeding in patients with hemophilia and rare bleeding disorders.

As a once-monthly low volume fixed dose subcutaneous prophylactic treatment option that could be shown to provide durable and consistent bleed prevention without the risk of antidrug antibodies and without the peaks and troughs found with factor replacement, we believe that fitusiran could positively change the paradigm of hemophilia treatment.

Data presented last week at the WFH meeting showed that monthly subcutaneous dosing with fitusiran achieved dose-dependent AT lowering, increases in thrombin generation and a median estimated annualized bleeding rate, or ABR, of 0 in patients with hemophilia A or B without inhibitors.

Furthermore, in the initial low dose cohorts, in patients with inhibitors, where patients received a once-monthly fixed dose of 50 milligrams, fitusiran achieved antithrombin lowering, increased thrombin generation, and preliminary evidence for reduced bleeding. We'd be interested in seeing how these data mature with longer follow-up, as well as how fitusiran performs in inhibitor patients in the second cohort, where they're now receiving an 80-milligram fixed dose.

We also remain encouraged by the safety profile for fitusiran. As reported at WFH, fitusiran administration was generally well tolerated in patients with and without inhibitors, with no SAEs related to study drug and no thromboembolic events or laboratory evidence of pathologic clot formation through the data transfer date. One patient discontinued due to a severe AE, being possibly related to drug, an event of non-cardiac chest pain that resulted in the symptomatic management using analgesics and antacids.

As we announced at WFH we updated our Phase 3 guidance following initial constructive discussions with U.S. and European regulators and now plan to be in pivotal trials in early 2017.

We're also actively enrolling Phase 1 patients over into fitusiran Phase 1/2 OLE study where 21 patients have now received up to 13 months of dosing. We look forward to sharing initial data from this study later in the year, likely at the ASH conference in December.

These are indeed very exciting times for people living with hemophilia and we believe that fitusiran has the potential of becoming an important treatment option for them in the future.

Turning now to our recent progress with ALN-CC5 in development for the treatment of complement-mediated diseases; at the European Hematology Association meeting in June we presented initial data from six patients with paroxysmal nocturnal hemoglobinuria, or PNH.

In patients who were eculizumab or Ecu naïve, we observed impressive knockdown of serum C5 of up to 99%. While there was an up to 50% lowering of lactate dehydrogenase, or LDH, a marker of red cell hemolysis, LDH levels were not reduced to a level below 1.5 times the upper limit of normal, which is the goal for management of PNH.

On the other hand, exploratory evidence was obtained demonstrating that ALN-CC5 has the potential to reduce the dosing frequency of Ecu administration. We also demonstrated that ALN-CC5 administration to an inadequate responder patient resulted in rapid reduction of LDH to below 1.5 times the upper limit of normal with associated clinical improvement.

ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events being mild or moderate in severity. While it's important to keep in mind that this is a small study with just fixed PNH patients, these findings have informed what we believe to be an exciting path forward for the program. Specifically, in PNH, durable hepatic C5 synthesis inhibition with ALN-CC5 could improve overall disease management and quality of life and also reduce the burdens associated with frequent intravenous infusions required for the anti-C5 monoclonal antibody therapy.

We plan to explore the potential for ALN-CC5 in patients who are inadequate responders to eculizumab as well as for sparing of anti-C5 monoclonal antibodies. We believe that at least 20% to 30% of PNH patients require higher than label doses of Ecu, and that significant unmet medical need exists for these patients and their caregivers. We look forward to evaluating ALN-CC5 further, both in ongoing analyses of PNH patients in the current Phase 1/2 study, and in a Phase 2 study initially in inadequate responder patients that we expect to start by year's end.

We also see a potential broader opportunity for ALN-CC5 as mono-therapy in a number of complement-mediated diseases, where there is no CD55, CD59 deficiency, including aHUS and myasthenia gravis and we expect to begin studies in one or more of these diseases in 2017.

We've also continued to make strong progress across the rest of our Genetic Medicines pipeline. In our ALN-AS1 program in acute hepatic porphyrias, we're targeting an enzyme ALAS1 in the heme biosynthesis pathway that's self-regulated and leads to accumulation of the toxic attack-causing heme synthesis intermediates ALA and PBG. By targeting ALAS1, we aim to decrease flux through the pathway, reducing levels of ALA and PBG and reduce porphyria attacks.

In our initial report last September, we presented preliminary data from asymptomatic porphyria patients, showing that we can silence ALAS1 and reduce levels of ALA and PBG. Next month, we plan on updating you on results from asymptomatic patients in Parts A and B of the Phase 1 study.

In the meantime, we are currently dosing symptomatic patients in Part C of the Phase 1 study, where ALN-AS1 is being evaluated in recurrent attack porphyria patients. Here, we will look to see whether ALN-AS1 can reduce the frequency and severity of porphyria attacks in these patients.

Our goal is to present initial data from Part C later this year. If these Phase 1 data are positive we plan to advance to a Phase 3 trial in 2017.

Turning to ALN-AAT for the treatment of alpha-1 antitrypsin deficiency associated liver disease, we continue with our ongoing Phase 1/2 study and we plan to present initial data at the OTS conference in September.

We are also developing ALN-GO1 for the treatment of primary hyperoxaluria type 1, or PH1. We believe ALN-GO1 has the potential to lower oxalate levels and prevent the formation of kidney stones and renal damage in patients with PH1. The ongoing Phase 1/2 trial is being conducted initially in normal healthy volunteers, and will soon move into patients with PH1.

We are pleased to announce today that we plan on sharing initial human healthy volunteer data from the trial at the IPNA meeting next month.

I will now turn to a review of progress from our Cardio-Metabolic Disease pipeline. Of course, our leading program in this STAr is ALN-PCSsc which targets PCSK9. As a reminder, ALN-PCSsc is an investigational RNAi therapeutic targeting PCSK9, with the potential for a once quarterly or even biannual subcutaneous dosing regimen. As John noted earlier, our partners at The Medicines Company recently announced completion of enrollment of the ORION Phase 2 trial for ALN-PCSsc with 501 patients with atherosclerotic cardiovascular disease.

The Medicines Company have guided that they expect to report initial data from the trial later this year, and more recently confirmed that they are on track. We'd expect that this report will occur at the AHA meeting in November, pending abstract acceptance. It's worth noting that these data constitute the largest single study safety database of an ESC-GalNAc conjugate to date.

Finally, we're also making strong progress in our hepatic infectious disease STArs and recently initiated our Phase 1/2 trial of the ALN-HBV, which we're developing for chronic hepatitis B virus infection. The study is being conducted initially in healthy volunteers to evaluate safety and will then move into patients infected with HBV.

We continue to be very excited about this program as we believe that it could emerge as the best-in-class RNAi therapeutic in the field with potential for subcutaneous, once-monthly or once-quarterly dosing profile and a wide therapeutic window. Initial data from the Phase 1/2 trial are expected in mid-2017.

In summary, we believe we're making excellent progress on programs in our RNAi therapeutics pipeline across all three STArs. It's really been an especially exciting and productive time for us as we continue to lead the translation of the science of RNAi toward the development of innovative medicines. We very much look forward to sharing additional clinical data with you in the back half of the year.

And with that, I'll now turn the call over to Mike for a review of our financials. Mike?

Michael Mason - Vice President of Finance and Treasurer, Alnylam Pharmaceuticals, Inc.

Thanks, Akshay.

I will be referring to slide 21 for a discussion of our second quarter 2016 financial results. We continue to maintain a strong balance sheet ending the second quarter of 2016 with approximately $1.28 billion in cash, including $150 million in restricted investments, from the credit agreements executed in April 2016, as compared coincidentally to the same amount at December 31, 2015.

Our financial strength allows us to continue to invest in a broad pipeline of investigational RNAi therapeutics across our three STArs, aligned with achieving our Alnylam 2020 goal. As for financial guidance this year, we remain on track to end 2016 with greater than $1 billion in cash including $150 million in restricted investments.

The GAAP net loss for the second quarter of 2016 was $90.1 million or $1.05 per share on both the basic and diluted basis as compared to a net loss of $71.8 million or $0.85 per share on both the basic and diluted basis for the same period in the previous year. Revenues were $8.7 million for the second quarter of 2016 and 2015.

Revenues for the second quarter of 2016 included $5.4 million from our alliance with Sanofi Genzyme and $3.3 million from our alliance with The Medicines Company. We expect net revenues from collaborators to increase during the remainder of 2016 due to an expected increase in expense reimbursement for our agreement with Sanofi Genzyme.

R&D expenses were $83.2 million in the second quarter of 2016, which included $9.3 million of non-cash stock-based compensation as compared to $67 million in the second quarter of 2015, which included $6.1 million of non-cash stock-based compensation. The increase in R&D expenses as compared to the prior year period was due primarily to higher compensation and related expenses and non-cash stock-based compensation expenses resulting from a significant increase in head count during the period as the company continues to advance and expand its development pipeline.

In addition, clinical trial manufacturing and external services expenses also increased during the second quarter as compared to the second quarter of 2015 as a result of the significant advancement of our Genetic Medicines pipeline. We expect that during the second half of 2016, R&D expenses will increase compared to the first half of 2016 as we continue to develop our pipeline and advance our product candidates. However, we expect that such expenses will be variable on a quarterly basis depending on the timing of manufacturing batches, clinical trial enrollment and non-cash stock-based compensation expenses.

Finally, G&A expenses were $18 million in the second quarter of 2016, which included $6.5 million of non-cash stock-based compensation as compared to $14.6 million in the second quarter of 2015, which included $4 million of non-cash stock-based compensation.

G&A expenses increased relative to the same period in 2015 due primarily to an increase in compensation related expenses due to an increase in head count. We expect that G&A expenses during the second half 2016 will remain relatively consistent with the first half of 2016.

I will now turn the call over to Barry.

Barry E. Greene - President & Chief Operating Officer

Thanks, Mike. As you heard from both John and Akshay, we had a tremendously productive second quarter in recent period as we continue to build the industry's leading pipeline of RNAi therapeutics and advance our innovative medicines to patients and very importantly to the market.

Let's now turn to our remaining 2016 goals and guidance. In January, as you know, we reached full enrollment in our APOLLO Phase 3 study with patisiran. We look forward to reporting data from this study in mid-2017. Assuming those data are positive, we expect APOLLO will enable a possible NDA submission by the end of 2017 putting us in position to potentially launch our first commercial product in 2018.

With revusiran, we're currently enrolling hereditary ATTR cardiomyopathy patients in our ENDEAVOUR Phase 3 study and are on track to complete enrollment by the end of summer. We expect to report data from this trial in early 2017. ALN-TTRsc02, we plan to report initial data from the ongoing Phase 1 study later this year. Assuming positive Phase 1 results and regulatory discussions, we also aim to advance directly to a Phase 3 study, which we expect to begin in 2017.

Moving to fitusiran, we look forward to reporting additional data from the ongoing Phase 1 study as well as initial data from the Phase 1/2 OLE study in late 2016. Likely, at the ASH conference, pending abstract acceptance. As Akshay noted earlier, we're now planning to begin two Phase 3 trials in patients with and without inhibitors in early 2017.

With ALN-CC5, we plan to present additional data from PNH patients that were treated in Phase 1/2 study later this year. Again, likely at ASH, pending abstract acceptance. In addition, we expect to initiate a Phase 2 trial in PNH patients for inadequate responders eculizumab treatment later this year.

With ALN-AS1 we plan to report complete data from Parts A and B of the Phase 1 study at the SSIEM Meeting in Rome on September 7. This dataset will include results from single and multiple subcutaneous doses of ALN-AS1 with asymptomatic porphyria patients. We also plan to report initial data from Parts C of the study in symptomatic patients with recurrent attacks by the end of this year, again, likely at ASH, pending abstract acceptance. With ALN-AAT, we expect to present initial data from the Phase 1 trial in the OTS meeting in September. With our ALN-GO1 program for the treatment of PH1 we've had an abstract accepted at an oral presentation at the IPNA meeting on September 24 in Brazil, where we plan to present initial Phase 1/2 data.

Turning to our Cardio-Metabolic Disease STAr with ALN-PCSsc, we expect our partner The Medicines Company to present initial data from the ORION-1 Phase 2 study in late 2016, likely at the AHA meeting in November, pending abstract acceptance.

Turning to our Hepatic Infectious Disease STAr, we'll continue enrolling subjects, in our Phase 1/2 trial of ALN-HBV and look forward to initial data from that trial in mid-2017. Now, as Mike said, we expect to end 2016 with greater than $1 billion in cash, including restricted investments. In summary, we are poised for a very data-rich back half of 2016.

You could see details of all of our upcoming presentations at medical conferences shown on slide 24. As you can see, we currently expect to present additional clinical results from at least six distinct clinical programs through the end of the year, again, making the back half of 2016 another data-rich period. In addition, we are planning on hosting an R&D Day on December 16, to round out the year, with a review of our pipeline progress.

Finally, we've confirmed dates and times, for additional events in our Third Annual RNAi Roundtable Webinar Series. You can see those details on slide 25. We hope that these more detailed reviews of our clinical programs, provide an opportunity to gain deeper understanding of our pipeline efforts from key opinion leaders as well as patients.

With that, I will now turn the call back to Christine to coordinate our Q&A. Christine?

Christine Regan Lindenboom - VP-Investor Relations & Corporate Communications

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

Question-and-Answer Session

Operator

Certainly. Our first question comes from Ritu Baral of Cowen. Your line is now open.

Ritu Baral - Cowen & Co. LLC

Hi, guys. Thanks for taking the question. My first question is on the ALN-AS1 porphyria program. Can you give us any narrowing of timing on the data that you will be presenting? Could we have it by SSIEM and also what constitutes good data in your eyes, Akshay and John, what's the meaningful reduction in attack rate given the disease burden in acute porphyria?

John M. Maraganore - Chief Executive Officer & Director

Thanks, Ritu. It's a great question. So, we are going to be presenting the complete results from Parts A and B, that's the single ascending dose, the multiple ascending dose in the asymptomatic porphyria patients at this meeting in Rome September 7. And we're looking forward to that presentation. I believe it's an oral presentation, yeah, it's a meeting, yeah, it is an oral presentation. And that I think will significantly expand the data that were presented last September which were really the initial data from our porphyria experience.

And then, we're planning on presenting the initial recurrent attack patient data, by the end of the year. And as Barry noted in his remarks, we believe that that is hopefully going to be also at ASH, it will be a very busy ASH for Alnylam, but that will be pending abstract acceptance. But we do believe that that's an appropriate venue to present those data.

Barry E. Greene - President & Chief Operating Officer

That's going to be the initial experience recurrent-attack patients. I think just in order to calibrate people's expectations, of course, we're still many months away from that. I think it will be encouraging to see as if we can lower levels of ALA and PBG in patients with recurrent attacks. I think probably it would be too soon to say anything about affects on attack rate, but I think if we can see impact on ALN and PBG as well as on ALN-AS1 in the actual recurrent attack patients that will be an informative data set. I don't know, Akshay, do you agree with that?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah, no. I think that would be an excellent translation of what we've already seen in the ASH subjects and central to the therapeutic hypothesis, and I think that would then set us off to more formally test, but it actually results in reduction in the attack frequency.

Ritu Baral - Cowen & Co. LLC

Got it. My second question has to do with the Norton plant and CMC readiness for fitusiran and FAP. Will fitusiran be manufactured at the Norton plant and where are you on the CMC portion of fitusiran?

John M. Maraganore - Chief Executive Officer & Director

Absolutely. Let me turn that over to Barry.

Barry E. Greene - President & Chief Operating Officer

Yeah. So I guess the bottom line is we will be ready on the CMC side to launch both with drug substance, drug product, as well as supply chain. And just to give you a little bit more color. The drug substance part of fitusiran is made by a third-party manufacturer who will be agency inspection ready, global for a launch, and we ourselves are making the drug product part of fitusiran in Cambridge in our Alewife facility and again our GMP ready there as well. So, I think we're in good shape.

John M. Maraganore - Chief Executive Officer & Director

Yeah. So, just to elaborate further, agree with everything Barry just said. The Norton facility really starts approaching the pipeline needs beyond fitusiran. And that is planned to be operational in 2018 and we'll still use third-party CMOs and leverage our third-party CMOs as well. But increasingly over time, the Norton facility will be doing the bulk of our drug substance manufacturing.

Ritu Baral - Cowen & Co. LLC

Great. Thanks for taking the questions.

John M. Maraganore - Chief Executive Officer & Director

Thank you, Ritu.

Operator

Thank you. Our next question comes from Gena Wang of Jefferies. Your line is now open.

Gena Wang - Jefferies LLC

Thank you very much for taking my questions. So the first one for Alnylam, the TTR subcu Phase I trial, based on ClinicalTrials.gov, it seems that enrollment hasn't started and it's not clear by the dosing. Just want to confirm with you that you will start with multiple ascending dose with once-quarterly dosing? And also are you confident that you will be able to present data later this year?

John M. Maraganore - Chief Executive Officer & Director

Yeah. I don't – I haven't looked at what our ClinicalTrials.gov entry says there but I can tell you that the study has enrolled volunteers in the study, we have multiple cohorts that have already been enrolled in the study and we're very well positioned to look at data by the end of the year. So, I don't know, Akshay, if you have anything to add to that?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

No, I don't.

John M. Maraganore - Chief Executive Officer & Director

Yeah.

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

I think that covers it.

John M. Maraganore - Chief Executive Officer & Director

Yeah. I'll certainly take a look and see what ClinicalTrials.gov says, but it's very actively enrolling and we will have data by the end of the year.

Gena Wang - Jefferies LLC

And the data will be multiple ascending dose with once-quarterly dosing, is that right?

John M. Maraganore - Chief Executive Officer & Director

Well, what we want to test and what you'll see by the end of the year is whether or not we've achieved a quarterly dose profile based on single injection data.

Gena Wang - Jefferies LLC

Okay.

John M. Maraganore - Chief Executive Officer & Director

Right. So you should be able to see from those data whether or not the durability of TTR knockdown goes out to 90 days or more. And we expect that that dataset will be quite robust by the end of the year.

Gena Wang - Jefferies LLC

Okay. Thank you. And then my next question is related to the second-gen GalNAc programs – I mean all the program, if you look at all the programs in clinical development with the second-gen GalNAc just wondering what are the most common drug related adverse events and how many drug related discontinuation?

John M. Maraganore - Chief Executive Officer & Director

Yeah. Akshay, you want to handle that?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah. I mean that's quite a few programs to summarize, at the high level Gena, is that the lower doses and infrequent administrations are associated with the second-generation ESC platform and typically as we've guided before once-quarterly or maybe even once every six months dosing has resulted in a very, very good and encouraging safety profile today. I actually, can't – the number is so small of the number of individuals that have dropped out discontinuing, I can't recall off the top of my hand, but it must be very low single-digit. In terms of the adverse event profile, really there is no consistent story to report at this point in time. Obviously, some of these studies are ongoing and placebo-controlled. So we need to look more into those data but at a high level, the safety profile and tolerability profile for the ESC GalNAc looks very different from revusiran.

Gena Wang - Jefferies LLC

Thank you.

John M. Maraganore - Chief Executive Officer & Director

Thanks, Gena.

Operator

Thank you. Our next question comes from David Lebowitz of Morgan Stanley. Your line is now open.

David N. Lebowitz - Morgan Stanley & Co. LLC

Thank you very much for taking my question. There has been some talk recently about taking the cardio data from the polyneuropathy trials and perhaps trying to get that into the labels somehow. What does that mean from the context of potentially some use in the cardiomyopathy?

John M. Maraganore - Chief Executive Officer & Director

Yeah. Great question, David, and by the way welcome to our team of covering analysts. Great to have you on board. Akshay, do you want to handle this?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah. I don't want to get into the commercial aspects, but from a clinical regulatory perspective, couple of things to bear in mind. Many of the patients with ATTR amyloidosis of the inherited form have both the polyneuropathy and cardiomyopathy and that's very evident in our APOLLO study where over half of them have some – significant coexisting cardiac disease is also evident in the Phase 2 extension study, the early study for fitusiran. So, the experience one can try and separate the disease into polyneuropathy versus cardiomyopathy. But the vast majority of the patients with detailed mutations have both forms of syndrome.

Now the hypothesis that TTR reduction should help both of them is great because our drug will do that and we hope to impact both those aspects of the phenotype. The APOLLO study will give us the first detailed look into that 50%-plus that have cardiac disease, where the TTR reduction cause some significant impact on the cardiac aspect of the phenotype. And if it did so, we would want to bring back to the attention of regulators and see, how it could be incorporated into the label to allow prescribers to use the drug appropriately.

Barry E. Greene - President & Chief Operating Officer

Yeah. And I'll just add, we want to be careful David, to be clear that we'll be taking the data set if there are encouraging results in the cardiac endpoints that have been collected, both secondary endpoints and exploratory endpoints. We'll certainly take those data to regulators and have discussions with them and based on those discussions we'll be able to hopefully inform the right label for the product. But it's certainly clear that we have a significant population within APOLLO, that have the cardiac symptoms, so the sample size for evaluating the effects of fitusiran versus placebo in that subgroup of the disease will actually be rather robust and that will certainly assist in any regulatory discussions.

David N. Lebowitz - Morgan Stanley & Co. LLC

Thanks for that. And one more question, what's the outlook on wild-type TTR? Any thoughts on how you might proceed in that area?

John M. Maraganore - Chief Executive Officer & Director

Yeah, we are still very committed obviously in developing our products across the whole spectrum of ATTR whether it's the inherited form or the wild-type form. And, David, we look forward to the ALN-TTRsc02 program as being one that could be explored in that broader wild-type population, especially with a profile where it's given once a quarter from a dosing perspective in that larger market, it could be quite attractive to patients. And so that's a study that we don't have any specific guidance on today, but it's certainly a study that we will aim to advance in the future.

David N. Lebowitz - Morgan Stanley & Co. LLC

Thanks for taking my questions.

John M. Maraganore - Chief Executive Officer & Director

Thank you, David.

Operator

Thank you. And our next question comes from Alan Carr of Needham. Your line is now open.

Alan Carr - Needham & Co. LLC

Hi. Thanks for taking my questions. I mean, when you talk of – actually continue to talk on ALN-TTRsc02, and give us a sense of what Phase 3 trial you might run there, which indication and early or late next year. And then also can you talk about the HBV program, a bit about that trial design, and you said that you'll have some initial data from that next year. What do you expect to have then? Thanks.

John M. Maraganore - Chief Executive Officer & Director

Yeah, no, Alan, those are both good questions. The first one is important for us to provide some context on. We probably won't be able to give you a specific answer on it though because it really does depend upon our regulatory discussions with the authorities. But I think as a general rule it's our belief that if we can really establish the relationship of TTR knockdown with clinical endpoints from APOLLO and ENDEAVOUR, that regulators, in discussions we have with them, would be open to considering how TTR knockdown could be used as surrogacy in the disease.

Now, that requires discussions, it requires alignment and there will be other, certainly other bells and whistles around that. But once we have those discussions with the regulators, we'll be able to really provide some better clarity on exactly how we go forward there. But in general terms that's how we're thinking about it.

Akshay, anything else to add to that?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

No, I think you've covered them.

John M. Maraganore - Chief Executive Officer & Director

Good. Great.

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah.

John M. Maraganore - Chief Executive Officer & Director

And then on HBV, Akshay, you want to cover that program?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah. So, we're in the healthy volunteer part of the study and of course the HBV is a complex disease. There are many patient segments of the different serologies (41:50) and different degrees of antigen expression, E antigen positive, E antigen negative. And what you're going to see from us as the program transitions from a healthy volunteer into the HBV part of the study is later next year we'll report data in the different HBV-positive segments and you'll also see data in segments with standard of care. As you know, there are a number of HBV antivirals. So that's what we'll look forward to discussing next year.

John M. Maraganore - Chief Executive Officer & Director

I think what's going to be exciting about that program, Alan, is obviously we're going to be in patients this year; we're going to have the initial data in 2017. And I think clearly from those initial data we'll be able to see the degree and extent and durability of S antigen knockdown.

And then I think before we get into whether or not we can create functional cures, that will take results from multi-dose studies – that will probably be a 2018 objective. But certainly in 2017 we would expect to see hopefully impressive results with S antigen levels.

Alan Carr - Needham & Co. LLC

Great. Thanks very much.

John M. Maraganore - Chief Executive Officer & Director

Sure. Thanks, Alan.

Operator

Thank you. Our next question comes from Alethia Young of Credit Suisse. Your line is now open.

Eliana Merle - Credit Suisse Securities (USA) LLC (Broker)

Hi, this is Eliana for Alethia. Thanks for taking my questions. So with fitusiran, beyond hemophilia, are you planning on starting any studies for other rare bleeding disorders, and if so CAN you update us on your thinking and potential timelines there? Thanks.

John M. Maraganore - Chief Executive Officer & Director

Yeah. Ellie, that's a great question. I think it highlights the key point about fitusiran which is that it's really a broad-based agent that can be used across the broad spectrum of bleeding disorders, not just hemophilia A and hemophilia B but also other congenital deficiencies of coagulation factors. And even potentially in some platelet disorders where there is clearly a deficiency of thrombin generation and where our drug may provide some benefit.

And we're quite interested in these opportunities. Obviously, these are areas of very high unmet need. There really are no competing drugs in those settings and we're going to begin to explore some of those studies as early as next year. But it's too soon to give you any more specific details on that at this time.

Akshay, anything else to add?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

No. I think you covered it.

John M. Maraganore - Chief Executive Officer & Director

Good.

Eliana Merle - Credit Suisse Securities (USA) LLC (Broker)

Thanks.

Barry E. Greene - President & Chief Operating Officer

Thanks, Ellie.

Operator

Thank you. And our next question comes from Anupam Rama of JPMorgan. Your line is now open.

Anupam Rama - JPMorgan Securities LLC

Hey, guys. Thanks so much for taking the question here. Maybe just a quick one on fitusiran and kind of thinking about population subsets here. How are you thinking about the acute trauma surgery setting here for Fitusiran with the dynamics of AT3 lowering with the drug? Thanks.

John M. Maraganore - Chief Executive Officer & Director

Yeah, that's a great question, Anupam. Do you want to handle that, Akshay?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah. So we already have very good accumulated data from the ongoing study of how to administer factor replacement if someone does have a bleed whilst they are on fitusiran. And as you know, it's happened on a number of occasions, particularly when the AT3 level hasn't gone down to the steady-state effect. So we know that you can combine the factor with AT3 knockdown in fitusiran-treated patients, you can do that safely and get effective hemostasis. But that's an excellent foundation to build on.

As the program goes on, we naturally will want to study the specific question that you're outlining and we will do that and we're going to have conversations obviously with regulators to define the best way to do that. But I think already from the accumulated information, it's clear that one can effectively manage patients in a variety of settings using a combination of AT3 knockdown with fitusiran and factor replacement.

John M. Maraganore - Chief Executive Officer & Director

And just as a reminder, Anupam – this is John. I mean, you can immediately reverse the effects of fitusiran with the administration of antithrombin, which is a commercially available product. And so that's always available. Now, obviously, I don't think it makes a lot of sense in the surgical procedure to reverse a pro-hemostatic agent instead of taking advantage of the fact the pro-hemostatic agent is onboard. But clearly, if somebody wanted to reverse the effects, they could do it right away, and that antithrombin can be administered with some frequency, it's got a relatively long half-life, compared to recombinant factor.

Anupam Rama - JPMorgan Securities LLC

Great. Thanks so much for taking our question, guys.

John M. Maraganore - Chief Executive Officer & Director

Thanks, Anupam.

Operator

Thank you. And our next question comes from Mike King of JMP Securities. Your line is now open.

Mike G. King - JMP Securities LLC

(46:28), you covered everything pretty comprehensively. I also have a fitusiran question which was a certain similar thing to what you guys have done or are planning to do with the ALN-CC5. Would you contemplate maybe combination therapy with fitusiran and there's a long [Technical Difficulty] (46:48) clotting factors or things like [indiscernible] (46:53) those novel agents are approved?

John M. Maraganore - Chief Executive Officer & Director

Yeah, Mike, thanks for the question. I think in the case of fitusiran, we're very confident that fitusiran as monotherapy would provide effective hemostasis in patients that have hemophilia A or hemophilia B with or without inhibitors. Obviously, if a patient has a bleed, and just to put this in context, Mike, even patients that are on routine prophylaxis will have bleeds. And when they have a bleed, they treat themselves with more factor. So, if and when a patient on fitusiran has a bleed, they will treat themselves with recombinant factor or with bypass agents if they have inhibitors, but of course the frequency of that is expected to be significantly reduced compared to normal.

So, it's not really – I don't think you could really make a comparison to ALN-CC5, that's a very different type of circumstance, because here with fitusiran in hemophilia we are clearly encouraged by the data we have so far showing that we can achieve ABRs – a mediated ABR of 0 in patients with hemophilia without any need for replacement factor altogether. But of course in the larger real world there will occasionally be bleeds that occur just like it does with routine prophy, and those patients will treat themselves with their recombinant factor or their bypass agent.

Mike G. King - JMP Securities LLC

Have you had a discussion with the regulators about what kind of data you might need in a NDA package (48:29-48:36) number of patients or...

John M. Maraganore - Chief Executive Officer & Director

Yeah, Mike, we've had extensive and very constructive and encouraging discussions with both EMA and FDA on the program, as it relates to the Phase 3 studies and the data that would be required for an approval, if those studies turn out to be positive. And we'll obviously provide those details when we initiate the Phase 3 studies in early 2017. Akshay, anything else to add to that?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

No, nothing.

John M. Maraganore - Chief Executive Officer & Director

Yep. Yeah. But Mike, I don't think there is anything that's particularly different than past guidance on this as it relates to the endpoint being the annualized bleeding rate, the fact that we would look to both patients with heme A and heme B that we would likely to do two separate studies, one in inhibitors, one in non-inhibitor patients, et cetera. Those are generally consistent and will be preserved.

Mike G. King - JMP Securities LLC

Yeah, no, I understood. I'm just trying to get a sense of sort of what kind of data the FDA and the EMA may need for sort of practice of medicine or management of the disease as opposed to (49:48) here is an ABR rate that we can generate. They often ask questions of that nature, that's why I ask.

John M. Maraganore - Chief Executive Officer & Director

Yeah. No, understood. Now, we have good clarity on that, and obviously when we start the studies, we'll provide the details of the study design as we always do at that time.

Mike G. King - JMP Securities LLC

Great. Thanks so much.

John M. Maraganore - Chief Executive Officer & Director

Thanks, Mike.

Operator

Thank you. Our next question comes from Madhu Kumar of Chardan Capital. Your line is now open.

Madhu Kumar - Chardan Capital Markets LLC

Hey, guys. I only have two questions. First one is for the ALN-AAT program. Besides suppression of antitrypsin, what do you think would be like the most measurable read-out for the liver disease?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah. It's a great question, Madhu. Do you want to ask your second one, and then we can go through them? Go ahead.

Madhu Kumar - Chardan Capital Markets LLC

Oh sure. So the other one with ALN-PCSsc, so obviously the main issue with the PCSK9 family is the cardiovascular outcome trials (50:45). So what would be like a hazard ratio that would make you feel really confident for ALN-PCSsc moving forward?

John M. Maraganore - Chief Executive Officer & Director

Okay. Those are two great questions. Akshay, do you want to handle both of them?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

I can handle the first one. The lip read out with respect to AAT, so beyond the AAT knockdown, what ultimately matters of course to patients is does that result in clinical benefit with improvement in liver outcomes. And there are a number of ways to look at that. There is liver elastography, which is increasingly validated as the measure of the degree of fibrosis in the liver. Secondly, there are panels of markers that reflect the extent of ongoing fibrosis in the liver, and a test for that is validated and used in Europe, and we can think about incorporating that.

And then finally, as being used very productively in trials, particularly in biologic liver disease, you can do pre- and post-biopsies and score the biopsies for degree of fibrosis. And so we're looking at the full range of possibilities there, and based on dialogue with regulators though, obviously we'll come back to you and let you know more.

One of the particularly interesting things about the biopsy approach in AAT liver disease is that there are these characteristic lesions seen on the biopsy, PAS positive lesions on AAT livers.

And it will be very interesting to see how AAT knockdown result is going to change in the number and size of those PAS-positive granules, and that can be a very important histologic predictor of benefits. So we'll bring that to the attention of regulators. The second question was...

John M. Maraganore - Chief Executive Officer & Director

What type of hazard ratio in the outcome studies with the PCSK9 antibodies would have us enthusiastic?

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Yeah. I mean...

John M. Maraganore - Chief Executive Officer & Director

You give your opinion, I'll give my.

Akshay K. Vaishnaw - Chief Medical Officer, EVP-Research & Development

Why don't you give your opinion?

John M. Maraganore - Chief Executive Officer & Director

Okay. Well, I mean I think, Madhu, clearly there is good reason to be encouraged based on the genetics as well as some other lines of evidence that these outcome studies will be informative. And I think as little as a 33% relative risk reduction would be a very impressive result. And the studies are powered to detect that, if not even less of a result, but I think that would be a meaningful difference that would of course further validate the importance of LDL management through the PCSK9 pathway mechanism and obviously that would be a very helpful and supportive data point for our colleagues at The Medicines Company as well as obviously for our economic interest in the program.

Madhu Kumar - Chardan Capital Markets LLC

All right, thanks, guys.

John M. Maraganore - Chief Executive Officer & Director

Sure. Thanks, Madhu.

Operator

Thank you. Our next question comes for Ted Tenthoff of Piper Jaffray. Your line is open.

Ted A. Tenthoff - Piper Jaffray & Co. (Broker)

Great. Thank you. Actually a lot of the questions have been answered here. I wanted to get a sense maybe for the longer term with respect to the (53:52) manufacturing at your facility that you're building out. What scale do you think that facility is going to be able achieve for the $150 million investment? I mean clearly patisiran will be the first test. But sort of high level, how much drug do you think you can push out of that, and maybe thinking it just in terms of a sequential list – patisiran, revusiran, and fitusiran, how many of these do you think you might be able to get out of that facility before having to expand?

John M. Maraganore - Chief Executive Officer & Director

That's a great question, Ted. You want to take it, Barry?

Barry E. Greene - President & Chief Operating Officer

Yeah. So we designed the Norton facility to be a multi-train facility, so that we can run multiple products simultaneously if we are as successful as we hope to be in our pipeline. And Ted, how much drug would be produced by the plant is highly dependent on dose and frequency of that drug. And we're gratifyingly seeing in particular GalNAc-ESC's highly potent, infrequent medicines. And if that continues play out we pretty much can support the entire Genetic Medicines pipeline from that manufacturing facility.

Now, as the Cardio-Metabolic and Hepatic Infectious Disease programs come online, given the end there of millions and millions of patients, that prompt up would probably require another investment in yet another facility, which if those programs hit, we're very prepared to do.

Ted A. Tenthoff - Piper Jaffray & Co. (Broker)

It's a good problem to have, exactly. I haven't thought about this in a while, but with GalNAc conjugation in the lower doses, what kind of cost of goods sold do you think we could actually get to with oligo-therapies, specifically your RNAi drugs?

John M. Maraganore - Chief Executive Officer & Director

Yeah. It's a great question, Ted. At a high level – and then maybe Barry will have some views as well – I don't foresee any challenge in us achieving very attractive gross margins on our product based on cost of goods. And that applies not only for the orphan products which of course – where typically the prices are higher, but it also includes the potential in Cardio-Metabolic Disease and Hepatic Infectious Disease with significantly lower prices per year from a therapy standpoint.

And it's encouraging, particularly given the potency of permits that have been made and the durability and the low frequency of administration. So we feel pretty good there.

Barry, you want to add anything?

Barry E. Greene - President & Chief Operating Officer

Yeah, Ted, the good news here is when we start talking about the higher volume indications, Cardio-Metabolic, Hepatic Infectious Disease, in the end, you likely increase your run sizes and cost of goods are highly dependent on how much drug you're making obviously. So, I think the good news is that if those diseases get down to the kind of small molecule branded prices we've seen, $10 a day, $11 a day, we have cost of goods even for those price ranges, if it gets there, where we have pharmaceutical margins.

Operator

Thank you. And at this time, I'm showing there are no further participants in the queue. I would like to turn the call back to management for any closing remarks.

John M. Maraganore - Chief Executive Officer & Director

Well, thanks to everyone for joining us this afternoon. We certainly expect the rest of 2016 to be an exciting period for Alnylam, with lots of clinical data that we'll be sharing. And then finally, I just want to end by saying how we grateful we are to the patients and investigators participating in our studies, and how we remain deeply committed in developing these medicines for all of you to make a difference in your lives. So with that, I will now close the call. And have a great day, everybody.

Operator

Ladies and gentlemen, thank you for your participation on today's call. This concludes your conference. You may now disconnect. Everyone, have a great day.

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