Q3 2019 Earnings Call

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Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals conference call about third quarter earnings. 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. Please do so.

Ladies and gentlemen, thank you for standing by welcome to the Alnylam Pharmaceuticals Conference calls third quarter earnings.

It would be a question answer session to follow.

Be advised that this call is being taped out the company's request I wouldn't I would like to turn the call over to the company. Please go ahead.

Christine Regan Lindenboom: Good morning, I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Muruganuri, Chief Executive Officer, Barry Green, President, Akshay Vaishnaw, President of R&D, Jeff Poulton, Chief Financial Officer, and Yvonne Greenstreet, Chief Operating Officer. For those of you participating via conference call, the slides are available via webcast and can also be accessed by going to the investor page of our website, www.alnylam.com.

Good morning, I'm, Christine Lindenboom, Vice President of Investor Relations and corporate Communications I don't Island with me today on the phone or John or sorry, Chief Executive Officer, very Green President I finish now President of R&D got Fulton, Chief Financial Officer, and about Green Street, Chief operating officer for those you participating via conference call to fly through.

Available via webcast. It can also be asset like on the Investor page our website www Dot com. During today's call is outlined on slide two John will provide some introductory remarks and provide general contact there will provide an update on our commercial progress actually overview recent clinical and preclinical update Jeff will review our financial.

Christine Regan Lindenboom: During today's call, as outlined in slide two, John will provide some introductory remarks and provide general context, Barry will provide an update on our commercial progress, Akshay will review recent clinical and preclinical updates, Jeff will review our financials, and Yvonne will provide a brief summary of upcoming milestones before we open 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 as a result of various important factors, including those discussed in our most recent quarterly report on file with the FDA. In addition, any forward-looking statements represent our views only as of the date of this recording. It should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update...

In a bottle provide brief a brief summary of upcoming milestones before we open the call for your question.

I would like to remind you that this call will contain remark starting on islands future expectations plans and prospects, which constitute forward looking statements for the purposes of the safe Harbor provision under the private private Securities Litigation Reform Act 1995 actual results may differ materially from those indicated by these forward looking statements result, various important factors, including.

As discussed in our most recently quarterly reports on file with the efficacy. In addition, any forward looking statements represent our views only as a date of this reporting it should not be relied upon as representing our views as of any subsequent date, we specifically disclaim any obligation to update such statements with that I'll turn the call over to John Thanks, Christine. Thank you everyone for joining the call today there with.

John Muruganuri: Thanks, Christine, and thank you everyone for joining the call today. Bear with me as I'm nursing a call.

Me as I've nursing the coal.

John Muruganuri: As we head into the final months of 2019, we are entering a very important period in Alnylam's history, one marked by strong commercial execution with continuous and steady patient and revenue growth, as well as robust productivity on the R&D side, marked by organic pipeline growth and progression, as evidenced by our large number of late-stage programs. Barry will get into the details on our commercial progress, and Akshay will review our R&D progress, but let me start by providing a few high-level comments. First, having now passed the one-year anniversary of Alpatro's approval and launch, we continue to be very pleased with Alpatro Uptake, with over 600 patients on commercial treatment at the end of the third quarter. We're seeing growth continuing in existing markets, even with competition, and now also coming from new markets, such as our recent commercial launches in Japan and Canada, and we believe this global expansion will continue to be a driver of revenue growth going forward, along with improved rates of patient diagnosis, leading to new patient finding in existing markets, and additional evidence generation activities providing further differentiation.

As we head into the final most of 29 team. We are entering a very important period no miles history, one mark with both strong commercial execution with continuous and steady patient and revenue growth as well as robust productivity of the R&D side, Mark by organic pipeline growth that progression as evidenced by our large number of late.

Progress.

Very well get into details on our commercial progress at auction will review, our R&D progress, but let me start by providing a few high level commas burst, having now passed the one year anniversary about Petros approval and launch we continue to be very pleased with apparel uptake with over 600 patients like commercial drug and.

The other third quarter.

We're seeing growth continuing in existing markets, even with competition and now also coming from new markets such as our recent commercial launches in Japan in Canada.

Believe this global expansion will continue to be a driver of revenue growth going forward, along with improved writes a patient diagnosis, leading to new patient by dig in existing markets as additional evidence generation activities, providing further differentiation.

John Muruganuri: We're also seeing very real growth and awareness of HATTR amyloidosis that we believe bodes well for Arpatro, Butresiran, and Alnylam. We are also hard at work preparing for the upcoming launch of Gobosaran, assuming positive regulatory reviews, marking the potential entry of the world's second RNAi therapeutic into the commercial market. The second point I want to make is on the R&D side. Here, we're gearing up for an additional phase 3 program readout with Lumasaran by the end of the year. And with Eclipse Saran, we'll support the efforts by our partners at the medicines company as they prepare for global regulatory filings to bring that innovative product to patients. In addition, we continue to advance our ongoing phase 3 development activities for Petit Saran and Petri Saran into the hereditary and wild-type ATTR amyloidosis cardiomyopathy settings, which we believe have the potential to unlock a very large commercial opportunity with what we believe is a best-in-class approach with our RNAi-PTR silencer mechanism of action.

We're also seeing very real growth in awareness of ha TTR amyloidosis that we believe bodes well for our Petro Patrice ran at a level.

We also hard at work and preparing for the upcoming launch of both Suresh assuming positive regulatory reviews, marking the potential next three of the world second RDR therapeutic to the commercial markets.

Second point I want to make is on the R&D side [noise].

Here, we're gearing up for an additional phase three program read out with less rent by the end of the year.

With that at least Erad will support the efforts by our partners at the medicines company as they prepare for global regulatory filings to break that innovative product to patients. In addition, we continue to advance our ongoing phase three development activities for two threat and Patrice ran into the hereditary and wild type Agee TR.

Abdullah doses cardiomyopathy settings, which we believe have the potential to unlock a very large commercial opportunity with what we believe as a best in class approach with our already I TTR silence or mechanism of action.

John Muruganuri: A robust product pipeline also includes earlier-stage clinical programs in areas such as complement-mediated diseases, hypertension, chronic HPV infection, and alpha-1 liver disease. We look forward to sharing initial clinical data from some of these programs as well as additional updates across our portfolio at our upcoming R&D day on November 22nd in New York City. The third point I'd like to make is that, based on our commercial and R&D accomplishments and near-term prospects, we believe we have a clear line of sight toward achieving our Alnylam 2020 strategy and goals of becoming a global multi-product biopharmaceutical company with a deep clinical pipeline to bolster continued growth and a robust product engine to fuel sustainable innovation, a profile rarely, if ever, achieved in bio

Our robust product pipeline also includes earlier stage clinical programs in areas such as complement mediated diseases hypertension, chronic HBV infection and now for what liver disease. We look forward to sharing initial clinical data from some of these programs as well as additional updates across our portfolio at our upcoming R&D day on November 22nd.

In New York City.

Third point I'd like to made is that based on our commercial and R&D accomplishments and near term prospects. We believe we have a clear line of sight toward achieving our outlook 2020 strategy and goals of becoming a global multi product Biopharma company with a deep clinical pipeline to bolster continued growth and it.

Robust product engine to fuel sustainable innovation in profile rarely if ever achieved in biotech.

John Muruganuri: Furthermore, we believe that our modular, reproducible, and, very importantly, organic platform for innovative medicines is hard to match, where, for many reasons, we believe our return on investment exceeds industry norms. And now, having launched the first RNI Therapeutic and having built a global, leverageable commercial capability with the potential to generate continuous revenue growth, we have greater confidence than ever in our ability to deliver on the promise of RNI Therapeutics. At the same time, we recognize that some of our stakeholders are eager to hear about our strategy for balancing revenue growth with our continued investment in our innovative pipeline and how this strategy will support the path toward a self-sustainable and attractive financial profile for Alnylam in the coming years. This is something that we as a management team are deeply focused on, and Jeff Poulton, our new CFO, is committed to helping us navigate through this transition and grow Alnylam for the future.

Furthermore, we believe that our modular reproducible and very importantly, organic platform for innovative medicines is hard to match where for many reasons. We believe our return on investment exceeds industry norms and now having lost the first already out there period and having built a global leverageable commercial.

Mobility with the potential to generate continuous revenue growth, we have greater confidence that ever in our ability to deliver on the promise of already I'd therapeutics.

At the same time, we recognize that some of our stakeholders are eager to hear about our strategy for balancing revenue growth with our continued investment in our innovative pipeline and how this strategy will support the path toward a self sustainable at attractive financial profile for al Milo in the coming years. This is something that we as a man.

It is from team are deeply focused on and Jeff Poulton, our new CFO is committed to helping us navigate through this transition and grow al Milo for the future.

John Muruganuri: Finally, I want to make note of last week's announcement that Alnylam received recognition by Science as the industry's number one top employer. This is a remarkable achievement by over 7,500 respondents who identified Alnylam's culture as the best in the industry. We continue to be more proud; we couldn't be more proud of this recognition and are so grateful to all the Alnylam employees who work tirelessly every day to bring potentially game-changing innovation to patients. With that, I'll now turn it over to Barry to review our commercial.

Finally, I want to make note of last weeks announcement that allow them received recognition by size as the industry is number one top employer. This is a remarkable recognition by over 7500 respond as well identified al miles culture as the best in the industry.

We continue to be more proud we couldn't be more proud of this recognition and our so grateful to all the l. mild employees, who work tirelessly everyday to break potentially game changing innovation to patients with that I'll turn it over to vary to commercial progress in more detail Barry Thanks, John and good morning, everyone.

Eric Green: Thanks John, and good morning everyone. Before I get into specific details, I'd like to comment on the broader ATTR market dynamics. As we anticipated and have commented on previously, we're seeing stronger and stronger disease awareness and patient diagnosis across all physician specialists, thanks in part to our own efforts and the efforts of others in the field. We're seeing evidence of this market expansion in our non-OMAC samples, as well as patient growth and new prescribers. So this growth is important for patients. And as John commented, we think this is very important for Ampato, for Truceran, and for patients at large with this disease. Now moving on to some specifics, let me begin by reviewing Ampato's commercial performance. We achieved $46.1 million in global Umpatua net product revenues in the third quarter.

Before I get into specific details I'd like to comment on the broader eight TTR market dynamic.

As we anticipated and I've commented on previously, we're seeing stronger and stronger disease awareness and patient diagnosis across all physician specialties. Thanks in part to our own effort and the efforts of others in the field. We're seeing evidence of this market expansion and I'll know mapped samples as well as patient group and new prescribers.

So this growth is important for patients and as John commented. We think this is very important for on Patrick good trend and patients that large with this disease.

Now moving on some specifics let me begin by reviewing on Petros commercial performance.

Achieved 46.1 million global on pass through net product revenues in the third quarter.

Eric Green: In terms of the geographic split, we achieved $33.6 million from the U.S., representing 19% U.S. quarter-on-quarter growth, and $12.5 million from the rest of the world, representing 24% quarter-on-quarter international growth. Now, as of September 30th, over 600 patients worldwide were receiving commercial on-patrol treatment. When we expand that number to include patients in clinical trials and our global expanded access programs, that number increases to approximately 850 patients worldwide who are being treated with Onpatriot. And we continue to believe that we're on track to achieve approximately 1,000 patients on Ompetro across commercial, expanded access, and clinical trials by the end of this year. An incredibly exciting milestone in our overall effort.

In terms of the geographic split we achieved 33.6 million from the U.S., representing 90% us quarter on quarter growth and 12.5 million from the rest of the world representing 24% quarter on quarter International growth.

As of September Thirtyth over 600 patients worldwide will receive in commercial and Petro treatment.

When we expand that number to include patients in clinical trials and our global expanded access programs that number increases to approximately 850 patients worldwide, we're being treated with on Petro.

And we continue to believe that we're on track to achieve approximately 1000 patients on a petro across commercial expanded access and clinical trials by the end of this year incredibly exciting milestone in our overall efforts.

Eric Green: It's important to note that for many drugs during the third quarter, it's not uncommon to see a seasonal slowdown of new patient starts due to peak vacation periods. We're actually quite pleased with the overall demand for Ampastor that we saw despite this potential seasonality, especially given increasing competition from recent market entrants and the availability of a number of investigational drugs through large expanded access programs and clinical trials. In sum, we're very pleased to see continuous and steady patient and revenue growth. Let me get into more specifics with a review of the U.S. market dynamics.

It's important to note that for many drugs during.

It's important to note that for many drugs during the third quarter, it's not uncommon to see a seasonal slowdown new patient starts due to peak vacation season, we're actually quite pleased with the overall demand from past that we saw despite this potential seasonality, especially given increasing competition from recent market engines and the availability we know.

Additional drugs through large expanded access programs and clinical trials in some we're very pleased to see continuous and steady patients and revenue growth.

Let me get into more specifics with a review of the U.S. market dynamics on the physician front, we're seeing continued growth in both the number of new prescribers as well as repeat prescribers in fact over 50% of US start forms received in the third quarter came from new prescribers encouraging statistic that.

Eric Green: On the position front, we're seeing continued growth in both the number of new prescribers as well as repeat prescribers. In fact, over 50% of U.S. starter forms received in the third quarter came from new prescribers, encouraging statistics that are evidence that our medical education efforts are working well. We believe this dynamic will continue as HCP disease awareness increases and is fueled by multiple players engaged in disease state education. Regarding the mix of prescribers, about 55% of start forms submitted in the U.S. in the third quarter were from neurology, and about 33% coming from cardiology, and we saw a good mix of other specialties prescribing like hemon. Now, while the cardiology percentage was down a bit in July and August from previous quarters, we did see the proportion of new forms from cardiologists return to the 50% range in September, and we're very encouraged by this continued trend during the initial part of the current quarter. We're also seeing the emergence of more and more multidisciplinary centers of excellence across the country. And these kinds of referrals are a key dynamic in earlier and proper diagnosis.

Litigation efforts are working well we believe this dynamic will continue as HCP disease awareness increases.

And fueled by multiple players engaged in disease State education.

Regarding the mix the prescribers about 55% of start form submitted us in the third quarter from neurologists and about 33% coming from cardiologists and we saw good mix of other specialties prescribing like he month.

Now while the cardiology percentage was down a bit in July and August from previous quarters. We did see the proportion of start forms from cardiologist returned to the 50% range in September and we're very encouraged by this continued trends during the initial part of the current quarter. We're also seeing emergence of more and more multi disciplinary centers of excellence across the country.

And these kinds of referrals are a key dynamic in earlier improper diagnosis.

Of note in the third quarter, we saw the beginning evidence in the use of the use of on Petro what's been prominent branded TTR stabilizers with reimbursement of 'em, Petro, which is positive for patients with multiple manifestations of hereditary TTR amyloidosis, we expect income that used to increase over time as these.

Eric Green: Of note, in the third quarter, we saw the beginning evidence in the U.S. of the use of Ompatro with concomitant branded TTR stabilizers with reimbursement of Ompatro, which is positive for patients with multiple manifestations of hereditary ATTR amyloidosis. We expect incommonate use to increase over time as ACPs experience favorable results with reimbursement for on-patch repairs. Now that we have over one year of launch experience, it's possible to comment for the first time on adherence rates. The good news here is that overall adherence to the therapy remains very strong, consistent with Apollo Phase 3 data. Specifically, we estimate an over 90% adherence rate for commercial Onpatro, a rate that we believe is outstanding and consistent with a favorable patient experience with Onpatro that we hear from our patient hub and that we hear from reports from the field.

Peas experienced favorable results with reimbursement for on Petro.

Now we have over one year launch experience, it's possible to comment for the first time on adherence rates. The good news here is the overall adherence to therapy remains very strong consistent with the Apollo phase three data, specifically, we estimate and over 90% adherence rate for commercial Petro rate that we believe is outstanding and consist.

It was a favorable patient experience without petro that we hear from our patient hub and that we hear from reports from the field.

Eric Green: Regarding U.S. market access, as reported by external coverage reports, we're very pleased that we now have confirmed access to Ompatro, if prescribed, for more than 98% of U.S. lives across commercial, Medicare, Medicaid, and other government paying groups, including VA. Even in an increasingly competitive landscape, we continue to effectively partner with U.S. payers and have avoided the payer headwinds often reported with other orphan drug launches. We're very proud of this result in a very complex U.S. market access environment and believe it reflects our constructive, collaborative, and proactive approach, including the use of value-based agreements we've adapted with the payer community. Turning to the rest of the world, we're also pleased with Ampatra's performance as a

Regarding us market access as reported by external coverage reports, we're very pleased that we now have confirmed access to and Petro is prescribed for more than 98% of us lives across commercial Medicare Medicaid and other govern pain groups, including VA.

Even in an increasingly competitive landscape, we continue to effectively partner with us payers and have avoided the pair headwinds off reported other orphan drug launches. We're very proud of this result in a very complex us market access environment and believe it reflects a constructive collaborative and proactive approach, including the use of value based agreements.

We've adapted with the payer community.

Turning to the rest of the world.

We're also pleased with on Patras performance as I noted earlier, we achieved 12.5 million international net product revenues in Q3.

Eric Green: As I noted earlier, we achieved $12.5 million in international...

Eric Green: A major achievement during the quarter was the launch of Ompatro in Japan. We built our team and are thrilled to have achieved our first sales in Japan and to be bringing Ompatro to a significantly underserved population in Japan and Asia more broadly. As we previously mentioned, we anticipate that Japan will likely be our second largest country after the U.S. for Ampato revenue and patients on the drug exiting 2020. Other notable achievements during the quarter include the launch of Ampatron Canada, and achievement of reimbursement in the United Kingdom, Belgium, and Germany. Now, through direct reimbursement, name patient sales, or paid access, we now have Ompatro being sold in over 10 countries outside of the United States. We are seeing the source of our international business coming both from defaminated switches and first-line treatment, highlighting the value that people are seeing with Onpatch.

A major achievement during quarter was the launch of them Patrick in Japan, we built our team and our thrilled to have achieve our first sales in Japan and to be bringing on pass through to a significantly underserved population in Japan and Asian more broadly.

As we previously mentioned, we anticipate that Japan is likely to be our second largest country. After the U.S. from Petro revenue and patients on drug exiting 2020.

Other notable achievements during the quarter includes launch of a Petro, Canada and achievement of reimbursement in the United Kingdom, Belgium, Germany.

Through direct reimbursement named patient sales or paid excess we now on Petro being sold in over 10 countries outside the United States, We're seeing the source of our international business coming both from to families switches and first line treatment highlighting the value that people are seeing with on Petro.

Eric Green: Globally, our team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis of polyneuropathy and HHTQI myelodosis. Improved medical education and diagnosis will help patients understand treatment options faster. When patients receive treatment earlier in their disease course, it improves their overall prognosis.

Globally. Our team also remains committed to addressing the challenge raising disease awareness and improving diagnostic diagnosis appalling are up the criminal Justice feast.

Improve medical education diagnosis will help patients re treatment options faster.

When patients receive treatment earlier in their disease course, it improves their overall prognosis.

Eric Green: Regarding patient diagnosis, and as we highlighted previously, our Alnylam ACT program is a third-party genetic testing initiative in the United States and Canada aimed at facilitating the diagnosis of patients suspected of having HATTR amyloidosis. As of late October, over 18,000 samples have been submitted, out of which nearly 1,200 have tested positive for a pathogenic TTR mutation. Of note, we're seeing an increase in the number of new tests per quarter from about 2,000 previously to over 3,000 this quarter.

Regarding patient diagnosis and if we highlighted previously our allowance Akt program as a third party genetic testing initiative, the United States in Canada in to facilitate diagnosis of patients suspected of having HCR amyloidosis as of late October over 18000 samples of submitted out of which nearly 12.

Hundred of tested positive for pathogenic TTR mutation.

Of note, we're seeing an increase in the number of new test per quarter for about 2000 previously to over 3000. This quarter. We believe the increase in requested tests reflects improvements in disease awareness as a reminder.

Eric Green: We believe the increase in requested tests reflects improvement in disease awareness. As a reminder, Alnylam Act is just one of several ways patients can be genetically tested. So we see, as we commented earlier, an overall growth in the market for genetic testing. In addition to Alnylam-X, we continue to partner with 23andMe to help customers... to help customers of their consumer genetic service learn more about the genetic risks of the three most common TTR variants in the United States.

Hi, Matt is just one of several methods were patients can.

Genetically tested so we see as commented earlier and overall growth in the market for genetic testing.

In addition to El Nio, Max we continue to partner with 23 me tell customers.

To help customers for their consumer generics service learn more about the genetic risk of the three most common teacher variance in the United States.

In summary, we don't Petro achieving approval and access and more and more countries with steadily improving diagnosis and patient funding and continued evidence generating efforts highlighting differentiating features of on Petro, we're very encouraged by commercial progress in incredibly competitive environment.

Eric Green: In summary, with Ampato achieving approval and access in more and more countries... With steadily improving diagnosis and patient outcomes, and with continued evidence-generating efforts highlighting differentiating features of Ampatro, we're very encouraged by commercial progress in an incredibly competitive environment. And with the addition of new competitors in the broader ATTR market, we believe overall disease awareness will continue to accelerate diagnoses, and we're enthusiastic about the benefits this will confer on Finally, let me turn to Govosran, which is now under review by both U.S. and European regulators, although I assume positive decisions from both agencies.

And with the addition of new competitors in the broader in your market. We believe overall disease awareness will continue to accelerate diagnoses and we're enthusiastic about the benefits. This will fund for the patients.

Finally, let me turn to go strength, which is now under review by both us and European regulators.

Assuming positive decisions from both agencies, we expect the gross rent will launch in these reasons in early 2020.

In the meantime, we're leveraging the capabilities built from Patra launch and following the best practice developed country by country.

At this stage our team is focused on improving the awareness and diagnosis of acute hepatic porphyria or HP in the HCP inpatient communities.

As part of these overall efforts, we've launched our HP physician and patient facing web sites to give patients resources and education materials about their disease and to provide EGPC content and tools help them recognize the signs and symptoms of HP and help them navigate through the appropriate tests to arrive at an accurate to diagnose.

Eric Green: We expect to boast about annual launch in these regions in early 2020. In the meantime, we're leveraging the capabilities built for Ampatra launch and following the best practices developed country by country. At this stage, our team is focused on improving the awareness and diagnosis of acute hepatic porphyria, or AHP, in the HCP and patient community. As part of these overall efforts, we've launched our AHP Physician and Patient-Facing Websites to give patients resources and educational materials about their disease, and to provide healthcare professionals with content and tools to help them recognize the signs and symptoms of AHP, and to help them navigate through Through the Alnylam Act, we sponsor access to third-party genetic testing for individuals in the U.S. or Canada who may carry a gene mutation known to be associated with AHP.

Yes.

Throughout Latin America, we sponsor access to third party genetic testing for individuals in the U.S. or Canada, who make carrier gene mutation known to the associated with HP.

Well this program for HP is still in a very early stage. We report 581 test submitted and 53 patients positive with HP mutations as of mid October accounting for an overall, 10% hit rate.

We're also very pleased in the third quarter, two now to collaboration with Ironwood Pharmaceuticals focused on HP disease education, and if approved promotions go strength among us gastroenterologist.

Guys are one of the most frequently seen specialty groups during the diagnostic journey of an H.B. station, so leveraging Ireland's us expertise and deep relationships with community represents a significant opportunity to expand medical education and diagnosis for patients with HP.

Eric Green: While this program for AHP is still in a very early stage, we can report 581 tests submitted and 63 patients positive for AHP mutations as of mid-October, accounting for an overall 10% hit rate. We're also very pleased in the third quarter to announce a collaboration with Ironwood Pharmaceuticals focused on HP disease education and, if approved, promotion of Gosturant among U.S. gastroenterologists. GIs are one of the most frequently seen specialty groups during the diagnostic journey of an AHP patient.

Turning to the addressable market the consensus estimate the global prevalence of HP is in the range of two to 500000 for People's systemic or systematic disease.

It's been estimated that there are roughly 1000 diagnosed pace you asked in Europe horses really affected and experienced recurrent attacks of course, many more estimated to have active disease with more sporadic attacks and additional patients of chronic symptoms and impaired quality of life.

Eric Green: So leveraging Iron One's U.S. expertise and deep relationships with the GI community represents a significant opportunity to expand medical education and diagnosis for patients with AHA. Turning to the addressable market, the consensus estimated global prevalence of AHP is in the range of 2 to 5 per 100,000 people for people with systemic or systematic disease. It's been estimated that there are roughly 1,000 diagnosed patients in the U.S. and Europe who are severely affected and experience recurrent attacks. Of course, many more are estimated to have active disease with more sporadic attacks and additional symptoms of chronic symptoms and impaired quality of life. AHP is challenging to diagnose, so many patients with active disease remain undiagnosed. Nevertheless, we estimate that there are around 3,000 patients with active disease who are currently diagnosed in the U.S. and Europe with debilitating, potentially life-threatening attacks, with about 1,000 of those patients having more frequent attacks.

He is challenging to diagnose so many patients with active disease remain undiagnosed. Nevertheless, we estimate that they're around 3000 patients with active disease were currently diagnosed newest in Europe debilitating potentially life threatening attacks.

Thousands those patients having more frequent attacks.

Assuming positive regulatory reviews were very excited with the new treatment option, we can bring to patients and the associated commercial opportunity for gross rent.

I look forward to the possibility of delivering this medicines HPP patients early next year as we've said in the past its our belief that this can be an attractive ultra orphan disease opportunity with over 500 million global peak revenue potential.

We expect gross rent to show growth pattern after months similar to that observed with other new treatments and ultra orphan and under diagnosed serious genetic diseases. So with that let me now turn over to Oxy to review, our recent R&D and pipeline progress auction. Thank you Barry and good morning, everyone.

The interest of time I'm going to live in my prepared remarks on multiple phase three clinical programs.

Eric Green: Assuming positive regulatory reviews, we're very excited about the new treatment option we can bring to patients and the associated commercial opportunity for Gavosar. We look forward to the possibility of delivering this medicine to AHP patients early next year. As we've said in the past, it's our belief that this can be an attractive ultra-orphan disease opportunity with over $500 million in global peak revenue potential. We expect the votes to show a growth pattern after launch, similar to that observed with other new treatments in ultra-orphaned and underdiagnosed serious genetic diseases. So with that, let me now turn it over to Akshay to review our recent R&D and pipeline progress. Okay, Akshay? Thank you.

I thought with Patese round, which is the on brand name for our own Patra.

One of the key clinical achievements during the third quarter was the initiation of the Apollo would be phase three study aimed at expanding beyond patter label to include Cardium opt to be in both the inherited add ball type 80, Conway doses patient setting.

Enrollment is underway and if the studies positive we plan to seek regulatory approval for an expanded label for peace Ron in approximately 2021 to 22 timeframe.

As you know we're also advancing butros around which is an investigational rnai therapeutic delivered by quarterly subcutaneous injection and old site development 80 Conway doses.

We've been enrolling ha TTR patients would pull in Europe . The ongoing he'll say phase three study and we were pleased to announce at our ordinary round table in September the design of Healios Pete.

Akshay K. Vaishnaw: Thank you Barry, and good morning everyone. In the interest of time, I'm going to limit my prepared remarks to our multiple phase three clinical program. Let me start with Patisran, which is the unbranded name for Ampatra. One of our key clinical achievements during the third quarter was the initiation of the Apollo B Phase 3 study aimed at expanding the Onpatra label to include cardiomyopathy in both the inherited and wild-type A-T teramyloidosis patient population. Enrollment is underway, and if the study is positive, we plan to seek regulatory approval for an expanded label 40s ran in approximately the 2021 to 22 timeframe. As you know, we're also advancing Butriceram, which is an investigational RNAi therapeutic delivered by quarterly subcutaneous injection, and also in development for AT cannabinoid dosing.

Yes be will be a phase three study of nutritious Rad inherited and while tech timely basis patients with colleagues biopsy.

The study is designed to include approximately 600 patients with 80 timely basis with colleagues MOSFET.

Patients will be enrolled with either a wild type or inherited disease and up to 30% of the technical study population, maybe I'm to find us at the time of randomization.

Eligible patients will have a medical history of symptomatic heart failure, a new a cop association plus equal to or less than three and meet minimum criteria for six minute walk distance and NTP MP levels baseline.

Patients will be randomized one to one to receive either 25 milligrams of nutritious around or placebo administered subcutaneously. Once every three months.

The primary endpoint of this study is a composite outcome of all cause mortality and cardiovascular hospitalizations, which will be assessed at month.

Secondly, endpoints will include a comprehensive assessment of cardiac disease burden, including six minute walk test quality of life imaging assessments at Mt Code BNP.

Akshay K. Vaishnaw: We've been enrolling HA-TTL patients with polyneuropathy in the ongoing Helios A Phase III study, and we were pleased to announce at our RNAi Roundtable in September the design of Helios B. EOS-B will be a phase 3 study of butyriceran in inherited and wild-type ATGY amyloidosis patients with cardiomyopathy. This study is designed to include approximately 600 patients with AT-Tran amyloidosis who are taking Calimartin.

The study design also includes an optional interim analysis, providing the opportunity for an earlier readout.

We're actively working through startup activities with global study now and we remain on track to initiate the study by the end, but yes. If successful speeds should allow for trust trying to enter the very large wildfire 18 retail market opportunity with clinical outcomes data.

Akshay K. Vaishnaw: Patients will be enrolled with either wild-type or inherited disease, and up to 30% of the total study population may be on taphambus at the time of randomization. Eligible patients will have a medical history of symptomatic heart failure, a new or cut association class equal to or less than 3, and meet minimum criteria for 6 minute walk distance and NT ProBNP levels at baseline. Patients will be randomized one-to-one to receive either 25mg of Gutriciran or placebo administered subcutaneously once every three months. The primary endpoint of the study is a composite outcome of all-cause mortality and cardiovascular hospitalization, which will be assessed at month 30. Secondary endpoints will include a comprehensive assessment of cardiac disease burden, including six-minute walk tests, quality of life, imaging assessments, and NT-ProBNP. This study design also includes an optional interim analysis, providing the opportunity for an earlier readout.

I'll now turn to recent progress when Lou Max around an investigational rnai therapeutic in development for the treatment of primary Hyperoxaluria type one or ph. One as you know we're now conducting aluminite a phase three study of the mass Rob. This is a randomized double blind placebo controlled study in ph, one patient eight six oral them with mild to moderate renal impairment.

The primary endpoint as percent of change from baseline in urinary oxalate excretion average across month three through six.

We completed enrollment in this pivotal trial earlier in the yet and we remain on track fruitful topline results, formerly may in late 2019, and it posted to submit regulatory filings from new mass Ron beginning in early 2020 .

Also conducting loom they'd be a phase three study of the mass run in ph, one patients with mild to moderate renal impairment under the age of six supplied too soon start a third of phase three trial in new may see mph, among patients with severe renal impairment although wages.

Akshay K. Vaishnaw: We're actively working through startup activities for this global study now, and we remain on track to initiate the study by the end of the year. If successful, Helios B should allow Vutrisran to enter the very large wild-type ATTR market opportunity with clinical outcomes data. I'll now turn to recent progress with Lumasaran, an investigational RNAi therapeutic in development for the treatment of primary hyperoxylurea type 1, or PH1. As you know, we're now conducting the Illuminate A phase 3 study of Lumasaran. This is a randomized, double-blind, placebo-controlled study in PH1 patients age 6 or older with mild to moderate renal impairment.

In addition to the progress we've made with our wholly owned late stage assets. Our parts of the medicines company added Safi have also been advancing our pilot phase three assets medicines company now report to complete results from the at around 11 phase three study of and Questran.

Then topline results from the arrive nine and 10 phase III studies.

All three study met the primary and old secondary endpoints, demonstrating remarkable efficacy for drug administered Subcu subcutaneously once every six months.

The results also demonstrated an excellent safety profile.

Akshay K. Vaishnaw: The primary endpoint is the percentage change from baseline in urinary oxalate excretion average across months three through six. We completed enrollment in this pivotal trial earlier in the year, and we remain on track to report top-line results for Illuminate A in late 2019 and, if positive, to submit regulatory filings for LumasRAM beginning in early 2020. We're also conducting Illuminate B, a phase 3 study of Lumasaran in PH1 patients with mild to moderate renal impairment under the age of 6. And we also plan to start a third phase 3 trial, Illuminate C, in PH1 patients with severe renal impairment of all ages. In addition to the progress we've made with our wholly owned late-phase assets, our partners at the medicines company and at Sanofi have also been advancing our partnered Phase III assets. Medicines Company has now reported complete results from the ORION 11 Phase 3 study of Inquisiran and top-line results from the ORION 9 and 10 Phase 3 studies. All three studies met their primary and all secondary endpoints, demonstrating remarkable efficacy for a drug administered subcutaneously once every six months. The results also demonstrated an excellent safety program.

So what do these results mean frown lines and Menarini IR genetics first these results to pull the safety of our our therapeutics platform provides the largest demonstration to date, suggesting that there was no systematic evidence for platform specific safety signal importantly, the Ryan Phase three studies were conducted in a generally gil population of.

CVD and have saga phage patients. So this is a stringent evaluation of safety and Tolerability. Secondly, these results greatly strengthened our conviction for the future of our therapeutics in highly problem chronic disorders, such as of the Dyslipidemia has a potential nash and opportunities in highly prevalent infectious diseases like HBV.

Moreover, we believe the pharmacology of Arnie high therapeutics as an infrequently administered medicine creates a very attractive profile for the treatment of common diseases.

Finally, assuming timely regulatory submissions by medicines company and positive regulatory review and Chris Ron will provide you with another source of near term revenues for outline them due to significant royalties of up to 20% on global sales of the product.

Akshay K. Vaishnaw: So, what do these results mean for Alnylam and RNAi Therapeutics? First, these results support the safety of our RNAi Therapeutics platform and provide the largest demonstration to date, suggesting that there is no systematic evidence for a platform-specific safety signal. Importantly, the Orion Phase III studies were conducted in a generally ill population of ASCVD and hepatitis FH patients, so this is a stringent evaluation of safety and tolerability. Secondly, these results greatly strengthen our conviction for the future of RNAi therapeutics in highly prevalent chronic disorders such as other dyslipidemias, hypertension, NASH, and opportunities in highly prevalent infections like HBV. Moreover, we believe the pharmacology of RNA high therapeutics as an infrequently administered medicine creates a very attractive profile for the treatment of common diseases.

As John mentioned earlier, we very much look forward to seeing you later this month at R&D day, and we're excited to update you on it.

At which time will be excited to update you on the entirety of our pipeline programs with that let me now turn the call if to Jeff to review our financials Jeff.

Thanks, Akshay and good morning, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the third quarter of 2019, I would like to take this opportunity to provide a brief overview of three key areas. Our third quarter 2019, TNL results summary of our cash balance and our 2019 financial guidance.

Let me start with our third quarter 2019 revenue total third quarter revenues were 70.1 million.

As very highlighted earlier, we recorded 46.1 million of on Petro net product global revenue during the third quarter 2019, which represents 20% growth from second quarter net product global revenues of 38.2 million U.S. product revenues were 33.6 million, representing 19% quarterly growth.

Jeff Poulton: Finally, assuming timely regulatory submissions by the medicines company and positive regulatory review, Inquisiran will provide yet another source of near-term revenues for Alnylam due to our significant royalties of up to 20% on global sales of the product. As John mentioned earlier, we very much look forward to seeing you later this month at our R&D day, and we're excited to update you on the entirety of our pipeline programs. With that, let me now turn the call over to Jeff to review our financials.

From second quarter, an international product revenues were 12.5 million, representing 24% quarterly growth.

Our global gross to net percentage remains in the mid twenties through the third quarter inline with our prior guidance.

Jeff Poulton: Thanks Akshay. Good morning everyone.

Cost of goods sold was 5.2 million for the third quarter 2019, which is approximately 11% as a percentage of net product sales.

Jeff Poulton: Please refer to our press release issued earlier today for a summary of our financial results for the third quarter of 2019. I would like to take this opportunity to provide a brief overview of three key areas. Our third quarter 2019 P&L results, a summary of our cash balance, and our 2019 Financial Guide. Let me start with our third quarter 2019 revenue. Total third quarter revenues were $70.1 million.

This result is still being favorably impacted by the zero cost on Petro inventory that was expensed R&D prior to on Petros regulatory approval, we anticipate on Retros cost of goods sold increasing into the mid high teens after depletion of zero cost inventory, which is expected in the first half of 2020.

We recognize 24 million of collaboration revenue during the third quarter 2019, as compared to 1.6 million during the third quarter prior year as expected. The increase in collaboration revenue was primarily due to our collaboration agreement with Regeneron, which generated 15.3 million of revenue in the quarter.

Jeff Poulton: As Barry highlighted earlier, we recorded $46.1 million of Onpatro net product global revenue during the third quarter of 2019, which represents 20% growth from second quarter net product global revenues of $38.2 million. U.S. product revenues were $33.6 million, representing 19% quarterly growth from second quarter, and international product revenues were $12.5 million, representing 24% quarterly growth. The increases were driven primarily by the addition of new patients to therapy, including in the UK and Japan, which both generated revenue for the first time following recent finalization of pricing and reimbursement from Patro.

Moving to our operating costs and expenses GAAP R&D expenses were 160.8 million for the third quarter 2019, as compared to 139.9 million in the prior year.

non-GAAP R&D expenses were 138.1 million as compared to 94 94.2 million for the third quarter 2018.

The increase in non-GAAP R&D expenses was primarily due to increased activity in support of our late stage pipeline programs.

Turning to SGN, a GAAP SGN a expenses were 120.4 million for the third quarter 2019, as compared to 116.5 million for the prior year.

Jeff Poulton: Our global gross net percentage remains in the mid-twenties through the third quarter, in line with our prior guidance. Cost of goods sold was $5.2 million for the third quarter of 2019, which is approximately 11% as a percentage of net product sales. This result is still being favorably impacted by the zero-cost Onpatro inventory that was expensed to R&D prior to Onpatro's regulatory approval. We anticipate Patro's cost of goods sold increasing into the mid-high teens after the depletion of its zero-cost inventory, which is expected in the first half of 2020. We recognized $24 million of collaboration revenue during the third quarter of 2019, as compared to $1.6 million during the third quarter of the previous year. As expected, the increase in collaboration revenue is primarily due to our collaboration agreement with Regeneron, which generated $15.3 million of revenue in the quarter.

non-GAAP SGX expenses were 97.1 million as compared to 74.4 million for the third quarter of 2018, the increase in non-GAAP EPS. Gina expenses was due primarily to an increase in commercial and medical affairs investment in connection with the continued global launch of and Petro.

Moving now to a summary of our cash balance in our 2019 financial guidance, our balance sheet remains strong with 1.74 billion of cash cash equivalents marketable debt securities and restricted investments on hand at the end of the third quarter as compared to 1.13 billion at the end of 2018 this cash balances.

Expected to support company operations for multiple years based on current operating plants.

Now moving to our 2019 financial guidance, we are reaffirming our 2019 annual non-GAAP R&D expense guidance to be in the range of 550 to 575 million and our 2019 annual non-GAAP SGN expense guidance to be in the range of 390 to 400 million.

Jeff Poulton: Moving to our operating costs and expenses, Gap R&D expenses were $160.8 million for the 3rd quarter of 2019 as compared to $139.9 million in the prior year. Non-GAAP R&D expenses were $138.1 million as compared to $94.2 million for the third quarter of 2018. The increase in non-GAAP R&D expenses was primarily due to increased activity in support of our late-stage pipeline program. Turning to SG&A, GAAP SG&A expenses were $120.4 million for the third quarter of 2019 as compared to $116.5 million for the prior year. Non-GAAP SG&A expenses were $97.1 million as compared to $74.4 million for the third quarter of 2018. The increase in non-GAAP FG&A expenses was due primarily to an increase in commercial and medical affairs investment in connection with the continued global launch of UNPATRO.

We do expect our actual results will be towards the lower end of both of our non-GAAP R&D and non-GAAP SGN a guidance ranges, reflecting good cost management discipline within the organization.

With that I'll now turn the call overdue Yvonne to review our goals for the remainder of the year Yvonne.

With that treats ramp we plan to continue enrolling the he is a phase three trial throughout the year and expect to initiate tedious bean and outcome study in late 2019.

We've got those ramp our planning is underway, but the potential knowledge of our second alright, and AI therapeutic in the coming months, assuming positive regulatory reviews.

Yvonne L. Greenstreet: Moving now to a summary of our cash balance and our 2019 financial guidance. Our balance sheet remains strong, with $1.74 billion of cash, cash equivalents, marketable debt securities, and restricted investments on hand at the end of the third quarter, as compared to $1.13 billion at the end of 2018. This cash balance is expected to support company operations for multiple years based on current operating plans. Now, moving to our 2019 Financial Guidance. We are reaffirming our 2019 annual non-GAAP R&D expense guidance to be in the range of $550 to $575 million. We do expect our actual results will be toward the lower end of both of our non-GAAP R&D and non-GAAP SG&A guidance ranges, reflecting good cost management discipline within the organization. Finally, I also look forward to our R&D day later this month when I will have the opportunity to provide some perspectives on how Alnylam aims to transition toward a self-sustainable financial profile in the future. With that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year.

We will also continue enrolling pediatric patients into new Neight GP and plan to stop if he can do make Ses study in ph one patients all ages with severe renal impairment in late 2019.

They also plan to submits an end da for increase around by the end of the App.

And of course, we plan to continue advancing our pipeline to earliest stage clinical efforts as well as our exciting preclinical assets and plan to highlight these milestones throughout the rest of the as they occur.

In particular that you should expect data read out through a number of early and mid stage clinical programs.

And finally at the remind that we very much look forward to reviewing all of this that's our R&D day in New York City on Friday November 20 seconds.

Let me now turn it back to Christine to coordinate talk you in a fashion Christine. Thank you have on operator, we'll now open the call for question, though style. Then we would like to ask you to limit yourself to one question and then get back in the queue at the of additional question.

Yvonne L. Greenstreet: Thanks Jeff, we've made tremendous progress so far in 2019, but we still have a number of exciting milestones to look forward to in the remainder of the year. For starters, we plan to continue our global commercialization of Ompatro and also focus on enrolling patients with ATTR amyloidosis with cardiomyopathy in the Apollo B Phase 3 study. With vitreceram, we plan to continue enrolling the Helios A Phase III trial throughout the year and expect to initiate Helios B, an outcome study, in late 2019. With Gewurztratz, our planning is underway for the potential launch of our second RNAi therapeutic in the coming months, assuming positive regulatory reviews. Turning to Maserat, we plan to report top-line results.

As you to signal for questions.

Well now take our first question from David Notebooks Morgan Stanley . Please go ahead, Sir your line is okay.

Clearly the ramp of 'em Petros gone pretty well out the gate. When do you think you might gain enough comfort to give some guidance going forward.

Yvonne L. Greenstreet: The Illuminate A

Yvonne L. Greenstreet: Illuminate A

Yvonne L. Greenstreet: phase 3 study in late 2019. We will also continue enrolling paediatric patients

Yvonne L. Greenstreet: and plan to start the Illuminate C study in PH1 patients of all ages with severe renal impairment in late 2019, With Inclisiran, we look forward to seeing complete results from the Orion 9 and 10 studies that the medicines company plans to present at the American Heart Association meeting being held November 16th to 18th in Philadelphia. They also plan to submit an NDA for Inclusiran by the end of the year. And, of course, we plan to continue advancing our pipeline of earlier stage clinical efforts, as well as our exciting preclinical efforts, and plan to highlight these milestones throughout the rest of the year as they occur. In particular, you should expect data readouts for a number of our early and mid-stage clinical programs. And finally, as a reminder, we very much look forward to reviewing all of this at our R&D Day event in New York City on Friday, November 22nd. Let me now turn it back to Christine to coordinate our Q&A session.

For sales.

Yes, Thats a great question, Dave Jeff do you want to handle that yes, it's something that we're talking about and thinking about internally, we're not prepared to provide guidance today for for the fourth quarter or for next year, but the plan would be guidance would be on a on a year end call and again. This is something that we're thinking about not ready to give you an answer yet.

Understand the question.

Thank you for that.

In one one additional if I may with the Healios b and the.

The potro.

Pollo be trials being so similar.

How are you going to deal with the dynamic of recruiting patients for both at the same time.

Christine Regan Lindenboom: Thank you, Yvonne. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.

So as such without extensive clinical operations group that have great experience and relationships with TD outside.

Operator: Thank you. Ladies and gentlemen, if you would like to ask a question, please signal by pressing star 1 on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, as a reminder, press star 1 to ask a question. We'll pause for a brief moment to allow everyone an opportunity to signal for questions. We will now take our first question from David Lebowitz of Morgan Stanley. Please go ahead; your line is open.

We're working through all of platinum with we're pretty comfortable that we can achieve goals for both studies in terms of.

Speedy enrollment and get to read outs.

Thanks for taking my questions.

Great. Thank you Dave.

And then move onto our next question from Paul My sense of Stifel. Please go ahead. Your line is open.

Great. Thanks, so much a one financial question and one clinical question. If I may just in your commentary surrounding cash and expectation for having parents on operation for multiple years I guess in a world where expenses are likely to continue to go up can you speak qualitatively about what you're expecting.

David N. Lebowitz: Thank you very much for taking my question. Curious, clearly the ramp for Ampatro has gone pretty well out of the gate. When do you think you might gain enough comfort to give some guidance going forward?

David N. Lebowitz: for sales of what you expect maybe in the fourth quarter and perhaps into 2020.

Regarding cash flow coming in over the next couple of years and I was curious on the royalty streams like increase around presenting internal discussion or thoughts surrounding.

Jeff Poulton: Yeah, that's a great question, Dave. Jeff, do you want to handle that?

Monetizing that and then separately on the Healios B study, we noticed that you're allowing patients and the trial, who are honest stabilizer, who are not on a stabilizer can you talk about your assumptions there for the mix and how you're contemplating that powering perspective in other words, how much benefit are you assuming on top of a stabilizer versus.

Jeff Poulton: Yeah

Jeff Poulton: It's something that we're talking about and thinking about internally. We're not prepared to provide guidance today for the fourth quarter or for next year, but the plan would be, guidance would be on the year-end call, and again, this is something that we're thinking about. I understand the question. I will say more to come.

David N. Lebowitz: Thank you for that. One additional question, if I may. With the Helios B and the Ampatro Apollo B trials being so similar, how are you going to deal with the dynamic of recruiting patients for both at the same time?

The stabilize or not you patients. Thanks, so much.

Two great questions Paul.

Maybe maybe for starters, Jeff do you want to give some context or an answer to yeah. I mean, let me just sort of restate. What we said we have achieved 1.74 billion in cash at the end of third quarter, which which we feel very good about.

Akshay K. Vaishnaw: Yeah, that's a great question, Dave. Akshay, do you want to handle that?

Akshay K. Vaishnaw: I would say there are two factors. One is that Apollo B got up and running and is enrolling well in advance of Helios B, which we intend to start by the end of the year. And the second is, remember, in both studies, the predominant population is wild-type ATTL cardiomyopathy, and that population, of course, is remarkably prevalent in most parts of the world, does not have access to therapy today. And so, with our extensive clinical operations group that has great experience in relationships with TTR sites, we're working through all of that, and we're pretty comfortable that we can achieve goals for both studies in terms of speedy enrollment and getting to readouts.

We're not providing specific guidance today for next year or the following years I think the one thing that I can says that we're very focused on this question of financial sustainability is something that we talked a lot about internally I'll talk more about that at at our R&D day I think the one thing we're prepared to say in that regard as that we.

David N. Lebowitz: Thanks for taking my questions.

John Muruganuri: Great. Thank you, Dave.

Paul Matteis: We'll now move on to our next question from Paul Matteis of Stifel. Please go ahead; your line is open.

Paul Matteis: Great, thanks so much. One financial question and one clinical question, if I may. Just in your commentary surrounding cash and the expectation of having cash on operations for multiple years, I guess in a world where expenses are likely to continue to go up, can you at least be qualitatively about what you're expecting regarding cash flow coming in over the next couple of years? And I was curious about the royalty streams, like in Quisaran, if there's any internal discussion or thoughts surrounding monetizing that. And then separately on the Helios B study, we noticed that you're allowing patients in the trial who are on a stabilizer who are not on a stabilizer. Can you talk about your assumptions there for the mix and how you're contemplating that from a powering perspective? In other words, how much benefit are you assuming on top of a stabilizer versus stabilizer-naive patients?

And I appreciate you want to handle clinical question, yeah with respect to that so far. This question. Paul I think we have to acknowledge that department. So obviously is out there in certain settings, it's still ramping up its not available to the vast majority of patients.

We think around the world with wild type disease and Asia.

So as such I think we have an opportunity to really enrolled a robust placebo controlled study now having said that some patients will be on to families and I think.

Paul Matteis: Thanks so much.

Jeff Poulton: Two great questions, Paul. Maybe for starters, Jeff, do you want to give some context or an answer to those? Yeah, I mean, let me just sort of restate what we said. We had $1.74 billion in cash at the end of the third quarter, which we feel very good about.

We have to acknowledge that and allow those patients in the study. This study is designed to enable gotten up to 30% of patients may have concomitant of how tough honest background, but I can assure everybody that the primary comparison as a placebo control comparison and so as such we're comfortable with the infrastructure of the trial in the way we've pouted.

Jeff Poulton: We're not providing specific guidance today for next year or the following years. I think the one thing that I can say is that we are very focused on this question of financial sustainability. It's something that we talk a lot about internally. I'll talk more about that at our R&D day. I think the one thing we're prepared to say in that regard is that we believe that 2019 is going to be our peak net loss year. We'll see improvement in that next year and in the following years, which obviously is impacting the question that you asked about the cash runway. That's about all I'm prepared to say on this today.

Does that answer your question Paul Great Smith.

Absolutely. Thanks for taking my questions appreciate it thanks Paul.

We will now move on to our next question from Ted Tenthoff of Piper Jaffray. Please go ahead, Sir your line is.

Jeff Poulton: Comments briefly on the I mean, I think it's a fair question. I think we're very excited about the profile of that drug if it's approved, and you know we would think about or consider the possibility.

Great. Thank you very much happy Halloween everybody and.

Thanks, Ed.

Pretty remarkable what you've achieved with the launch in the year, so hats off to that getting up to over 6000 prisons by year end, that's really incredible execution.

Jeff Poulton: [inaudible]

Akshay K. Vaishnaw: Potential Drug. Akshay Vaishnaw, Yvonne Greenstreet, Eric Green, Gena Wang, Maury Raycroft, Leland Gershell, Yvonne Greenstreet, Eric Green, Konstantinos Biliouris, William Pickering, Ali Murad, Anna

For patients, who really need therapy.

One of the kind of look towards to those who are in a five day and I'm still did you have to be patient with grew from it because I still don't totally understand how we're going to be treating this disease. So maybe can you kind of walk us through you know sort of what the first approval might look like sort of how do you anticipate.

Eric Green: We have to acknowledge that profoundness is out there in certain settings, and it's still ramping up.

Akshay K. Vaishnaw: It's not available to the vast majority of patients around the world with wild type disease and HATTR. As such, I think we have an opportunity to really enroll a robust placebo-controlled study. Now, having said that, some patients will be on tefamidis, and I think we have to acknowledge that and allow those patients in the study. The study is designed to accommodate that, and up to 30% of patients may have concomitant tefamidis in the background. But I can assure everybody that the primary comparison is a placebo-controlled study. And so, as such, we're comfortable with the, you know, infrastructure of the trial and the way we've powered it so we can do that very key analysis and hopefully demonstrate, hopefully, the efficacy of Rutrice Ran-over Placebo. And, of course, this design has been vetted extensively.

Getting to consent to women, who could move to reverse order and then maybe longer term sort of so maybe prophylactic could be years. Thanks for answering that question.

Yeah, Great Great question, Ted actually if you want to answer that yeah, Pat you know.

I have as we've discussed before and I'm sure. Many of you are familiar at this this is a terrible disease.

So a striking in the prime of life and.

The issue. Unfortunately for patients is that when they present that first attack is not necessarily the end of the disease for what they can have many subsequent attacks. It can be wanting yet it can be one every five years. It can be 12, 24 year and patients battery remarkably and the.

The fact that any given attack can be life threatening and in fact people do die from this disease leave you with terrible visibility from the neuropathic impact.

Paul Matteis: Does that answer your question, Paul? Great.

John Muruganuri: Yeah, absolutely. Thanks for taking my question. Thank you all.

No it was disorders or peripheral neuropathy or of course in patients end up having laparotomy is for the abdominal pain wrongly means that this this constant fear once you have your first time when is the next attack calming How's it going to leave me and this is with respect to something that should be out studying.

Ted Tentoff: We will now move on to our next question from Ted Tentoff of Piper Jaffray. Please go ahead; your line is open.

Ted Tentoff: Great, thank you very much. Happy Halloween, everybody.

Akshay K. Vaishnaw: Pretty remarkable what you've achieved with the launch in a year. So hats off to that, getting up to almost a thousand patients by year, and that's really incredible execution for patients who really need therapy. I wanted to kind of look towards Javosiran, if I may, and I still, you have to be patient with me for a minute, because I still don't totally understand how we're going to be treating this disease. So maybe you can kind of walk us through, you know, sort of what the first approval might look like, sort of how you anticipate getting Javosiran to patients and women who need it, and then maybe longer term Thanks for answering that question.

Looking we're enjoying life and so I think physicians have this terrible dilemma of how to manage these patients and the study we design was to take patients were enrich for multiple attacks.

On average for older and to unequivocally I think demonstrate that we get a remarkable reduction in the annualized attack rate, 90% or Saturday. The median attack rate as designed in the envision study. So that shows a drug has this fundamental property to prevent attacks and I think we obviously await the label.

Akshay K. Vaishnaw: Yeah, great question, Ted. Akshay, do you want to answer that?

But but I do think we're providing a very new an important treatment option options. These patients.

Akshay K. Vaishnaw: Yeah, Ted, you know, as we've discussed before, and I'm sure many of you are familiar, this is a terrible disease, generally a disease of women, 9 to 1 women to men, often striking between the years of 15 to 45 in that prime of life. Oh, I'm 57, so maybe I'm past the prime of my life.

Great. Thanks.

It does seem or New York, we'll just a couple of weeks.

Thanks Ted.

I would take our next question from Ritu Baral of Cowen. Please go ahead. Your line is open.

Good morning, everyone. Thanks for taking your question I want to ask a little bit about what you were seeing in the field competition wise from two stamatis and what's sort of prescribers are what sort of patients.

Akshay K. Vaishnaw: So striking in the prime of life, and the issue, unfortunately, for patients is that when they present, that first attack is not necessarily the end of the disease for them. They can have many subsequent attacks. It can be one every year or it can be one every five years. It can be 12, 24 attacks a year, and patients vary remarkably, and the fact that any given attack can be life-threatening and, in fact, people do die from this disease or leave you with terrible disability from the neuropathic impact, either from nervous disorders or peripheral neuropathy, or, of course, patients end up having laparotomy for the abdominal pain, wrongly, means that there's this constant fear once you've had your first attack When is the next attack coming? How is it going to affect me? And this is with respect to someone that should be out studying or working or enjoying life.

Was that the reason that you had the dip in the proportion of new prescribing cardiologists.

Great question over to thanks for that very what analysts yeah. Let me talk about kind of the mix and then we can back up to Europe in specific physician type so.

We expect the prescriber base.

Akshay K. Vaishnaw: And so I think physicians have this terrible dilemma of how to manage these patients, and the study we designed was to take patients who are enriched for multiple attacks a year, on average four or more, and unequivocally, I think, demonstrate that we get a remarkable reduction in the annualized attack rate, 90% or so in the median attack rate as designed in the Envision study. So that shows that the drug has this fundamental property to prevent attacks, and I think we obviously await the label from the FDA and EMA. All of that work is ongoing right now, and physicians will have a very powerful new drug once approved to prevent attacks. And they'll have to make the choice, of course, but I do think we're providing a very new and important treatment option.

Pat showed to evolve overtime, there is always ebbs and flows in prescribing and I'll comment on the call. We're very pleased the number of new prescribers accounting for new patient starts and we believe the disease in the proportion of cardiology subscribing third quarter.

What was in fact associated in the United States with cardiologists very busy with their hundreds and hundreds of wild type patients getting them on a drug for the first time were drugs, we're no longer.

So we see we see others in cardiology, specifically really talking about TTR cardio. My obviously now is a comment on the call.

Once we got through sort of the early summer months into September October we did see the prescribing rate and cardiologist return to about 50%, but I will note that we are getting a number of additional prescriber types outside of Nurown cardio. So again, those those percentage rates will ebbs and flows the other dynamic and read to you asked about this.

Akshay K. Vaishnaw: I agree. Awesome. Thanks. I'm looking forward to seeing you in New York in just a couple weeks.

Some previous calls I don't have specific numbers, but there are more and more centers of excellence popping up around the country, where we're seeing multidisciplinary approach has been utilized.

Ted Tentoff: Great. Thanks, Taz.

Ritu Baral: We'll now take our next question from Ritu Baral of Cohen. Please go ahead; your line is open.

Ritu Baral: Good morning, everyone. Thanks for taking the time to answer the question. I wanted to ask a little bit about what you were seeing in the field competition-wise from tifamitis and what sort of prescribers or what sort of patients were the most impacted, I suppose, in Q3. Specifically, you know, was that the reason that you had the dip in the proportion of new prescribing cardiologists? And why do you think you saw the rebound? And what are you seeing in Europe with that physician breakout, commercial, competitive?

Now in Europe . The as soon as you know to feminist has previously been approved and Polyneuropathy. So there are countries with experience and we think that's the primary uptake that we've seen in what we're hearing from the field is in pure cardium out to see or the wild type population, which is very interesting.

Eric Green: Great question, Ritu. Thanks for that. Barry, you want to handle it?

Eric Green: Let me talk about the mix, and then we can back up to Europe and specific physician types.

Eric Green: The prescriber base of Ompatro is expected to evolve over time. There's always ebbs and flows in prescribing, and as we commented on the call, we're very pleased with the number of new prescribers, accounting for new patient starts, and we believe the disease in the proportion of cardiologists prescribing third quarter was, in fact, associated in the United States with cardiologists very busy with their hundreds and hundreds of wild-type patients, getting them on a drug for the first time when drugs were no So we see others in cardiology specifically really talking about TTR cardiomyopathy. Now as a comment on the call, once we got through sort of the early summer months into September, October, we did see the prescribing rate in cardiologists return to about 50 percent, but I will note that we are getting a number of additional prescriber types outside of neuro and cardio, so again, those percentage rates will ebb and flow.

More more actually in the community.

We talked about this dynamic and it's in fact, what we're seeing it you know at the beginning of launch.

Physicians are putting the p. patients and patients known to site on drugs and then as patients returned back to the community setting those physicians are getting more and more educated comfortable in diagnosing and treating so we're seeing kind of the pattern stretch outside the centers of excellence, who remain very busy but really busy doing clinical studies.

Versus training as many commercial patients.

Either naive to treatment or progressing or have progressed on the positive amadeus, but the other dynamic I want to come back to redo and we've talked about this offline, which I think is quite interesting in the U.S. is the is the occurrence of accommodate use now of on Petro and teach our stabilizers and we think thats dynamic that.

Eric Green: The other dynamic, and Rita, you've asked about this on previous calls, I don't have specific numbers, but there are more and more centers of excellence popping up around the country where we're seeing multidisciplinary approaches being utilized and cardiology being a key center referral pattern for all of TTR amyloidosis. Now in Europe, as you know, tefamus has previously been approved in polyneuropathy, so there are countries with experience, and we think that the primary uptake that we've seen and what we're hearing from the field is in pure cardiomyopathy or the wild-type population, which is very interesting to be getting reimbursed at this time, but that's the dynamic we're seeing outside the United States.

We will continue to grow in.

Great I'll hop back into queue. If my other questions. Thanks, great. Thanks for too.

Well move onto our next question from Sabine richer of Goldman Sachs. Please go ahead.

Good morning, Thanks for taking my question could you just provide further details on the patients that you mentioned were switching from to Sameer. This time petrol and perhaps if that's occurring in the opposite direction and then just comment on the concomitant use and where you're seeing this and if there's a specific type of patient.

Eric Green: Great. Just a quick follow-up. The new prescribers, are they in the Centers of Excellence, or are you starting to see that sort of filter out to the community as well?

Subset and then also to the mix phenotype patients what are you hearing from physicians on how they're choosing between stabilizer for instance, the silence or at this point.

Eric Green: More actually in the communities, you know, we talked about this dynamic, and it's in fact what we're seeing, you know, at the beginning of launch, physicians are putting the EAP patients and patients known to site on drugs, and then as patients return back to their community settings, those physicians are getting more and more educated and comfortable in diagnosing and treating. So we're seeing kind of the pattern stretch outside the centers of excellence who remain very busy but really busy doing clinical studies. Compared to treating as many commercial patients,

Yes, great great questions.

Just to just on the switching of course has to be clear that's happening predominantly in Europe , where to them and as has been on the market for many many years and these are patients that have progressed other to feminists.

Eric Green: And can I just add two other points? One is a clarification on PATCHO in Europe, just to be very clear. The uptake we're seeing is in the polyneuropathy patients with HATTR amyloidosis, and it's in the patients that are either naive to treatment or progressing or have progressed on defamidus. But the other dynamic I want to come back to, Ritu, and we've talked about this offline, which I think is quite interesting in the U.S., is the occurrence of concomit And we think that's a dynamic that will continue to grow in the U.S. market as physicians realize that they're able to continue to get reimbursement for Onpatro in that type of setting.

Patients have reached physicians have experienced patients continue to progress on their disease. In fact, Teresa published a paper recently out of our Portugal that.

About a third of patients seem to benefit by to them as the two thirds of patients rapidly progress so with that experience with in patients with polyneuropathy, there or is there a rapid switches to a ton Petro thats a dynamic we're also seeing in Japan.

And and Canada in terms of concomitant use we've seen concomitant use with generic nonsteroidal anti inflammatory that foods and offer some amount of time, it's hard to get a specific read on that because it's less specific and it's very easy to be reimbursed, but as John mentioned in the United States in patients with hereditary peers.

Eric Green: Great. I'll hop back in the queue with my other questions. Thanks.

Ritu Baral: Great, thanks Ritu.

Salveen Richter: We move on to our next question from Salveen Richter of Goldman Sachs. Please go ahead.

Salveen Richter: Good morning, thanks for taking my question. Could you just provide further details on the patients that you mentioned were switching from Typhamatous to Onpatro and perhaps if that's occurring in the opposite direction, and then just comment on the concomitant use and where you're seeing this, and if there's a specific type of patient subset. And then also for the mixed phenotype patients, you know, what are you hearing from physicians on how they're choosing between a stabilizer versus a silencer at this point?

You are and like doses with Polyneuropathy that may have had significant cardium out the and were started on a branded stabilizer as those patients progress in their polyneuropathy worsens, we're seeing physicians reach for on Patrick to treat the polyneuropathy part of hereditary TTR amyloidosis, which as you know we have very.

Strong data and importantly, and it speaks really to the relationship you have with payers, we are seeing reimbursement of on Petro even in the face of concomitant branded.

Eric Green: Yeah, great questions. Just on the switching, of course, just to be clear, that's happening predominantly in Europe, where defaminase has been on the market for many, many years, and these are patients that have progressed on their defaminase with their neuropathy. So they're switching to Ompatra at that point in time.

Products and something Barry mentioned Teresa without her last name Thats Teresa Quello who's the investigator in Portugal, and the paper he's referred to as a Monteiro paper, which I think is worth worth reading.

Great. Thank you.

Eric Green: Yeah, so I think what you just said is a very important dynamic. Outside the United States, where there's been significant experience of defaminants in patients with polyneuropathy, patients have, and physicians have experienced patients continuing to progress. In fact, Teresa published a paper recently out of Portugal that about a third of patients seem to benefit from tefamocin, but two-thirds of patients rapidly progress. So with that experience, in patients with polyneuropathy, there are rapid switches to empetra. That's a dynamic we're also seeing in Japan and Canada.

We will now move on to our next question from Geno Wang of Barclays. Please go ahead. Your line is okay.

Thank you for taking my questions I think two questions one new preclinical.

Question for he will be.

You do allow up to 30% patient baseline to sadness that continue all throughout the study just wondering is the powering assumption.

Now to detect statistic.

If they can benefit in this particular patient population, so I'm asking mainly in the company.

Eric Green: In terms of concomitant use, we've seen concomitant use with the generic non-steroidal anti-inflammatory difluzinol for some amount of time. It's hard to get a specific read on that because it's less specific, and it's very easy to be reimbursed. But as John mentioned, in the United States, in patients with hereditary TTR amyloidosis with polyneuropathy who may have had significant cardiomyopathy and were started on a branded stabilizer, as those patients progress and their polyneuropathy worsens, we're seeing physicians reach for empetra to treat the polyneuropathy part of hereditary TTR amyloidosis, about which, as you know, And importantly, and this speaks really to the relationship we have had with payers, we are seeing reimbursement of empetra even in the face of concomitant branded products.

Generic to Fadiman [laughter] 2029.

Yeah.

Thats a quick question Gino auction, what hill that gene if I answer the question right at the answer is no. The primary comparisons of placebo controlled comparison between.

Good trips around and placebo so.

So we're not powered to show differences between those combinations upsize.

So how would you address you know the few true to fed I Miss generic entry.

Well, let me just starts so you know active comparator going falling for the trial design.

Yeah, I mean first of all Jade I think it's a it's an open question as to as to what the real generic entry Dave will be given bid the Max and the the new solve for both of them and as we don't expect there are necessarily to be a generic version of indicates how.

John Muruganuri: And Salveen, Barry mentioned Teresa, without her last name, that's Teresa Coelho, who's the investigator in Portugal, and the paper he's referring to is the Montero paper, which I think is worth reading.

Actually so I think theres not a dynamic there that we think commercially we need to navigate through.

Salveen Richter: Great, thank you.

Gena Wang: We will now move on to our next question from Gena Wang of Barclays. Please go ahead; your line is open.

Gena Wang: Thank you for taking my questions. I think I have two.

You know if we look at how to Affimed is performing in peripheral neuropathy component of HIV TTR.

Gena Wang: One is a clinical trial question for Helios B. You do allow up to 30% patients on baseline tefadimus and continue on throughout the study. Just wondering, is the powering assumption allowed to detect statistically significant benefits in this particular patient population? So I'm asking mainly in the context of generic tefadimus entry in 2029.

And as Barry just outlined from the Monteiro tell paper by the quite a group.

It didn't seem to have a strong result is the primary endpoint, we had a very different result in a much tougher to treat population.

That is widely acknowledged now again I'm not formally comparing cross studies ESMO feasible, but I think people up to draw their own conclusions from that and we remain very optimistic that Pts I was going to purchase all the.

Akshay K. Vaishnaw: Yeah, that's a great question, Gena. Akshay, do you want to handle that? Yeah, Gena, if I understood the question right, the answer is no. The primary comparison is a placebo-controlled comparison.

Potent wait to treat this disease and.

Gena Wang: [inaudible]

Akshay K. Vaishnaw: So how would you address, you know, the future ephanimous generic?

Akshay K. Vaishnaw: Any thoughts on active comparator going forward in terms of the trial design? Yeah, I mean, first of all, Gina, I think it's an open question as to what the real generic entry date will be given Vindemax and the new cell form of defaminase. We don't expect there necessarily to be a generic version of Vindickel in the timeframe that you're talking about, actually. So I think there's not a dynamic there that, commercially, we need to navigate through.

Great and then another quick question regarding the cashman.

Hi, good ask a lot of fighting that comes to a annual been close to 1 billion.

Thoughts on the cost can you know mostly spin on the program. So early stage Lee stage and then into the DNA.

[laughter], how soon should we expect Allen become a self testing company.

Akshay K. Vaishnaw: Yeah, and I would just add to that that as far as TTR lowering approaches are concerned, whilst you can't compare across studies, you know, if we look at how TEFAM is performing in the peripheral neuropathy component of HA-TTR, and as Barry just outlined from the Montero et al. paper by the Quailer Group, it didn't seem to have a strong result, and it missed the We had a very different result in a much tougher-to-treat population, and that is widely acknowledged. Now again, I'm not formally comparing across studies; that's not feasible, but I think people have to draw their own conclusions from that, and we remain very optimistic that TTR silencing approaches are the most potent way to treat this disease, and that primary comparison should be very enlightening as to the ability of Futriseran to help these patients.

Yeah, let's Jeff do you want to handle yeah, we're not prepared to give you specific day today I think I mentioned earlier, it's something that we're talking a lot about it's a it's a focus for US. We think we're starting on that journey. We expect that this is going to be our our peak that last year as it relates to operating expenses I anticipate lower operating.

Expense growth going into 2020 than what were generated in 2019, and we also have a lot of things to be optimistic about on the top line in terms of growth for next year, both with on Petro as well as if go Saran is approved.

So hopefully that answers. Your question again this is a big focus for us I anticipate.

Gena Wang: And then another quick question regarding the cash burn, because I got asked a lot by the investors. So the annual burn is close to $1 billion. Any thoughts on the cost, you know, mostly spent on the programs or early stage, late stage, and then the FG&A perspective? How soon should we expect Alnylam to become self-sustaining?

Again on the SGN Isight in particular for next year that we're gonna be able to leverage what's been built.

From the standpoint of our royalties and how and how that plays out for our profile will also be a very important component of this transition towards self sustainability and then we have high confidence.

Jeff Poulton: Yeah, let's Jeff handle it. Do you want to handle it? Yeah, we're not prepared to give you a specific date today.

Jeff Poulton: I think I mentioned earlier that it's something that we're talking a lot about. It's a focus for us. We think we're starting on that journey. We expect that this is going to be our

Jeff Poulton: [inaudible]

John Muruganuri: And I would just add that obviously, the very positive Eclisiran results from the standpoint of our royalties and how that plays out for our profile will also be a very important component of this transition towards self-sustainability. And then we have high confidence that Lomaceran will be a positive result later this year in December, and that obviously will add yet another product to our overall revenue mix. So when you look at the staging of product launches, both organic or proprietary that we have in Alnylam, but also the royalties that we get, and promising new guidance from Sanofi in their call about Fitusiran, you put all this together, and we've got some very nice revenue growth that we're going to be seeing in the years to come that will assist the company's transition toward self-sustainability. Thank you very much.

New guidance from from Saturday and their call about Fitusiran you put all those together we've got we've got some very nice revenue growth that we're going to seeing of the years to call that will assist the company's transition towards sustainability.

I guess can you talk a little bit more about the clip of patients that you're seeing in the U.S. in Europe , I mean, I typically at a steady clip of adding pay sense. It should we think about as we go into next maybe six seven quarters.

Aletha Young: We will now move on to our next question from Aletha Young of Cantor Fitzgerald. Please go ahead; your line is open.

That's the same clips and she basically are finding people as well. So I just wanted to kind of reflect on that and then I just wanted to get like your temperature potentially yeah, I've got those around label that might be potentially broad and how you're thinking about that and how that ties into the world the pricing. Thanks.

Eric Green: Hey guys, thanks for taking my question. I got like 10. No, I'm just joking. Maybe I have one or two. I guess, could you talk a little bit more about the number of patients that you're seeing in the U.S. and Europe? I mean, you know, I feel like there's a steady rate of adding patients, and should we think about as we go into the next maybe six, seven quarters, you know, the same rate, since you basically are finding people as well? So I just wanted to kind of reflect on that. And then I just wanted to get your temperature on potentially a caposaran label that might be potentially broad, and how you're thinking about that, and how that ties into the world of pricing things.

Not descent [laughter], yet as we commented previously we continue to see continuous and steady both patient and revenue growth.

In the quarters to come as Weve as we've commented that growth comes from really three areas. Its opening new markets as we saw this quarter in Japan in Canada. For example, it's continued evidence generation.

Eric Green: Great. All right, Barry, do you want to start with the first one and then...

Eric Green: Yeah, thanks Alicia. Thanks for the two questions, but not the ten.

Eric Green: As we've commented previously, we continue to see continuous and steady both patient and revenue growth in the quarters to come. And as we've commented, that growth comes from really three areas. It's opening new markets, as we saw this quarter in Japan and Canada, for example. And it's continued evidence generation, allowing physicians to be more and more comfortable with Patrick prescribing. And then it's de novo patient finding in markets where we've already launched, and those efforts are going well. As we commented, with our disease education and awareness efforts and those of others, as we talked about previously, we do see the market continuing to grow, and the number of hereditary patients with polyneuropathy being identified. So that's how we see the growth continuing quarter on quarter in a continuous and steady fashion.

Eight patients with Polyneuropathy being identified so that's how we see the growth continuing quarter on quarter and continuous and steady fashion.

Now regarding your closer end question Alexia, Let me just start by saying we learned from our last experience that we should not be label soothsayers. So I don't I don't want to get ahead of our skis on that issue, but we're in regulatory review now and our PDUFA dates February four and I think thats, where we should move.

Sounds good.

And then move onto our next question from Maury Raycroft of Jefferies. Please go ahead. Your line is not won't but.

Hi, everyone. Congrats on the progress and thanks for taking my question I'm, just going to ask about be optional interim analysis in healios be being just remind how you decide to do the interim what could happen there and when that could happen and what's you're going to be looking forward that.

John Muruganuri: Now, regarding your Govosaran question, Alethea, let me just start by saying, you know, we learned from our last experience that we should not be labeled soothsayers, so I don't want to get ahead of ourselves on that issue, but we're in regulatory review now, and our PDUPA day is February 4th, and I think that's where we should move it at this point. Sounds good.

Great terrific Laurie and thanks for your thanks for your congratulations at the beginning auction you want to handle the question, Yes, I mean, I think it's a little premature to get into those details now there's some stuff we wont work through first before we share but.

Eric Green: Sounds good!

Maury Raycroft: We'll now move on to our next question from Maury Raycroft of Jeffreys. Please go ahead; your line is now open.

The issue of interest depend so much on how things again with the study and how quickly enrolls for example, we learn from the envision study the enrollment because it's such a pace that.

Maury Raycroft: Hi everyone, congratulations on the progress and thanks for taking my question. I'm just going to ask about the optional interim analysis in Helios B. If you can just remind me how you decide to do the interim, what could happen there, when that could happen, and what you're going to be looking for with that.

The entry movements became a few talk because the full data so that was going to be available in a very timely fashion off so the trend. So there's a lot to work through here I think in due course will come back and visit or not.

Akshay K. Vaishnaw: Great. Terrific, Maury. Thanks for your congratulations at the beginning. Akshay, do you want to handle the question?

Got it okay. Thanks for taking my question.

Thanks Marty.

And then move onto our next question from Whitney Ijem of Guggenheim. Please go ahead. Your line is on.

Akshay K. Vaishnaw: I mean, I think it's a little premature to get into those details now. There's some stuff we want to work through first before we share, but you know, the issue of the interim depends so much on how things are going with the study and how quickly it enrolls. For example, we learned from the Envision study that enrollment occurred at such a pace that, you know, the interim almost became futile because the full data set was going to be available in a very timely fashion after the interim. So there's a lot to work through here. I think in due course, we'll come back and visit that point.

Morning, guys. A couple of follow ups on cupolas ran as the first in terms of the patient number you gave I think you said 3000 diagnosed in the U.S. in Europe I just wanted to double check I recall, a 5000 number at some point. So just wanted maybe I misheard, but I'm kind of rectify those two numbers and then in terms of the breakout of the 1000 pace.

We have more frequent attacks I guess can you compare and contrast, the frequency in those patients versus kind of the broader 3000 number.

Maury Raycroft: Got it. Okay. Thanks for doing my hair.

John Muruganuri: Thanks, Maury.

Yeah, Let me let me start in the Barry you might you might want to add some some more as you can imagine when as we get closer to the approval we've been sharpening our pencils to really they'll nailed down the prevalence rates and the diagnosed patients versus the other diagnose patients Theres no change in the overall estimate of the 1000 worker.

Whitney Ijim: We'll now move on to our next question from Whitney Ijim of Guggenheim. Please go ahead; your line is open.

John Muruganuri: Good morning, guys. A couple follow-ups on Govosran. So first, in terms of the patient numbers you gave, I think you said 3,000 diagnosed in the U.S. and Europe. I just wanted to double-check. I recall a 5,000 number at some point, so just wanted to – maybe I misheard, but kind of reconcile those two numbers. And then, in terms of the breakout of the 1,000 patients who have more frequent attacks, can you compare and contrast the frequency in those patients versus kind of the broader 3,000 number?

Patients in the 5000 of sporadic patients that Weve had out there. We believe those are still the right numbers, but as we get as we get really granular on the patients that have active disease and are diagnosed there are a total we believe there are a total of 3000 in the U.S. and Europe obviously.

We have a larger number in the rest of world a 3000 to us in Europe of which a thousand those 3000 are doing those recurrent attack patients set up for attacks or more and then 2000. Those 3000 are the less recurrent patient so the sporadic attack patients now the.

John Muruganuri: Yeah, let me start, and then Barry, you might, you might want to add some, some more, as you can imagine Whitney, as we get closer to the approval, we've been sharpening our pencils to really nail down the prevalence rates and the diagnosed patients versus the undiagnosed patients, you know, there's no change.

The 5000 number is still the real lumber.

Eric Green: The overall estimate of the 1,000 recurrent patients and the 5,000 sporadic patients that we've had out there, we believe those are still the right numbers, but as we get really granular on the patients that have active disease and are diagnosed, there are a total of 3,000 in the U.S. and Europe, obviously a larger number in the rest of the world, but 3,000 in the U.S. and Europe, of which 1,000 of Now, the 5,000 number is still the real number, and we believe that that's where it goes, but when we talk about actual diagnosed patients, we've always said it's smaller than that 5,000 number. Barry, anything else to add to that?

And we believe that that's where it goes but when we talk about actual diagnosed patients. We've always said, it's smaller than that 5000 number very anything else to add to that nothing you covered it well John .

Okay and then just one quick follow up if you commented on how many patients are ongoing in the allele or the early access protocol. Thanks.

We haven't we haven't yet and it's a protocol that was only opened up relatively recently as well, but you know will provide more color as we get closer to approval for the product.

Thanks.

All right. Thank you Wendy.

We will now move onto a final question from non Jacob of U.S. Please your line is open.

Hi, everyone. Thanks for taking my question is actually shriek or 94 I'm on for anything Jacob.

Just first on Petro just can you give us an initial sense of the number of patients Japan and how the average dose in Japan compares to the average does the U.S.

John Muruganuri: I think you've covered it well, John.

And then maybe I missed this on the on the Cogs assumption when do you expect to run through the R&D expense product.

Eric Green: Okay, and then just one quick follow-up. Have you commented on how many patients are ongoing in the OLE or the Early Access Protocol?

And then I have a just a longer term question I saw the regeneron collaboration that that's the N.S. asset was included Alan a P.P. that could possibly have applications. The all time or is that these with the news. The recent news or you guys have any updated thoughts on the priority of this program versus the others.

John Muruganuri: We haven't, and we haven't yet. And it's a protocol that was only opened up relatively recently as well. But, you know, we'll provide more color as we get closer to approval for the product.

Whitney Ijim: Alright, thank you, Wendy.

Navin Jacob: We will now move on to our final question from Navin Jacob of UBS. Please go ahead; your line is open.

Thanks very much.

Great. Those are those are three great question, so, let's start with dairy and they're going to Jeff and then obviously and I can do the last one yeah. Thanks for the question. So we're not providing any breakout other than the international breakout I can tell you from a just to give some color that of the Japan Pan launch is going very well the care walls are very well aware and as mentioned.

Navin Jacob: Hi everyone, thanks for taking my questions. This is actually Srikar Naziporam on Fernandine Jacob.

Navin Jacob: First on Patro, can you give us an initial sense of the number of patients in Japan and how the average dose in Japan compares to the average dose in the U.S.? And then, maybe I missed this on the COGS assumption. When do you expect to run through the already-expensed product? And then, I have just a longer-term question. I found in the Regeneron collaboration that a CNS asset was included, ALN APP, that could possibly have applications to Alzheimer's disease. With the recent news, do you guys have any updated thoughts on the priority of this program versus the other? Thanks very much.

To feminism patients were very known in Japan. So we're seeing both de novo starts up and and significant numbers of patients, which is now yes, but dosing. It's a weight based dosage pan patients tend to be a little bit lighter, but thats about all we can say right now yeah. The price per vial is very strong in Japan as well.

Digital color, we can provide Jeff do you want to yeah, I'm going on on Cogs today, we're at about 11% of sales, but that's benefiting from the zero cost.

Eric Green: Great, those are three great questions. So let's start with Barry, and then go to Jeff, and then Akshay and I can do the last one.

Eric Green: Yeah, thanks for the question. We're not providing any breakout other than the international breakout.

Cogs that have previously been Expensed R&D, we expect the transition to be first half of 2021, we'll see fully cost cost of goods sold for on Petro and when that occurs we expect to see that Cogs percentage as a percentage of revenue step up into the to the mid to high teens.

Eric Green: I can tell you from a, just to give you some color, that the Japan launch is going very well. The KOLs are very well aware. And as we mentioned, families and patients were very well known in Japan, so we're seeing both NovoStarts and significant numbers of patient switches.

And then thanks for asking the question of Regeneron and ATP. We are obviously excited about evolent precursor protein as we characterize before it is our lead CNS program option you want to comment further on that and I I think it will be our first time be into CNO space and we continue to believe that the work is going.

Eric Green: It's a waste-based dose, so Japanese patients tend to be a little bit lighter, but that's about all we can say right now.

Jeff Poulton: Yeah, the price per vial is $ 9.99.

Jeff Poulton: and as well as Digital Color, we can provide.

John Muruganuri: Unknown Speaker Yeah, on COGS today, we're at about 11% of sales, but that's benefiting from the zero cost COGS that have previously been expensed to R&D. We expect the transition to be in the first half of 2020, when we'll see fully cost-based cost of goods sold for Onpatro, and when that occurs, we expect to see that COGS percentage as a percentage of revenue step up into the mid to high teens.

Meanwhile, our.

Primary target is the industry glemba load on geography, which we've discussed before whereas of genetically validated target for the inherited formed the disease and many of hard to believe it's very heavily implicated in the wild type of more sporadic from the disease, which your tax hundreds of thousands if not millions around the world.

And.

Akshay K. Vaishnaw: Thanks for asking the question about Regeneron and APP. We are obviously excited about amyloid precursor protein, as we've characterized before. It is our lead CNS program. Akshay, do you want to comment further on that? I think it will be our first R&D in the CNS space.

With respect to the broader question I think.

Pp, a beta and alpine business. We've had recently from pricing continues to be an ongoing ongoing discussion and debate and it will be very interesting to see how.

The various excess regulatory agencies and elsewhere.

Akshay K. Vaishnaw: With respect to the broader question, I think, you know, APP, A-beta, and Alzheimer's, as we've heard recently from Bhajan, continues to be an ongoing, ongoing discussion and debate, and it will be very interesting to see how the various experts at regulatory agencies and elsewhere evaluate the out-of-county map data set, Very important in further fueling the need to have a beta-suppressing agent, so what better than to turn the tap off, or substantially turn the tap off, and reduce the production of the protein as we've done with TTR, and we would be optimistic that that would have a profound impact. I'll see you next time.

Evaluate the out to kind of map data set I think it could be very important further fueling the need to have a a beta suppressing agents and was better than to turn the top awful substantially to the top off and reduce the production of the protein as we've done with TTR and we would be optimistic but that would have a profound impact on the nature.

But as you know much more development, yeah, and obviously, we're we were pleased to see that there might be some.

Light at the end of the tunnel for attic into Maben and approaches.

Targeting the Evolent hypothesis in Alzheimer's and that's obviously good for medicine to patients.

John Muruganuri: Yeah, and obviously, we were pleased to see that there might be some light at the end of the tunnel for Adekinumab and approaches targeting the amyloid hypothesis in Alzheimer's, and that's obviously good for medicine and patients, and that could also be instructive for our program as well, which is good. Okay, so I think that's... Alright, thank you.

And that's that could also be instructive for our program as well.

Okay, So I think Jeff.

Alright. Thank you. So I think that was our last questions I do want to thank everybody for joining us on the call. We're obviously very pleased with the R&D in commercial progress that we've been making at a level and we believe that we're really doing our best to build a remarkable company focused on improving laws of patients and capable of creating significant shareholder value.

Operator: So, I think that was our last question, so I do want to thank everybody for joining us on the call. We're obviously very pleased with the R&D and commercial progress that we've been making at Alnylam, and we believe that we're really doing our best to build a remarkable company focused on improving the lives of patients and capable of creating significant shareholder value. So with that, we look forward to updating you again at our R&D day in the coming weeks and then again toward the beginning of next year. Thank you very much. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. Thank you for watching!

So with that we look forward to updating you next at R&D day in the coming weeks and then again.

For the beginning of next year. Thank you very much.

Ladies and gentlemen, this concludes todays conference call. Thank you for your participation you may now disconnect.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

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