Q4 2019 Earnings Call

Ladies and gentlemen, thank you for standing by welcome to the Old Island Pharmaceuticals conference call to discuss fourth quarter and 29 team.

Operator: Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss fourth quarter and year-end 2019 financial results. There will be a question and answer session to follow. Please be advised that this call is being made at the company's request. Now, I'd like to turn the call over to the company. Good morning.

Central itself.

There will be a question answer session to follow.

Please be advised that these cool [laughter] at the company's request.

Let's turn to go over to the company.

Good morning, I'm, Christine Lindenboom, Vice President Investor Relations and corporate Communications I don't know with me today, or John nursing or <unk> Chief Executive.

Christine Regan Lindenboom: I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganori, Chief Executive Officer; Barry Green, President; Pushkal Garg, Chief Medical Officer; Jeff Poulton, Chief Financial Officer; and Yvonne Greenstreet, Chief Operating Officer. Akshay Vaishnaw, our President of R&D, is traveling today and unable to join us for today'

<unk> SAR Barry Green President Bush go Kart, Chief Medical Officer, Jeff Fulton, Chief Financial Officer in a Bunkering Chief operating officer observation, our Vice President of R&D is traveling today on April and unable to join US for today's call for those participating via conference calls the accompanying slides can be assets I got to be event.

Christine Regan Lindenboom: For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of our newly redesigned investor page of our website at alnylam.com slash events. During today's call, as outlined in slide 2, John will provide some introductory remarks and provide general context. Barry will provide an update on our commercial and medical affairs progress, and Pushkal will review recent clinical updates. Jeff will review our Q4 and year-end 2019 financials and discuss our 2020 guidance, and Yvonne will provide a brief summary of upcoming milestones before opening the call to 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 purpose of our safe harbor provision under the Private Securities Litigation Reform Act of 1995. However, actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the following.

That said, our newly redesigned for paper website and on island.

[laughter].

During today's call is no one likes to Donald for my introductory remarks for my General.

Very provide an update on our commercial and medical affairs progress clinical work the recent clinical update John.

Q4.

And your in 2019 financials are 2020 guidance.

Bob will provide a brief summary of upcoming milestones before opening the call for your question.

I'd like to remind you that this call getting remark starting on island future expectations plans and crop, which constitute forward looking statements for the purpose of our safe Harbor provision under I'm sorry.

Securities Litigation Reform Act of 1995 actual results may differ materially from those indicators like these forward looking statement as a result was very important factor, including those discussed in remote recently quarterly reports on file with that you see in addition, any forward looking statements represent our views only up to date, if this recording and should not be relied upon as representing.

Christine Regan Lindenboom: In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such a statement. And with that, I'll now turn the call over to John.

Yes, as if any.

[laughter] disclaims any obligation to update such statement with that I'll now turn the call over to John well bankruptcy and thanks, everyone for joining this call. This call. This morning, I can make a few key points to provide some overall context for our discussion first and fourth.

John Maraganori: Thank you everyone for joining us on this call this morning. I'd like to make a few key points to provide some overall context for our discussion.

John Maraganori: First, in the fourth quarter and recent period, we made tremendous progress advancing our commercial products, bringing RDI therapeutics to patients around the world. With Onpatro, we saw greater than 20% quarter-on-quarter growth in global Onpatro net revenue. Driven by significant new patient ads in the U.S. and the EU, along with a strong launch, With the FDA approval of Goodlary this past November and the positive CHIP opinion just last week, we became a multi-product commercial company and are pleased to now be making this medicine available to ACAP acute hepatic porphyria patients in the U.S. and soon in Europe. In 2020, we look forward to continued global commercial execution with Alpatro and the global launch of Givlari, bringing the benefits of these innovative therapies to patients around the world.

We're in recent periods, we made tremendous progress advancing of commercial products bring already I therapeutics to patients around the world without Pembroke, we saw greater than 20% quarterly order growth in global not show net revenues driven by significant patient and Wes you.

Along with a strong launch in Japan.

With the FDA approval of good Laurie this past November.

Cost of CHF. He opinions just last week, we became a multiproduct commercial company and are pleased to now be making this medicine available to a cap acute hepatic porphyria patients in the U.S. and soon.

In Europe.

2020, we look forward to continued global commercial execution without Petro and local launch up your board, bringing the benefits of these innovative therapies to patients around the world.

John Maraganori: Secondly, in the fourth quarter, we made strong progress on our pipeline, and we're excited to report positive top-line results in the Illuminate A phase 3 study of Lumasarac in primary hyperoxalaria type 1, marking our third program to achieve positive phase 3 data in 2019 alone. We're now focused on completing our regulatory filings for Maseran, and, assuming favorable regulatory reviews, we believe we should be in a position to bring this medicine to the market by the end of the year. Another notable milestone of Q4 was positive phase 3 results for Eclixirab, leading to the $9.7 billion acquisition of the medicines company by Novartis. We're very pleased to now be partnered with Novartis and look forward to supporting their efforts as they prepare to bring Eclisirab to patients around the world.

Secondly in the fourth quarter, we made strong progress on our part one and we're excited to report positive top line results.

Often do you want a phase three study well that's right in primary Hyperoxaluria type one marking our third program.

See positive phase three data in 29 seeing a low.

We're now focused on completing a regulatory filings for the mass ran and assuming favorable rent ready for reviews, we believe.

You should be in a position to bring this medicine to the market Buddy ended the year.

No notable well sort of Q4 was positive phase three results for at least crane, leading to the 9.7 billion dollar acquisition of the best company by Novartis. We're very pleased that will be partnered with Novartis and look forward to supporting their.

As they prepare to bring increase around the patients around the world.

John Maraganori: We believe that, if approved, Eclipse Red has the potential to be a transformative medicine for patients, representing an important future source of potential product revenues for Alnylam and also a potential opportunity to strengthen our balance sheet outside of the equity market. In addition, we continue to advance our ongoing phase 3 development activities for Petriceran, the unbranded name for Ampetro, and Butreserin in the hereditary and wild-type KQTR amyloidosis cardiomyopathy setting. We believe that our approach of silencing the production of TTR with an RNAi therapeutic has the potential to be the best-in-class mechanism for treating TTR amyloidosis. We also believe that the potential opportunity for Petitseran and then Goutriseran in the ATTR indication, assuming positive phase III results from regulatory review, could represent a multi-billion dollar anchor opportunity for building ELAL, similar to what Regeneron had with ILEA or Celgene with Revlimid.

We believe that Froome includes threatened has the potential to be a transformative medicines for patients representing an important future source of potential product revenues for awhile.

Also in potential opportunities to strengthen our balance sheet.

Hi to the equity Mark.

In addition, we continue to advance our ongoing phase three development activities properties ran yup brand name from Petro and which we spread into the hereditary wildfire.

I will address this party mom with these settings.

We believe that our purpose silencing to production that you all have already out there.

Thank you to has the potential to be the best in class mechanism and they are amyloidosis.

I also believe that potential opportunity for piece right and that in Threeq thread it'd be a you are absolutely. This is part of the quality education, assuming positive picture results right, where you could represent a multi.

Billion dollar acre opportunity for building a level similar to what it for general I've had with idea for Celgene will wrap on it.

John Maraganori: Now, as you know, our robust product pipeline also includes some earlier stage clinical programs in areas such as common and mediated diseases, hypertension, chronic HPV infection, and alpha-1 liver disease. We were pleased to share some of the initial data from these programs at our R&D day this past November, and you should expect to see more data from these efforts throughout 2020, highlighting Elnylam's next wave of potential opportunities for sustainable innovation and growth. The final point I'd like to make is that Alnylam is now very much focused on achieving a self-sustainable financial profile. Our CFO, Jeff Poulton...

Now as you know our robust product pipeline also some earlier stage clinical programs and area.

Mediated diseases hypertension, chronic HBV infection, and now for whatever disease for.

We're pleased to share some of the initial data from these programs at R&D day. This past November and you should expect to see more data from these efforts throughout 2020, highlighting help mile next wave of potential opportunities for sustainable innovation and growth.

What it might make a lot of itself very much focused on achieving.

Self sustainable financial our CFO, Jeff Wolcott will elaborate on this later in the call but to be very clear. Realizing this goal is not a question of yes, but rather a question of optimizing the land and the how with the goal of achieving significant applications and delivering strong.

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John Maraganori: Thank you very much. We believe that we have a clear line of sight to get there, and over the next five or six years, we see an opportunity to build a top five biopharmaceutical company, bringing transformative medicine for both rare and common diseases to patients around the world and growing with excellence, innovation, and responsibility. We're committed to this future for all four Alnylams, and we believe that we're very well positioned to achieve it. With that, I'll now turn the call over to Barry to review our commercial and medical affairs progress in more detail. Barry?

Value for shareholders. We believe that we have a clear line of sight to get there and over the next five or six years, we see an opportunity to building a top five Biopharma company brain transformative medicine control rare and common diseases, the patients around the world and growing with excellent innovation and responsibility.

Committed to the speech profile for a model and we believe that we're very well positioned to achieve.

With that I'll now turn the call over to vary to review, our commercial and medical affairs progress in more detail Barry Thanks, John and good morning, everyone.

Eric Green: Thanks, John, and good morning, everyone. I'll begin by reviewing Ampatra's commercial performance. We achieved $55.8 million in global Ampato Net product revenues in the fourth quarter, representing 21% quarter-on-quarter growth compared with Q3, and we achieved $166.4 million in global Onpatria Net revenues for the full year 2019. As far as geographical split is concerned, we achieved $35.8 million from the U.S. and $20 million from the rest of the world. U.S. Ampato net sales in the fourth quarter represented 6% quarter-on-quarter growth, while underlying demand sales growth was 12% driven by new patients initiating therapy. Jeff will comment on the differences between reported and underlying demand sales growth later in the call.

I'll begin by reviewing on catchers commercial performance we achieved.

85.8 million in global and patch with net product revenues in the fourth quarter, representing 21% quarter on quarter growth compared with Q3.

And we achieved 166.4 million in global and Patrick net revenues for the full year between 90.

In terms of geographic split we achieved 30.

5.8 million from the U.S. and 20 million from the rest of world.

Yes, I'll pass through net sales in the fourth quarter, representing 6% quarter on quarter growth, while underlying demand sales growth was 12% driven by new patients initiating therapy.

Jeff will comment on the differences between reported and underlying demand sales growth.

Later in the call.

Eric Green: International sales represented 61% quarter-on-quarter growth, which was driven by continued execution in EU countries where pricing reimbursement exists, and with strong recent launches in both the UK and Japan. Now, most importantly, as of year-end, over 750 patients worldwide were receiving commercial Onpatio treatment. When we include patients in clinical trials and in our Expanded Access Program, or EAP, we have achieved over 1,000 patients worldwide who are being treated with Onpatio or Pitucerin as of year-end. An exciting milestone in our overall efforts and highly encouraging for the overall HATTR community. Now let's move on to review some of the market dynamics in the U.S. specifically. On the physician front, we continue to see growth in both the number of new prescribers as well as repeat prescribers, with our total number of unpatched U.S. prescribers now at over 230 since launch.

International sales represented 61% quarter on quarter growth, which was driven by continued execution you countries, we're pricing and reimbursement exists and with strong recent launches in both the UK and Japan.

Most importantly as of year end over 750.

These worldwide, receiving commercial and Patrick season. When you include patients in clinical trials and in our expanded access program or you see we achieved over a thousand patients worldwide will be treated with him Patrick Houston as of yearend, an exciting milestone in our overall afterwards and highly encouraging for the overall.

Aged 18 to your community.

Let's move onto review some of the market dynamics in the U.S. specifically on the physician front, we continued to see growth in both number of new prescribers as well as repeat prescribers their total number of and Petrie U.S. prescribers now it over 230 since launch.

Eric Green: We believe continued growth in new prescribers reflects an ever-increasing disease awareness on the part of HCPs, driven largely by Congress presentations and the benefits of multiple players engaged in disease state education. Regarding the mix of U.S. prescribers in the fourth quarter, based on START forms received, about 41% of START forms were from neurologists. About 37% come from cardiology. As a reminder, all START forms, regardless of specialty, are for the treatment of the polyneuropathy of HHTQM1 doses. For 29...

We believe.

Continued growth new prescribers reflect ever increasing disease awareness on part of HCP.

Driven largely by Congress presentation, and the benefits of multiple players engaged in disease State education.

Regarding the mixed reviews prescribers in the fourth quarter based on start forms received about 41% to start forms.

Well from neurologists was up 37% coming from cardiologists as a remainder all as a reminder, allstar forms regardless of specialty are for the treatment of the Polyneuropathy of EG German business.

Were 29 cute overall cardiologist accounted for 44% to start from submitted the 38% coming from.

Eric Green: Thank you to all.

Eric Green: Cardiologists accounted for 44% of the initial forms submitted, with 38% coming from neurologists and 18% from other physician specialties. Overall, and as many of you heard at R&D Day, we believe HCPs across specialties in the U.S. are growing increasingly comfortable with treating the polyneuropathy of HAT Traumatosis with on-path treatment. Adherence to therapy also remains very strong to date, a very encouraging sign and consistent with the Apollo Phase 3 data when real-world evidence lines up with clinical trial results. We continue to estimate over 90% adherence rates for commercial on-patch therapy. Regarding U.S. market access, as reported by external coverage reports, we're very pleased that we now have confirmed access to Empatro, if prescribed, for more than 99% of U.S. lives across commercial, Medicare, Medicaid, and other government-paying categories. Even in an increasingly competitive landscape, we continue to effectively partner with U.S. payers and have avoided the payer and patient out-of-pocket headwinds often reported We're very proud of its role in the complex U.S. market access environment.

Just an 18 from other physician specialties.

Overall and as many of you heard at R&D day, we believe HCP across specialties and the U.S., our growing increasingly comfortable treating the polyneuropathy of AG German doses with on Petro.

Hearings to.

Therapy also remains very strong to date, a very encouraging.

Side and consistent with the Apollo phase three data when real world evidence lines up with clinical trial results. We continue to estimate over 90% adherence rate for commercial on Petro.

Regarding us market access as reported by external.

Average reports, we're very pleased that we now have confirmed access to an petro it prescribed for more than 99% of us lives across commercial Medicare Medicaid and other government and categories.

Even in an increasingly competitive landscape, we continue to effectively partner with us payers and have avoided the payer.

Sure and patient out of pocket headwind often reported with other orphan drug launches.

We're very proud of result in the complex you guys market access environment and believe it reflects the constructive collaborative proactive approach, we've adopted with the payer community, including the use of value based agreements were VVA.

Eric Green: This is a very proactive approach we've adopted with the payer community, including the use of value-based agreements or VBAs. In the United States, we've now completed definitive VBAs for Ampatcho with 15 commercial payers, including each of the top 5 commercial payers and 8 of the top 10. These VBAs now cover over 130 million U.S. lives.

Yes.

States. We've now completed definitive EPA is rough patch over 15 commercial payers, including each for the top five commercial payers and eight of the top 10. These DBS now cover over 130 million useless.

Eric Green: Let's now turn to the rest of the world, where we're also very pleased with our past year of performance. As I noted earlier, we achieved $20 million in international net product revenues in the fourth quarter, reflecting 61% quarter-on-quarter revenue growth and 63% growth from new patient ads. This is also the first full quarter in which we recognize sales in Japan, where we saw strong demand and initial performance in this important region where there is an endemic disease. As we previously mentioned, we anticipate that by the end of 2020, Japan will likely be our second largest country after the U.S., both in terms of patients on commercial drugs and, of course, revenue. Other notable achievements during the quarter include

Let's now turn to the rest of World. We're also very pleased with on Petro performance as I noted earlier.

Earlier, we achieved 20 million in international net product revenues in the fourth quarter, reflecting 61% quarter on quarter revenue growth and 63% growth new pipe patient.

This is also the first full quarter in which we recognize sales in Japan, we saw strong demand and initial performance in this important region.

Where there isn't demick disease.

As we previously mentioned, we anticipate that exiting 2020, Japan will likely be our second largest country. After the U.S. foreign pass through both in terms of patients on commercial drug and of course revenue.

Other notable achievements during the quarter.

Eric Green: This includes the continued launch of Ampatro in the UK and achievement of pricing and reimbursement in several countries, including Belgium, Israel, and Italy. Through direct reimbursement, named patient sales, or paid expanded access, we're now selling patches in 16 countries outside the United States. We're seeing the source of our international business coming from both frontline treatment as well as switches from other products such as TTR stabilizers. We believe this highlights the value that the hereditary ATTR community is seeing with UNPATCHED. Further, as we achieve reimbursement in different EU countries, we're seeing patients who have been on our expanded access program convert to commercial drug, as we saw recently in the UK. Our team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis of new t-contaminant doses. As we've highlighted previously, our Al-Ma'am Act program is a third-party genetic screening initiative in the U.S. and Canada aimed at facilitating diagnosis for the benefit of patients. I'm suspected of having HATTR amyloidosis.

Include <unk> launch of on Petro.

In the UK and achieving a pricing in Pearson in several countries, including Belgium, Israel in Italy.

Good direct reimbursement named patient sales for paid expanded access we're now selling and pass through 16 countries outside the United States.

We're seeing the source of our international business coming from both frontline treatment as well.

But just from other products such as teachers stabilizers. We believe this highlights the value that the hereditary TTR community seen within Patrick.

Further as we achieve reimbursement in different view countries, we're seeing patients within our expanded access program convert commercial drug as we saw recently in the UK.

Our team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis in Utica generally doses as we've highlighted previously.

Akt program has a third party genetic screening initiative in the U.S and Canada aimed to facilitate diagnosis for the benefit to patients suspected of having age 80, GR MD doses.

Eric Green: As of January, over 21,700 samples have been submitted, out of which over 1,300 have tested positive for pathogenic PTR mutations, continuing a consistent percentage of positive mutation results. We see this highly encourage Let me now turn to Kiblari and the initial progress you've made in a short period since the drug's early approval in November. Through the initial six weeks from approval of the law in the U.S. through the end of 2019, a total of 13 initial forms were submitted. Net product revenues for the fourth quarter were approximately $200,000, which represents initial channel stocking.

As of January over 21700 samples have been submitted.

1300 have tested positive for pathogenic TTR mutation.

Continuing a consistent percentage of positive mutation results, we see this highly encouraging.

Let me now turn to give Laurie and the initial progress.

If you need in the short period since the drugs early approval in November.

Through the initial six weeks from approval who are in U.S. through the end of 2019 totaled 13 start forms were submitted.

Net product revenues the fourth quarter were approximately $200000, which represents initial channel stocking.

Very please.

Eric Green: We're very pleased with the strong initial interest from patients, physicians, and payers, which continues in the first few weeks of 2020. We've been in discussions with multiple commercial and government payers and have made progress towards establishing DBAs for Ghazlari, including the implementation of our newly formed prevalence-based adjustment. As mentioned, we're highly leveraging the capabilities built for Ompatro's launch. And following best practices developed country by country, our team is focused on improving the awareness and diagnosis of acute patient-impaired communities.

The strong initial interest from patients physicians and payers, which continues in the first few weeks of 2020.

We've been in discussions with multiple commercial and government payers have made progress towards establishing BBAM forgive already including the implementation of our newly formed prevalence based adjustments.

As mentioned we're.

Leveraging the capabilities built for on Petro launch and following the best practice developed country by country. Our team is focused on improving the awareness.

No system acute hepatic porphyria, the HCP patient appear communities and laying the groundwork for successful launch.

To that end, the ironwood and on my own.

We are fully staffed train and in the field and as I mentioned being received very well.

Eric Green: To that end, the Ironwood and Elm Island teams are fully...

As you're aware Thrill now act, we provide access to third party genetic testing for individuals in the U.S. or Canada may carry for gene mutation known to be associated with agency.

Eric Green: and, as I mentioned, being received very well. As you're aware, through the Alnylam Act, we provide 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. While this program for AHP is still in the early stages, we report 7 out of 5 tests submitted in 78 patients, so approximately 11% of AHP-associated gene mutations as of

While this program for HP is still in early stages.

We reported 75 test submitted and 78 patients. So approximately 11% confirmed of HP associated gene mutations as of January 22.

As we noted last week, we received positive CGEN 15 for gross rent for the treatment of age, peaking adults in adolescence.

Eric Green: Last week we received positive CHMP opinions for Dvoserin for the treatment of age, peak in adults and adolescents age 12 and over in the youth. We now look forward to the expected decision for Gublot.

12 and over in the U.

We now look forward to expected decision forgive Laurie, but you're in commission this year, which we followed by commercial launch in the EU following pricing and reimbursement negotiations country by country.

Pushkal Garg: This year, which will be followed by Commercial Long-Term EU Following Pricing and Reimbursement Negotiations Country-by-Country With that, I now turn the call over to Pushkal to review our recent R&D and pipeline progress.

With that I'd now turn the call overcomes Gulf review, our recent R&D and pipeline progress but go.

Thanks, Barry and good morning, everyone.

In the interest the time I'm going to focus my comments on our progress in advancing or six late stage programs.

Pushkal Garg: Thank you.

Pushkal Garg: Thanks Barry, and good morning everyone. In the interest of time, I'm going to focus my comments on our progress in advancing our sixth late-stage program. Starting first with the recent FDA approval for Givlari. As John and Barry mentioned, we were really excited to receive early approval for Givlari, our second RNAi therapeutic, last November in the United States. This was followed by a positive CHMP opinion just last week in the European Union. And while we eagerly await the European Commission decision.

Starting first with the recent FDA approval forgive Laurie as John and very mentioned, we're really excited to receive early approval forgive Laurie our second R&D I'd therapeutic last November.

The United States.

Which was followed by positive cgmp opinion, just last week in European Union.

And while we eagerly await European Commission decision.

We're delighted that both health authorities have granted broad indications forgive Laurie for the treatment of acute hepatic porphyria based on the efficacy and safety data from the pivotal envision study.

Which will enable us to address a broad range of patients suffering from this devastating diseases.

Pushkal Garg: We are delighted that both health authorities have granted broad indications for Givlari for the treatment of acute hepatic porphyria based on the efficacy and safety data from the Pivotal and Vision Studies, which will enable us to address a broad range of patients suffering from this devastating disease. Let me now turn to our efforts in ATTR amyloidosis, where we are working diligently. And to advance our two product candidates, Petit Saran and Boutrisse. While petiteran is currently approved in multiple markets around the world to treat polyneuropathy associated with hereditary ATTR amyloidosis, we're also conducting the Apollo B Phase 3, as a potential path towards expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis. Apollo V is a study in approximately 300 patients using a 6-minute walk test as the primary endpoint with other important secondary objectives, including rates of death and hospitalization. Enrollment is ongoing and expected to complete late this year.

Let me now turn to our efforts in 18, CRM, we doses, where we're where we are working diligently to advance our two product candidates TCIR in ambulatory surgery.

Now well by well Putties trend is currently approved in multiple markets.

Around the world to treat the polyneuropathy associated with hereditary TTR amyloidosis. We're also conducting the Apollo be phase three study as a potential path toward expanding the product label for the treatment of cardiac my apathy in both hereditary and wild type page and sharing with us as patients.

I'll be in the study in approximately.

300 patients using a six minute walk test primary endpoint with other important secondaries, including the rates death and hospitalizations.

Enrollment is ongoing and expected to complete late this year.

And at the study is positive we plan to seek regulatory support for an expanded label for Patese ran in approximately the late two.

The 21 early 2022 timeframe.

In parallel we're also advancing Patrice right, which is delivered by a quarterly subcutaneous injection is also in development for 18 CRM low doses.

Here, we are conducting two phase three studies.

First is helio say, which is enrolling hereditary.

Create TTR amyloidosis patients with Polyneuropathy, we're really pleased with enrollment and Helio say and as announced last month at JP Morgan we've enrolled over 85% of the study and expect to report topline results in early 2021.

Pushkal Garg: If the study is positive, we plan to seek regulatory support for an expanded label for Petitstrand in approximately the late 2021 to early 2022 time period. In parallel, we're also advancing Boutrisse, delivered by a quarterly subcutaneous injection, which is also in development for ATTRM-1. Here, we're conducting two phase three studies. The first is Helios A, which is enrolling hereditary ATTR amyloidosis patients with polyneuropathy. We're really pleased with enrollment in Helios A, and as announced last month at J.P. Morgan, we've enrolled over 85% of the study and expect to report top-line results in early 2021. Back in November, we also initiated the second phase three study of a tree strand, Heliospeed. This is being conducted in both hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy.

Back in November we also initiated the second phase three study Patrice.

Sure in Helio speed, which is conducted being conducted in both hereditary and wild type eight TTR amyloidosis patients with Cardium apathy.

This study if successful and following regulatory approval could allow the trees trend to enter the very large wild type may TTR market within outcomes based label that we believe would be optimal.

For competitive positioning the product.

Memory endpoint of the study is a composite outcome of all cause mortality in recurrent CB hospitalizations, which will be assessed at March 30.

They also conducted interim analysis, providing the opportunity for an earlier data readout.

I'll now turn to recent progress with mass.

Investigational rnai therapeutic we're developing for the treatment of primary Hyperoxaluria type one or ph one.

Each one is an ultra rare autozone recessive disease caused by genetic defect in liver enzyme AGTC.

Pushkal Garg: This study, if successful and following regulatory approval, could allow NutriStrand to enter the very large wild-type ATTR market with an outcomes-based label that we believe would be optimal for competitive positioning of the product. The primary endpoint of the study is a composite outcome of all-cause mortality and recurrent CV hospitalization, which will be assessed at month 30, and we may also conduct an interim analysis providing the opportunity for an earlier data readout. I'll now turn to recent progress with Lumatran.

The results that in hepatic overproduction of an insoluble metabolite called oxalate.

This oxalate in deposit first in the kidney, causing recurrent painful kidney stones, leading to end stage renal disease and also some significant systemic complications.

There are about 3000 to 5000 patients with the serious disease and their treatment options are very limited today, primarily medically manage with Piper hydration and dialysis.

In severe cases, and ultimately require a dual liver and kidney transplant.

Pushkal Garg: Investigational RNA

The dress this need we are evaluating the safety and efficacy of new Master in India ILLUMENATE program.

Pushkal Garg: We are developing the treatment of primary hyperoxyluria type 1 or PH1. PH1 is an ultra-rare autosomal recessive disease caused by a genetic defect in the liver enzyme AGT that results in the hepatic overproduction of an insoluble metabolite called oxalate. This oxalate can deposit first in the kidney, causing recurrent, painful kidney stones, leading to end-stage renal disease, and also significant systemic complications. There are about 3,000 to 5,000 patients with this serious disease, and their treatment options are very limited. Today, they're primarily medically managed with hyperhydration and dialysis, and in severe cases, can ultimately require a dual liver and kidney transplant. To address this need, we're evaluating the safety and efficacy of Lumasaran in the Illuminate program. This is a comprehensive set of studies across the entire spectrum of PH1 disease and includes Illuminate A, our pivotal study in patients aged six and older with mild to moderate renal impairment. It also includes the Illuminate Bees study in pediatric patients less than 6 years old with mild to moderate renal impairment.

This is a comprehensive set of studies across the entire spectrum of ph when disease.

Includes ILLUMENATE eight our pivotal study in patients.

Ages, six and older with mild to moderate renal impairment.

It also includes the eliminate these study in pediatric patients less than six years old with mild to moderate renal impairment, which as we announced our press release today has now completed enrollment.

And it also includes a third study eliminate C, which is being conducted in patients with severe renal and.

Parents.

Together you eliminate program is the most comprehensive set of studies ever conducted in ph one.

Back in December we reported positive topline results from the eliminated phase three trial.

Mr and showed a highly significant effect on the primary endpoint or the percent change from baseline.

And in 24 hour urinary oxalate excretion average across month three to six.

In drug treated patients compared with placebo.

The study also achieved statistically significant results for all tested secondary endpoints, including the proportions of patients who achieved near normalization or normalization of urinary oxalate.

Pushkal Garg: which

Pushkal Garg: All of these studies, as we announced in our press release today, have now completed enrollment. And it also includes a third study, Illuminate C, which is being conducted in patients with severe renal impairment. Together, the Illuminate Program is the most comprehensive set of studies ever conducted in PH1. Now, back in December, we reported positive top-line results from the Illuminate A Phase III trial. The master endpoint showed a highly significant effect on the primary endpoint of the percent change from baseline in 24-hour urinary oxalate excretion averaged across months 3 to 6, in drug-treated patients compared with placebo. This study also achieved statistically significant results for all tested secondary endpoints, including the proportions of patients who achieved near-normalization or normalization of urinary oxygen. And on the safety side, we were very encouraged by the results There were no serious or severe adverse events, and the safety profile was very much in line with what we've reported previously for Lumasaran, including no significant LFT elevation. The full study results will be presented in late March at the OXL Europe meeting in Amsterdam.

And on the safety side, we're very.

We're encouraged by the results there as well there were no serious or severe adverse events and the safety profile was very much in line with what we've reported previously for the master and including no significant Lf televisions.

The full study results we presented in late March So Europe meeting in Amsterdam.

And as John mentioned, we recently initiated a rolling.

Submission for the master in and plan to complete our NDA submission as well as army submission in early 2020.

As you also know we have two additional late stage programs that are in development partners.

This includes includes ceramic in development for Hypercholesterolemia, which is part and now with Novartis.

Fitusiran and development for hemophilia, a or b with or without inhibitors partnered with Sanofi.

We're very excited about the prospects for both of these products.

Both cases, they have highly differentiated profiles compared to agents that are either on the market or in development.

As the brightest recently announced at the end da enemy.

Because ran have now been filed.

Of course in addition to our late stage clinical programs are robust our robust pipeline of early stage programs as being advanced into a sustained innovation growth and we look forward to updating you on these programs throughout 2020.

Pushkal Garg: And, as John mentioned, we recently initiated our rolling NDA submission for Lumasaran and plan to complete our NDA submission as well as our MAA submission in early 2020. As you also know, we have two additional late-stage programs that are in development with partners. This includes Inclisiran in development for hypercholesterolemia, which is now partnered with Novartis, and the two strands in development for hemophilia A or B with or without inhibitors, partnered with Sanofi. We're very excited about the prospects for both of these products. In both cases, they have highly differentiated profiles compared to agents that are either on the market or in development. And, as Novartis recently announced, the NDA and MAA for Inquisiran have now been filed. Of course, in addition to our late-stage clinical programs, our robust pipeline of early-stage programs is being advanced to sustain innovation growth, and we look forward to updating you on these programs throughout 2020. So with that, I now turn it over to Jeff to review our financial results and outlook. Jeff?

So with that let me now turn it over to Jeff to review our financial results.

Okay and outlook Jeff.

Thanks, Good call. Good morning, everyone I'm pleased to present common islands Q4, and full year 2019 results 0.9 here was a significant year from island as it marked our first full year of commercial operations with the launch of Uncaptured occurring in the second half of 2018 as Barrick has already highlighted.

The 19 was a year strong commercial execution as we now have more than 750 patients on commercial on Tatro Cross 17 markets globally.

After commenting on our fourth quarter and full year 2019 results I will also provide our financial guidance for 2020.

We now please turn to slide 24 for.

Our summary of our Q4 and full year 2019 results.

Barry noted global on Petro net product revenues in the fourth quarter were 55.8 million, representing 21% global growth from the third quarter, driven by new pacing new patient growth across all markets.

Yes on Petro revenue grew six.

Reset in the fourth quarter in comparison to Q3, while underlying demand sales growth was 12% in the quarter.

The reason for the difference between reported and underlying demand sales growth was higher sales deductions in the fourth quarter.

Full year gross to net percentage from Patrick on the US was approximately 20% and in line with our.

Jeff Poulton: Thanks Pushkal and good morning everyone. I'm pleased to present Alnylam's Q4 and full year 2019 results. 2019 was a significant year for Alnylam as it marked our first full year of commercial operation, with the launch of Unpatril occurring in the second half of 2018. As Barry has already highlighted, 2019 was a year of strong commercial executions. We now have more than 750 patients on Commercial On Patrol across 17 markets globally

Patients.

Additionally, USA Q1 capital sales included a modest amount of inventory stocking, but this had minimal impact on reported growth versus the third quarter as a similar amount of March the stocking that occurred in Q3.

Inventory levels in the us at year end remain within target levels of two to three.

That's very as already noted the growth in our international markets was particularly strong in the quarter at 61% compared with Q3, driven by strong launches in both the UK Japan.

Full year on Petro Global net revenue was 166.4 million driven by growth in both existing and new markets over the course.

Jeff Poulton: After commenting on our fourth quarter and full year 2019 results, I will also provide our financial guidance for 2020. Now, we turn to slide 24 for a summary of our Q4 and full year 2019 results. Very noted, Global On Patro net product revenues in the 4th quarter were $55.8 million, representing 21% global growth from the 3rd quarter, driven by new patient growth across all markets. U.S. On Petro revenue grew 6% in the fourth quarter in comparison to Q3, while underlying demand sales growth was 12% in the quarter. The reason for the difference between reported and underlying demand sales growth was higher sales deductions in the fourth quarter.

Of the year US represented about 70% of full year on patio sales in our international markets represented 30%.

We also recognized our first sales of deploring the quarter. Following FDA approval on November Twentyth net sales of approximately 0.2 million represent initial channel stocking.

We look forward to updating you on the progress of our people our launch throughout 2020.

Net revenue from collaborations was 15.7 million in the fourth quarter and approximate 75% increase from the fourth quarter over prior year.

The primary driver for the increase was revenue recognized under the Regeneron collaboration that was a.

Tablets in the second quarter of 2019.

Net revenue from collaborations was 53.2 million for the full year, representing a 15% decrease from the prior year, primarily due to reduced revenue from our Sanofi Genzyme collaboration offset by revenues from our Regeneron collaboration.

Jeff Poulton: The full year gross net percentage for Ampatro in the U.S. was approximately 20% and in line with our expectations. Additionally, U.S. Q4 on Patro sales included a modest amount of inventory stocking, but this had minimal impact on reported growth versus the third quarter, as a similar amount of modest stocking occurred in Q6. Inventory levels in the U.S. at year-end remain within target levels of 2 to 3 weeks.

Cost of goods sold in Q4.

It was 12.2 million, resulting in a 78% gross margin on product sales gross margin in the quarter was impacted by an approximate 5 million write down for excess and obsolete on Petro inventory that had been manufactured conservatively to ensure adequate stock was available to support initial launch demand.

Jeff Poulton: As Barry has already noted, the growth in our international markets was particularly strong in the quarter, at 61% compared with Q3, driven by strong launches in both the UK and Japan. Full year on, Patro's global net revenue was $166.4 million, driven by growth in both existing and new markets over the course of the year. The U.S. represented about 70% of full year Patro sales, and our international markets represented 30%. We also recognized our first sales of Dublari in the quarter following FDA approval on November 20th. Net sales of approximately $0.2 million represent initial channel stocking. We look forward to updating you on the progress of our Dublari launch throughout 2020. Net revenue from collaborations was $15.7 million in the fourth quarter and approximately $1.5 million in the third quarter.

Since this write off gross margin for Q4 would've been approximately 87% consistent with gross margin in prior quarters of 2019 gross margin on product sales was 85% for the full year.

Non-GAAP research and development costs were 166.5 million in Q4, representing the peak quarterly R&D.

He spent during the year.

Q4 spend was impacted by high level of clinical material manufactured for future trials.

Full year non-GAAP R&D expenses were 566.2 million, representing a 33% increase from the prior year.

Majority or R&D spend or approximately 70% in 29.

18 went towards supporting late stage clinical programs, Patese, Ryan who treat strength ghosts ran low mass around it.

Non-GAAP selling general and administrative expenses were 124.9 million in Q4 also representing the peak quarterly EPS DNA spend during that year.

Jeff Poulton: The primary driver for the increase was revenue recognized under the REGENERON collaboration that was established in the second quarter of 2020. Net revenue from collaborations was $53.2 million for the full year, representing a 15% decrease from the prior year, primarily due to reduced revenue from our Sanofi Genzyme collaboration, offset by revenues from our Regeneron collaboration. Cost of goods sold in Q4 was $12.2 million, resulting in a 78% gross margin on product sales. Gross margin in the quarter was impacted by an approximate $5 million write-down for excess and obsolete on-patrol inventory that had been manufactured conservatively to ensure adequate stock was available to support initial launch demand. Absent this write-off, gross margin for Q4 would have been approximately 87%, consistent with gross margin in prior quarters of 2019. Gross margin on product sales was 85% for the full year.

Q4 expense was.

By spend on get bar and given that the November 20, FDA approval and preparations for commercial launch SGN expense for the full year was 393.1 million representing 29% growth from 2018 due primarily to the continued expansion of our global commercial infrastructure to support the ongoing.

The launch of on Petro and initial launch activity for good Laurie.

Our balance sheet remains strong as we ended 2019 with a cash cash equivalents in investments balance of 1.55 billion compared with 1.13 billion at the end of 2018. The increase was due to proceeds received under our equity.

During the first quarter 2019, and proceeds received under our collaboration and equity agreements with Regeneron offset by cash used in our operations and capital expenditures.

Now turning to slide 25 in our 2020 financial guidance.

Starting with our global net product sales guidance from pad for which we are.

Providing for the first time.

We project our global net sales in 2020 will be between 285 million and 315 million from Patrick.

Jeff Poulton: Non-GAAP research and development costs were $166.5 million in Q4, representing the peak quarterly R&D spend during the year. Q4 spend was impacted by a high level of clinical material manufactured for future trials. The full year non-GAAP R&D expenses were $566.2 million, representing a 33% increase from the prior year. The majority of our R&D spend, or approximately 70% in 2019, went towards supporting late-stage clinical programs, Patisaran, Hutrisaran, Gavosaran, and Lumasaran. Non-GAAP selling general and administrative expenses were $124.9 million in Q4, also representing the peak quarterly SG&A spend during the year.

The midpoint of guidance range represents 80% growth versus 2019, we believe growth will continue to be driven by both new patient finding in existing markets and expansion.

Into new markets.

Please note that we're not providing that product sales for give laurie given that 2020 represent its initial commercial launch year.

Our guidance for net revenue.

Aberrations in the range between 101 hundred $50 million with the midpoint of the range representing 135% growth.

Compared with 2019 growth in 2020 is expected to come primarily from our collaboration with Regeneron.

Our guidance for non-GAAP R&D NSG inexpensive as a range between 1.025 billion and $1.125 billion the midpoint of the guidance range represents a projected 12%.

Jeff Poulton: Q4 expense was impacted by spend on Givlari given the November 20th FDA approval and preparations for commercial launch. SG&A spending for the full year was $393.1 million, representing 29% growth from 2018, due primarily to the continued expansion of our global commercial infrastructure to support the ongoing launch of Onpatro and initial launch activity for Giblari. Our balance sheet remains strong as we end 2019 with a cash, cash equivalents, and investments balance of $1.55 billion, compared with $1.13 billion at the end of 2018.

Increase in 2020 compared with 2019.

Drivers of expense growth are expected to include investments in our early stage R&D pipeline, our regeneron collaboration and continued espina investment in on Petro and now give Laurie.

Importantly, as we're now focused on becoming a self sustainable business.

This 2020 projected 12% operating expense growth significantly below the 31% growth in 2019, and combined R&D SGN expense.

Jeff Poulton: The increase was due to proceeds received under our equity offering in the first quarter of 2019 and proceeds received under our collaboration and equity agreements with Regeneron, offset by cash used in our operations and capital expended. Now turning to slide 25 in our 2020 financial guidance. Starting with our Global Net Product Sales Guidance for Onpatro, which we are providing for the first time, we project our global net sales in 2020 will be between $285 million and $315 million per unpacked unit. The midpoint of the guidance range represents 80% growth versus 2019. We believe growth will continue to be driven by both new patient finding in existing markets and expansion into new markets. Please note that we are not providing product sales for Giblari given that 2020 represents its initial commercial launch.

Moderating growth and operating expenses reflects disciplined in our in our approach to capital allocation and the initial benefit of operating leverage from the commercial one.

Restructure we have developed to support on past showing now give laurie.

As we've discussed previously we believe 2019 were represents our peak non-GAAP net net operating loss year, the topline and non-GAAP operating expense guidance. We have provided today for 2020 is consistent with this and we believe represents an important.

So on our path to becoming a profitable company.

And finally, our balance sheet remains strong as we project a 1.55 billion in cash and investments on hand at the end of 2019 will support company operations for multiple years based on current operating plants.

With that I'll now turn the call over to move on to review our.

Goals for the remainder of the year.

Ron.

Thanks, Jeff and Hello, everyone.

We believe twentytwenty is poised to be another catalyst rich gas from long Island.

Jeff Poulton: Our guidance for net revenue collaborations is a range between $100 million and $150 million, with the midpoint of the range representing 135% growth compared with 2019. Growth in 2020 is expected to come primarily from our collaboration with Regeneron. Our guidance for non-GAAP R&D and SG&A expense is a range between $1,025,000,000 and $1,125,000,000. The midpoint of the guidance range represents a projected 12% increase in 2020 compared with 2019. Key drivers of expense growth are expected to include investment in our early-stage R&D pipeline via our Regeneron collaboration and continued SG&A investment in Onpatro and now Giblari. Importantly, as we are now focused on becoming a self-sustainable business, this 2020 projected 12% operating expense growth is significantly below the 31% growth in 2019 in combined R&D and SG&A expense.

Okay.

We plan to continue on global commercialization alone Patrick.

But as the global loans, just give lottery, including in.

Well, we have a positive six ft opinion, and expect to European Commission decision in the coming up.

We also expect two additional regulatory approvals by the end yes.

Correct on that piece right.

Executing on six late stage programs in nine states clinical trials, including upon it.

And our heaviest hey, and he'd get Skinny studies.

And as mentioned in today's press release, we plan to highlights additional clinical data from all parties front development program.

I'd say anything adding launch and target in Spain.

The mass or are we continue to.

We continue to.

Look forward to presenting for without the dividends a phase three study at the Aucs all your international congrats on them offset declines in Amsterdam.

Now having completed enrollment if you make these funding NPH one patients on the 60 as a base we remain on track to report topline.

Jeff Poulton: The moderating growth in operating expenses reflects discipline in our approach to capital allocation and the initial benefit of operating leverage from the commercial infrastructure we have developed to support Onpatro and now Giblari. As we've discussed previously, we believe 2019 represents our peak non-gap net operating loss year. The top line and non-gap operating expense guidance we have provided today for 2020 is consistent with this, and we believe represents an important step on our path to becoming a profitable company. And finally, our balance sheet remains strong, as we project the $1.55 billion in cash and investments on hand at the end of 2019 will support compounding operations for multiple years based on current operating plans. With that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne?

The results from that study in mid Twentys frenzy.

Of course will also continue advancing the rest of our pipeline that's what it's exciting preclinical assets.

Lifelong friends, we achieved these programs throughout the gap as they had no.

Notably, we aim to sort of a two to four new R&D fine.

Including.

HSD fund, Max and payout and back for that to amyloidosis, and Twentytwenty from our organic product engine feeding sustainable innovation.

Let me now kind of back to Christine coordinate QNX.

Christine Thank you Yvonne operator, we'll now open the call.

First question valve and we'd like to ask you limit yourself to one question each and they get back into queue you have any additional questions.

Thank you Madam as a reminder to ask a question at this time, Please press star one.

I find that your question has already been on since you may removed from the cubit pricing start to please make sure.

Yvonne L. Greenstreet: Thanks, Jeff, and hello, everyone. We believe 2020 is poised to be another catalyst-rich year for Alnylam. To start with, we plan to continue our global commercialization of Ampatro, as well as the global launch of Kiflare,

And on your phone switched off.

First question comes from.

Felicia.

Fitzgerald. Please go ahead.

Hi, This is an eye on for me. So forgive bar you are all 13 attention.

Financial performance and address any comes really aren't Lucky I Trust questionnaires many others.

Yvonne L. Greenstreet: Inc.

Yvonne L. Greenstreet: Will you have a positive CHMC opinion and expect a European Commission decision in the coming months? We also expect two additional regulatory approvals by the end of the year for Lumasaran and Inquisaran. We're executing on six late-stage programs in nine distinct clinical trials, including Apollo B and our Helios A and Helios B studies. And, as mentioned in today's press release, we plan to highlight additional clinical data from our Patisserie and Development Program at the upcoming ISA meeting in early March in Tarragona, Spain.

Okay.

Okay. So am I think.

And here you that clearly I think you're I think you were asking about the ironwood collaboration as what we're learning on the good Laurie.

From our colleagues Theyre very you want to take that yes. Thanks for the question. So as I mentioned on the call both PL Mylan.

Forward forces are out there educating the healthcare community engaging with.

Patient Association. The 13 start forms came from a variety of prescribers is we're not really give you much color on exactly where they came from yet, but we can say right now they are coming from for your centers and local physicians treating these patients and we.

Yvonne L. Greenstreet: We continue to look forward to presenting full results from the Illuminate A phase 3 study at the OXOI Europe International Congress on March 31st in Amsterdam. Furthermore, now having completed enrolment in the Illuminate Bee Study in PH1 patients under 6 years of age, we remain on track to report top-line results from...

We are seeing success in some of the handoff from Ironwood already and will comment more with more data next quarter on all of that that's right Barry and I would just add and we're really excited about how this is how this launch is going so far.

We are seeing very strong demand from physicians and patients and we're looking forward to.

How this proceeds directory of course the year.

Yvonne L. Greenstreet: We remain on track.

Christine Regan Lindenboom: And, of course, we'll also continue advancing the rest of our pipeline, as well as exciting pre-clinical efforts, and we'll highlight milestones we achieve in these programs throughout the year as they occur. Now, I'll turn it back to Christine to coordinate our Q&A session. Thank you.

Thank you for your question.

Great and do you intend to continue updating on NIM touching from present for 2020 or is that something in listen only found no evidence.

I mean, we'll continue to provide the patient numbers, our commercial drug and also the.

Operator: Thank you, Yvonne. Operator, we will now open the call for questions. 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 any additional questions. Thank you, madam. As a reminder, to ask... At this time, please press star 1. If you find that your question has already been answered, you may remove yourself from the queue by pressing star 2. Please make sure the mute function is on your phone.

Sort of broader umbrella number that we provide outpatient setting include our expanded access program and clinical studies. We think it's in addition to the revenues. We think it continues to be an important metric.

That people will.

I will like to see so we do plan by continuing to but thanks for your question on it.

Thank you, we'll now move to our next question from.

One of Barclays. Please go ahead.

I think thats for the call. This is David for Gina.

unknown: First question: Alicia Young of Counterfeit Journal, Hi, this is Emma from Aletheia. So for Gislari, were all 13 of the initial start forms from the major portfolio centers, or did any come through the Ironwood GI Salesforce or many other specialties?

Question on.

No signs for MPT are pulling empathy do you see a positive.

Packed for ATP are picking up speed that losses from sizes efforts on day TTR cardiomyopathy diagnosis with this launch.

Yes, David that's actually a fabulous question.

Eric Green: Okay, so Emma, I think we didn't hear you that clearly. I think you were asking about the Ironwood collaboration and what we're learning on the Guillory side from our colleagues there. Barry, do you want to take that?

And one that let me just make some initial comments is that maybe portfolio and talk a little bit about.

Some of the diagnostic evolution in the whole landscape.

Very can comment as well, obviously, we're very focused on on Petros.

Eric Green: Thanks for the question. As I mentioned on the call, both the Alnylam and Ironwood forces are out there educating the healthcare community and engaging with the patient association. The 13 starter forms came from a variety of prescribers. We're not really giving much color on exactly where they came from yet, but we can say right now that they are coming from preferred centers and local physicians treating these patients. We are seeing success in some of the handoff from Ironwood already. We'll comment more with more data next quarter on all of that.

Potential value for treating the polyneuropathy hereditary TTR amyloidosis in adult patients and as we.

As we continue on that effort we also.

Realize that polyneuropathy use being recognized in a significant number of patients.

Throughout the spectrum of ha TTR, including even to be wants you to why patient population that historically have been viewed as just cardiomyopathy patients but it.

Many of these is potentially over 50%.

Being found to have Polyneuropathy, so as a result.

John Maraganori: I would just add that we're really excited about how this launch is going so far. We are seeing very strong demand from physicians and patients, and we're looking forward to how this progresses during the course of the year. Thank you for your questions.

The work that's going on the field to identify patients with HCR amyloidosis.

You don't really can potentially lead to patients being discovered have polyneuropathy and thats.

John Maraganori: Great. And do you intend to continue updating on the NPATRA patient numbers over 2020, or is that something you're moving away from now that you're focusing on revenues?

Really important dynamic.

Place right now, it's maybe push so you can say a few words on the diagnostic method evolution and the vary a little bit on what we're hearing in the field out there. So absolutely David just a follow on on some of John's comments I think I think is greatly increased awareness around this disease first of all based on.

John Maraganori: I mean, we'll continue to provide the patient numbers on commercial drugs and also the sort of broad umbrella number that we provide around patients that include our Expanded Access Program and clinical studies. You know, we think it's, in addition to revenues, an important metric that people will like to see. So we do plan on continuing that, but thanks for your question on it.

Now therapeutics that have become available for patients with this what was your support unrecognized diseased cells seems to be sort of consider two separate diseases polyneuropathy form a cardiomyopathy form it I think as John alluded to really seeing overlap.

David N. Lebowitz: Thank you. We will now move to our next question from Gena Wang of Barclays. Please go ahead. Hey, thank you guys for the call. This is David from Gena. My first question is about the diagnosis for ATTR polyneuropathy. Do you see a positive impact on the ATTR polyneuropathy diagnosis from Pfizer's efforts on the ATTR cardiomyopathy diagnosis with Zagdis' launch?

In patients.

That is really one disease, so I think what you're seeing in guidelines starting to emerge.

And physician starting to congregate around how to treat diagnose and treat these patients looking for red flags symptoms that carpal tunnel soon.

Syndrome, and other manifestations recommending Gina typing so that we can understand who has the genetic mutations and they're ready to trade forms of this.

And then importantly, the advent of noninvasive waste to diagnose these.

John Maraganori: Yeah, David, that's actually a fabulous question. And one that, let me just make some initial comments, and then maybe Pushkal can talk a little bit about some of the diagnostic evolution in the whole landscape, and then Barry can comment as well.

For example, looking at technetium scanning to identify where patients have cardiac involvement.

And then because of this sort of mixed phenotype that we're seeing increasing the fact of patient staff to get devaluated amyloidosis centers and by a multi disciplinary positions to actually in clinics to look for.

John Maraganori: Obviously, you know, we're very focused on Patro's potential value for treating the polyneuropathy of hereditary ATTR amyloidosis in adult patients. And as we continue to pursue that effort, we also realize that polyneuropathy is being recognized in a significant number of patients throughout the spectrum of HATTR, including even the B.1.2.2i patient population that historically had been viewed as just cardiomyopathy patients. But it turns out that many of these [inaudible]

Both the Polyneuropathy and cardiac manifestations the disease and I think that's leading to.

Increased awareness diagnosis and then the discussion of treatments for these patients maybe Barry can pick it up from there that you covered it concluded the only thing I'll add is it's our efforts and other companies efforts doing disease State education.

But very importantly, the emley doses.

Pushkal Garg: David, just to follow on some of John's comments, I think there's greatly increased awareness around this disease, first of all, based on now, you know, therapeutics that have become available for patients with this, what was heretofore an unrecognized disease. It also used to be sort of considered two separate... Polyneuropathy Form and Cardiomyopathy Form. And I think, as John alluded to, we are really seeing

Society, the physicians and cardiac neurology and even gastroenterology clinics have whole tracks educating broad swath of physicians to look for teacher family doses and to make sure that they do genetic testing in the case of hereditary TTR amyloidosis in this multi.

The system multi function disease.

Great. Thank you Dave for that question.

I think you're paying for color I'll hop back on the Q.

We will now move to our next question from the line of Salveen Richter of Goldman Sachs. Please go ahead.

Pushkal Garg: Overlap

Pushkal Garg: So, I think what you're seeing is guidelines starting to emerge and physicians starting to congregate around how to treat, diagnose, and treat these patients looking for red flag symptoms like Carpal Tunnel Syndrome and other manifestations, recommending genotyping so that we can understand who has the genetic mutations in their hereditary form.

Good morning, Thanks for taking my question.

Could you just walk to the dynamics behind your 2020 guidance, particularly as the ramp continues and in Japan here.

And just talk about external factors that are play and then secondly on you talked about this higher sales production that played out in Q4 and you think that's something we should monitor.

Pushkal Garg: and importantly, the advent of non-invasive ways to diagnose these patients. For example, looking at technetium scanning to identify where patients have cardiac involvement. And then, because of this sort of mixed phenotype that we're seeing, increasing the fact that patients have to get evaluated in amyloidosis centers and by multidisciplinary physicians to actually, in clinics, look for both the polyneuropathy and cardiac manifestations of the disease. And I think that's leading to, you know, increased awareness, diagnosis, and then discussion of treatments for these patients.

Turning to go forward basis. Thank you.

Yeah, Thanks, Tony and I'm going to handed over to Jeff. Let me just say one thing that guidance in the first time, obviously, providing revenue guidance as a company.

And we do think Thats, an appropriate thing to do now that we've got we've got one your launch behind us without Petro.

So this is an approach that we do intend to take with other products as we bring to market.

After the first year or so where we don't yet have visibility like indicates is Laurie right now we've all provide guidance on that after about a year's worth of experience we will.

Eric Green: Concluding, the only thing I will add is, you know, it's our efforts and other companies' efforts doing disease state education, but very importantly, the amyloidosis society, the physicians at cardiac, neurology, and even gastroenterology clinics have whole tracks educating broad swaths of physicians to look for, teach your amyloidosis, and make sure that they do genetic testing in the case of her Thank you, David.

So this you'll see more of this going forward from from L., Milo, but let me I'll turn it over to Jeff the comments on the specific questions. You asked so selling the guidance ranges to 85 to 315 for on Patra, which represents 80% growth.

Year over year, if we hit the midpoint of that.

We expect that growth to be driven.

By new patients coming on to therapy in existing markets and bringing new markets online when we get access and reimbursement I would say, we expect the growth outside the U.S. to be higher in 2021 than in the U.S., just given that the dynamics of getting access and reimbursement outside the U.S. have taken longer so many of the markets that came online.

David N. Lebowitz: Thank you, Dave, for that question. I think he's in for color; I'll be a while back on the queue.

Salveen Richter: We will now move to our next question from the line of Salveen Richter of Scotland. Good morning. Thanks for taking my question. Could you just walk through the dynamics behind your 2020 guidance, particularly as the RAM continues in Japan here, and just talk about external factors that are at play? And then secondly, you talked about this higher sales deduction that played out in Q4. Do you think that's something we should monitor on a going forward basis? Thank you.

Outside the U.S. rolling online for partial year in 2019, Barry can comment further if the once after I answer. Your your next question that question about sales deductions in the fourth quarter, and whether or not that should be something that would be monitored in terms of a trend I think not.

The way, we the way sales deductions work as you make estimates that the.

Time of sales are booked for sales deductions and as you get actuals against those estimates the true those numbers out but overtime quarter to quarter that can really lead to some changes some distortions quarter to quarter and that's what happened in the fourth quarter we had.

Jeff Poulton: Thanks, Salveen. I'm going to hand it over to Jeff.

John Maraganori: Let me just say one thing about guidance. This is the first time we're obviously providing revenue guidance as a company, and we do think it's an appropriate thing to do now that we've got one year of launch behind us with Alpatro. This is an approach that we do intend to take with other products as we bring them to market after the first year or so where we don't yet have visibility, like in the case of Gublari right now. We will provide guidance, and then after about a year's worth of experience, we will. So you'll see more of this going forward from Alnylam. But now, let me turn it over to Jeff.

I just meant that.

Resulted in slightly higher number in the fourth quarter, but for.

The full year, our gross to net deductions both in the U.S. and globally, we're right in line with what we expected globally right in line with the 25% guidance. We provided for the year I don't expect that to be dramatically different and in 2020.

Very anything to add yes, just emphasize and Jeff covered incredibly well just emphasize.

Again the.

Growth will come from can pick patients continuing on therapy were very enthusiastic that there is over 90% adherence rate representing what we saw new pollo clinical trials of over half the patients are stabilized or improved in their poly dropped due its quite remarkable to see and anecdotally here those.

Jeff Poulton: Let me know.

Salveen Richter: Any specific questions you may ask?

Jeff Poulton: Salveen, the guidance range is 285 to 315 for Onpatra, which represents 80% growth year-over-year if we hit the midpoint of that. We expect that growth to be driven by new patients coming on to therapy in existing markets and bringing new markets online when we get access and reimbursement. I would say we expect growth outside the U.S. to be higher in 2020 than in the U.S., just given that the dynamics of getting access and reimbursement outside the U.S. have taken longer. So many of the markets that came online outside the U.S. were only online for a partial year in 2019.

Stories, and then as Jeff said, we will continue to bring new patients on the markets that are opened we'll continue to open new markets and we'll continue evidence generation all our growth drivers of.

Patients the only other thing to add is right now is the pricing and reimbursement we're getting outside the United States continues to be very strong.

Renting the value that on patches, bringing to the treatment upon or office use hereditary TTR patients.

Jeff Poulton: Barry can comment further if he wants after I answer your next question. The question about sales deductions in the fourth quarter and whether or not that should be something that would be monitored in terms of a trend, I think not. The way sales deductions work is you make estimates at the time the sales are booked for sales deductions, and as you get actuals against those estimates, [inaudible]

Yeah.

And does that answer your questions, yes very helpful. Thank you.

Thank you very much.

For the move to our next question from the line of David Lebowitz falling and steadily.

Go ahead.

Thank you very much for taking my question. When you look at CEOC Petro launch tends to beginning has there been any evolution and that type of patient the incremental patients diagnosed and put on drugs from the beginning of the launch to six months into the launch to now.

Jeff Poulton: Jeff covered it incredibly well, just to emphasize again the growth will come from patients continuing on therapy. We're very enthusiastic that there's over 90% with the Adherence Rate, representing what we saw in the Apollo clinical trials where over half the patients are stabilized or improved in their polyneuropathy, which is quite remarkable to see and anecdotally hear those stories. And then, as Jeff said, we'll continue to bring new patients to markets that are open. We'll continue to open new markets. And we'll continue evidence generation; all our growth drivers are new patients. The only other thing to add is that, right now, the pricing and reimbursement we're getting outside the United States continues to be very strong, representing the value that Ampatua is bringing to the treatment of polyneuropathy in these hereditary ATTR patients.

How might you expect that profile the patients to change six months or a year from now.

Yes, that's a great question Barry you want to handler, yes. They have great question, Let me, let me first day that based upon.

The genetic makeup of any different country each country quite frankly is very different dynamics.

The United States dynamic has a significant amount of the one to two Ivy 30, m. other other countries of different mutations.

I'd say if you go back a couple of years ago and as Pushkal mentioned.

Most people thought of hereditary TTR as either a polyneuropathy or cardiome up disease in the big fundamental shift.

Salveen Richter: Salveen, does that answer your question?

We've seen is it appreciation that this is a mixed phenotype disease in fact, most patients including the one to two patients have have mixed disease. So the ability to see and look for Polyneuropathy has has increased over the years and should continue to increase as education continues in health care community.

Salveen Richter: Yes, very helpful. Thank you.

Operator: Thank you very much.

Operator: Thank you very much for taking my question. When you look at Onpatro launch since the beginning, has there been any evolution in the type of patient, the incremental patient diagnosed and put on the drug from the beginning of the launch to six months into the launch to now? And how might you expect that profile of the patient to change six months or a year from now?

The only thing I would add.

David which relates to the us market, which certainly did evolve over the course of the year was the advent of combination years.

And we're aware of a significant.

Eric Green: Yeah, that's a great question. Barry, do you want to?

We will be growing number we don't have precise numbers on this but growing number of patients where.

Eric Green: Yeah, so Dan, great question. Let me first say that based upon the genetic makeup of any different country, each country, quite frankly, has very different dynamics. The United States has a significant amount of V122I and V30M; other countries have different mutations. I'd say if we go back a couple years ago, and as Pushkal mentioned...

Understand that there.

Receiving the TCR stabilizer in addition to there on Patrick So it reflects.

Physicians, who are choosing to treat the cardium off the with the stabilizer drug is approved for that indication and the polyneuropathy without patch Roe.

And that really is.

Something which has changed over time and physicians are fighting.

Eric Green: Most people thought of hereditary TTR as either a polyneuropathy or cardiomyopathy disease. And the big fundamental shift we've seen is an appreciation that this is a mixed phenotype disease. And in fact, most patients, including V1 to V2I patients, have mixed disease. So the ability to see and look for polyneuropathy has increased over the years and should continue to increase as education continues in the healthcare community.

Maybe to continue to receive robust reimbursement for a patch Roe in that specific setting.

So that is something which did change over the course the year are expected to continue to change.

All during 2020.

Okay. Thank you very much strengthened the question.

Yes. Thanks.

Moving them over next question from the line of.

CMO capital markets. Please go ahead.

Hi, good morning, Thanks for taking my question.

Eric Green: The only thing I would add, David, which relates to the U.S. market, which certainly did evolve over the course of the year, was the advent of combination products. And, you know, we're aware of a significant and, you know, probably growing number. We don't have a precise number. A growing number of patients where, you know, we understand that they're receiving the TTR stabilizer in addition to Onpatro, so this reflects physicians who are choosing to treat the cardiomyopathy with the stabilizer drug that's approved for that indication and the polyneuropathy with Onpatro. And that really is something that has changed over time, and physicians are finding the ability to continue to receive robust reimbursement for Onpatro in that specific setting I expect it to continue to change and evolve during 2020.

On on Petro are the fourth quarter U.S. sales with her.

Or any other factors besides the gross to net production.

That impacted the growth.

Were there increased competition from the ongoing clinical trials at least through this patient population and also on your 2020 Petro guidance are you assuming any first quarter seasonality.

Any headwinds from reimbursement resets.

Yes, let's turn that over to Jeff Jeff. So first question related to the growth dynamics and the fourth quarter. So underlying demand growth so products shipped to patients to fulfill patient orders was 12% growth in the quarter.

Operator: Thank you very much for answering the questions.

Good product sales for the quarter were only 6%. The reason for the Delta was gross to nets. The gross to net deductions that we booked in Q4 or about 5% higher than what we booked in Q3, which was the reason for lower reported net sales growth.

Operator: Yeah, thank you.

Operator: Hi, good morning. Thanks for taking my question. On Patro, for the fourth quarter U.S. sales, were there any other factors besides the gross student production that impacted the growth? Were there increased competition from the ongoing clinical trials in this patient population? And also, on your 2020 Patro guidance, are you assuming any first quarter seasonality, any headwinds from reimbursement resets?

Maybe you could repeat the second question.

Just a question on your.

Thats, a whether you expect any seasonality.

No. We don't expect any seasonality I wouldn't look again expect continued and steady growth quarter to quarter.

Jeff Poulton: Yeah, let's turn that over to Jeff. So first

Yes, just just just emphasize that as we presented multiple times, we've built a very robust.

Jeff Poulton: Next question related to the growth dynamics in the fourth quarter. So, underlying demand growth. So, products shipped to patients to fulfill patient orders were 12% growth in the quarter, but the reported product sales for the quarter were only 6%. The reason for this delta was gross to net. The gross to net deductions that we booked in Q4 were about 5% higher than what we booked in Q3, which was the reason for the lower reported net sales growth. Maybe you could repeat the second question.

Position capability and in the United States have alnylam assists, which proactively reaches up patients to ensure drug continuity. So we are seeing as we mentioned patients who are benefiting staying on drugs and a significant number of patient adds across the country and feel really good that that we've been through the both to the United States and but we continue.

To see really nice patient growth.

Jeff Poulton: The second question is on your guidance, whether you expect any seasonality. No.

Great. Thank you spread on the part question.

Yes.

Jeff Poulton: No.

Thank you.

Jeff Poulton: No, we don't expect any seasonality. I would, again, expect continued and steady growth.

We will move to my next question from three to Rob Lowe Cowen. Please go ahead.

Good morning, everyone. Thanks for taking the questions.

Jeff Poulton: ....

Eric Green: Just to emphasize that, as we presented multiple times, we built a very robust commercialization capability, and in the United States, we have Alnylam Assist, which proactively reaches out to patients to ensure drug continuity. So we are seeing, as we mentioned, patients who are benefiting from staying on drugs and a significant number of patient ads across the country and feel really good that we've been through the bullets in the United States, but we continue to see really nice patients.

Can you comment on how much Japan represented.

For Q us on sales and.

Sales growth.

As well as on switching patterns, you mentioned switching pattern in Europe and Japan.

And then as a follow up on the policy.

Yes, Great question review, let me on the breakdown, we are going to provide that breakdown for rest of world. Yes, we probably will need to start in the first quarter of as as Japan grows and becomes a more significant proportion of our rest of world sales. So for right now is.

Eric Green: Great, thank you. Great

Operator: Thank you. We will now move to our next question from Ritu Baral. Good morning, everyone.

Lumped together, what we can't say that Japan was very strong.

Operator: Thanks for taking the question. Can you guys comment on how much Japan represents 4QXUS sales and the sales growth, as well as switching patterns? You mentioned switching patterns in Europe and Japan. And then I have a follow-up question on Apollo B. Yeah.

And we're very pleased with the growth in Japan, but we also had some markets in Europe, notably the UK wherever we had four full quarter of reimburse drug.

During Q4, so that was also a notable inkjet to add to that.

Jeff Poulton: Let me explain. On the breakdown, we aren't going to provide that breakdown for the rest of the world yet. We probably will need to start in the first quarter as Japan grows and becomes a more significant proportion of our rest of world sales. So for right now, it's lumped together. What we can say is that Japan was very strong, and we're very pleased with the growth in Japan. But we also had some markets in Europe, notably the UK, where we had a full quarter of reimbursed drug during Q4. So that was also notable.

I think you hit it I mean for sure in the fourth quarter and 61% growth outside the us the UK in Japan were significant contributors to that growth from the quarter, Yes, yes, yes. Thanks.

Switching yes, I'm in Japan.

Patients that have been on I'm stabilizes for.

Okay. This time continues to progress I think with acquisitions switching that patients to Patrick so it varies.

Jeff Poulton: I think you hit it; I mean, for sure, in the fourth quarter, again 61% growth outside the U.S. The U.K., and Japan were significant contributors to that growth.

I was going to decide what would have on said the dynamics the dynamics in countries, where physicians have extensive experience fem as against the Polyneuropathy and quite frankly.

Eric Green: Transcripts provided by Transcription Outsourcing, LLC.

The not a positive experience it's been mostly a switch in the United States were experiences is a little bit newer and as John mentioned, the cardiac indication, we're seeing a little bit more combination use. We're also seeing newly diagnosed patients on petro countries around the world. So it's not only have switched dynamic.

Operator: I was going to ask...

Eric Green: The dynamics in countries where physicians have extensive experience with Defemis, again for the polyneuropathy, and quite frankly, not a positive experience, it's been mostly a switch. In the United States, where experience is a little bit newer, and as John mentioned, the cardiac indication, we're seeing a little bit more combination use. We are also seeing newly diagnosed patients on Ampatero in countries around the world. So it's not only a switch.

Does that help right.

Very helpful. Thank you and then my question on a policy now that we're getting.

Closer to enrollment completion as you mentioned later this year can you remind us what the powering around six minute walk the six minute walk endpoint for that study will be and can you just any general.

John Maraganori: Great. Very helpful. Thank you. And then my question on Apollo B, now that we're getting closer to enrollment completion, as you mentioned, later this year, can you remind us what the powering around six minute walk, the six minute walk endpoint for that study will be? And do you have any general thoughts on what that data could mean as we look at and model Patro into 2021 and 2022? You know, how do you think that six, six minute walk data compares meaningfulness-wise versus outcomes data from Tysamnida?

Thoughts on what that what that data could mean and as we look at as we look at and model when Tatro into 2021 in 2022, how do you think that six six minute walk data.

Compares.

Meaningfulness wise versus.

Outcomes data.

From Sandy.

Well, that's a really great question, we're going to I'm going to make a couple of comments I will go to push fold as Barry Let me just safe to say for stores that we really are excited about Pablo B and then healios fee and we really do you view these that.

Pushkal Garg: Well, that's a really great question. I'm going to make a couple of comments, then we'll go to Pushkal and then to Barry. Let me just say for starters that we really are excited about Apollo B and then Helios B, and we really do view these two trials as being critical elements to the potential expansion, assuming the trials are positive and regulatory reviews are positive, of our broader ATTR program. So we do think this is very, very critical for the company, and we think it's a very important value creation opportunity for Helmahelm. So with that, Pushkal, do you want to comment on the Apollo B design?

These two trials as being critical elements to the potential expansion assuming the trials are positive and regulatory reviews are positives expects a potential expansion of our broader HCR franchise into the very very large while you are.

Cardium off a few setting very specifically.

So we do think your this is very very critical for the company and we think it's a very important value creation opportunity.

For a mile so with that personal do you want to comment on the Apollo design, yes, absolutely. Thanks Ritu for your question. So just as to the Big picture on this study right does that.

Pushkal Garg: Yeah, absolutely. Thanks, Ritu, for your question. So, you know, just as to the big picture on this study, right, this is a 300-person study enrolling both patients with wild-type and hereditary TTR with cardiomyopathy, and we're following them for 12 months with a six-minute walk distance endpoint. You know, and I think in terms that it's a global study, in terms of, I think what we're seeing in terms of enrollment is great enthusiasm, and I think that's really spurred on by the fact that the investigators are very enthusiastic about some of the post-hoc and exploratory data that were published last year in circulation coming out of the Apollo suggesting that Ontatra may have favorable effects on some of the cardiac aspects of the disease and really In terms of the end point, the 6 minute walk distance test is a validated end point that's been recognized by health authorities as registered.

The 300 person study.

Enrolling both patients with wild type in hereditary TTR with credit my apathy.

And we're following them for 12 months for a six minute walk distance endpoint.

And I think in terms that it's a global study in terms of.

I think what we're seeing in terms of enrollment is good.

Great enthusiasm I think thats really spurred on by the fact that investigators are very enthusiastic about some of the post talking exploratory data that were published last year in circulation coming out of the Apollo study, suggesting that on Castro may have favorable effects on some of the cardiac aspects of the disease and really want to do and support this definitive study to.

Or stand that.

In terms of the endpoint the six minute walk distance test is a validated endpoint that's been recognized by the health authorities as registered double.

And so we're encouraged by that and obviously, we have secondary endpoints look at symptomatology using the KCC.

You death, and hospitalization outcomes as well that we can follow.

Pushkal Garg: And so, you know, we're encouraged by that. And obviously we have secondary endpoints to look at symptomatology. KTCQ death and hospitalization outcomes as well that we can follow in terms of powering you know the powering we obviously informed by prior studies including the ATTRACT study and so we can use that to really understand how to well to really well power this study so it's a very well powered study for the primary endpoint and so we're quite encouraged that we'll be able to see a positive result as that reads out assuming

In terms of powering.

The powering we obviously informed by prior studies, including the attract study and we can use that to really understand how to wealth to really well powered. This study. So it's a very well powered study for the primary endpoint.

And so were.

Quite encouraged that we'll be able to see a positive result, as that reads out assuming.

Underlying hypothesis is south which we do believe it is.

Right and Barry you want to comment a little but yes. The only thing I'd add is implicit thanks recovering that so well as as we know patches currently indicated for the treatment of Polyneuropathy.

Eric Green: And Barrett, you want to comment a little bit? Yeah, the only thing I'd add, and Pushkal, thanks for covering that so well, is, you know, as we know, patchwork is currently indicated for the treatment of polyneuropathy.

Editorial TTR patients as evidenced by the Apollo study, we saw a stabilization and even a reversal of polyneuropathy the majority of patients.

Fiscal explains we've got a number of endpoints in Apollo be that.

Eric Green: As evidenced by the Apollo study, we saw stabilization and even reversal of polyneuropathy in a majority of patients. So, as Pushkal explained, we've got a number of endpoints in Apollo B that a profile similar to that would be very competitive, particularly in an opportunity where we might see patients or aspects of the disease getting better.

Profile similar to that would be very competitive, particularly an opportunity where we might see.

Patients are aspects of disease getting better.

Richard is that does that answer your question.

Yes, and so what all this together imply intentional.

Acceleration potential on positive data potential reacceleration.

Ritu Baral: So Ritu, does that answer your question?

Growth in the 2020 120.

John Maraganori: Would all this together imply a potential re-acceleration of growth in the 2021-2022 timeframe upon potential legal expansion?

The 22 timeframe on potential label extension.

Well you absolutely we would expect that based on based on the opening up a wildfire indication absolutely.

John Maraganori: Well, yeah, absolutely.

Operator: Thanks. Thanks for taking the questions. Thank you. Thank you. We will now move to our next question from Paul Matteis of Stiefel. Great.

Okay.

Thanks, Thanks for taking questions.

Thank you. Thank you.

We will now move during next.

Paul Montes Stifel. Please go ahead.

Great. Thanks, so much for taking my questions I had one follow up to reduce question and then one quick question on good most or add.

Paul Matteis: Thanks so much for taking my questions. I had one follow-up to Ritu's question and then one quick question on Gibosaran. To Ritu's question, I was wondering if you could just talk about Apollo B and what you have any assumptions or any expectations for what you might see in mortality or hospitalization, understanding that cardiologists really care about outcomes data even more so than maybe neurologists in the TTR space. And then, second, on Gibosaran, I totally understand that it's too early to give guidance. I was wondering if I could just kind of bounce qualitatively off you what the consensus seems to imply. It feels like analysts that cover Alnylam are assuming that this rollout will be a lot slower than on Patro and that this is a market that really requires a lot more building. So I was wondering if you could speak to at least some agreement or disagreement with that assumption since consensus here really is a lot more conservative than what you accomplish in TTR.

To reduce question I was wondering if you could just talk about Apollo B and and if you have.

The assumptions or any expectation for what you might see on on mortality or hospitalization understanding that cardiologists really care about outcomes data even more so than maybe neurologists met GTR space and then second on I'll get closer and I totally understand that it's too early to give guidance.

I was wondering just kind of.

Sales qualitatively off you what consensus seems to imply it feels like analysts that cover our model them are assuming that this rollout will be a lot slower than on patch ROE and that this is a market that really requires a lot more building I was wondering you could speak to at least.

Obama agreement or disagreement with that assumption since consensus here.

Really it's a lot more conservative than what you accomplish and TTR. Thanks, so much.

John Maraganori: Thanks so much.

Pushkal Garg: Yeah, thanks, Paul. Great questions. So Pushkal, if you want to handle the first one, Barry, the second.

Yeah. Thanks, Paul at Red question. So push goes you want to handle the personal bear the second absolutely. Thank Paul for your questions. I think as you were asking is really what our expectations were around the outcome measures in the Apollo B study.

Pushkal Garg: Absolutely. Thanks, Paul, for your questions. I think, as you were asking, what our expectations were around the outcomes measures in the Apollo B study. And so maybe, you know, a couple things. Again, the study was primarily powered around the six-minute block test, and the mortality and hospitalization endpoints were captured as secondaries and hierarchically tested there. I think in terms of context around that, you know, I think if we look at the ATTRACT data as sort of an example and then a similar population, there we saw with that drug that hospitalization started to separate at around nine months, and mortality differences started to emerge at around 18 months So, by that token, a 12-month study, you know; we have to see what it looks like.

And so maybe a couple of things again this study was.

Primarily powered around the six minute walk test and the mortality hospitalization endpoints are captured a secondaries and hierarchy. We tested there I think in terms of context around that I think if we look at the attract data is sort of an example in a similar unrelated pop patient population there we saw.

With that drugs that hospice.

Elevation started to separated around nine months and mortality differences started to emerge at around 18 months. So by that token at 12 months study.

We consistently we have to see what it looks like it's very encouraging to us. However is that we did the post hoc analysis out of the Apollo study.

And there as you may recall from the data that were.

Published in circulation, we started to see separation in these post hoc analysis in the cardiac subpopulation relatively early in terms of recurrent mortality in the current hospitalization events.

Pushkal Garg: What's very encouraging to us, however, is that we did the post-hoc analyses out of the Apollo study. And there, as you may recall from the data that were published in circulation, we started to see separation in these post-hoc analyses in the cardiac subpopulation relatively early in terms of recurrent mortality and recurrent hospitalization events. And that was in a subset of patients. You know, Apollo had 225 patients. This is a 300-person study. So I think, you know, we obviously have included them because we're hopeful that we'll see those differences emerge, and we'll be capturing that in the context of this.

And that was in a subset of patients pilot was 225 patients. This is a 300 person study so I think.

We are.

We obviously have included them because we're hopeful that we'll see those differences emerge and will be capturing that in the context. The study right very good Florida, Yes, uncut Laurie so Paul I'm not going to comment on.

What we're thinking relative to consensus of course, we're not giving that guidance, but qualitatively we have a situation where.

We have a remarkable drug and give laurie and a very unmet.

Unmet need here in a population desperate.

For a treatment, but it is a market we need to build removing this market from patients suffering a 13 to 15 year Odyssey, the multiples inappropriate operations and trying to speed diagnosis in a mentality.

Eric Green: Paul, I'm not going to comment on what we're thinking relative to consensus, of course, we're not giving that guidance, but qualitatively, we have a situation where we have a remarkable drug in Gavlari and a very unmet need here and a population desperate. For a treatment, but it is a market we need to build, removing this market from patients suffering a 13 to 15 year odyssey, the multiple inappropriate operations to try to speed diagnosis, and a mentality from treating attacks to prevent, [inaudible] for these porphyria patients.

From treating attacks to preventing.

And treating the holistic aspect of the disease. So what is the marketing transition that we are really building on our own there are there aren't the same competitive landscape through the same dynamics. We've seen in TTR that said, we feel great about start and where we're headed with building glory into a very important medicines.

For the spring.

For patients.

Paul does that answer your questions Yep. Thanks for the thoughts guys appreciate it.

Thank you very much.

We'll now move to our next question from that I know Maury Raycroft of Jefferies. Please go ahead.

Hi, Good morning, everyone. Thanks for taking my question I've got another one on.

Eric Green: Great. Paul, does that answer your question?

I'm not sure I'm just wondering for the launch of you can provide more specifics on drivers for wide doctors and patients are switching from stabilizers are deciding to add on potrero onto stabilizers as hambone. One these lines Howard doctors to finding progression of disease, where patients are on stabilizers.

Paul Matteis: [inaudible]

Operator: Yep, thanks for the thoughts guys; I appreciate it. Thank you very much.

Operator: Hi, good morning, everyone. And thanks for taking my question. I've got another one on Padra. I'm just wondering for the launch, if you can provide more specifics on drivers for why doctors and patients are switched.

Operator: [inaudible]

Does that definition evolved.

Operator: Does that definition need to evolve?

Eric Green: That's great; those are great questions, Maury.

That's a great because a great questions Mark Barry you want to have about yes. So it's more just as we've talked about the dynamics are different depending on what country in country in general and countries outside the United States.

Eric Green: If you want to hand the ball,

Eric Green: Yeah, so, Maury, as we've talked about, the dynamics are different depending on what country you are in. In general, in countries outside the United States... For hereditary TTR patients with polyneuropathy, PATCHO is being used front-line when patients are newly diagnosed, and they're being switched as patients progress. Progression is being defined differently across various physician groups, but in general, as we know from the ATTRACT study, all the patients progress, so it's not, it's not... The question if they're going to progress is how quickly they progress. And as John highlighted appropriately, in the United States, given different indications and some of U.S. medical practice, we're seeing a bit of combination use, but that's a bit more of a U.S. dynamic.

For hereditary TTR patients with Polyneuropathy.

Patches being used frontline when.

And your newly diagnosed.

And they're being switched as patients progress progressions being defined differently across various physician groups, but in general and as we know from the attract study all the patients progress so it's not.

It's not.

A question, if they're going to progress, it's how how quickly they they.

Dress and as John highlighted appropriately in the United States given different indications in somewhat of the U.S. medical practice, we're seeing a bit of combination use but that's a bit more of a U.S. dynamic.

Eric Green: More at azure.

More does that answer your question.

Eric Green: Yeah, that does. And any idea as to the proportion of patients that are getting Tombo?

Yeah that.

Any idea as to the proportion of page.

And that are getting top of use.

John Maraganori: You know, we don't have great numbers on that, but we know that it's a double-digit number, for sure, maybe more over time, but we know some practices. At our R&D day, we had a physician from the University of Chicago, a great institution, by the way, where she has, she said she has over 10 patients that are on ComboU. So we do think this will increase in number.

We don't have great numbers on that we know we know that it's a double digit number for sure maybe more over time, but but we know south practices at R&D day, we had to physician for the University Chicago, Great institution by the.

Which.

Where where she has two cents. She has over 10 patients that are on combo use. So we do think this will increase in physicians are finding that they're able to get reimbursement for their apache tailwind as well as or to have it as if that's what they're using and so that's that's good.

John Maraganori: [inaudible]

Operator: Got it. Thank you very much. Next question from the line of Anupam Ramachandran.

Operator: Hey guys, thanks so much for taking the question. Maybe following on Salveen's question earlier, just thinking about the guidance. So what's that delta in sort of market dynamics that's assumed in achieving, say, the lower bound of 285 versus the higher bound of 315 in the guidance? Is that, layering on a couple more countries, is it increased penetration, is it a combination?

Got it thank you very much.

We will not motoring next question from the line of a number of JP Morgan. Please go ahead.

Hi, guys. Thanks, so much for taking my question.

Maybe following on selling question earlier.

But the guidance.

That delta in sort.

The market dynamics that seemed in achieving say the lower bound to lead by versus the higher bound.

315 in the guidance that.

Layering on a couple more countries in the increased penetration into the combination of thing if you could give us a little more color on that would be helpful. Thank you so much.

Perfect.

Got you want to handle that I'll start mental at the very comment again the range that we provided to 85 to freeze it seems in mid 0.8, 80% growth.

Operator: If you could give us a little more color on that, that would be awesome. Thank you so much.

We understand the importance of achieving that guidance, we're confident in our ability to do so we've provided a range just like we had with all the other elements of our.

Operator: Thank you so much.

Jeff Poulton: Terrific. Jeff?

Jeff Poulton: I'll start.

Jeff Poulton: [inaudible]

Jeff Poulton: We see growth coming from growth in countries where we have pricing and reimbursement with new patient finding and evidence generation, and then opening up new countries where we achieve pricing and reimbursement. As I said earlier, it's going very, very well, and we believe it will continue throughout the course of this year into the years to come.

Our guidance just given general uncertainties.

That's all I have varying anything further you want to comment on around that range from Petro Jeff I think you covered it well and just just to emphasize in a pump we see growth coming from growth in countries, where we have pricing and reimbursement with new patient finding and evidence generation and.

And opening up new countries, where we achieved pricing and reimbursement as I said earlier, it's going very very well and we believe it will continue throughout the course of this year in two years to come.

Hi, Thanks that probably answer as much as you'd like but but.

Jeff Poulton: On a positive note, that probably doesn't answer as much as you'd like, but that's, I think, the color that we'd like to provide at this point.

I think the color than we'd like to provide at this point.

Great. Thanks for taking my question.

Thanks.

We will now to cover mix I would final question today from Leland Gershell of Oppenheimer. Please go ahead.

Operator: Great, thanks for taking our questions.

Hey, guys. Thanks for taking my question just a financial question again on the gross to net.

Operator: Alright, thanks. Bye.

Operator: All right, thanks. Bye.

Operator: We will now take our next, and final question today from Leland Gershell. Hey guys, thanks for taking my question.

I think you'd said that you were meeting coming right in line with your sort of 25% between us and new you is there any way you could break down if there's any differences in the gross to nets between those two regions I mean, I've a follow up.

Operator: Question on the growth to net, I think you said you were meeting, coming right in line with your 25% between the US and EU. Is there any way you could break down if there are any differences?

Great Jeff, Yes, sure the the gross to net in the U.S. is approximately 20% outside.

The us it's closer to 40% the blend is 25% all those figures were in line with our expectations for the year.

Operator: Question between those two regions, and then I have a follow-up.

Operator: [inaudible]

Jeff Poulton: Jeff? Yeah, sure.

Right. So you had a follow up.

Jeff Poulton: The growth net in the U.S. is approximately 20%. Outside the U.S., it's closer to 40%. The blend is 25%. All those figures were in line with our expectations for the year, so you have a follow-up.

Great. Thanks, and then just just touch on cluster and on the royalties I think you had said that you do.

Royalties up to.

About 20%, but those are skilled any color you can provide on what the.

Operator: Oh great, thanks, and then just on, just actually on glycerin on the right.

Scaling of Israel pieces, or just 20% is kind of the mix.

Operator: [inaudible]

Well the the the blend.

John Maraganori: Well, the blend is going to be in the high teens. When you look at how the SPAC is structured and how the market potential for the product is expected to play out, and obviously, that gets higher and higher as the product meets expectations that Novartis is driving toward. So it's a very attractive share. I think one way to look at it is, just on an MTV basis, it's about a quarter to a third of the value alone of that asset, depending on the spend that is associated with ultimately driving the revenues. So that's a very significant portion of the value that we have in the product, and we're obviously very pleased and excited to have Novartis as our partner. Jeff or Yvonne, anything to add to that? I think you nailed it. I don't have anything to add.

That was a blend is going to be into high teens. When you look at when you look at how the stack is structured.

And how the how the market potential for the product is expected to play out and obviously that gets higher higher as the product.

These expectations at Novartis.

You know is driving toward so it's a very attractive share I think one way to look at it is.

Just on MTV basis.

It's about a quarter to a third of the value alone of of that asset.

Depending on spend that is associated with ultimately driving revenues. So that's a very significant portion of value.

That we have in the product.

We're obviously very.

Please and excited to have novartis as their partner.

John Maraganori: I think we may have to

Jeff or bought anything to add to that I think you nailed it I don't have anything that.

Operator: Great. All right. Thanks, Leland.

Let me either great alright, thanks, Leo Okay, great. Thank very much.

Operator: Okay, great. Thank you very much.

Operator: Thank you, ladies and gentlemen. That's all the time we have today for questions, and now I would like to send the call back to the company for any additional or closing remarks.

Thank you.

John was that all time would have to say for questions.

Next on the call back to the company.

For any additional in closing remarks.

John Maraganori: Well, great. Thanks, everybody, for joining us this morning for the call. We are, you know, really pleased with the R&D and commercial progress that we've been making. We're excited about where 2020 will take us, and we look forward to updating you in the weeks and months to come. Thanks very much.

Great. Thanks, everybody for joining us this morning for the call. We're really pleased with our R&D and commercial progress that we've been making we're excited about where 2020 will take us and we look forward to updating you in the weeks and months to Tom Thanks very.

Operator: Thank you. That will conclude today's conference call. Thank you for your participation, ladies and gentlemen. You may now disconnect.

As much.

Thank you Doug Spool conclude todays conference call. Thank for your participation, ladies and gentlemen, you may now disconnect.