Ladies and gentlemen, thank you for standing-by. Welcome to the Alnylam Pharmaceuticals Conference Call Second Quarter 2020. There will be a question-and-answer session to follow. Please be advised that this call is being taped at the company’s request. I would now like to turn the call over to the company..

Good morning. I’m Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam.

With me today on the phone are John Maraganore, Chief Executive Officer; Barry Greene, President; Akshay Vaishnaw, President of R&D, Jeff Poulton, Chief Financial Officer; and Yvonne Greenstreet, Chief Operating Officer; Andy Orth, Head of the US Business is also on the phone and available for Q&A.

For those of you participating via conference call, the accompanying slides can be accessed by going to the event section of the Investor page of our website at www.alnylam.com/event. During today’s call, as outlined in Slide 2, John will provide some introductory remarks and general context.

Barry will provide an update on our commercial and medical affairs progress. Akshay will review recent clinical and pre-clinical updates, Jeff will review our financials and Yvonne will provide a brief summary of upcoming milestones before opening the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam’s future expectations, plans and prospects, which constitute forward-looking statements for the purposes of Safe Harbor provision under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to provide such statements. With that, I would turn the call over to John..

Thanks Christine and thank you everyone for joining us on the call today. Let me start by expressing online support for Black Lives Matter and our support for the efforts to end systemically within our country. At Alnylam, we stand against all forms of discrimination and our core we believe in justice, equity and inclusion.

We stand in support a peaceful protest aimed at achieving real and sustainable change. Enough is enough, and it is time to finally cure the refractory scourge of hate. I would also like to comment briefly on the Trump Administration’s recent announcement on drug prices.

While we fully support the need to reduce or even eliminate patient out of pocket costs for prescription drugs, the administration’s proposal to potentially introduce a so called most favored nations, executive order is both unfortunate and misguided. Importing foreign price controls will harm American innovation and hurt our patients.

Even if this executive order is finalized, we don’t believe it will stand without results for a core business. As all of you know, the COVID-19 pandemic remains dynamic, uncertain, and unpredictable.

That said, we continue to view the situation in the same framework we discussed last quarter, a pandemic phase in Q2, the recovery phase in Q3, and a new normal starting in Q4. While the pandemic continues or even worsen in many states in the US, we believe Alnylam’s business is benefiting from our broad global presence.

In spite of the ebbs and flows, we are seeing healthcare systems now remaining open, and we don’t currently expect to repeat shutdown of health care systems, like what was seen in Q2, especially in the April, May timeframe. Our confidence in the second half is reflected in an upward revisions in our ONPATTRO revenue guidance range.

Overall, we are really proud of our field teams around the world and their ability to adapt quickly and safely to meet the needs of patients embodying our challenge accepted mentality. We are extremely pleased with global ONPATTRO and GIVLAARI top line performance in Q2, which Barry will elaborate on shortly.

We are also proud of the significant progress we made across our pipeline in the quarter as Akshay will discuss. Another highlight for the quarter was our landmark strategic financing collaboration and increase around royalty monetization. We completed with Blackstone, Life Sciences worth up to $2 billion.

We believe this collaboration secures our bridge toward a self sustainable financial profile without the need for any future equity financing. Before I share my closing remarks, I want to take a moment to acknowledge the news we announced earlier this morning about Barry Greene’s planned departure from Alnylam at the end of quarter.

Barry and I have been working side by side for over 20-years, first at Millennium and then for 17-years at Alnylam and I know that I speak for everyone at Alnylam in thanking Barry for his exceptional contributions and dedication to the company.

We all owe him tremendous gratitude for his outstanding leadership and track record that have contributed to the delivery of RNAi therapeutics as a whole new class of medicines for patients. I have no doubt Barry will continue to be a highly impactful leader in the Life Sciences.

I’m grateful for his agreement to consult with Alnylam as needed for a two year period, and I wish him all the very best in his next endeavors. We are also very pleased to share that Yvonne Greenstreet, our current Chief Operating Officer will step into the expanded roles of President and Chief Operating Officer on October 1st.

We believe Yvonne is uniquely suited to this opportunity, given her strong command of our business, strategic leadership and proven ability to drive results. We are initiating a search for a Chief Commercial Officer and during the search we anticipate no impact through our ongoing commercial execution.

Please join me in wishing Barry well as he pursues the next chapter of a remarkable career and congratulating Yvonne on her expanded role at Alnylam. I like to finish with my perspective on the big picture of the company. We continue to lead the advancement of RNAi therapeutics as a whole new class of medicines.

And we remain on track to achieve and exceed our Alnylam 2020 goals, exiting 2020 as a multi-product global commercial company with a deep clinical pipeline for future growth and they a robust and organic product engine for sustainable innovation.

Without a doubt we are excited for the promising future that Alnylam is poised to deliver as a top tier biopharmaceutical company focused on advancing medicines with transformative potential for patients around the world.

With that, I will turn the call over to Barry for one last time Barry to review our commercial progress and medical affairs activities in more detail. Barry the it away..

Thanks John and good morning, everyone. Before I provide the quarterly highlights, I would like to make some brief remarks about my planned transition for Alnylam. First, congratulations again for [indiscernible] remarkable person and deserves the presidency overall.

I know that Yvonne will make sure that Alnylam continues to be a company doing the right things and focusing on patients and I’m counting on it. For me it has been a tremendous privilege to serve as president of Alnylam for such a long period of time.

I’m very proud of what we have been able to accomplish during my 17-years having built a global fully integrated multiproduct company. There is recognition for excellence in R&D and recently of our commercial strength as well. Now, decision to transition is based on the desire to assume a new leadership opportunity in next chapter of my career.

I’m fully confident Alnylam will achieve its ambitious goals with quality and excellence, with a great team we have in place. I will continue to support Alnylam throughout this transition and have no doubts about the company’s future prospects as a top tier biopharmaceutical company.

[Technical Difficulty] for ONPATTRO we achieved 66.5 million in global net product revenues as a June 30th, over 1050 patients were on commercial ONPATTRO treating worldwide representing an increase of over a hundred patients in the end of Q1. A very impressive accomplishment in the height of the global pandemic during Q2.

Let’s start with some more color on the US as anticipated. The COVID-19 pandemic has impact on our business in the second quarter, the patient demand decreasing due to reduced adherence as some patients skip doses, experience dose delays while move into new parasites.

Also hasn’t dissipated the pace of new patients gene therapy slow in the US during the quarters in reduce generic testing diagnosis and patient flow through the healthcare system.

Finally, our US business was also impacted by inventory destocking and increase [Technical Difficulty] in quarter, Jeff will provide more color on these details later in the call.

While our focus today is on Q2 as we enter Q3 are now seeing what looks like a healthy return of generic testing and patient flow through the U.S Health Care System, even in states where COVID-19 patients are rising. In fact, our July online estimate was nearly January numbers we saw earlier in the year, a really good sign.

In the second quarter we continue to see great progress -. In the second quarter, 40% of - came from new writers a unique mix of neurologist and cardiologist. In US the [Technical Difficulty] ONPATTRO with future stabilizers in the quarter.

We believe this trend will continue to grow as physicians seek progression of polyneuropathy on stabilizers and treat the different manifestations of HTTR Amyloidosis. Now turning to the rest of the world, we made very positive progress with ONPATTRO in the second quarter.

[indiscernible] and relative to US benefited from continued geographic expansions with launches in Spain, Italy and other countries. In addition, we saw relative strength in ex-US partners including Europe and relative to fair management of the pandemic.

As John noted this is a nice validation of a decision to building a global fully integrated business. But today’s announcement of achieving pricing and reimbursement agreement in France, we are pleased to report that access has been secured in all priority markets in Western Europe.

Notably, our [indiscernible] in all major European markets in under two years post approval by the EMA. This is a much faster rate than most orphan medicines are able to achieve. Japan was again a country of strength from ONPATTRO.

Japan has now become our second largest country after US for our ONPATTRO [indiscernible] and we expect, continued growth in patient [indiscernible] a larger therapy.

In medical care side, our team remains committed to addressing the challenge of raising disease awareness, improving diagnostics of [indiscernible] doses, including [pozelimab] (Ph) a third-party genetic screening initiatives in the US, Canada and Brazil.

As of July over 27,000 samples have been submitted out of which over 1,600 positive for pathogenic mutation. With this tracking at store 6% to 8% positivity rate. These numbers show the testing slowdown in Q2 we mentioned on our last earnings call. The good news is third-party mark those numbers to picked up near January levels.

In the month of July, we are really pleased with the progress in our launch, most of which has been - virtually, we achieved 11 billion in global net product revenues, we received over 85 start firms in the US with over 100 patients globally on commercial treatment from launch through June 30th.

As we have now begun to open Ex-US territories and also because currently 25% to 30% of US patients come from outside to start from channel will discontinue providing start for metrics. In future quarters as we did last year for ONPATTRO.

In the US, we observe a broad prescribing mixed including [indiscernible] and other specialties both in for - centers of excellence and industry. Of notes 76% of our Q2 starts were from new writers. Our progress and value based agreements has been extremely strong with [indiscernible] completed in US payers.

We now have confirmed access for over 35% of covering the size cost in other government payers. [indiscernible] very large today pleased to see plans adopt medical policies not more restrictive than our regular medication.

In three years, we saw strong initial performance as well with a successful and admitted virtual launch in Germany, as well as being patient sales and other countries, including French cohort 18 programs.

We have been positively encouraged by the sponsors of European payers despite the COVID-19 pandemic of those -- an improvement of medical benefits or ASMR core score two in France, concluded that offers significant additional therapeutic value. This is an most accomplishment since contest to commercial an SMR rating 2019.

Our medical affairs team has also focused on improving awareness and diagnosis of HP. Through viral mass we can report at 937 tests admitted to patients with HIV patients as of mid July, through a continued 10% positivity rate.

Of a notable diagnosis trend emergence is the robust use of urinary PPG test, inform diagnosis, and the expectation identification efforts, new ***4*** efforts uniquely enhanced by this non-genetic testing method. Of course, we are now also preparing for the launch of the mastermind later this year.

Importantly, we will be leveraging our existing commercial infrastructure for this launch small additions of resources for fuel based teams, when we get approval,[Technical difficulty] virtualization medically third party therapeutic receptive markets.

In conclusion, the second quarter was challenging to prevent damage, particularly United States, who did much better than the downside case we anticipated as we enter in Q2, the credit goes for our teams around the world who face the obstacles to deliver these medicines for efficiency.

With that I will now turn the call over to Akshay, to give you recent R&D pipeline progress. Akshay..

Yes. Good morning, everyone. And thank you, Barry. I should say thank you, Barry for guiding me by helping build our company, and most of all working so tirelessly to help all the patients we seek to serve. So with that, I will start without efforts in ATTR Amyloidosis where we are advancing are two product candidates patisiran and givosiran.

ONPATTRO currently approved in multiple markets around the world to treat polyneuropathy associated with HSD [indiscernible] doses. We are connected to expanding the products label to include the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients.

To this end we continue to enroll patients in APOLLO-B and continue to expect its completion of enrollment in 2021. We have seen enrollment pick up over the last month as clinical sites start to open up around the world.

In addition, we are also advancing vutrisiran an investigational RNAi therapeutic delivered by quarterly subcutaneous injection that is also in development for the treatment of ATTR amyloidosis. Here we are conducting two Phase III studies. The first is HELIOS-A which is evaluating vutrisiran in hATTR amyloidosis patients with polyneuropathy.

Enrollment is complete in HELIOS-A, and we remain on track to report top line results early next year. The second Phase III study of vutrisiran is HELIOS-B, which has been conducted in inherited and wild-type ATTR amyloidosis patients with cardiomyopathy. As we proposed B site activation enrollment and HELIOS-B are now picking up.

If HELIOS-B is positive, it could allow vutrisiran entry into the very large wild-type ATTR amyloidosis market opportunity with the product label that includes cardiovascular outcomes. Let’s move to GIVLAARI, which is approved in the US, EU and now in Brazil to treat Acute Hepatic Porphyria in adults.

Of course, the highlight for GIVLAARI in the recent periods was our Brazilian approval. And we are continuing our geographic expansion for this product with MAA submitted in Switzerland and Israel and plans to submission in Japan in the coming months.

During the second quarter, we also present a new 12-month interim data from the Envision Phase III study, demonstrating sustained efficacy and acceptable safety to 12-months of treatment with evidence for potentially improved efficacy overtime.

In addition, we are proud to publish have pivotal results from the Envision Phase III study in the New England Journal of Medicine. This is our nice paper on RNAi therapeutic published in the journal.

I will now turn to recent progress with lumasiran, an investigational RNAi therapeutic that we are developing for the treatment of Primary Hyperoxaluria Type 1, or PH1.

At the ERA EDTA meeting in June, we reported the full set of positive results from an ILLUMINATE A which demonstrated that lumasiran significantly reduced ureaoxide levels, the cause of progressive kidney failure in PH1. In addition lumasiran showed new encouraging safety profile.

Our overall lumasiran program also includes our ILLUMINATE B study in pediatric patients under six years of age, enrollment is complete and we remain on track report top line results soon in the mid-2020. ILLUMINATE C study in sever PH1 continues to enroll and is being proceeding well, even during the pandemics.

We completed our NDA and MAA submissions in the second quarter. The FDA granted pontoon review for the NDA and has set an action date of December 3, 2020. EMA has gone to the accelerated assessment of the MAA. As you know, we have two additional late-stage programs that are in development with partners.

It includes inclisiran in development for hypercholesterolemia partnered with Novartis, which is currently under review for approval in the US and EU. If NDA and MAA filing has been accepted, and Novartis expect initial approval in the U.S in late 2020.

Novartis indicated that they remain on track for approval this year with a December action date in the US Now late stage pipeline also includes for FITUSIRAN in development for hemophilia A or B with or without inhibitors, partnered with Sanofi.

Sanofi has recently disclosed that two of the ATLAS Phase III studies have completed enrollment and that they remain on track to report top line ATLAS Phase III in the first half of 2021.

Sanofi also presented new positive results from an interim analysis of the phase III study FITUSIRAN showing impressive reductions in the annualized bleeding rate with encouraging safety. Now in addition to our late-stage clinical programs, we believe we have also been making great progress without early and mid-stage programs.

The highlights for the quarter was the positive top line results from our ALN-AGT Phase I study in patients with hypertension, specifically ALN-AGT demonstrate over 90% knockdown of angiotensinogen and greater than 10 millimeters of mercury lower in systolic blood pressure with the durability that caused of quarterly or even less frequent dosing regimen.

We were also encouraged by the tolerability profile of ALN-AGT. We now look forward to presenting more complete data from the ongoing Phase I study and the Scientific Meeting in the second half assuming abstract acceptance.

We are very excited about the potential for ALN-AGT to reimagine the treatment of high hypertension with tonic controlled blood pressure that we believe could result in important benefits to patients. Our next clinical program is ALN-HSD and investigational RNAi therapeutics for the treatment of NASH, for which we recently filed a CTA.

This program is being advanced in collaboration with Regeneron. We are also making strong progress on our many RNAi therapeutic opportunities beyond the liver.

For our COVID-19 RNAi therapeutic collaboration with VIA, we selected the development candidate LNCRE or VIA2783 with potent and highly cross-reactive activity towards SAARS COVID-2 the virus that causes COVID-19. We continue to expect an RND filing around year end 2020.

We are also pleased to announce today that Regeneron is elected to opt in to the ALN-APP program. We aim to get an R&D filed for ALN-APP in mid-2021 and this is expected to be our first - program to enter clinical development. And with that, let me now turn it over to Jeff to review our financial results. Jeff..

Thanks Akshay and good morning, everyone. I’m pleased to be presenting Alnylam’s Q2 2020 results. As Barry has already highlighted it was a very strong quarter of commercial execution with outstanding results for both on ONPATTRO and GIVLAARI.

Turning to our results first for ONPATTRO generated 66.5 million in global net ONPATTRO revenue for the quarter, which was impacted by the pandemic, particularly in the US, with global growth being flat versus the first quarter of 2020 and a 74% increase compared to Q2 2019.

US growth decreased 13% during the quarter compared with Q1 and was primarily impacted by the following. 4% decrease in demand from reduced patient adherence due to the COVID-19 pandemic as Barry previously mentioned.

An 8% reduction due to inventory destocking during the quarter, an ending inventory now at 1.5 half weeks in the distribution channel at the end of Q2, and a 1% decrease due to a modest increase in gross to net deductions in the quarter. We continue to expect gross to net deductions will remain in the mid-20s globally for on ONPATTRO in 2020.

In our international markets performance was very strong in spite of the pandemic of growth of 16% versus Q1.

Growth in Europe was highlighted by strength and recently launched markets in Italy and Spain, while in Asia, growth in Japan remains robust, with Japan now representing our second largest market for ONPATTRO based on dollar sales as Barry mentioned.

First time this quarter the contribution of our international markets to global ONPATTRO sales exceeded the US contribution. We are pleased to have a strong and global brand, which we believe is beneficial to long-term growth. Turning to our results for GIVLAARI.

We had a strong second quarter, generating 11 million global net revenue in the quarter, representing over 100% growth compared to the first quarter.

This growth was driven by ongoing success of US launch where we did not experience reductions in patient adherence at the same level as ONPATTRO, as well as an additional contribution from our international markets with a successful launch in Germany and the name patient sales in other countries, including France.

Our combined product sales for ONPATTRO and GIVLAARI was 77.5 for the quarter, representing 6% growth versus Q1, a strong result given the challenges associated with COVID-19 in the quarter. Turning now to a summary of our full P&L results for the quarter.

Net revenue from collaborations for the second quarter was 26.4 million a significant increase from last year, primarily due to revenue recognized from our Regeneron and VIR collaborations.

Gross margin as a percentage of total revenue was 81% for the quarter, down from 90% in Q2 2019, primarily due to the current utilization of ONPATTRO full cost inventory, while last year benefited from zero cost ONPATTRO inventory, as well as having a higher proportion of sales in the second quarter of 2020 coming from lower margin international markets, and a write-off of ONPATTRO inventory at our contract manufacture.

Our R&D expenses decreased on a non-GAAP basis in the second quarter of 2020, compared to the same period in the prior year, primarily due to non-recurring expenses in 2019 and license fees related to the execution of our collaboration agreement with Regeneron, as well as the decrease in expenses associated with materials manufactured for clinical trials.

Conversely, SG&A expenses increased modestly on a non-GAAP basis in the second quarter of 2020 compared to the same period in the prior year, primarily due to increased investment in commercial and medical affairs activity to support the ongoing launches of ONPATTRO and GIVLAARI an initial launch preparation activities for the lumasiran.

Importantly, our non-GAAP operating loss for the second quarter decreased by approximately 40 million compared with the same period in 2019, driven by a combination of strong top line growth and very moderate growth and operating expenses.

We remain confident that 2019 represents our peak non-GAAP operating last year, as we expect the trend of strong top line growth, and moderate growth and operating expenses will continue for the balance of the year.

At the end of the quarter with cash and investments of 1.95 billion, which includes 600 million in proceeds received in the second quarter from the partial sale of future increase around royalties, and issuance of common stock of Blackstone.

Finally, turning to our financial guidance, we believe our results for the second quarter demonstrate the strength of a commercial teams in challenging circumstances as a result of the strong commercial performance of ONPATTRO that exceeded our initial expectations.

Back in the earlier phase of the pandemic in May, we are further revising our full-year revenue guidance from ONPATTRO with an increase in the midpoint of our guidance as we narrow the range from 270 million to 300 million to 280 to 300 million.

Guidance range for combined non-GAAP R&D and SG&A expenses as well as our guidance for net revenues and collaborations remain unchanged. Please note that we have revised the midpoint of our GAAP combined R&D and SG&A operating expense guidance downward by $25 million, reflecting a reduction in expected stock based compensation during the year.

Regarding cash we believe our strategic financing collaboration of Blackstone, adding up to $2 billion in cash secures Alnylam’s bridge towards a self-sustainable financial profile without the need for future equity financing. And with that I will now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne..

Thanks, Jeff. And hello everyone. Looking ahead to the second half of 2020. We have a number of important milestones lined up. Of course, we plan to continue our global commercialization of both on ONPATTRO and GIVLAARI. We are looking forward to GIVLAARI launch in Brazil and an upcoming NDA filing for GIVLAARI in Japan.

We are also expecting two additional regulatory approvals by the end of the year for the lumasiran and inclisiran. We plan to continue enrollments in our ATTR cardiomyopathy studies, specifically, APOLLO-B with patisiran and HELIOS-B with vutrisiran.

With lumasiran, we are on track to share top line results from the ILLUMINATE-B Phase III study in mid 2020. And of course, we will also continue advancing the rest of our pipeline, as well as exciting preclinical assets. And we will highlight these milestones throughout the years as they occur.

Among these will be our presentation of additional clinical results from the ongoing Phase I trial of ALN-AGT in hypertension, a program we are very excited about. We also plan to initiate the Phase I trial that ALN-HSD for NASH, having now filed the CCA for that program.

And our partner Regeneron plans to initiate the Phase I study of vutrisiran in combination with poelimab having now filed the CCA for that study. We also hope that you will join us for our remaining RNAi roundtable focused on lumasiran, the vutrisiran and our TCR program later in August and September.

Let me now turn it back to Christine to coordinate for our Q&A session. Christine..

Thank you, Yvonne. I just wanted to quickly acknowledge the sound issue with Barry’s prepared remarks, there were some storms that are rolling through his area that impacted the audio quality and we will plan to have Barry rerecord his remarks for the replay of this call.

So Operator, let’s now open the call for questions to those out there and 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. [Operator Instructions] We will now take our first question from Paul Matteis from Stifel. Please go ahead. Your line is open..

Great. Thanks so much. And congrats, Barry. You are definitely going to be missed and Yvonne, congratulations to you as well. I guess, just a couple of quick commercial things. So on the dynamics that impacted on patisran this quarter, you grew patients on drug, but revenues were down.

As you think about the inventory net price, as you expand globally and compliance in the second half, given the pandemic, can you just help us understand how these variables are looking maybe in July and, and what you expect later this year, and then just on the commercial transition, it would be helpful if you could comment on your competence at this more disruptive GIVLAARI launch.

This is obviously a launch that requires a lot of blocking and tackling and finding patients, and you are really in the midst of the ramp up. So how do you kind of manage that the transition in the midst of that? Thanks so much..

Yes. Paul thanks. Great question. So let’s start Jeff with you and then maybe Andy or if you can comment as well on some of them emerging Q3 dynamics in our conference there. So Jeff, do you want to start..

Yes. Sure. I think Barry made a couple of comments in his prepared remarks that we did start to see some encouraging signs towards the end of the second into the third quarter notably on genetic testing. [indiscernible] we saw recovery rates that were close to what they were prior to the pandemic setting in.

I think we are also seeing improvements in adherence, which was the major headwind that we saw in the earlier part of the quarter in the US. And then lastly, I think there was a question about stocking and there were at the lower end of the range.

So our distribution partners contractually hold between one and three weeks and we are at one and a half weeks right now. So there could be some additional build in the second half of the year..

Great. And Andy do you want to comment a little bit further on the dynamics here as we entered the third quarter..

Sure and Paul as you mentioned here, even a midst the Mitch healthcare shutdown in the US we were able to increase the patients on ONPATTRO. It was the adherence, which was the main driver of the demand impact as Jeff just mentioned as well.

And in June and July, we have seen dramatic progress in both the resumption of patient flows to the healthcare system and the [indiscernible] volumes and other things we metrics as well as the adherence rates, improving across all the sites of care..

Yes.

And I would just add on ONPATTRO that, for example, Paul, you know, PYP scans is an important way that patients get diagnosed with this disease and if they have polyneuropathy, then they become appropriate patients for ONPATTRO and our July PYP scans were comparable to what we saw in January, for example, this is what things that we can track across the country.

So that is a good sign. But let’s turn to the GIVLAARI question. Barry, do you want to comment a little bit more on the GIVLAARI question in terms of our confidence in the second half of the launch given the ebbs and flows of the pandemic..

Absolutely. Yes. So, Paul, great question on GIVLAARI. You know, I will remind you that in these kinds of rare diseases where diagnosis rates are very low, because physicians aren’t really looking. Patients come from three different buckets. They come from patient transition from EDP, patients known sites and the brand new newly diagnosed patients.

And as we mentioned, at the beginning of the pandemic, we were highly prepared with digitization virtualization already for GIVLAARI given the diverse prescriber base and the fact that patients can be anywhere in the world.

So we in fact have done virtual launches and we have done very well and have not been really detriment, as we have seen based upon results to our success in getting to healthcare providers and educating them reaching out to patient advocacy groups and patients who are prescribed to access new payers. So all clearly have been going very well.

I guess the other comment I will have is the fact that the healthcare providers now due to the COVID situation are also being forced to get online is actually aided the strategy we have had the digital virtual interactions, because now they are more used to it, they are willing to do it and you’ve had really remarkable outcomes in secret programs, the numbers that you had never seen before when they were local in life.

So, while not getting as good as in person, we have really taken advantage to help patients as best we can during this time..

And I will just one last point on GIVLAARI, which is that we do benefit from a drug that has been proven in clinical studies to decrease hospitalizations related to the annualized attack rate reductions that we see. And that that obviously is good in this current circumstance.

So, Paul does that answer your questions?.

Absolutely. Yes it does. Thanks so much for the added color. I appreciate it..

Thank you..

We will now take our next question from Alicia Young from Cantor. Please go ahead. Your line is open..

Hey guys, thanks for taking my question and congrats Barry and Yvonne we look forward to working with you further, it is always a pleasure. So, I just wanted to ask a little bit about kind of a little bit [indiscernible] here.

How you are thinking about the hemophilia landscape into patisran, and how that is positioned in light of what is going on with gene therapy. I know it is a Sanofi product but I just wanted to kind of get your perspective on that since we are getting relatively close to data? Thank you..

Yes, absolutely. Let me make some comments and then I would welcome and welcome Akshay’s perspectives as well. Obviously the hemophilia market is a multi-product, multi-company market there are many players already, there are over a dozen products that are available for patients with hemophilia A or B with and without inhibitors, which is great.

You know patisran really fits in as the only once monthly subcutaneous medicine that shows ABR levels annualized bleeding levels that are a round one. And that really is a unique positioning for the product in our view, and Sanofi’s view.

And so if that holds up in the Phase III trials and the safety continues to hold up, as was encouragingly shown in their updated open label study. This could be a very important medicine in that landscape and offer competitive profile compared to and [indiscernible] as the potentially only really effective once monthly subcutaneous medicine.

Akshay, do you want to comment any further on that?.

Yes, it is a very interesting and dynamic time in the hemophilia landscape and lead better the gene therapy, but I think, at premium with all of these approaches of course is safety, this is a very delicate population, where there have been significant safety events in the past, and I think both would [indiscernible] gene therapy this would continue to be a discussion.

Obviously, they’ve completed their Phase III studies.

And the primary in Phase III studies with the - a therapy, but durability of effects with gene therapy, the long-term safety, including the potential for oncogenesis, this remains a question in our opinion, there have been recent - studies that showed that very late long-term, cancer events can occur with gene therapy hemophilia.

But look, it is a good time for patients to have more therapies come on, as John said, a therapy for hemophilia A and B that is convenient and safe once a month sub Q would obviously be very attractive when we think the vutrisiran can offer that both for on-demand peripheral access and inhibitor patients, and even beyond that in the other bleeding disorders.

So perhaps a unique and differentiated offering and we eagerly await Phase III data..

Yes, early next year, as you said Alethia, which is exciting.

Does that answer your question?.

Yes. Very helpful. Thank you, guys..

Alright. Thank you..

We will now move to our next question from Anupam Rama from J.P. Morgan. Please go ahead. Your line is open..

Hey, guys. Thanks so much for taking the question. And for APOLLO-B what is the primary end point analysis, there is a 12-month extension in the trial.

Will you be continuing that on a blinded basis, so that you will be able to get sort of outcome data in the Placebo controlled manner, or will you really be relying on vutrisiran to get some of those outcomes beyond 12-month and or Barry you know always in-line with the [indiscernible]..

Yes. Alright, so, Akshay, I think the APOLLO-B question is right up your alley..

Yes.

The principal focus for APOLLO-B as you said, Anupam, is on the 12-month analysis and vutrisiran will be coming in close succession after that read of the 12-month read out for patisiran in APOLLO-B and circles, that will form the principle demonstration of our [indiscernible] approaches and what they can do in terms of morbidity and mortality in the long-term..

Yes, I will just add, obviously, we are capturing mortality and see the hospitalization data in APOLLO-B Anupam. So we will obviously collect those data and see with a report, one year’s worth of treatment is probably not in the powers to show something there, but we will certainly be collecting those data.

And those type of data may inform how we think about the interim analysis for HELIOS-B, which is our vutrisiran study. And that is obviously going to be a nice, helpful set of data as we consider what that IA looks like..

Thanks for taking the question..

Thanks Anupam..

We will now take our next question from Tazeen Ahmad from Bank of America. Please go ahead. Your line is open..

Hi, good morning, guys. Thanks for taking my questions. A quick one.

As it relates to ONPATTRO sales with Ex-US now higher than the US, did you relate that at least near-term as an impact from COVID? And do you expect that trend to continue for the duration of COVID as a meaningful factor, at least here in the US? And then I do want to get your early thoughts about what Regeneron opting in for your ALN-APP program.

Your plan on starting development of that program, can you give us a little bit of color on what you think the opportunity could be in IGA neuropathy..

Okay. So let me start with the second half, which the second part of the question which I think was mixed to different programs in it Tazeen, and then Barry you should answer the first question..

Yes, sorry, yes..

Yes. Regarding APP. That is our amyloid precursor protein program that they opted into and that is going to that is on track to have a filed IND or CTA in middle 2021. That will be our first CNS program.

So the opted into that program that is different than [indiscernible] which is our C5 program, which they already have opted into this part of our original agreement with them, which is currently in a Phase II study in IGA nephropathy, what they are also doing is they are doing combination studies with some [indiscernible] which is their anti C5 antibody to get the benefit of a infrequent subcutaneously delivered treatment for many compliment mediated diseases PNH and [indiscernible] amongst others.

So that is, that is that part of the question Tazeen. Barry, do you want to answer the first one on US rest of world on ONPATTRO and how we see that going forward..

Absolutely just provided the call. We have upped our guidance, reflecting our belief sets that we are in recovery phase. So in particular, we believe that we are going to continue to see growth in the U S I will remind you this as a neutral market of the US is really a pure patient find market right now.

And its patients are again flowing through the healthcare systems. We are finding the proportion of patients that are registered with polyneuropathies. So we continue to see growth in US. In terms of rest of the world, many countries continued benefits by patients on site, as well as finding new patients. And then we are opening new territory.

So every time a country opens we benefit by EAPs in those countries and patients down the site. So again, we see growth in all regions around the world..

Yes. And Jeff, anything you’d want to add to that or Andy..

Nothing for me to add..

Andy?.

Agreed. I think Berry got it..

I think the increasing use of combination therapy in the US that I think is a very interesting one for us. I think we are beginning to see physicians appreciate the profile on ONPATTRO in this mixed population phenotype.

So isn’t that something to keep an eye on as well?.

Yes, absolutely..

Okay. I’m sorry, I mangled my second question.

I did want to ask why APP would start development Ex-US?.

There is no plan to do it in Ex-US necessarily Tazeen. We often start studies in different parts of the world, including sometimes in the US, so there is no - it is a plan to do an Ex-US per se..

Okay..

Okay. Thank you..

We will now take our next question from Maury Raycroft from Jefferies. Please go ahead. Your line is open..

Hi everyone. Good morning and congrats on the progress and thanks for taking my question. First one is just on Apollo B. So, when you open your floor to the endpoint in the Phase III Apollo A, that ONPATTRO or shared activity in cardio mass in that types.

I’m wondering if you are collecting data from the commercial patient ONPATTRO that provides read through to Apollo B and when you present those data at some point and can you comment on some key base point similarity between patients using drug commercial this is low enrollment Apollo B..

Yes. That is a great question. I’m going to maybe provide some context maybe, Akshay you can comment as well and Berry. We are obviously in the original Apollo study, Apollo A as you said.

There were very encouraging exploratory data generated in patients with cardiomyopathy pre-specified cardiomyopathy that are hypothesis generating, they form the foundation of our confidence in Apollo B.

And I think to your point, there has been some interesting data that have been generated investigationally in the field in patients that have polyneuropathy, but also with cardiomyopathy where patisiran is being used specifically looking at cardiac amyloid imaging and some of the data that have been, in one case published by a Dutch Group.

And then the national amyloidosis center in the UK is presented some data are really quite encouraging and give us give us encouragement for Apollo B, of course, we will await the results of that study before we can comment definitively on the patisiran activity in cardiac patients. Akshay, anything to add to that from your perspective..

No, I think you have covered it John..

Yes, great. And I will just add that, they are all always investigational studies that are done by individual centers or groups of physicians that that might explore these types of features. And that is something which does occur out there.

Barry, anything else to add on the commercial side?.

No. I think you covered as well..

Terrific. Thank you.

Maury does that answer your question?.

Yes it does and it is very helpful. And just a quick follow-up for AGT. So, when your top line data you guys recorded on 48 patients for that and you are going to have additional data at the end of this year.

I think you can enroll up to 184 for that study, just wondering if you can comment more on how many patients you plan on enrolling, and I think how much cold data could you see at the end of the year?.

Yes, I mean, we a lot of these things where studies are engineered with optional cohorts that allow us to add additional subjects patients in this case to the study design. I think we still haven’t decided at what point we will have completed that study.

But we are still answering important questions, including potentially on combination with other antihypertensive meds to explore that in the study, both from activity and safety perspective. Akshay, anything else to add to that.

No, I think you covered that. Yep..

Great.

Does that help Maury?.

Yes that helps. Thanks for taking my questions..

Thanks Maury..

And we will now move to our next question from Ritu Baral from Cowen. Please go ahead. Your line is open..

Hi, guys, thanks for taking the question. Barry, great to work with you over the years and best of luck and Yvonne. Really. Congratulations. Looking forward to working with you more.

I would like to ask about trends in home administration for ONPATTRO, I guess is there any difference between what you are seeing in the US and Europe and what is being done in the US as far as allowances for COVID and, and reimbursements and uptake is something we see - that will be better going forward to stabilizing US?.

It is a great question.

Barry, do you want to give the global view and then maybe, and Andy you could add additional color or the US dynamics on that?.

Yes, absolutely. And great question; home infusion has been critical care of site that you utilize though this pandemic. So, if you see a reason on home use was about 17%, pre-pandemic and it is doubled to about 35% in the age of pandemic. France.

In fact, these cohort patients confusion, and one of the sites reported infectivity with COVID is very important. And that comment you have the US has also doubled from 9% to about 20.

And then globally, in countries that allow them to the US, Brazil, Canada, most of the European countries, we have effectively been able to move patients to home infusions.

There are times where a dose is delayed or a dose skip in that transition, but as we, as we have now got the capabilities down, most of the patients are moving without dose interruption -. And it has been a very important [Technical difficulty]..

And is that still growing.

Is that still growing like the home infusion rate?.

Yes. And maybe I can touch on the US without specifically and the yes, as Barry mentioned, we doubled it from nine to 20, essentially from the end of 2019 to currently. And we expect that to continue to grow. Our teams have been in sight of care optimization mode since the onset of COVID.

I mean that both homecare as well as more local infusion centers if they were going to larger institutions. So we expect our patients and physicians to continue to take advantage of home care..

And could you just got to reimbursement [indiscernible] question for that, yes..

So just in terms of growth, as the pandemic ebbs and flows, both the United States and other countries we have seen patients move to home infusion. And then when possible back to a local infusion center. Keep in mind patients really like getting out of the house and social aspect of infusion center [Technical difficulty] infusion centers..

Right, thanks Barry.

Ritu, does that answer your question?.

Yes. And I just wanted to - could you just review reimbursements like -..

Reimbursement out of it?.

Yes..

Yes.

Do you want to handle that, Andy?.

Yes, certainly. So the reimbursement clearly on the commercial side of our population is very straightforward. And we have many patients, they are taking advantage of it. But we also know right that CMS released in late June, regulation that allowed a temporary reimbursement scheme for Medicare Part B patients.

And we also have many hospitals that are beginning to take advantage of that. And that is an area where we expect to see more growth and utilization of that going forward..

Does that answers your question Ritu?.

Yes. Thank you so much..

Great..

We will now move to our next question from David Lebowitz from Morgan Stanley. Please go ahead. Your line is open..

Thank you very much for taking my question. Given your experience thus far, GIVLAARI.

Have you I guess made any decisions on lumasiran, what you might want to keep and what you might want to modify as far as the launch given the similarities of the markets?.

Yes, great, great question. Let me make some initial comments and then Barry, you should comment as well. I mean, obviously lumasiran like GIVLAARI is addressing a very devastating disease.

That is an ultra rare orphan population based on prevalence, as with GIVLAARI, there are 100 diagnosis rates and PH1 are also well known and so there is a need for patient finding work. We have a commitment, as you know, David to be focused on the value that our medicines deliver.

And we have been very successful in that approach proactively engaging with payers, forming value based agreements.

And that effort will occur with all medicines in our pipeline, including lumasiran and so as we begin to get ready for launch and get ready for this important new medicine to come in the playbook that we develop for ONPATTRO, the playbook that we have been executing on for GIVLAARI is one that we will absolutely be using for lumasiran.

Of course, we will be leveraging, importantly leveraging the existing infrastructure that we have built now globally for the company. Barry, anything to add to that..

The only color, I would add is that we have gotten very, very good now as to digital virtual inside of care optimization, that was necessary to COVID, [Technical Difficulty] launch of a disease like PH1 where again, the diagnosis rates 50%, there are 50% of patients out there are home diagnosed to being able to reach them to virtual meet means to be highly advantageous..

Yes. Thanks Barry.

David does that answer your question?.

Fine, yes. Thank you for taking my questions..

Okay. thank you..

We will now move to our next question from Vincent Chen from Bernstein. Please go ahead. Your line is open..

Thank you very much for taking the question. Two quick ones, one conversely oriented and one the R&D side. First for GIVLAARI we realize that you are not going to provide any guidance. I’m curious what you are seeing as far as the trajectory of start forms coming out Q2 and going into Q3.

I know incremental start from slowed in Q2 relative to Q1, I imagine some of these is because you have initial blow of patients in Q1 somebody who is impacted from COVID but adversely impact from Q2, just trying to get a sense for reasonable near-term run rate might look like between those two.

And then second on the R&D side, a quick one on ALN-APP IND filing. In terms of watching very closely for moving to the DNS delivery, which could open up a range of very large and higher net engagement, it seems like taken some time. What are the gaiting factors on the ALN-APP, R&D filings, what less done before you can enter human trials..

Yes, those are great questions. Let me start with the first one. Akshay you will get the second one just a minute. But your question on GIVLAARI, I mean, we are, we are extremely pleased with the performance that we saw in Q2 even though we were going through the pandemic.

And keep in mind Vincent that the star forms that we saw in Q1 of course, were benefited greatly by patients that were either in the US, EAP or that were known to side sort of that initial bolus, if you will.

But we do expect growth from that point and we are saying continue to grow in the US About 25% of our patients in the US are also coming outside of our patient hub. And therefore they are not on the star form metric, if you will. And that accounts for the over a hundred patients that we believe are now on GIVLAARI commercial treatment.

Now that includes a small part of the US. Whereas we said, in our prepared remarks we are now going to stop providing star for metrics for GIVLAARI just like we did with ONPATTRO last year, because we now have a global source of patients, not just the US alone.

And we still have a significant number of patients that are coming outside of our patient hub. But you will see the growth in our total patient number quarter-by-quarter GIVLAARI, and we are optimistic with that growth in the US and also in other markets around the world.

Now Europe of course has now been launched in Germany and the name patient sales or many countries. So I think that we don’t need to say anything more about GIVLAARI. Do you want to know Akshay talk about APP and what is between now and our filing..

Sure, yes I mean. We are delighted with the progress Vincent, it is about a year since we singed the [indiscernible] next year is exciting and we think represents the progress. What we have to do now is simply complete the toxicology and CNC packages. We have already had the good engagement with regulators.

And so we are looking forward to defining that IND in due course in mid 2021..

Does that help Vincent?.

Yes. Very helpful. Thank you very much..

Alright. Thank you..

And will now move to our next question from Salveen Richter from Goldman Sachs. Please go ahead. Your line is open..

Good morning. Thanks for taking my question. In the context of competitive dynamics in the TNH.

How you are thinking about your upcoming study looking into setting what would be meaningful to differentiated share or where you sit in between paradigm and just a comment on based on your work in a certain part of tissues where you feel most optimistic?.

Great. Thanks Salveen. Well, let me start and then Akshay you can comment as well. On the first question with the combo work that Regeneron is leading with some vutrisiran and pozelimab. I mean, look there is no Sub cue alternatives that is currently approved today.

This is an opportunity to having a Sub cue treatment for intermediate diseases with a very infrequent dose regimen.

Even with potential for formulation of the two, of the two drugs, we feel very encouraged by data that that from both animal studies, but even from human studies, that would suggest that combination of an RNAi based approach with an antibody approach would provide very significant protection against the complement pathway with an infrequent Sub cue dose regimen.

So, I will stop here. Akshay Maybe you comment on that, but also on our extrahepatic work and where we are most confident these days..

Yes, so certainly, in frequent presentation, I also think that we have the opportunity to have the most complete blockade of the continent system and hopefully the best efficacy profile now.

The current drugs already have good efficacy, but we would like to see no breakthroughs for these patients and for them to be able to maintain their hemoglobin levels without need for any transfusion at all. And we think complete blockade in the form of a combination products could offer that.

Looking beyond TNH and at the extrahepatic pipeline, we just touched on the CNS. It is indeed exciting. But within a year of announcing that deal with Regeneron, CNS and ocular cloud, we have now announced that we will be finding IND next shift from nervous systems.

That will be the first of many, we think we have very exciting phase and also the compartment as well. And most recently, of course, we share data on long delivery. So, I can’t really say one is my favorite.

But that is a recurring theme for us over the years has been that when we have had strong, replicable data in animal systems, first in rodents, and then in the non-human primate, that then has invariably led to translation into not in the human setting.

And so with all three compartments, as designed to hit the clinic, we are looking forward to replicating successes of our work in the liver with evidence of knockdown clinical efficacy and safety in the brain, in the eye, in the lung et cetera.

And we are not going to stop there, because there are many other efforts ongoing for other compartments, which we will get to in due course. So, that is just a little bit on the extrahepatic thinking..

I would just add to that part that what is exciting about the CNS opportunity, of course, is that there are many neurodegenerative diseases that are gain of function polyneuropathy, with genetic validation. And we have shown in human primates, some exciting data that we fully expect will replicate in the human setting based on our past experiences.

And what is really key there is a durability that we see, that is going to be important because with infrequently administered drugs, being able to have significant knockdown of the pathogenic protein within frequent dose administration is going to be something which is highly differentiated.

Not only for the EAP program that will be the first one to go but the Huntington’s program that will come shortly thereafter, programs that were obviously advancing in diseases like ALS and Parkinson’s and Alzheimer’s, et cetera.

So this is really going to be an exciting story for the company and we do expect starting in 2021 to have one to two INDs per year that are coming out of that CNS Ocular Regeneron pipeline together with them. So it is an exciting new frontier for the company..

Great. Thank you..

Thanks Salveen..

And we will now take our next question from Gena Wang from Barclays. Please go ahead. Your line is open..

Thank you for taking my questions. And of course very agree working with you past many, many years. My best wishes to your next journey. Yvonne just want to looking forward to working with you more. I have two questions.

One is ONPATTRO just wondering if you can share how much revenue is contributed from Japan, and for vutrisiran when the COVID-19 impact on collecting the data?.

Great, great questions. So let’s, Jeff, why don’t you answer the first question and then Akshay you can answer the HELIOS-A question, secondly. Go ahead, Jeff..

Yes. If I heard the question correctly. The question was about Japanese contributions ONPATTRO revenue in the quarter, we don’t break out the detail by countries, Gena.

But Japan was a meaningful contributor to the growth that we saw outside the US in the quarter and we highlighted in the prepared remarks that Japan now has become the second largest market for ONPATTRO on a dollar sales basis based on the Q2 results..

And Akshay, do you want to comment a little on the vutrisiran, management of the study?.

Yes, I mean, both for vutrisiran and vutrisiran in the respective Cardiomyopathy study, maintaining study integrity officers been at the priority during this COVID period, and we have used a variety of approaches successfully telemedicine where physicians and priced off speak to patients over the phone and other means, we have had home administration of drugs.

And there is of course, the ability to take blood samples at home and finally for key visits that required in clinic assessments that we was building a little bit of buffer around the timing of events that don’t have to come in exactly on a given date, there can be a few days or a few weeks before or after, depending on the endpoint.

So using these different means. It is not been trivial but we have certainly maintained study integrity, and we are pleased with that. And we are also pleased with the fact that the things working up as we have seen on the commercial side, we are seeing very good pickup in enrollment well in these studies..

Yes and I would just like to, because I think Gena your question was also focused on HELIOS A, which of course was completed. Yes, completed enrollment, we are still on track for early 2021 data from that.

And we have obviously all the things that are actually course have been critical in terms of making sure that we have maintained it integrity and no missed doses or minimal miss doses during the course of that study. So that is what applies to, HELIOS A..

Thank you..

Great. Thanks Gena..

We will now move to our next question from Alan Carr from Needham and Company. Please go ahead. Your line is open..

Hi, thanks for taking questions and congratulations Barry on the seat. So you mentioned, that you have submitted IND for the [indiscernible] NASH and I wonder if you can give us any update on your new plans and strategy how differentiated in total..

Great. Thanks Alan.

So Akshay that question was on ALA-HSD and NASH and or plans, do you want to comment future?.

Yes. Alan, we are excited to follow the IND CTA and get going with this program. We are excited about the target because it is a genetically validated target and uniquely So I think in the NASH landscape compared to many of the other targets that have been addressed to date, most of which have fallen short, unfortunately.

And HSB17B13 seems to be a gateway to the later consequences of the accumulation of hepatic fat. So 50% knockdown because know heterozygous loss of function protects people from NASH. We think even 50% knockdown should be sufficient that we know from our liver programs we can do a lot better than that.

And we know we can achieve that 50% from animal work without a candidate. So is great to get this to the clinic. Phase I will be all about safety and we will collect a number of exploratory biomarkers.

HSB17B13 is not a target that is secreted into the circulation, but we have some very good extraordinary biomarkers that will help assess the target engagement.

And then from that, you will go into, into Phase II and that is where we will have a dose and regimen selected, which I imagine will be a load those given rather infrequently given the protocol of the drug, we are seeing animals once every three months or six months or so.

And that is where we will test the key hypothesis of preventing progression to NASH itself. That those details have to come from that way, you know, we have to focus on the Phase I..

Okay. That is all my question..

Thanks Alan..

We will now take our next question from Mani Foroohar from SVB Leerink. Please go ahead. Your line is open..

Thanks for taking my question and congrats Barry, Yvonne as well. Although with Barry gone I guess Yvonne you are going to be in much better [indiscernible] bout ONPATTRO obviously there was a little bit of a decline in terms of patient adherence, which not surprising.

I know the [indiscernible] assets is very unique it has pharmacokinetics or is there other drugs, but is there an avenue to any catch up dosing patients potentially getting back temporarily on an IV dosing schedule that could be a little more frequent than what is labeled? I.e., could be recapture something that loss revenue, what do you think people will end up back on the label dose on frequency.

And then secondarily in thinking about HELIOS-B, you talked about potential inference.

And that would look like, how do you think about timing first to make a decision on whether or not to take that voluntary interim? And on what time horizon, might you be just telling us, hey, we are going to take an interim or not, in terms of just giving us some sense of when you should expect that event?.

Yes, those are great questions. Maybe on the first question Mani, I mean your question makes sense, of course. But I think that is our expectation that patients would stay on label and due to her weekly dosing, we have no reason to believe that that would change whatsoever. And we have heard nothing about that in the field.

So, but I think the good news is that adherence rates, with some miss doses that occurred in Q2, are showing great strength as we enter Q3, and we don’t expect to see any significant impact, like was expect we experienced during the pandemic phase. So, I think that is really behind us at this point in time.

Andy do you want to comment any further on that, I think I covered it. But you might have some other perspective..

No, John, you covered it. Right. Everything we are hearing is a resumption to the original schedule for any folks who were paused for whatever reason..

Yes. And then your second question on HELIOS-B. Also, one that makes a lot of sense. But very specifically at HELIOS-B. We will do an interim analysis, we made the commitment to do that. Now we have left it open with the agency on exactly how that will be designed. And we are not we are not going to come against our timing.

And I will just say again, that one of the benefits of the APOLLO-B is that as we read our data from that study, it will inform how we should think about the interim analysis for HELIOS-B specifically. Akshay, do you have anything also to add to that..

No, nothing to add..

Thanks guys..

Thank you..

We will now take our final question from Navin Jacob from UBS. Please go ahead. Your line is open..

hi everyone. Thanks for taking the question. This is [indiscernible] on for Navin Jacob. Just on ONPATTRO, Yvonne mentioned combination therapy and you previously stated that just on both - ONPATTRO.

Can you give us an update, what percentage patients on both now and can tell if anything on the outcomes of these patients versus patients on just monotherapy. And then just on pricing, just mentioned some reduction in growth summit. How should we think about pricing trends as the year goes on? Thanks very much..

Okay, so let me start on the combination use of common uses that is occurring out there, as we hear from the marketplace, these are use words to specific data being generated, we are just aware that patients that have a mixed phenotype, or the dot polyneuropathy, are receding on Castro.

And in some cases, those patients are also on a future stabilizer. So, we are just aware of that. And we have market research that says that it is somewhere in the range of 15% to 30% now and it could double by the end of the year.

We just recently published some data on combination use with from our previous Phase II open label study, and that published paper showed that the combination was safe and the level of [indiscernible] knockdown was as good as monotherapy. But there was no formal assessment of - it was empowered to show anything on the efficacy side.

So I don’t think anything can be concluded at this point in time about any improved activity. But Andy do you want to comment a little bit further on dynamic on contaminant use that we are seeing in the marketplace. I’m sorry, Andy just one thing is I want to highlight also that this is really a US phenomenon.

We don’t see this in the rest of the world. But Andy go ahead..

That is right. Yes, happy to. So since the fourth quarter of 2019. In the US, we have been seeing growing evidence of reimbursement from ONPATTRO were used concomitantly with TTR stabilizer products, which at the end of the day is a positive for patients with multiple manifestations of the disease.

And barring any unforeseen changes to the COVID or other we expect the concomitant us to continue to increase in the US over time for patients whose disease manifestations include polyneuropathy. And as John said, right outside of the US is more of a switch dynamic..

Right.

And then your pricing question, Jeff, do you want to handle that?.

Yes, sure. The comment on ONPATTRO for Q2 was that there was a very modest increase in gross to nuts relative to Q1, which created a slight headwind and growth quarter-to-quarter. Now there is variability and growth for next quarter-to-quarter we have talked about that on the last several calls.

It is just based on the way the accounting works and the estimates and the truth of those estimates, but we are very confident that the full-year gross the nets from ONPATTRO will be very consistent with what we experienced in 2019. And the expectation is mid 20s for the year..

Right.

Does that answer your questions?.

Yes. Thanks very much..

Good. Okay. So with that, we are going to close our call. Thank everyone for joining us on the call and again for all of our employees for their dedication and their hard work. Of course, Barry, we wish you all the best in your next chapter and Yvonne, so excited for you in this expanded role at Alnylam.

So with that we look forward to updating you in future calls on our progress. And please stay safe and please stay healthy. Bye, Bye now..

Bye everyone..

Ladies and gentlemen, this concludes today’s call. Thank you for your participation. You may now disconnect..