Alnylam Pharmaceuticals - Earnings Call - Q2 2020
August 6, 2020
Transcript
Operator (participant)
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. Please go ahead.
Christine Lindenboom (Head of Investor Relations)
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 U.S. 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 Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined in slide two, 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 preclinical 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 purpose of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our view only as of the date of this recording. It should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to John.
John Maraganore (CEO)
Thanks, Christine, and thank you, everyone, for joining the call today. Let me start by expressing Alnylam's support for Black Lives Matter and our support for the efforts to end systemic racism in our country. At Alnylam, we stand against all forms of discrimination, and in our core, we believe in justice, equity, and inclusion. We stand in support of peaceful protests aimed at achieving real and sustainable change. Enough is enough, and it's time to finally cure the refractory scourge of hate. I'd 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 nation 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. With that, let's now turn to our 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, a recovery phase in Q3, and a new normal starting in Q4. While the pandemic continues or even worsens in many states in the U.S., 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 a repeat shutdown of healthcare systems like what was seen in Q2, especially in the April-May timeframe. Our confidence in the second half is reflected in an upward revision in our patisiran revenue guidance range.
Overall, we're 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're 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 arrangement 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 financings. Now, 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 the 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 role of President and Chief Operating Officer on October 1st.
We believe Yvonne is uniquely suited for 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 to 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'd like to finish with my perspective on the big picture for 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 a robust and organic product engine for sustainable innovation.
Without a doubt, we're 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 now turn the call over to Barry for one last time, Barry, to review our commercial progress and medical affairs activities in more detail. Barry, take it away.
Barry Greene (President)
Thanks, John, and good morning, everyone. Before I provide the quarterly highlights, I'd like to make some brief remarks about my planned transition from Alnylam. First, congratulations again to Yvonne Greenstreet. She is a remarkable person and well deserves the President and CEO role. I know that Yvonne will make sure that Alnylam continues to be a company doing the right things and focusing on patients and counting on it. As for me, it's been a tremendous privilege to serve as President of Alnylam for such a long period of time. I'm very proud of what we've been able to accomplish during my 17 years, having built a global, fully integrated multi-product company that is recognized for excellence in R&D and recently for our commercial strength as well. My decision to transition is based on the desire to pursue new leadership opportunities in the next chapter of my career.
I'm fully confident Alnylam will achieve its ambitious goals with quality and excellence with the great team we have in place. I'll continue to support Alnylam throughout this transition and have no doubts about the company's future prospects as a top-tier biopharmaceutical company. For Onpattro, we achieved $66.5 million in global net product revenues. As of June 30th, over 1,050 patients were on commercial Onpattro treatment worldwide, representing an increase of over 100 patients from 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 had an impact on our business in the second quarter, with patient demand decreasing due to reduced adherence, as some patients skipped doses or experienced dose delays while moving to new care sites.
Also, as anticipated, we saw a pace of new patient initiating therapy slow in the U.S. during the quarter, reduced genetic testing, diagnosis, and patient flow through the healthcare systems. Finally, our U.S. business was also impacted by inventory restocking and an increase in costs during the quarter. Jeff will provide more color on these details later in the call. While our focus today is on Q2, as we enter Q3, we're now seeing what looks like a healthy return of genetic testing and patient flow through the U.S. healthcare system, even in states where COVID-19 cases are rising. In fact, our July Alnylam numbers are nearing the January numbers we saw earlier in the year. A really good sign. In the second quarter, we continue to see great progress in new prescribers.
In the second quarter, 40% of submitted start forms came from new prescribers, with an equal mix of neurologists and cardiologists. In the U.S., we saw continued use of Onpattro with TTR stabilizers in the quarter. We believe this trend will continue to grow as physicians see progression of polyneuropathy on stabilizers and treat the different manifestations of hATTR amyloidosis. Comparing to the rest of the world, we made very positive progress with Onpattro in the second quarter. The rest of the world's sales for Onpattro were $34.2 million, and relative to the U.S., benefited from continued geographic expansions with launches in Spain, Italy, and other countries. In addition, we saw relative strength in our ex-U.S. partners, including Europe and Japan, after their management of the pandemic. As John noted, this is a nice validation of a decision to build a global, fully integrated business.
With today's announcement of achieving pricing and reimbursement agreement in France, we're pleased to report that access has been secured in all priority markets in Western Europe. Notably, our team has secured pricing and reimbursement approval in all major European markets in under two years post-approval by the EMA. This is a much faster rate than most orphaned medicines are able to achieve. Japan was again a country of strength for Onpattro. Japan has now become our second largest country after the US for Onpattro revenue, and we expect continued growth with new patient numbers following Onpattro on stabilizer therapy. On the medical care side, our team remains committed to addressing the challenge of raising disease awareness and improving diagnostics of hATTR amyloidosis, including with Alnylam Act, our third-party genetic screening initiative in the US, Canada, and Brazil.
As of July, over 27,000 samples have been submitted, out of which over 1,600 have tested positive for a pathogenic mutation, which is tracking at our historic 6%-8% positivity rate. These numbers show the testing slowdown in Q2 we mentioned on our last earnings call. The good news is, as I've already marked, those numbers have picked up to near January levels. Moving on to Givlaari, we were really pleased with the progress in our launch, most of which has been done virtually. We achieved $11 million in global net product revenues. We received over 85 start forms 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%-30% of US patients come from outside the start form channel, we'll discontinue providing start form metrics in future quarters, as we did last year for Onpattro. In the US, we observed a broad prescriber mix, including hematologists, gastroenterologists, and other specialties, both in preferred centers of excellence and in the community. Of note, 76% of our Q2 starts were from new writers. Our progress with value-based agreements has been extremely strong, with seven VBAs completed with US payers, and we now have confirmed access for over 75% of covered unit supplies across commercial, Medicaid, and other government payers. We've not experienced any care hindrance with Givlaari to date. We're pleased to see plans adopt medical policies not more restrictive than our labeled indication.
Givlaari recently saw strong initial performance as well, with a successful, and as noted, virtual launch in Germany, as well as named patient sales in other countries, including French cohort ATU program. We've been positively encouraged by the responsiveness of European payers despite the COVID-19 pandemic. Of note, Givlaari received an improvement of medical benefit, or ASMR, score of two in France, concluding that Givlaari offers significant additional therapeutic value. This is an enormous accomplishment since, in context, only two new commercial medicines were granted an ASMR rating of two in 2019. Our medical affairs team is also focused on improving awareness and diagnosis of AHP. Through the Alnylam Act, we can report 937 tests submitted and 92 patients with positive AHP mutations as of mid-July, showing a continued 10% positivity rate.
A notable diagnosis trend emerging is the robust use of urinary PBG tests to inform diagnosis, and we expect patient identification efforts to be meaningfully enhanced by this non-genetic testing method. Of course, we're now also preparing for the potential launch of the lumasiran later this year. Importantly, we'll be leveraging our existing commercial infrastructure for this launch with small additions of resources for field-based teams. When we gain approval, we'll focus more on our specific commercialization of Onpattro and Givlaari, and third RNAi therapeutics we expect to market. In conclusion, the second quarter was challenging due to the pandemic, particularly in the United States, but we did much better than the downside case we anticipated as we entered Q2. The credit here goes to our teams around the world who faced the obstacles head-on to deliver these important medicines to our patients in need.
With that, I'll now turn the call over to Akshay to review our recent R&D and pipeline progress. Akshay?
John Maraganore (CEO)
Akshay, are you on mute?
Akshay Vaishnaw (President of R&D)
All right. Yeah. Good morning, everyone, and thank you, Barry. I should say thank you, Barry, for guiding me, for helping build our company, and most of all, for working so tirelessly to help all the patients we seek to serve. So with that, I'll start with our efforts in ATTR amyloidosis, where we're advancing our two product candidates, patisiran and vutrisiran. While Onpattro is currently approved in multiple markets around the world to treat polyneuropathy associated with hATTR amyloidosis, we're committed to expanding the product's 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 completion of enrollment in 2021. We've seen enrollment pick up over the last month as clinical sites start to open up around the world.
In addition, we're also advancing vutrisiran, an investigational RNAi therapeutic delivered by a quarterly subcutaneous injection that's also in development for the treatment of ATTR amyloidosis. Here, we're 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 is being conducted in inherited and wild-type ATTR amyloidosis patients with cardiomyopathy. As with APOLLO-B, site activation and enrollment in Helios B are now picking up. If Helios B is positive, it could allow for 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 U.S., E.U., and now in Brazil to treat acute hepatic porphyria in adults. Of course, the highlight of Givlaari in the recent period was our Brazilian approval, and we're continuing our geographic expansion for this product with MAA submitted in Switzerland and Israel and plans for 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 through 12 months of treatment, with evidence for potentially improved efficacy over time. In addition, we're proud to have published pivotal results from the ENVISION phase III study in the New England Journal of Medicine. This is our ninth paper on RNAi therapeutics published in the journal.
I'll now turn to recent progress with lumasiran, an investigational RNAi therapeutic that we're 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 Illuminate A, which demonstrated that lumasiran significantly reduced urinary oxalate levels, the cause of progressive kidney failure in PH1. In addition, lumasiran showed an 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 to report top-line results soon in mid-2020. The Illuminate C study in severe PH1 continues to enroll and has been proceeding well even during the pandemic. We completed our NDA and MAA submissions in the second quarter. The FDA granted priority review for the lumasiran and has set an action date of December 3, 2020.
EMA has granted accelerated assessment of the MAA. As you know, we have two additional late-stage programs that are in development with partners. This includes inclisaran in the development for hypercholesterolemia partnered with Novartis, which is currently under review for approval in the U.S. and EU. Both NDA and MAA findings have been accepted, and Novartis expects initial approval in the U.S. in late 2020. Novartis has indicated that they remain on track for approval this year with a December action date in the U.S. Our late-stage pipeline also includes fitusiran in development for hemophilia A or B with or without inhibitors partnered with Sanofi. Sanofi has recently disclosed that two of the three Atlas phase III studies have completed enrollment and that they remain on track to report top-line Atlas phase III data in the first half of 2021.
Sanofi also presented new positive results from an interim analysis of the phase II OLE study of fitusiran showing impressive reductions in the annualized bleeding rate with encouraging safety. Now, in addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. A highlight for the quarter was the positive top-line results from our ALN-AGT phase I study in patients with hypertension. Specifically, ALN-AGT demonstrated an over 90% knockdown of angiotensinogen and a greater than 10 mL Hg lowering systolic blood pressure with a durability that's caused a quarterly or even less frequent subcutaneous dosing regimen. We're also encouraged by the tolerability profile for ALN-AGT. We now look forward to presenting more complete data from the ongoing phase I study at a scientific meeting in the second half, assuming abstract acceptance.
We're very excited about the potential for ALN-AGT to reimagine the treatment of hypertension with tonic-controlled blood pressure that we believe could result in important benefit for patients. Our next clinical program is ALN-HSD, an investigational RNAi therapeutic for the treatment of NASH, for which we recently filed a CTA. This program is being advanced in collaboration with Regeneron. We're also making strong progress on our many RNAi therapeutic opportunities beyond the liver. For our COVID-19 RNAi therapeutic collaboration with Vir, we selected a development candidate, ALN-COV or VIR-2703, with potent and highly cross-reactive activity towards SARS-CoV-2, the virus that causes COVID-19. We continue to expect an IND filing around year-end 2020. We're also pleased to announce today that Regeneron has elected to opt in to the ALN-APP program.
We aim to get an IND filed for ALN-APP in mid-2021, and this is expected to be our first CNS program to enter clinical development. With that, let me now turn it over to Jeff to review our financial results. Jeff?
Jeff Poulton (CFO)
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 Onpattro and Givlaari. Turning to our results first for Onpattro, we generated $66.5 million in global net Onpattro revenue for the quarter, which was impacted by the pandemic, particularly in the U.S., with global growth being flat versus the first quarter of 2020 and a 74% increase compared with Q2 2019.
U.S. growth decreased 13% during the quarter compared with Q1 and was primarily impacted by the following: a 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, with ending inventory now at one and a 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 Onpattro in 2020. In our international markets, performance was very strong in spite of the pandemic, with growth of 16% versus Q1.
Growth in Europe was highlighted by strength in 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 U.S. 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 in global net revenue in the quarter, representing over 100% growth compared to the first quarter.
This growth was driven by ongoing success of the U.S. 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 named patient sales in other countries, including France. Our combined product sales for Onpattro and Givlaari were $77.5 million 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 manufacturer. 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 from license fees related to the execution of our collaboration agreement with Regeneron, as well as a decrease in expenses associated with material 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 and initial launch preparation activities for 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 in operating expenses. We remain confident that 2019 represents our peak non-GAAP operating loss year, as we expect the trend of strong top-line growth and moderate growth in operating expenses will continue for the balance of the year.
We ended 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 inclisaran royalties and issuance of common stock to Blackstone. Finally, turning to our financial guidance, we believe our results for the second quarter demonstrate the strength of our commercial teams in challenging circumstances. As a result of the strong commercial performance for 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 for Onpattro with an increase in the midpoint of our guidance as we narrow the range from $270 million-$300 million to $280 million-$300 million. Guidance range for combined non-GAAP R&D and SG&A expenses, as well as our guidance for net revenue from 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 with Blackstone, adding up to $2 billion in cash, secures Alnylam's bridge towards a self-sustainable financial profile without the need for future equity financings. And with that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne?
Yvonne Greenstreet (COO)
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 Onpattro and Givlaari, and we're looking forward to our Givlaari launch in Brazil and an upcoming NDA filing for Givlaari in Japan. We're also expecting two additional regulatory approvals by the end of the year for lumasiran and inclisaran. We plan to continue enrollment in our ATTR cardiomyopathy studies, specifically APOLLO-B with patisiran and Helios B with vutrisiran. With lumasiran, we're on track to share top-line results from the Illuminate B phase III study in mid-2020. And of course, we'll also continue advancing the rest of our pipeline, as well as exciting preclinical efforts, and we'll highlight these milestones throughout the year as they occur.
Among these will be our presentation of additional clinical results from the ongoing phase I trial of ALN-AGT and hypertension, a program we're very excited about. We also plan to initiate a phase I trial of ALN-HSD for NASH, having now filed the CTA for that program, and our partner Regeneron plans to initiate a phase I study of cemdisiran in combination with pozelimab, having now filed the CTA for that study. We also hope that you'll join us for our remaining RNAi roundtables focused on lumasiran, givosiran, and our TTR programs later in August and September. Let me now turn it back to Christine to coordinate our Q&A session. Christine.
Christine Lindenboom (Head of Investor Relations)
Thank you, Yvonne. I just wanted to quickly acknowledge the sound issue with Barry's prepared remarks. There are some storms that are rolling through his area that impacted the audio quality, and we will plan to have Barry re-record his remarks for the replay of this call. So, operator, let's now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions.
Operator (participant)
Thank you. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, that's star one to ask a question. We will now take our first question from Paul Matteis from Stifel. Please go ahead. Your line is open.
Paul Matteis (Analyst)
Great. Thanks so much. And congrats, Barry. You're 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 Onpattro this quarter, you grew patients on drug, but revenues were down. As you think about inventory net prices, you expand globally in compliance in the second half given the pandemic. Can you just help us understand how these variables are looking maybe in July and what you expect later this year? And then just on the commercial transition, it would be helpful if you could comment on your confidence that this won't disrupt the Givlaari launch. This is obviously a launch that requires a lot of blocking and tackling and finding patients, and you're really in the midst of the ramp-up.
So how do you kind of manage the transition in the midst of that? Thanks so much.
John Maraganore (CEO)
Yeah, Paul, thanks. Great question. So on Onpattro, let's start, Jeff, with you and then maybe Andy or if you can comment as well on some of the emerging Q3 dynamics and our confidence there. So, Jeff, do you want to start?
Jeff Poulton (CFO)
Yeah, sure. I think that 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 quarter and into the third quarter, notably on genetic testing for Alnylam Act. We saw recovery rates that were close to what they were prior to the pandemic setting in. I think we're also seeing improvements in adherence, which was the major headwind that we saw in the earlier part of the quarter in the U.S. And then lastly, I think there was a question about stocking in there. We're at the lower end of the range. So our distribution partners contractually hold between one and three weeks, and we're at one and a half weeks right now. So there could be some additional build in the second half of the year.
John Maraganore (CEO)
Great. And Andy, do you want to comment a little bit further on the dynamics here as we enter the third quarter?
Andy Orth (Head of US Business)
Sure. Sure. And Paul, as you mentioned here, even amidst the healthcare shutdown in the U.S., we were able to increase the net 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 Alnylam Act volumes and other metrics, as well as the adherence rate improving across all the sites of care.
John Maraganore (CEO)
Yeah. And I would just add on Onpattro that, for example, Paul, 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 things that we can track across the country. So that's a good sign. But let's turn to the Givlaari question. Barry, do you want to comment a little bit on the Givlaari question in terms of our confidence in the second half of the launch given the ebbs and flows of the pandemic?
Barry Greene (President)
Absolutely. Is my audio better? The storm has passed.
Jeff Poulton (CFO)
It is much better.
Barry Greene (President)
As I was speaking, the lights literally went out as I opened my starting remark. So I apologize for the muffling. Yeah. So, Paul, great question on Givlaari. I'll 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 patients transitioning from EAP, patients known to sites, and then brand newly diagnosed patients. And as we mentioned at the beginning of the pandemic, we were highly prepared with digitization and 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 they've done very well and have not been really detrimental, as we've seen based upon results, to our success in getting to healthcare providers and educating them, reaching out to patient advocacy groups, and ensuring that patients who are prescribed get access to the payers. So all three have been going very well. I guess the other comment I'll have is the fact that the healthcare providers now, due to the COVID situation, are also being forced to get online, has actually aided the strategy we've had for digital and virtual interactions because now they're more used to it. They're willing to do it. And we've had really remarkable adcoms and speaker programs with numbers that we'd never seen before when they were local and live.
While nothing is as good as in person, we've really taken advantage to help patients as best we can during this time.
John Maraganore (CEO)
I'll just add one last point on Givlaari, which is that we do benefit from a drug that's been proven in clinical studies to decrease hospitalizations related to the annualized attack rate reductions that we see. And that obviously is good in this current circumstance. So, Paul, does that answer your question?
Paul Matteis (Analyst)
Absolutely.
Yeah, it does. Thanks so much for the color. Appreciate it.
John Maraganore (CEO)
Thank you.
Operator (participant)
We will now take our next question from Alethia Young from Cantor. Please go ahead. Your line is open.
Alethia Young (Analyst)
Hey, guys. Thanks for taking my question. And congrats, Barry. You killed it. And Yvonne, we look forward to working with you further. Always a pleasure. So I just wanted to ask a little bit about kind of off-kilter here, how you're thinking about kind of the hemophilia landscape in fitusiran and how that's positioned in light of what's going on with gene therapy. I know it's a subQ product, but I just wanted to kind of get your perspective on that since we are getting relatively close to data. Thank you.
John Maraganore (CEO)
Yeah. Absolutely. Let me make some comments, and then I'd welcome Akshay's perspectives as well. Obviously, the hemophilia market is a multi-product, a 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. fitusiran really fits in as the only once-monthly subcutaneous medicine that shows ABR levels, annualized bleeding levels that are around 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 a competitive profile compared to Hemlibra as the potentially only really effective once-monthly subcutaneous medicine.
Akshay, do you want to comment any further on that?
Akshay Vaishnaw (President of R&D)
Yeah. It's a very interesting and dynamic time in the hemophilia landscape. Hemlibra, the gene therapies, I think at a 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 with Hemlibra and gene therapy, this will continue to be a discussion. Obviously, they've completed their phase III studies and the BioMarin phase III study with the hemophilia A therapy. But durability of effect with gene therapy, the long-term safety, including the potential for oncogenesis, this remains a question in our opinion. There have been recent dog studies that showed that very late long-term cancer events can occur with gene therapy for hemophilia. But look, it's a good time for patients to have more therapies come on.
As John said, a therapy for hemophilia A and B that's convenient and safe once a month subcutaneously would obviously be very attractive. And we think fitusiran can offer that both for on-demand prophylaxis and inhibitor patients, and even beyond that in the other bleeding disorders. So this represents a unique and differentiated offering, and we eagerly await phase three data.
John Maraganore (CEO)
Yeah. Early next year, as you said, Alethia, which is exciting. Does that answer your question?
Alethia Young (Analyst)
Yes. Very helpful. Thank you, guys.
Jeff Poulton (CFO)
Great. Thank you.
Operator (participant)
We will now move to our next question from Anupam Rama from JP Morgan. Please go ahead. Your line is open.
Anupam Rama (Analyst)
Hey, guys. Thanks so much for taking the question. And for APOLLO-B, post the primary endpoint analysis, there's a 12-month extension in the trial. Will you be continuing that on a blinded basis so that you'll be able to get sort of outcome data in a placebo-controlled manner? Or will you really be relying on vutrisiran to get some of those longer-term outcomes beyond 12 months? And for Barry, always admired the hustle, man.
John Maraganore (CEO)
Yeah. All right. So Akshay, I think the APOLLO-B question is right up your alley.
Akshay Vaishnaw (President of R&D)
Yeah. 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 readout for vutrisiran and APOLLO-B. And so, of course, that will form the principal demonstration of how TTR-lowering approaches and what they can do in terms of morbidity and mortality in the long term.
John Maraganore (CEO)
Yeah. And I'll just add, obviously, we are capturing mortality and CV hospitalization data in Apollo-B on patisiran. So we'll obviously collect those data and see what they report. One year's worth of treatment is probably not, and the study is not powered to show something there, but we'll certainly be collecting those data. And those types of data may inform how we think about the interim analysis for Helios B, which is our vutrisiran study. And that's obviously going to be a nice, helpful set of data as we consider what that IA looks like.
Anupam Rama (Analyst)
Thanks for taking our question.
Jeff Poulton (CFO)
Thanks, Anupam.
Operator (participant)
We will now take our next question from Tazeen Ahmad from Bank of America. Please go ahead. Your line is open.
Tazeen Ahmad (Analyst)
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, would you attribute that at least near-term to an impact from COVID? And do you expect that trend to continue for the duration that COVID is a meaningful factor, at least here in the US? And then I do want to get your early thoughts about 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 nephropathy?
John Maraganore (CEO)
Okay. So let me start with the second half, the second part of the question, which I think was mixed two different programs in it, Tazeen. And then, Barry, you should answer the first question.
Tazeen Ahmad (Analyst)
I'm sorry. Yep.
John Maraganore (CEO)
Yeah. Regarding APP, that's our amyloid precursor protein program that they opted into, and that's on track to have a filed IND or CTA in middle 2021. That'll be our first CNS program, so they opted into that program. That's different than cemdisiran, which is our C5 program, which they already had opted into. That's part of our original agreement with them, which is currently in a phase two study in IgA nephropathy. What they're also doing is they're doing combination studies with cemdisiran together with pozelimab, which is their anti-C5 antibody, to get the benefit of an infrequent subcutaneously delivered treatment for many complement-mediated diseases like PNH and myasthenia, among others. So that's that part of the question, Tazeen. Barry, do you want to answer the first one on US, rest of the world, on Onpattro, and how we see that going forward?
Barry Greene (President)
Yeah. Absolutely. As Jeff provided in the call, we've upped our mid-guidance, reflecting our belief set that we're in the recovery phase. So in particular, we believe that we're going to continue to see growth in the U.S. I'll remind you that as a mature market, the U.S. is really a pure patient-find market right now. And as patients are, again, flowing through the healthcare systems, we're finding the proportion of patients with TTR that are hereditary with polyneuropathy. So we continue to see growth in the U.S. In terms of rest of the world, many countries continue to benefit from patients known to the site, as well as finding new patients. And then we are opening new territories. So every time a country opens, we benefit from EAPs in those countries and patients known to the site. So again, we see growth in all regions around the world continuing.
John Maraganore (CEO)
Yeah, and Jeff, anything you'd want to add or Andy to that?
Jeff Poulton (CFO)
Nothing for me to add.
Andy?
Andy Orth (Head of US Business)
No. Agreed. Agreed. I think Barry got it.
Jeff Poulton (CFO)
Great.
John Maraganore (CEO)
Okay. John, I'm sorry.
Yvonne Greenstreet (COO)
I think, John, just one thing to add. It's Yvonne here. I think the increasing use of combination therapy in the U.S. is a dynamic that I think is a very interesting one for us. But I think we're beginning to see physicians appreciate the profile of Onpattro in this mixed population phenotype. So I think that's something to keep an eye on as well.
John Maraganore (CEO)
Yeah. Absolutely.
Tazeen Ahmad (Analyst)
Okay. And I did want to just, I'm sorry, I mangled my second question. I did want to ask why APP would start development ex-US.
John Maraganore (CEO)
Oh. There's no plan to do it ex-US necessarily, Tazeen. We often start studies in different parts of the world, including sometimes in the US. So it's not a plan to do it ex-US per se.
Tazeen Ahmad (Analyst)
Okay.
John Maraganore (CEO)
Okay. Thank you.
Operator (participant)
We will now take our next question from Maury Raycroft from Jefferies. Please go ahead. Your line is open.
Maury Raycroft (Analyst)
Hi, everyone. Good morning and congrats on the progress, and thanks for taking my questions. First one is just on APOLLO-B. So we know from your exploratory endpoints in the phase III APOLLO-A that Onpattro or vutrisiran showed activity in cardiomyopathy phenotypes. I'm wondering if you're collecting data from the commercial patients on Onpattro that provides read-through to APOLLO-B, and will you present those data at some point, and can you comment on some key baseline characteristics, similarities between patients using the drug commercially versus those enrolled in APOLLO-B?
John Maraganore (CEO)
Yeah. That's a great question. I'm going to maybe provide some context. Maybe Akshay, you can comment as well. And Barry, look, we're 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 formed the foundation of our confidence in APOLLO-B. And I think to your point, there's been some interesting data that have been generated investigationally in the field in patients that have polyneuropathy, but also with cardiomyopathy where vutrisiran 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 has presented some data, are really quite encouraging and give us encouragement for APOLLO-B.
Of course, we'll await the results of that study before we can comment definitively on vutrisiran activity in cardiac patients. Akshay, anything to add to that from your perspective?
Akshay Vaishnaw (President of R&D)
No. I think you covered it, John.
John Maraganore (CEO)
Yeah. Great. And I'll just add that there are always investigational studies that are done by individual centers or groups of physicians that might explore these types of features. And that's something which does occur out there. Barry, anything else to add on the commercial side?
Barry Greene (President)
No. I think you covered it well.
John Maraganore (CEO)
Terrific. Thank you. Maury, did that answer your question?
Anupam Rama (Analyst)
That does. It's very helpful. And just a quick follow-up for AGT. So in your top-line data, you guys reported on 48 patients for that. And you're 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 guess, how much total data could we see at the end of the year?
John Maraganore (CEO)
Yeah. I mean, a lot of these phase 1 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 an activity and safety perspective. Akshay, anything else to add to that?
Akshay Vaishnaw (President of R&D)
No. I think you covered it. Yeah.
John Maraganore (CEO)
Great. Does that help, Maury?
Maury Raycroft (Analyst)
Yeah. That helps. Thanks for taking my question.
Jeff Poulton (CFO)
Thanks, Maury.
Operator (participant)
We will now move to our next question from Ritu Baral from Cowen. Please go ahead. Your line is open.
Ritu Baral (Analyst)
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 wanted to ask about trends in home administration for Onpattro. I guess, is there any difference between what you're seeing in the U.S. and Europe? And what is being done in the U.S. as far as allowances for COVID and reimbursement and uptake? Is this something we could see that'll be a lever going forward to stabilize the U.S.?
John Maraganore (CEO)
Yeah. I mean, it's a great question. Barry, do you want to give the global view? And then maybe, Andy, you can add additional color on the US dynamics on that.
Barry Greene (President)
Absolutely. And great question. Home infusion has been a critical site of care that we've utilized during the pandemic. So in the CEMEA region, home use was about 17% pre-pandemic. And it's doubled to about 35% in the age of pandemic. It was a dynamic for France. In fact, we were able to move a huge cohort of patients into home infusion when one of the sites reported inactivity with COVID. So it's been very important. Any comment, Yvonne? But the U.S. has also doubled from 9% to about 20%. And then globally, in countries that allow home infusion, U.S., Brazil, Canada, most of the European countries, we've effectively been able to move patients to home infusion. There are times where a dose is delayed or a dose is skipped in that transition.
But as we've now got the capability down, most of the patients are moving without dose interruption at all. And it's been a very important step for us.
Ritu Baral (Analyst)
Is that still growing? Is that still growing, the home infusion rate?
Barry Greene (President)
Yeah. And maybe I can touch on the U.S. with that specifically. And the answer is 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 site of care optimization mode since the onset of COVID. And that's both home care as well as more local infusion centers if they were going into larger institutions. So we expect our patients and physicians to continue to take advantage of home care.
Ritu Baral (Analyst)
Could you just go to reimbursement on Alnylam reimbursement for that? Yep.
Barry Greene (President)
Thank you.
Sorry, Ritu. Just in terms of growth, as the pandemic ebbs and flows, both in the United States and other countries, we've seen patients move to home infusion and then, when possible, back to a local infusion center. Keep in mind that patients really like getting out of their house and the social aspect of the infusion center. So I think they do prefer very often the infusion centers.
John Maraganore (CEO)
Great. Thanks, Barry. Ritu, does that answer your question?
Ritu Baral (Analyst)
Yeah. And I just wanted to. Could you just review reimbursement?
John Maraganore (CEO)
Oh, reimbursement side of it.
Ritu Baral (Analyst)
Yep.
John Maraganore (CEO)
Yeah. Do you want to handle that, Andy?
Andy Orth (Head of US Business)
Yeah. Certainly. Certainly. So the reimbursement, clearly, on the commercial side of our population is very straightforward. And we have many patients there taking advantage of it. But we also know that CMS released in late June a 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's an area where we expect to see more growth and utilization of that going forward.
John Maraganore (CEO)
Did that answer your question, Ritu?
Ritu Baral (Analyst)
Thank you so much. Yep. Thank you so much.
Andy Orth (Head of US Business)
Great.
Operator (participant)
We will now move to our next question from David Lebowitz from Morgan Stanley. Please go ahead. Your line is open.
David Lebowitz (Analyst)
Thank you very much for taking my question. Given your experience thus far with 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?
John Maraganore (CEO)
Yeah. 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's an ultra-rare orphan population based on prevalence. As with Givlaari, the underdiagnosis rates in PH1 are also well-known, and so there's a need for patient finding. 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 developed for Onpattro, the playbook that we've been executing on for Givlaari, is one that we will absolutely be using for lumasiran. Of course, we'll be importantly leveraging the existing infrastructure that we've built now globally for the company. Barry, anything to add to that?
Barry Greene (President)
No, John, the only color I'd add, David, is that we've gotten very, very good now at the digital virtual and site of care optimization that was necessary during COVID. But it's advantageous to launch with a disease like PH1 where, again, while the diagnosis rate's 50%, there are 50% of patients out there undiagnosed. So being able to reach them in virtual means is going to be highly advantageous.
John Maraganore (CEO)
Yeah. Thanks, Barry. David, does that answer your question?
David Lebowitz (Analyst)
Yes. Thank you for taking my question.
John Maraganore (CEO)
Great. Thank you.
Operator (participant)
We will now move to our next question from Vincent Chen from Bernstein. Please go ahead. Your line is open.
Vincent Chen (Analyst)
Thank you very much for taking the questions. Two quick ones. One commercially oriented and one on the R&D side. First, for Givlaari, we realize you're not going to provide any guidance. But I'm curious what you're seeing as far as the trajectory of start forms coming out of Q2 and going into Q3. I note that incremental start forms slowed in Q2 relative to Q1. I imagine some of this is because you had initial bullets of patients in Q1. Some of it is impact from COVID that adversely impacted Q2. Just trying to get a sense for what a reasonable near-term run rate might look like between those two. And then second, on the R&D side, a quick one on the ALN-APP IND filing.
We've certainly been watching very closely for a move into the CNS delivery, which could open up a range of very large and high-unit need medications. So it seems like it's taken some time. What are the gating factors on the ALN-APP IND filing? What's left to be done before you can enter human trials?
John Maraganore (CEO)
Yeah. Those are great questions. Let me start with the first one. Akshay, you'll get the second one just in a minute. But your question on Givlaari, I mean, we're 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 strong start that we saw in Q1, of course, was benefited greatly by patients that were either in the US EAP or that were known to sites sort of that initial bolus, if you will.
But we do expect growth from that point. And we're seeing continued growth in the US. About 25% of our patients in the US are also coming outside of our patient hub. And therefore, they're not on the start form metric, if you will. And that accounts for the over 100 patients that we believe are now on Givlaari commercial treatment. Now, that includes a small part of the US. We said in our prepared remarks, we're now going to stop providing start form 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'll see the growth in our total patient number quarter on quarter for Givlaari.
And we are optimistic with that growth in the U.S. and also in other markets around the world. Now, Europe, of course, has now been launched in Germany and made patient sales around many countries. So I think that we don't need to say anything more about Givlaari. Do you want to now, Akshay, talk about APP and what's between now and our filing?
Akshay Vaishnaw (President of R&D)
Sure. Yeah. I mean, a bit of an accent. We're delighted with the progress, Vincent. It's about a year since we signed the deal with Regeneron next year. It's exciting, and we think it represents good progress. What we have to do now is simply complete the toxicology and CMC packages. We've already had good engagement with regulators, and so we're looking forward to filing that IND in due course in mid-2021.
John Maraganore (CEO)
Does that help, Vincent?
Vincent Chen (Analyst)
Yeah. Very helpful. Thank you very much.
Jeff Poulton (CFO)
All right. Thank you.
Operator (participant)
We will now move to our next question from Salveen Richter from Goldman Sachs. Please go ahead. Your line is open.
Salveen Richter (Analyst)
Good morning. Thanks for taking my questions. And Barry, you'll be next here. So in the context of competitive dynamics in PNH, how are you thinking about your upcoming study looking in this setting? And what would be meaningful to be differentiated here or where you could fit in the treatment paradigm? And then just a comment on, based on your work in extrahepatic tissues, where you feel most optimistic at this point.
John Maraganore (CEO)
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 cemdisiran and pozelimab, I mean, look, there is no subQ alternative that's currently approved today. This is an opportunity to have a subQ treatment for complement-mediated diseases with a very infrequent dose regimen, even with potential for co-formulation of the two drugs. We feel very encouraged by data 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 subQ dose regimen. So I'll stop there. Akshay, maybe you can comment on that, but also on our extrahepatic work and where we're most confident these days.
Akshay Vaishnaw (President of R&D)
Yeah. So certainly, infrequent presentation. I also think that we have the opportunity to have the most complete blockade of the complement system and hopefully the best efficacy profile now. The current drugs already have good efficacy. But we'd 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 product could offer that. Looking beyond PNH and at the extrahepatic pipeline, we just touched on the CNS. It is indeed exciting that within a year of announcing that deal with Regeneron on CNS and ocular, we've now announced that we'll be filing an IND next year for the nervous system. That'll be the first of many, we think. We have very exciting data in the ocular compartment as well.
Most recently, of course, we shared data on lung delivery. I can't really say one is my favorite. A recurring theme for us over the years has been that when we've had strong replicable data in animal systems, first in rodents and then in the non-human primate, that then has invariably led to translation in the human setting. With all three compartments, as these INDs hit the clinic, we're looking forward to replicating and replicating the success of our work in the liver with evidence of knockdown and clinical efficacy and safety in the brain, in the eye, in the lungs, etc. We're not going to stop there. Of course, we have many other efforts ongoing for other compartments, which we will get to in due course. That's just a little bit on the extrahepatic thinking.
John Maraganore (CEO)
I would just add to that part that what's exciting about the CNS opportunity, of course, is that there are many neurodegenerative diseases that are gain-of-function proteinopathies with genetic validation. And we have shown in non-human primates some exciting data that we fully expect will replicate in the human setting based on our past experiences. And what's really key there is the durability that we see. That is going to be important because with intrathecally administered drugs, being able to have significant knockdown of the pathogenic protein with infrequent dose administration is going to be something which is highly differentiated, not only for the APP program that'll be the first one to go, but the Huntington's program that'll come shortly thereafter, and programs that we're obviously advancing in diseases like ALS and Parkinson's and Alzheimer's, etc. So this is really going to be an exciting story for the company.
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. It is an exciting new frontier for the company.
Salveen Richter (Analyst)
Great. Thank you.
John Maraganore (CEO)
Thanks, Salveen.
Operator (participant)
We will now take our next question from Gena Wang from Barclays. Please go ahead. Your line is open.
Gena Wang (Analyst)
Thank you for taking my questions. First, Barry, it's been great working with you over the past many, many years. My best wishes to your next journey. Yvonne, certainly looking forward to working with you more. I have two questions. One is, on Onpattro, just wondering if you can share how much revenue is contributed from Japan. And for vutrisiran, wondering any COVID-19 impact on collecting the data.
John Maraganore (CEO)
Great. Great question. So Jeff, why don't you answer the first question? And then, Akshay, you can answer the HELIOS-A question secondly. Go ahead, Jeff.
Jeff Poulton (CFO)
Yeah. If I heard the question correctly, the question was about Japanese contribution to Onpattro revenue in the quarter. We don't break out the detail by country, 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 result.
John Maraganore (CEO)
Akshay, do you want to comment a little on the vutrisiran management of the study?
Akshay Vaishnaw (President of R&D)
Yeah. I mean, both for vutrisiran and patisiran in their respective cardiomyopathy studies, maintaining study integrity obviously has been of the highest priority during this COVID period. And we've used a variety of approaches successfully: telemedicine, where physicians and site staff speak to patients over the phone and other means. We've had home administration of drug. And there's, of course, the ability to take blood samples at home. And finally, for key visits that require in-clinic assessment, we always build in a little bit of buffer around the timing of the visit so they 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's not been trivial. But we've certainly maintained study integrity. And we're pleased with that.
We're also pleased with the fact that with things opening up, as we've seen on the commercial side, we're seeing very good pickup in enrollment as well in these studies.
John Maraganore (CEO)
Yeah, and I would just make because I think, Gena, your question was also focused on HELIOS-A, which, of course, was completed.
Akshay Vaishnaw (President of R&D)
Oh, sorry.
John Maraganore (CEO)
Yeah. Completed enrollment. We're still on track for early 2021 data from that. And we've obviously all the things that Akshay just commented on, of course, have been critical in terms of making sure that we maintain data integrity and no missed doses or minimal missed doses during the course of that study. So that's what applies to HELIOS-A.
Gena Wang (Analyst)
Thank you.
Jeff Poulton (CFO)
Great. Thanks, Gina.
Operator (participant)
We will now move to our next question from Alan Carr from Needham & Company. Please go ahead. Your line is open.
Alan Carr (Analyst)
Hi. Thanks for taking my questions. And congratulations, Barry. I'll miss you. So you mentioned that you've submitted an IND for the HSD program. So there's been some developmental regulatory challenges around NASH. And I'm wondering if you can give us an update on your plans and kind of strategy with that one, how you differentiate that sort of thing. Thanks.
John Maraganore (CEO)
Great. Thanks, Alan. So Akshay, that question was on ALN-HSD and NASH and our plans there. Do you want to comment further?
Akshay Vaishnaw (President of R&D)
Yeah. So Alan, we're excited to have filed the IND CTA and get going with this program. We are excited about the target because it's 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, and most of which have fallen short, unfortunately. And HSD17B13 seems to be a gateway to the later consequences of the accumulation of hepatic fat. So even 50% knockdown, because we know heterozygous loss of function protects people from NASH, we think even 50% knockdown should be sufficient. But we know from our liver programs we can do a lot better than that. And we know we can achieve greater than 50% from our animal work with our drug candidates. So it's great to get this to the clinic. Phase I will be all about safety, PK.
And we'll collect a number of exploratory biomarkers. HSD17B13 itself is not a target that's secreted into the circulation. But we have some very good exploratory biomarkers that will help assess the target engagement. And then from that, we'll go into phase II. And that's where we'll have a dose and regimen selected, which I imagine will be a low dose given rather infrequently given the profile of the drug we're seeing in animals once every three months or six months or so. And that's where we'll test the key hypothesis of preventing progression to NASH itself. But those details are to come. For now, we have to focus on the phase I.
Alan Carr (Analyst)
Okay. Thanks very much, Akshay.
John Maraganore (CEO)
Thanks, Alan.
Operator (participant)
We will now take our next question from Mani Foroohar from SVB Leerink. Please go ahead. Your line is open.
Mani Foroohar (Analyst)
Thanks for taking the question and congrats, Barry, Yvonne, as well. Although with Barry gone, I guess, Yvonne, you're going to get to be much better at telling me how I'm wrong all the time about everything. I have a quick commercial question. A quick commercial question about Onpattro. Obviously, there was a little bit of a decline in terms of patient adherence, which is not surprising. I know the PK and RNAi assets is very unique in terms of pharmacokinetics versus other drugs. But is there an avenue to any catch-up dosing, any patients potentially getting back temporarily on an IV dosing schedule that could be a little more frequent than what's labeled? I.e., could we recapture some of that lost revenue? Or do you think people will end up back on the labeled dosing frequency?
And then secondarily, in thinking about HELIOS-B, you guys have talked about potential interim, when that would look like. How do you guys think about timing to make a decision on whether or not to take that voluntary interim? And on what time horizon might you be telling us, "Hey, we're going to be taking an interim or not," in terms of just giving us some sense of when we should expect that event?
John Maraganore (CEO)
Yeah. Those are great questions. Maybe on the first one, Manny, I mean, your question makes sense, of course. But I think that it's our expectation that patients would stay on label and do Q3 weekly dosing. We have no reason to believe that that would change whatsoever. And we've heard nothing about that in the field. But I think the good news is that adherence rates with some missed doses that occurred in Q2 are showing great strength as we enter Q3. And we don't expect to see any significant impact like we experienced during the pandemic phase. So I think that's 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.
Andy Orth (Head of US Business)
No, John, you covered it, right? Everything we're hearing is a resumption to the original schedule for any folks who were paused for whatever reason.
John Maraganore (CEO)
Yeah, and then your second question on HELIOS-B, also one that makes a lot of sense, but very specifically on HELIOS-B, we will do an interim analysis. We've made the commitment to do that. Now, we've left it open with the agency on exactly how that will be designed, and we're not going to comment yet on timing. I'll just say again that one of the benefits of the APOLLO-B study is that as we read out data from that study, it will inform how we should think about the interim analysis for HELIOS-B specifically. Akshay, do you have anything else to add to that?
Akshay Vaishnaw (President of R&D)
No. No. Nothing to add.
Jeff Poulton (CFO)
Okay. Good.
Mani Foroohar (Analyst)
Thanks, guys.
John Maraganore (CEO)
Thank you.
Operator (participant)
We will now take our final question from Navin Jacob from UBS. Please go ahead. Your line is open.
Srikanth Gururaj (Analyst)
Hi, everyone. Thanks for taking the question. This is Srikanth Gururaj on for Navin Jacob. I've just gone on Onpattro. Yvonne mentioned combination therapy. And you previously stated that 15% are on both Vyndaqel and Onpattro. Can you give us an update of what percentage of patients are on both now? And can you tell us anything on the outcomes of these patients versus patients on just monotherapy? And then just on pricing, you just mentioned some reduction in gross to net. How should we think about pricing trends as the year goes on? Thanks very much.
John Maraganore (CEO)
Okay. So let me start on the combination use that's occurring out there as we hear from the marketplace. These aren't studies where specific data are being generated. We're just aware that patients that have a mixed phenotype where they've got polyneuropathy are receiving Onpattro. And in some cases, those patients are also on a TTR stabilizer. So we're just aware of that. And we have market research that says that it's somewhere in the range of 15%-30% now. And it could double by the end of the year. We just recently published some data on combination use from our previous phase II open label study. And that published paper showed that the combination was safe. And the level of TTR knockdown was as good as monotherapy. But there was no formal assessment of, or was it powered 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 the dynamics of concomitant use that we're seeing in the marketplace? And I'll just.
Andy Orth (Head of US Business)
Yeah.
John Maraganore (CEO)
I'm sorry, Andy. Just one thing is I want to highlight also that this is really a U.S. phenomenon. We don't see this in the rest of the world. But Andy, go ahead.
Andy Orth (Head of US Business)
Right. Right. Yeah. Happy to. So since the fourth quarter of 2019, in the U.S., we've been seeing growing evidence of reimbursement for Onpattro where used concomitantly with TTR stabilizer products, which in the end is a positive for patients with multiple manifestations of the disease. And barring any unforeseen changes due to COVID or other, we expect concomitant use to continue to increase in the U.S. over time for patients whose disease manifestations include polyneuropathy. And as John said, right, outside of the U.S., it's more of a switch dynamic.
John Maraganore (CEO)
Right. And then your pricing question, Jeff, do you want to handle that?
Jeff Poulton (CFO)
Yeah. Sure. The comment on Onpattro for Q2 was that there was a very modest increase in gross to nets relative to Q1, which created a slight headwind in growth quarter to quarter. There is variability in gross to nets quarter to quarter. We've talked about that on the last several calls. It's just based on the way the accounting works and the estimates and the true-up of those estimates. But we're very confident that the full year gross to nets for Onpattro will be very consistent with what we experienced in 2019. And the expectation is mid-20s for the year.
John Maraganore (CEO)
Great. Does that answer your questions?
Srikanth Gururaj (Analyst)
Yeah. Thanks very much.
John Maraganore (CEO)
Good. Okay. So with that, we're going to close our call. Thank everyone for joining us on the call. And again, to 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.
Akshay Vaishnaw (President of R&D)
Bye, everyone.
Operator (participant)
Ladies and gentlemen, this concludes today's call. Thank you for your participation. You may now disconnect.