Alnylam Pharmaceuticals (NASDAQ:ALNY) Q2 2020 Earnings Call

0:01 Ladies and gentlemen, thank you for standing by. Welcome to the Al Nilem 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.

0:20 Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Al Nilem. With me today on the phone are John Merriganori, Chief Executive Officer, Barry Green, President, Pasha Deschanel, President of R&D, Jeff Poulton, Chief Financial Officer, and Yvonne Greenstreet, Chief Operating Officer. Andy Orris, 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.lnylam.com slash events. During today's call, as outlined in slide two, Jeff will provide some introductory remarks in general context. Daria will provide an update on our commercial and medical affairs progress. Akshay will review recent clinical and preclinical updates.

1:08 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 LNN'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 to 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.

1:54 With that, I'd like to turn the call over to John.

1:57 Thanks, Christine, and thank you, everyone, for joining the call today. Let me start by expressing El Milo's support for Black Lives Matter and our support for the efforts to end systemic racism in our country. At El Milo, 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.

3:01 With that, let's now turn to our business. As all of you know, the COVID-19 pandemic remains dynamic, uncertain, and unpredictable. and a new normal starting in Q4. While the pandemic continues or even worsens in many states in the U.S., we believe our Lyle'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.

3:47 Our confidence in the second half is reflected in an upward revision in our OnPatro 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 their challenge-accepted mentality. We are extremely pleased with global OnPatro and Givlari top-line performance in Q2, which Barry will elaborate on shortly. were 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 financings.

4:42 Before I share my closing remarks, I want to take a moment to acknowledge the news we announced earlier this morning about Barry Green's planned departure from El Nile 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 El Nile. And I know that I speak for everyone at El Nile 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 El Milam as needed for a two-year period, and I wish him all the very best in his next endeavors.

5:37 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 El Milo. I'd like to finish with my perspective on the big picture for the company. Thank you for joining us.

6:43 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 to 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.

7:07 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 El Nile. First, congratulations again to Yvonne Greenstreet. She is a remarkable person and well deserves the President's CEO role. I know that Yvonne will make sure that El Nile continues to be a company doing the right things and focusing on patients and accounting on it. As for me, it's been a tremendous privilege to serve as President of El Nile 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 Alman will achieve its ambitious goals with quality and excellence with the great team we have in place.

8:02 I'll continue to support Elm Island throughout this transition and have no doubts about the company's future prospects as a top-tier biopharmaceutical company. For Onpatro, we achieved $66.5 million in global net product revenues. As of June 30th, over 1,050 patients were on commercial Onpatro 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 U.S. As anticipated, the COVID-19 pandemic had 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.

8:52 Also as anticipated is the pace of new patient initiative therapy slow in the U.S. during the quarter, Produce genetic testing, diagnosis, and patient flow through the healthcare systems. Finally, our U.S. business was also impacted by inventory destocking and an increase in costs during the quarter. Jeff will provide more color of these details later in the call. While our focus today is on Q2, as we enter Q3, we're now seeing to see 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. and, in fact, our July monolith numbers are near to the January numbers we saw earlier in the year, a really good sign. In the second quarter, we continue to see great progress from new prescribers.

9:40 In the second quarter, 40% of submitted seroforms came from new writers, with an equal mix of neurologists and cardiologists. In the U.S., we saw continued use of Lompatria with future stabilizers in the quarter. We believe this trend will continue to grow as physicians see progression of polyneuropathy, unstabilizers, and treat the different manifestations of HATTR hemodiosis. The parents of the rest of the world made very positive progress with Ampatro in the second quarter. The rest of the world's sales for Ampatro 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.

10:25 partners in Europe and Japan throughout 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. Our team has secured pricing and reimbursement approval of 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 our patchwork. Japan has now become our second largest country after the U.S. for our patchwork, and we expect continued growth in patient health to the final of the test week on stabilizer therapy.

11:15 On the medical care side, our team remains committed to addressing the challenge of raising disease awareness and improving diagnosis of each ATDRM doses, including with Elnalimab, a 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 care mutation, which is tracking at a historic 68% positivity rate. These numbers show the testing slowdown in Q2 we mentioned on our last earnings call. The good news is that as I have already marked, those numbers have picked up to near January levels. Moving on to February, 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.

12:02 We received over 85 start forms in the U.S. with over 100 patients globally on commercial treatment from launch through June 30th. As we have now begun to open ex-U.S. territories, and also because currently 25 to 30% of U.S. patients come from outside the Starform channel, we'll discontinue providing Starform metrics in future quarters as we did last year for Ampatro. In the U.S., we observed a broad prescriber mix, including ethetologists, gastroenterologists, and other specialties, both in preferred centers of excellence and in the community. Of note, 75% of our Q2 starts were from new writers. Our progress with value-based agreements has been extremely strong, with seven VBAs completed with U.S. payers, and we now have confirmed access for over 75% of covered U.S. lives across commercial, Medicaid, and other government payers.

12:54 We've not experienced any pair-hands-in-the-pillar debate, so we need to see plans to adopt medical policies not more restrictive than our label indications. This year, we saw strong initial performance as well, with a successful and, as noted, virtual launch in Germany, as well as main patient sales in other countries, including French cohort ATU program. We've been positively encouraged by the responsiveness of European players despite the COVID-19 pandemic. Of note, Gavlari received an Improvement of Medical Benefit, or ASMR, score of 2 in France, concluding that Gavlari offers significant additional therapeutic value. This is a new accomplishment since, in the context, only two new commercial medicines were granted an ASMR rating of 2019.

13:43 Our medical affairs team is also focused on improving awareness and diagnosis of AHP. Through our manual math, we can report 937 tests submitted and 92 patients with positive AHP mutations as of mid-July, showing continued 10% positivity rate. A notable diagnosis trend emerging is the robust use of urinary PPG test-informed 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 master end 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.

14:28 from the Department of Pharmaceutical Medicine, and third, RNA 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 targets. Akshay? Akshay, are you on mute?

15:11 Sorry. 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 effort in ATTR amyloidosis, where we're advancing our two product candidates, Patisran and Butrisran. Whilst Onpato is currently approved in multiple markets around the world to treat polyneuropathy associated with HAT to amyloidosis, we're committed to expanding the product's label to include the treatment of cardiomyopathy in both hereditary and wild-type HAT to amyloidosis patients. To this end, we continue to enroll patients in Apollo B and continue to expect completion of enrollment in 2021.

16:03 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 Gutrisran, an investigational RNAi therapeutic delivered by quarterly subcutaneous injection that's also in development for the treatment of AT-tramyloidosis. Here, we're conducting two phase three studies. The first is Helios A, which is evaluating Gutrisran in HAT-tramyloidosis 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 three study of Butrisran is Helios B, which is being conducted in inherited and wild-type ATT amyloidosis patients with cardiomyopathy. As with Apollo B, site activation and enrollment in Helios B are now picking up.

16:52 If Helios B is positive, It could allow for vitreous trans entry into the very large wild-like AT cannabinoidosis market opportunity with the product label that includes cardiovascular outcomes. Let's move to Givlari, which is approved in the US, EU, and now in Brazil to treat acute hepatic porphyria in adults. Of course, the highlight of Givlari in the recent period was our Brazilian approval and we're continuing our geographic expansion for this product with MA 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 3 study demonstrating sustained efficacy and acceptable safety through 12 months of treatment with evidence for potentially improved efficacy over time.

17:45 In addition, we're proud to have published pivotal results from the Envision Phase 3 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 Lumaciran, an investigational RNAi therapeutic that we're developing for the treatment of primary hydroxyurea 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 Lumaciran significantly reduced urinary oxalate levels, the cause of progressive kidney failure in PH1. In addition, the MASRAN showed an encouraging safety profile. Overall, the MASRAN 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.

18:42 We completed our NDA and MA submissions in the second quarter. The FDA granted priority review for the NDA 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 Inclisiran 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 Fetuceran in development for Haemophilia A or B with or without inhibitors partnered with Sanofi.

19:35 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 two early study for 2-SRAM, 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 one study in patients with hypertension. Specifically, ALN-AGT demonstrated an over 90% knockdown of angiotensinogen, and a greater than 10 millimetres mercury-lowering systolic blood pressure with a durability that's caused a quarterly or even less frequent subcutaneous dosing regimen.

20:29 We're also encouraged by the tolerability profile for ALNAGT. We now look forward to preserving more complete data from the ongoing phase one study at a scientific meeting in the second half, assuming abstract acceptance. We're very excited about the potential for ALNAGT 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 Veer, we selected a development candidate, ALN-CoV, or VF2703 with potent and highly cross-reactive activity towards SARS-CoV-2, the virus that causes COVID-19.

21:26 We continue to expect an IMD 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 IMD file for ALN-APP in mid-2021, and this is expected to be our first CNS program to enter clinical development. And with that, let me now turn it over to Jeff to review our financial results. Jeff?

21:54 Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting our NILAM's Q2 2020 results.

22:00 As Barry has already highlighted, it was a very strong quarter of commercial execution with outstanding results for both Onpatro and Javari. Turning to our results for Onpatro, generated 66.5 million in global net Onpatro revenue for the quarter, Thank you for joining us. Thank you for joining us.

23:11 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 Onpatro based on dollar sales, as Barry mentioned. First time this quarter, the contribution of our international markets to global Onpatro 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 Giblari, 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 on PATRO, as well as an additional contribution from our international markets with a successful launch in Germany and main patient sales in other countries, including France.

24:06 Our combined product sales from Patro and Givlory 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 Deere 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 on-patro full-cost inventory, but last year benefited from zero-cost on-patro 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 on-patro inventory at our contract manufacturer.

25:04 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 Onpatro and Giblari and initial launch preparation activities for LeMessurier. 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.

25:57 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. 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 and increasing 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 of Ron Patro 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 Ron Patro with an increase in the midpoint of our guidance as we narrow the range from $270 to $300 million to $280 to $300 million.

26:55 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 with Blackstone, adding up to $2 billion in cash, secures Elm Island's bridge towards a self-sustainable financial profile without the need for future equity financing. And with that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne?

27:36 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 Onpatro and Givlari, and we're looking forward to our Givlari launch in Brazil. and an upcoming NDA filing for Givalari in Japan. We're also expecting two additional regulatory approvals by the end of the year for Lumassaran and Atreceran. We plan to continue enrollment in our ATTR cardiomyopathy studies, specifically Apollo B with Atreceran and Helios B with Atreceran. With Lumassaran, we're on track to share top-line results with 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 one trial of ALN-AGT and hypertension, a program we're very excited about.

28:40 We also plan to initiate a phase one trial of ALN-HSD for NASH, having now filed the CTA for that program. and our partner Regeneron plans to initiate a phase one study of Femdesiran in combination with Posalimab, having now filed the CTA for that study. We also hope that you'll join us for our remaining RNAi roundtables focused on Imaciran, Divociran and our TTR programs later in August and September. Let me now turn it back to Christine to coordinate our Q&A session. Christine.

29:14 Thank you, Yvonne. I just wanted to quickly acknowledge the sound issue with Barry's prepared remarks. There's 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. Thank you. If you would like to ask a question, please signal by pressing star 1 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 1 to ask a question. We will now take our first question from Paul Matias from Stifle. Please go ahead.

30:01 Your line is open. 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 quick commercial things. So on the dynamics that impacted on Petro this quarter, you grew patients on drugs, but revenues were down. As you think about inventory, net prices, 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 what you expect later this year? and then just on the commercial transition, it'd be helpful if you could comment on your confidence that this won't disrupt the Glavari 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.

30:47 So how do you kind of manage the transition in the midst of that? Thanks so much.

30:53 Yeah, Paul, thanks. Great question. So, on Alpatra, let's start, Jeff, with you and then maybe Andy or if you can comment as well on some of the emerging Q3 dynamics in our conference there. So, Jeff, you want to start?

31:09 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. on ILMAC. 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.

31:51 Great. And, Andy, do you want to comment a little bit further on the dynamics here as we enter the third quarter?

31:57 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 Patro. 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 through the healthcare system and El Nido MAC volumes and other things we metric, as well as, you know, the adherence rate improving across all the sites of care.

32:32 Yeah, and I would just add, on El Patro, 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 Patro. 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's a good sign. But let's turn to the Gablari question. Barry, do you want to comment a little bit on the DeVore question in terms of our confidence in the second half of the launch given, you know, the ebbs and flows of the pandemic?

33:10 Absolutely. Is my audio better? The storm has passed.

33:13 It is much better.

33:16 As I was speaking, the lights literally went out as I opened my starting remarks, so I apologize for the muffling. Yeah, so, Paul, great question on DeVore. You know, 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 knowing the sites, and then brand new, newly diagnosed patients. And as we mentioned at the beginning of the pandemic, we were highly prepared with digitization and virtualization already for Givori, given the diverse prescriber base and the fact that patients can be, you know, anywhere in the world. So we, in fact, have done virtual launches, and they've done very well and have not been really a detriment, 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 payer.

34:13 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 you'd never seen before when they were local and live. So while nothing is good as in person, we've really taken advantage to help patients as best we can during this time.

34:49 And I'll just add one last point I'd give Laurie, 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? Yeah, it does. Thanks so much for being out of color. Appreciate it.

35:10 Thank you. We will now take our next question from Alicia Young from Kantor. Please go ahead. Your line is open. 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 a little bit off-kilter here, how you're thinking about kind of the hemophilia landscape in Pituceran and how that's positioned in light of what's going on with gene therapy. I know it's 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.

35:47 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 or without inhibitors, which is great. Patuciran really fits in as the only once-monthly subcutaneous medicine that shows ABR levels, annualized bleeding levels, that are a run of 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 three trials and the safety continues to hold up, as was encouragingly shown in their updated open label study.

36:40 This could be a very important medicine in that landscape and offer 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?

36:56 Yeah. You know, it's a very interesting and dynamic time in the hemophilia landscape. Hemlibra, the gene therapies. I think You know, 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 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 Hymn for the A therapy. But, you know, durability of effect with gene therapy, the long-term safety, including The potential for oncogenesis, you know, this remains a question in our opinion. There have been recent DOF studies that showed that very late, long-term cancer events can occur with gene therapy for haemophilia.

37:46 But look, it's a good time for patients to have more therapies come on. As John said, a therapy for haemophilia A and B that's convenient and safe once a month, sub-Q, would obviously be very attractive. And we think Pitusharan can offer that both for on-demand both laxus and inhibitor patients, and even beyond that in the other bleeding disorders. So this is a unique and differentiated offering, and we eagerly await phase three data.

38:15 Yeah, early next year, as you said, which is exciting. Does that answer your question? Yes, very helpful. Thank you, guys. Great. Thank you. We will now move to our next question from Anupam Rama from J.P. Morgan. Please go ahead. Your line is open.

38:34 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 the two strands to get some of those longer-term outcomes beyond 12 months?

38:59 And for Barry, you know, always admire the hustle, man.

39:04 Yeah. All right. So, Akshay, I think the Apollo B question is right up your alley.

39:11 Yeah. You know, the principal focus for Apollo B, as you said, Anupam, is on the 12-month analysis, and the first round will be coming in close succession after that readout of the 12-month readout for Patisran and Apollo B. And so, of course, that will form the, you know, principal demonstration of our PTL learning approaches and what they can do in terms of morbidity and mortality in the long term.

39:37 Yeah, I'll just add, obviously, you know, we are capturing mortality and CP hospitalization data in Apollo B on a bomb. So, you know, we'll obviously collect those data and see what they report. You know, one year's worth of treatment is probably not and the study's not powered to show something there, but we'll certainly be collecting those data. And, you know, those types of data may inform how we think about the interim analysis for Helios B, which is our Retrieve Saran study, and that's obviously going to be a nice, helpful set of data as we consider what that IA looks like. Thanks for taking our question.

40:16 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 sales with ex-U.S. now higher than the U.S., would you relate that at least near term as an impact from COVID, and do you expect that trend to continue for the duration that COVID is a meaningful Doctor, at least here in the U.S. And then I do want to get your early thoughts about Regeneron opting in for your ALN APP program. You know, your plan on starting development, you know, of that program, can you give us a little bit of color on what you think the opportunity could be in IGA and this opportunity?

41:13 Okay, so let me start with the second part of the question, which I think was mixed two different programs in it, Dazeem. And then, Barry, you should answer the first question. Regarding APP, that's our amyloid precursor protein. Program that they opted into, and that's on track to have the filed IND or CTA in middle 2021. That'll be our first TNS program. So they opted into that program. That's different than Semdesiran, which is our C5 program, which they already have opted into as part of our original agreement with them, which is currently in a Phase II study in IgA nephropathy. What they're also doing is they're doing combination studies with Semdesiran and together with Tazelumab, 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, amongst others.

42:11 So that's that part of the question, Tazine. Barry, do you want to answer the first one on U.S., rest of the world, on PATRO and how we see that going forward?

42:23 Yeah, absolutely. As Jeff provided on the call, we've upped our mid-guidance, reflecting our belief 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-fine market right now, and as patients are, again, flowing through the healthcare systems, we're finding the proportion of patients TTI that are hereditary with polyneuropathy. So, we continue to see In terms of the rest of the world, many countries continue to benefit by patients knowing the site as well as finding new patients. And then we are opening new territories. So every time a country opens, we benefit by EAPs in those countries and patients knowing the site. So again, we see growth in all regions around the world continuing.

43:12 Yeah. And Jeff, anything you'd want to add or Andy to that?

43:17 Nothing for me to add.

43:20 No, I agree. I agree. I think Barry got it.

43:23 Right. Okay. Actually, John, just one thing to add. 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, you know, I think we're beginning to see physicians appreciate, you know, the profile of onpatro in this, you know, mixed population phenotype. So I think that's something to keep an eye on as well.

43:47 Yeah, absolutely. 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 at QS.

43:58 Oh, there's no plan to do it at QS necessarily, Christine. We often start studies in different parts of the world, including sometimes in the U.S. So there's no – it's not a plan to do it at QS per se. Okay. Okay. Thank you. and we'll now take our next question from Maury Waycroft 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, you know from your exploratory endpoints in the phase three Apollo A that Onpatro or Piticerin showed activity in cardiomyopathy phenotypes.

44:50 I'm wondering if you're collecting data from the commercial patients and Onpatro that provides read-through to Apollo B. And when 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?

45:09 Yeah, that's a great question. I'm going to maybe provide some context. Maybe, Akshay, you can comment as well and Barry. You know, 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 form 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 paticerat 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.

46:09 Of course, we'll await the results of that study before we can comment definitively on Petit Saran's activity in cardiac patients. Akshay, anything to add to that from your perspective?

46:22 No, I think you covered it, John.

46:24 Yeah, great. And, you know, I'll just add that, you know, there are always investigational studies that are done by, you know, individual centers or, you know, 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?

46:44 No, I think you covered it well.

46:47 Perfect. Thank you. Maury, I'm going to ask you a question. That does. It's very helpful. And just a quick follow-up for AGT. So in your top-line data, you guys reported around 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?

47:16 Yeah, I mean, we, you know, a lot of these phase one studies are engineered with optional cohorts that allow us to add, you know, additional subjects, patients in this case, to the study design. You know, I think it's still, we still haven't decided, you know, at what point we will have completed that study. But we are still answering important questions, including potentially a 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?

47:51 No, I think you covered it, yeah.

47:55 Great. Does that help, Marty? Yeah, that helps. Thanks for getting my question. Thanks, Marty. We will now move to our next question from Ritu Baral from Cohen. 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 wanted to ask about trends in home administration for Bon Patro. 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?

48:41 and reimbursements and uptake. Is this something we could be, that'll be in the weather going forward to stabilize the U.S.?

48:50 Yeah, that's a great question. Barry, do you want to give the global view and then maybe, Andy, you can add additional color on the U.S. dynamics on that?

49:01 Absolutely, and great question. Home infusion has been a critical care of site that we've utilized through the pandemic. So, in the CDF region, home use was about 17% pre-pandemic, and it's doubled to about 35% in the age of pandemic. France, in fact, was able to move a huge cohort of patients into home infusion when one of the sites reported infectivity with COVID. So, it's been very important. In comment, 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.

50:01 And is that still growing? Is that still growing, like the home infusion rates?

50:08 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 9 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. And could you just go through reinforcement, in terms of allowed reinforcement for

50:48 that? Yep. Thank you. 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 want to say thank you.

51:09 All right, thanks, Barry. Richard, does that answer your question? Yeah, and I just wanted to, could you just review reimbursement?

51:21 Oh, reimbursement. Yeah. Do you want to handle that, Andy?

51:28 Yeah, certainly, certainly. So the reimbursement, clearly, on the commercial side of our population, is very straightforward, and we have many patients that are taking advantage of it. But we also know, right, 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. Does that answer your question? Thank you so much. Yes, thank you so much. Great. We will now move to our next question from David Liebowitz from Morgan Stanley.

52:14 Please go ahead. Your line is open. Thank you very much for taking my question. Given your experience thus far, Steve Laurie, have you, I guess, made any decisions on Lumaceran, what you might want to keep and what you might want to modify as far as the launch given the similarities of the market?

52:35 Yeah, great question. Let me make some initial comments and then Barry, you should comment as well. I mean, obviously, Lumaceran, like Giblari, is addressing a very Thank you for joining us. 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.

53:22 and that effort will occur with all medicines in our pipeline, including Lamassaran. 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 Ampatro, the playbook that we've been executing on for Givlari is one that we will absolutely be using for Lamassaran. Of course, we'll be leveraging, importantly leveraging the existing infrastructure that we've built now globally for the company. Terry, anything to add to that?

53:55 No, this is my question. 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 for COVID. That has all had an advantage to a launch of a disease like PH1 where, again, while the diagnosis rates 50%, there are 50% of patients out there undiagnosed. but being able to reach them in virtual means is going to be highly advantageous. Yeah. Thanks, Barry.

54:26 David, does that answer your question? Yes. Thank you for taking my question. Great. Thank you. We will now move to our next question from Vincent Chen from Bernstein. Please go ahead. Your line is open.

54:42 Thank you very much for taking the questions.

54:44 Two quick ones, one commercially oriented and one on the R&D side.

54:48 First, for Gilari, we realize you're not going to provide any guidance, but I'm curious what you're seeing as far as the trajectory of SART forms coming out of Q2 and going into Q3. I note that incremental SART forms slowed in Q2 relative to Q1.

55:01 I imagine some of this is because you had an initial bolus of patients in Q1, some of this 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.

55:19 We've certainly been watching very closely for a move into the T&S delivery, which could open up a range of very large and high-end medications.

55:29 So it seems like it's taking some time. What are the gating factors on the ALN, APP, IND filing?

55:35 What's left to be done before you can enter human trials?

55:38 Yeah, those are great questions. Let me start with the first one. I'm sure you'll get the second one just in a minute. But your question I give Laurie, 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, you know, the start forms that we saw in Q1, of course, were benefited greatly by patients that were either in the UICAP or that we're known to cite sort of that initial bolus, if you will. But we do expect growth, you know, from that point that we're seeing continued growth, you know, in the U.S. About 25% of our patients in the U.S. are also coming outside of our patient hub.

56:23 Thank you very much. Thank you for joining us. with that growth in the U.S. and also in other markets around the world.

57:10 Now Europe, of course, has now been launched in Germany and in main patient sales around many countries. So I think that we don't need to say anything more about Givlari. Do you want to now actually talk about APP and what's between now and our filing? Sure, yeah.

57:31 I mean, we're delighted with the progress, Vincent. It's about a year since we signed the deal with Regeneron. Next year is exciting and we think 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.

58:01 Does that help, Vincent? Yeah, very helpful. Thank you very much. All right. Thank you. And we'll 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 questions. And, Barry, you'll be next here. So in the context of competitive dynamics in TNH, 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? in the treatment paradigm, and then just a comment on, you know, based on your work in osteohepatic tissues, where you feel most optimistic at this point.

58:48 Great. Thanks, Sabine. 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 Sub-G Saran and Tozolumab, I mean, look, there is no sub-Q alternative that's currently approved today. This is an opportunity to having a sub-Q 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. Thank you very much.

59:54 You know, in frequent presentation, I also think that we have the opportunity to have the most complete blockade of the confidence 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.

1:00:44 We have very exciting data in the ocular compartment as well. And most recently, of course, we shared data on lung delivery. I can't really say, you know, one is my favorite, but 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. And so with all three compartments, as these IMGs hit the clinics, We're looking forward to replicating and replicating the success of our work in the liver with evidence of knockdown clinical efficacy and safety in the brain, in the eye, in the lung, etc.

1:01:30 And 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. So that's just a little bit on the extra hepatic thinking.

1:01:42 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. You know, 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 ATP program that will be the first one to go, but the Huntington's program that will come shortly thereafter and programs that we're obviously advancing in diseases like ALS and Parkinson's and and Alzheimer's, et cetera.

1:02:45 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, Elvin. Thanks, Elvin. I will now take our next question from Gina Wang from Barclays. Please go ahead. Your line is open. Thank you for taking my questions. First, Barry, I agree 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.

1:03:30 I have two questions. One is on Patrick. Just wondering if you can share how much revenue is contributed from Japan. and then for Patrice Ren, wondering any COVID-19 impact on collecting the data.

1:03:47 Great, great question. 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.

1:03:59 Yeah, if I heard the question correctly, the question was about Japanese contribution to Onpatro revenue in the quarter. We don't break out the detail by country, Gina, but Japan was a meaningful contributor to the growth that we saw outside the U.S. in the quarter, and we highlighted in the prepared remarks that Japan now has become the second largest market for Onpatro on a dollar sales basis based on the Q2 results.

1:04:26 and Akshay, do you want to comment a little on the Vutrisaran management of the study?

1:04:34 Yeah, I mean, both for Vutrisaran and Patisaran 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 Sitesoft speak to patients over the phone and other means. We've had home administration of drugs. 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.

1:05:24 And we're also pleased with the fact that with things opening up, as we've seen on the commercial side, you know, we're seeing very good pickup in enrollment as well in these studies.

1:05:34 Yeah, and I would just make, because I think, Gina, your question was also focused on Helios A, which, of course, was completed. Oh, sorry. 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 misdoses or minimal misdoses during the course of that study. So that's what applies to Helios A. Thank you.

1:06:06 Great. Thanks, Gina. 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 my questions and congratulations, Barry. I'll miss you. So you mentioned there that you've submitted an IMD for the HSD program. So there's been a development of regulatory challenges around NASH. I'm wondering if you can give us an update on your plans and strategies on how you differentiate it.

1:06:44 Great. Thanks, Alan. So I'll show you that question was on ALNHSD and NASH and our plans there. Do you want to comment further?

1:06:53 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. 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 better than 50% from our animal work with our drug candidates. So it's great to get this to the clinic.

1:07:41 Phase one will be all about safety, PK, and we'll collect a number of exploratory biomarkers. HST17B13 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 two, 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.

1:08:26 But those details are to come. For now, you know, we have to focus on the phase one. Okay. Thanks very much, Anthony.

1:08:34 Thanks, Alan. We will now take our next question from Mani Foroohar from SCB Learing. Please go ahead. Your line is open. Thanks for taking the question and congrats Barry and Yvonne as well. Although with Barry gone, I guess Yvonne, you're going to have to get much better at telling me how I'm wrong all the time about everything. A quick commercial question about Ampatra. Obviously, there was a little bit of a decline in terms of patient adherence, which is not surprising. I know the PKM-RNAI assets is very unique because of pharmacokinetics, but is there an avenue to any catch-up dosing in any situation, potentially getting back temporarily on an IV dosing schedule that could be a little more frequent than what's labeled?

1:09:24 I.e., could you recapture something at lost revenue, or do you think people will end up back on the labeled dosing frequency? And then secondarily, in... In thinking about Helio B, you talked about potential interim, when that would look like. How do you 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 interim or not, in terms of just giving us some sense of when we should expect that event?

1:10:01 Yeah. 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 two, three 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 are and some misdoses 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.

1:10:49 Andy, do you want to comment any further on that? I think I covered it, but you might have some other perspectives.

1:10:54 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.

1:11:04 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. And 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?

1:11:42 No, no, nothing to add.

1:11:45 Okay, good.

1:11:47 Thanks, guys. Thank you. We will now take our final questions from Navin Jacob from UBS. Please go ahead. Your line is open. Hi, everyone. Thanks for taking the question. This is a shriek on for Naveen Jacob. Just on Onpatro, Yvonne mentioned combination therapy, and you previously stated that there's teams that are on both and Onpatro. Can you give us an update of what percentage 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, Just mentioned some reduction in gross to net.

1:12:32 How should we think about pricing trends as the year goes on? Thanks very much.

1:12:36 Okay. So let me start on the combination use, the common use that's occurring up there as we go. Here from the marketplace, these are 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 Onpatro. And in some cases, those patients are also on a TPR stabilizer. So we're just aware of that. And we have market research that says that it's 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 from our previous phase two of the label study, and that published paper showed that the combination was safe and the level of TTR knocked down was as good as mammotherapy, but there was no formal assessment of, you know, 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.

1:13:46 But, Andy, do you want to comment a little bit further on dynamic, on concomitant use that we're seeing in the marketplace? Sure. 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.

1:14:03 Yeah, happy to. So since the fourth quarter of 2019, in the U.S., we've been seeing growing evidence of reimbursement for Ampatro where used concomitantly with TPR stabilizer products, which at 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. Right.

1:14:37 And then your pricing question, Jeff, do you want to handle that?

1:14:41 Yeah, sure. The comment on PATRO 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. You know, 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 from PATRA will be very consistent with what we experienced in 2019. And the expectation is mid-20s for the year.

1:15:16 Great. Does that answer your questions? Yeah, thanks very much.

1:15:21 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 El Milo. 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. Ladies and gentlemen, this concludes today's call. Thank you for your participation. You may now disconnect.