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Alnylam Pharmaceuticals Inc
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Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call Q3 2020 Earnings Call. 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'd now like to turn the call over to the company.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, Chief Executive Officer; Andy Orth, Senior Vice President and Head of the U.S. Business; Akshay Vaishnaw, President of R&D; Jeff Poulton, Chief Financial Officer; and Yvonne Greenstreet, President and Chief Operating Officer.
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 on slide two, John will provide some introductory remarks and provide some general context. Andy will provide an update on our global commercial progress. Akshay will review recent clinical and preclinical updates. Jeff will review our financials and Yvonne will provide a brief summary of upcoming milestones, before opening the call to your questions.
I would like to remind you that this call will contain certain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual and quarterly reports and 8-Ks on file with the SEC.
In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.
With that, I'd like to turn the call over to John.
Thanks, Christine, and thank you everyone for joining the call today. We believe the third quarter and recent period highlight the tremendous progress Alnylam has made as a global commercial organization, with a highly productive R&D platform.
Starting with our commercial execution, we saw strong ONPATTRO and GIVLAARI performance in Q3, which Andy Orth will review momentarily. We have continued confidence for the rest of this year, with another upward revision of our ONPATTRO revenue guidance range for 2020 and another beat for GIVLAARI relative to estimates.
Akshay will review our recent R&D progress shortly, but the highlight in the recent period is the positive CHMP opinions recommending approval of OXLUMO, or lumasiran, and LEQVIO, or inclisiran, which set us up with the potential to achieve four RNAi therapeutic approvals and launches in less than three years, a truly remarkable achievement.
You'll also hear from Jeff on our financial performance and our progress towards achieving a self-sustainable financial profile. We believe we're on our way. Indeed, at Alnylam, we're focused on continued global commercial execution on potentially transformational medicines, excellence in productivity from our organic R&D efforts, while maintaining a clear line of sight towards financial self sustainability.
In fact, this is what we envisioned when we established our Alnylam 2020 goals back in 2015, that we’d be a multi-product global company with a deep clinical pipeline for future growth and an organic product engine for sustainable innovation. That moment is now upon us and we couldn't be prouder of our achievements toward those variable goals which we're on track to actually exceed. And we couldn't be more excited for the next phase of Alnylam's evolution.
We will lay out our multi-year vision soon. And we look forward to delivering on our potential as a top-tier biopharmaceutical company focused on advancing medicines, with transformative potential to patients around the world.
Now before I hand it over to Andy, I'd like to mention that we plan to host a virtual R&D Day event on the mornings of December 15 and 16, where we'll be reviewing progress across our pipeline of investigational RNAi therapeutics. We hope you'll be able to join us online.
So with that, let's now turn to a review of our commercial and medical affairs progress. Andy?
Thanks, John, and good morning, everyone. I'll begin by reviewing our commercial performance in the third quarter, as well as our medical affairs progress. For ONPATTRO, we achieved $82.5 million with cardiologists making up more than half of new prescribing physicians. In the United States we also continue to see a steady rate of concomitant use of ONPATTRO with TTR stabilizers and expect this trend to continue to grow.
Turning to the rest of the world. We made very encouraging progress with ONPATTRO in the third quarter with $43.5 million in revenues from ex-U.S. markets. As noted last quarter, we have secured access in all priority markets in Western Europe including Portugal following our Q3 launch. We are also pleased with the continued growth in Japan, a country of strength for ONPATTRO. An important dynamic observed in ex-U.S. is patients switching to ONPATTRO from stabilizers for the potential to halt or reverse disease progression in hATTR patients with polyneuropathy. This dynamic represents greater than 50% of new ONPATTRO patients outside the U.S.
Our medical affairs team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis rates of hATTR amyloidosis, including with Alnylam Act, our third-party genetic screening initiative in the U.S., Canada and Brazil. As of October, greater than 30,000 samples have been submitted out of which approximately 1,800 have tested positive for pathogenic TTR mutation. We are encouraged by the recovery in Alnylam Act genetic testing volumes we've seen in recent months and we believe these volumes will continue into the fourth quarter.
We've also seen continued recovery in the number of PYP scans conducted for detection of cardiac amyloid. As you know, hATTR amyloidosis is a multi systemic disease. And in the U.S. detection of cardiac amyloid is often the first step in an overall diagnosis of the disease as many of these patients also had polyneuropathy. ONPATTRO continues to be recognized as a breakthrough for patients with hATTR amyloidosis with polyneuropathy and we're honored to have received the highly prestigious Prix Galien USA Award just last week.
Moving on to GIVLAARI. We achieved $16.7 million in global net product revenues in the quarter with over 150 patients now on commercial drug. Our progress with patient access in the U.S. has been strong having now finalized 10 value-based agreements or VBAs with U.S. payers. We currently have confirmed access for over 90% of covered U.S. lives. We've not experienced any payer headwinds with GIVLAARI to date and we're pleased to see the majority of plans adopt medical policies without restrictions to the number of baseline attacks.
The SEMEA region saw great progress as well, with a successful ongoing GIVLAARI launch in Germany and name patient sales in other countries including France. We're off to a very strong start for market access in SEMEA. In France, GIVLAARI received an improvement of medical benefit or ASMR score of two concluding it offers significant additional therapeutic value. Additionally, GIVLAARI obtained a considerable added benefit rating in Germany with only 15% of all orphan drugs achieving such a high rating and we secured a strong HCA rating in Italy. We're also excited to assume that our launch underway in Canada, following the recent approval and look forward to the completion of the ongoing review of our NDA and Japan which was submitted in September.
Finally, our commercial fairs teams are prepared for the upcoming launch of OXLUMO the brand name for lumasiran. With a positive CHMP opinion in hand in the EU and an FDA PDUFA date just weeks away on December 3rd, we look forward to soon bringing our third RNAi therapeutic to patients around the world. We are well prepared with our OXLUMO supply chain and are ready to deploy our trained U.S. field team upon approval to help get this important medicine to the underserved primary hyperoxaluria type one or PH1 community. As with our other launches and guided by our patient access philosophy, we are hard at work making sure that patients who need OXLUMO are able to access it. Constructive conversations are ongoing with payers regarding DBA arrangements and we look forward to updating you further upon launch.
In conclusion, the third quarter highlighted the broad capabilities of our commercial and medical affairs operations including the continued growth of ONPATTRO, the continued launch of GIVLAARI and the preparation for the launch of OXLUMO. And we'll be watching with excitement as Novartis prepares to launch LEQVIO or inclisiran, which will mark the entry of RNAi therapeutics into a highly prevalent chronic disease indication.
With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay?
Thanks, Andy, and good morning everyone. I'll start with our efforts in ATTR Amyloidosis where we're advancing our two product candidates patisiran and vutrisiran. ONPATTRO is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATG amyloidosis, we committed to expanding the products label for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients.
To this end, we're conducting the APOLLO-B Phase III study. We continue to enroll patients in APOLLO-B and continue to expect completion of enrollment in 2021 due to impacts from the COVID-19 pandemic. During Q3 we saw a pickup in the pace of enrollment and are still aiming to make up for lost time that we experienced during Q2 due to the pandemic.
We're also advancing vutrisiran for the treatment of ATTR. Vutrisiran is delivered by a quarterly subcutaneous injection. Here we're conducting two Phase III studies. The first Phase III study is HELIOS-A which is evaluating patisiran in hATTR patients with polyneuropathy. Enrollment is complete in EFA and we remain on track to report top line results early next year.
The second Phase III study of vutrisiran is HELIOS-B which has been conducted in hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy and this study is actively enrolling. On NTKR RNAi roundtable in September, we shared modeling data suggesting the potential for a biannual dosing regiment for vutrisiran which can further differentiate vutrisiran from other products currently approved or in development are actively advancing our efforts to bring a Q6 monthly dose of the regimen to the market in parallel with our ongoing development of the Q3 monthly regimen.
Moving now to GIVLAARI which is approved in the U.S., EU, Brazil and in Canada to treat acute hepatic porphyria. We're pleased with continued base supporting a positive risk benefit profile. For example during the third quarter, we presented new interim data from the Phase I/II OLE study of GIVLAARI showing maintenance, clinical activity with continuous monthly dosing with a further numeric reduction in the annualized attack rate. The safety profile remains consistent with no new safety findings.
I'll now turn to recent progress with lumasiran an investigational RNAi therapeutic that we're developing for the treatment of primary hyperoxaluria type one or PH1. And we're also thrilled to receive last month a positive CHMP opinion, recommending approval of lumasiran for the treatment of PH1 in all age groups. Recently we presented full results from the ILLUMINATE-B study of lumasiran pediatric patients less than six years old.
In the study, treatment with lumasiran led to a 71% mean reduction in spot urinary oxalate creatine ratio from baseline to month 6 which was the primary endpoint of the study. Lumasiran also demonstrated positive results across secondary end points including 50% of patients that have seen very late levels at/or below 1.5x the upper limit of normal.
The most common drug-related adverse events were mild and transient injection site reactions reported in 17% of patients. The overall efficacy and safety profile of lumasiran was consistent with that observed in adults and children six years or older in the ILLUMINATE-A study.
In both ILLUMINATE-A and B studies, we continue to see encouraging evidence towards certain clinical events such as nephrocalcinosis and Renal Stone Events or RSE. In ILLUmiNATe-A, we previously reported on encouraging results with improvements in nephrocalcinosis and exploratory endpoint.
At ASM we showed some initial results from ILLUMINate-A on improved RSEs with continued dosing. Based on the preliminary analysis of exploratory endpoints and ILLUMINATE-B treatment with lumasiran led to bilateral or unilateral improvements in nephrocalcinosis in 44% of patients with no patients worsening and eGFR is remaining stable. These results were similar to effects on nephrocalcinosis seen in ILLUMINATE-A study.
We now await regulatory decisions and continue to believe that lumasiran will be approved by the FDA by the PDUFA action date of December 3 and by the EMA later this year as well. In the meantime, we continue to enroll patients in the ILLUMINATE-C Phase III study of lumasiran for the treatment of advanced PH1 patients of all ages with data expected in 2021.
As you know we have two additional late-stage programs that are in developing with partners. This includes inclisiran, in development for hypocholesterolemia partnering with Novartis which is in registration in the United States and the EU. We're delighted that inclisiran has also received a positive CHMP opinion recommending approval of the drug in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia.
If approved, it will be marketed under the brand name LEQVIO. Our late-stage programs also includes, FITUSIRAN in development for hemophilia A or B with or without inhibitors partner with Sanofi. FITUSIRAN is under evaluation in the Phase III ATLAS program.
Now in addition to our late-stage clinical programs we believe, we have also been making great progress with our early and mid-phase programs. Our partner VIA has initiated dosing of ALN-HBV02 or VIR-2218 with interferon in a Phase II study in patients with chronic hepatitis B infection.
We're very excited about the clinical data already presented to this molecule. As a reminder Alnylam's retained the right to opt into a 50-50 shift program prior to the start of Phase III. In our ALN-AGT program, we believe we have an opportunity to re-imagine the treatment of hypertension with chronic controlled blood pressure.
We look forward to presenting results from the Phase I study of ALN-AGT, at the American Heart Association Meeting next week. Also in the recent period, we made progress with ALN-HSD an investigational RNAi therapeutic for the treatment of NASH that is being advanced in collaboration with Regeneron. We were pleased to report today that we've initiated dosing, in the Phase I study of ALN-HSD.
We also continue to make strong progress on our many preclinical RNAi therapeutic opportunities beyond the liver. Notably, we continue to advance our CNS and ocular efforts with Regeneron. Our ALN-AGT program remains on track for a CTA filing in mid-2021. and we're pleased that Regeneron has elected to exercise its co-development co-commercialization option on this program with Alnylam retaining the lead.
ALN-CoV [ph] or ALN-COV is our investigational RNAi therapeutic targeting the genome the SARS-CoV-2. The virus that causes COVID-19 is partnered with COV [ph]. Based on recent preclinical studies and animal model of COVID-19 infection, we've decided to generate additional animal model data prior to further program advancement.
Accordingly, our IND filing timeline will be delayed. As John previously mentioned, we look forward to highlighting all of this progress an upcoming R&D day virtual event planned for December 15th and 16th later this year.
With that, let me now turn it over to Jeff to review our financial results.
Jeff? Thanks Akshay and good morning everyone. I'm pleased to be presenting now Alnylam's third quarter 2020 financial results. As Andy has already highlighted, it was a very strong quarter with outstanding results for both ONPATTRO and GIVLAARI.
Turning to our results first for ONPATTRO, we generated $82.5 million in global net ONPATTRO revenue for the quarter, which represents a return to growth driven by strong commercial execution and improving market conditions, following Q2 which was negatively impacted by the pandemic.
Global sales increased 24% versus the second quarter of 2020 and 79% compared with Q3 2019. U.S. sales ONPATTRO increased 21% versus Q2 2020 with primary sources of growth from the following. Patient demand increased 14%, driven by an improvement in patient compliance, which returned to pre-pandemic levels as well as the addition of new patients during the quarter.
Modest inventory stocking during the quarter, compared with destocking during Q2 offset by a slight increase in gross to net sales reductions, favorably impacted Q3 growth by 7%. We ended the quarter with less than two weeks of inventory in the channel. We are really pleased with the strength of the results in the U.S. in the quarter with Q3 sales representing the highest level since launch.
Our international markets ONPATTRO performance remained strong with growth of 27% versus Q2 of 2020, with primary sources of growth from the following. An increase in patient demand contributed 19% growth and was primarily from major markets in Europe, where we achieved recent PNR outcomes, including from Portugal. We also saw continued excellence from Japan.
Source of new patients in our international markets remains balanced between patient switches, from ATTR stabilizer in new patients naive to treatment. Additionally, there were one-time benefits associated with finalizing our pricing brands. And we're completing our initial access agreement in Canada, which contributed an additional 8% growth in the quarter.
Turning to our results for GIVLAARI, we had a strong third quarter, generating $16.7 million in global net revenue, representing 52% growth compared to the second quarter of 2020. This positive performance continues to be driven by ongoing launches in both, the U.S. and Europe. And we now have more than 150 patients on commercial therapy globally.
Turning now to a summary of our full P&L results for the quarter, net revenue from collaborations for the third quarter was $26.6 million, primarily due to revenue recognized from our VIR and Regeneron collaborations. Gross margin as a percentage of total revenue was 83% for the quarter, down from 93% in Q3 2019, primarily due to the current utilization ONPATTRO full cost inventory, while last year benefited from zero cost ONPATTRO inventory as well as having a higher proportion of sales in the third quarter of 2020 coming from lower margins in international markets and a write-off of ONPATTRO inventory at our contract manufacturer.
Our R&D expenses increased on a non-GAAP basis in the third quarter 2020 compared to the same period in 2019, primarily due to the continued investment in advancing our late-stage pipeline programs.
SG&A expenses increased on a non-GAAP basis in the third quarter of 2020, compared to the same period in 2019, primarily due to increased investment in commercial and medical affairs activities to support the ongoing launches of ONPATTRO and GIVLAARI and the launch of preparation activity stroke hemo.
Our non-GAAP operating loss for the quarter decreased by approximately $12 million compared with the same period in 2019, driven by strong top line growth and 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 remainder of the year.
We ended the quarter with cash, cash equivalents and marketable securities of $1.8 billion, which includes $600 million in proceeds received in the second quarter of 2020 from the partial sale of future inclisiran royalties and issuance of common stock to Blackstone.
Finally, turning to our financial guidance. We believe our results for the third quarter continue to demonstrate successful commercial execution in challenging circumstances. As a result of the strength of our Q3 ONPATTRO results, we are increasing our full year 2020 revenue guidance for ONPATTRO from $280 million to $300 million to $295 million to $310 million, representing a 4% increase from the midpoint of the prior range and the midpoint of the new range.
Our guidance for net revenue and collaborations and our guidance range for combined non-GAAP, R&D and SG&A expenses remain unchanged. However, we are expecting our combined non-GAAP, R&D and SG&A expenses to end the year towards the upper end of our guidance range, driven by an expected increase in Q4 in both R&D expense as we continue to make good progress in advancing key clinical stage programs and SG&A expense, primarily driven by increased spend in support of our planned launch of OXLUMO.
Please note we have revised the midpoint of our GAAP combined R&D and SG&A operating expense guidance range upward by $30 million, primarily reflecting an increase associated with the contingent liability related to our arbitration with Ionis.
Regarding cash, as mentioned in our second quarter call, we continue to believe our strategic financing collaboration with Blackstone, adding up to $2 billion, 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?
Thanks, Jeff and hello, everyone. As we look to close out 2020, we have a number of very important and exciting milestones lined up. For starters we plan to continue our global commercialization of both ONPATTRO and GIVLAARI. We're also expecting two additional regulatory approvals by the end of the year for lumasiran and inclisiran in both the U.S. and Europe.
We expect to launch OXLUMO in the U.S. by year-end. We plan to continue enrollment in our ATTR cardiomyopathy studies, specifically APOLLO-B with patisiran and HELIOS-B with vutrisiran. We look forward to presenting additional clinical results from the ongoing Phase I trial of ALN-AGT in hypertension at a AHA meeting on November 13.
And our partner Regeneron plans to initiate a Phase I study for cemdisiran in combination with pozelimab, as a potential therapeutic option for the treatment of complement-mediated diseases. We also look forward to updating you on our overall pipeline progress and strategy. It's our virtual R&D day event in December.
As John noted earlier, these are very exciting times for our Alnylam, as we expect to exceed our original Alnylam 2020 guidance. Exiting this year as a global multiproduct commercial company with a robust clinical pipeline for continued growth and an organic product engine delivering sustainable innovation.
Let me now turn it back to Christine to coordinate our Q&A session. Christine?
Thank you, Yvonne. Operator, we will now open the call for questions. [Operator Instructions]
Thank you. [Operator Instructions] We'll take our first question from Gena Wang from Barclays. Please go ahead. Your line is open.
Thank you. Thank you, for taking my questions, and congrats on a very strong quarter. So one question regarding the commercial. First for the ONPATTRO, do you expect for the full Q, any thoughts on the inventory and where the major driver would be for the remaining of the year? And also for lumasiran, could you share with us the number of patients in early access program right now?
Yes. So, thank you Gena. Let's -- I'll go to Andy and Jeff on the ONPATTRO question specifically. Regarding the lumasiran EAP, we're not giving out specifics on patients that are in the program. But I will say at a high level that, obviously we do have patients in our expanded access program. And obviously, as lumasiran gets approved, we will be transitioning those patients onto commercial product on a country-by-country basis based on TNR being achieved. So, that's where we'll leave that question. Andy, do you want to start? And then, maybe Jeff you can comment on the impact of inventory. But I think, Andy you can give a bigger picture, a Q4 expectations for ONPATTRO?
Sure. Happy to. So as we noted Q3, the growth was a mixture of both, net new patient demand, as well as a return to an increased compliance rate specifically in the United States post that Q2 COVID impact. In Q4, we expect the growth to come primarily from that net new patient demand. And I'll turn it over to Jeff here on the inventory side.
Yes. Hi everybody. In terms of where we are in inventory, Gena, at the end of the third quarter for ONPATTRO were less than two weeks. And based on the distribution agreements we have, that that range is typically in the one to three weeks range. So, again we're right -- maybe right in the middle of that at this point.
Okay. Great. Thank you, very much.
Thanks Gena.
We'll now take our next question from Tazeen Ahmad from Bank of America. Please go ahead. Your line is open.
Okay. Thanks so much for taking our questions. So, I wanted to get a sense of what information we should expect to see when the topline readout from the HELIOS-B study early next year. And whatever that data does show, should we have any reason to think that there would be read-through into the population that you guys are spending in cardiomyopathy in the HELIOS-B study? Thanks.
Yes, that's a great question Tazeen, and I'll let Akshay handle it. Let me just start by saying, we're very excited about vutrisiran because it is obviously going to enable a once quarterly subcutaneous dose administration and potentially with additional work we believe that we can introduce a biannual dosing regimen for patients with hATTR. Initially, it will be for the polyneuropathy setting with the HELIOS-A study. And then, obviously, the focus will be in HELIOS-B and cardiomyopathy, both hereditary and wild-type. So Akshay, do you want to comment specifically on Tazeen's questions around what will be available at the topline and what potential read through there will be on the cardiomyopathy from HELIOS-A?
Yes. Thanks, John. So vis-à-vis, HELIOS-A topline, we continue to believe that we'll have the data early next year. So that's very exciting. Our general habit, when we present topline is to give the primary endpoint and none of the secondaries and also of course the safety information on the study at a high level that's relevant to the report. We then report more fully on all the details at an upcoming scientific meeting after that. So it should be very informative as to how the studies done I think, and vis-à-vis the read-through into cutting myopathy in HELIOS-B.
If we come back to APOLLO, the original APOLLO study with ONPATTRO, I think we learned a lot there about the impact on biomarkers, impact on findings heart. In about 50% of the patients that had some evidence of cardiomyopathy within that study population from ONPATTRO. Now it remains to determine exactly what proportion of patients have cardiac involvement here in HELIOS-A, but it will be exciting to see what the impact have been on not just biomarkers, osteoblastic disease in terms of further read through but very much dependent on the info population.
Thanks Akshay. Does that -- Tazeen, does that answer your question?
Yes. And when you say early next year, can you -- is it possible that the data would be in January, or are you not providing that level of granularity?
Yeah. We're not going to provide that level of granularity Tazeen. Our early period as you know is Q1 or Q2. But I think it's going to be early.
Okay. Thank you.
We'll now take our next question from Paul Matteis from Stifel. Please go ahead. Your line is open.
Great. Thanks so much, and congrats on the quarter. Two questions, one, on vutrisiran, do you think you could bridge to the six-month dose with just TTR lowering data and safety? And if so what's the status of that clinical work?
And then second on lumasiran on the Wall Street side expectations of this drug are materially lower than that vutrisiran, but I think some of the prevalence data for PH1 and two, three that you've outlined are not that dissimilar to HP. So do you think that vutrisiran is a realistic analogue for this? If so or if not, can you give any context? Thanks.
Yeah. Thanks Paul and great questions. I think for starters on the vutri two, six monthly at a high level, it is certainly our belief that TTR lowering combined with safety should support that approach. And we've been encouraged by engagement that we've had with regulators on that point. So I think that is certainly a path we're forward. And that would be consistent with other types of medicines and we're dose regimens with a strong biomarker have been supported in future labeling. But, obviously, that will require those data to be generated and then obviously submitted as part of an SNDA and that would be the overall plan.
Regarding OXLUMO and the market size, I'll let Andy comment a little bit on that further. But I think in general when we look at the prevalence out there, we do believe that there are somewhere between $1,000 and $1,700 patients that are diagnosed and would be on label if you will patients that have mild to moderate PH1, which would be the initial label prior to then expanding it to include severe PH1.
Andy do you want to comment any further on the PH1 population and how we should think about lumasiran relative to GIVLAARI?
Sure John. Thanks. And as you said here we're at this point expecting that number somewhere between 1,000 and 1,700, it will be addressable and on-label. And overall market opportunity we do see luma becoming a $500 million brand as it launches globally. And furthermore right, we're excited to get out there and continue to shape this market, which is largely to this point pretty underserved. So we'll be learning a lot as we go.
Terrific. Does that answer your question?
Thank you.
We'll now take our next question from Anita Gupta from Cowen. Please go ahead. Your line is open.
This is Anita for Ritu today. Congrats on the quarter. So two questions from my side. Do you expect the fourth quarter, new lockdown impacting better or worse than the second quarter lockdown impact?
And then secondly, understood that it's unclear how my cardiomyopathy patients would be in HELIOS-A study, but if you do plan to provide a subgroup cardiac analysis, what would be the primary function outcome of such an analysis? Thank you.
Great. Well, I'm going to have Akshay answer the second part -- second question. But regarding the first question, let me just give a high level and then Andy you can comment. Look at a high level it's our belief that the medical system is more adapted at this point than it was in Q2. This is -- I'm saying this globally from a global perspective. And for the most part we have seen a return to medical procedures and diagnostic testing done in -- globally. And therefore, we believe that even with shutdown of countries that will occur -- would occur as we go into Q4 to deal with the second wave or third wave depending on where you are. We do expect the medical system to stay relatively open. Relative to what it was up in Q2. Andy do you want to add any more color to that?
Yes. You've got it right, John. And furthermore, yes, the health care systems learn how to navigate and are showing that now was increased patient flows coming through maintenance of therapy for all levels of all patients continuing, but we have learned as well how to navigate this both on a promotional basis and continuity of care. So we're in a much better position here to weather what may come.
Fantastic. And Akshay do you want to answer the HELIOS-A question?
Yes. Thanks. You've got to remember that the primary goal of the studies is to study the neuropathic aspects the disease. So most of the endpoints are focused on that primary endpoint and so forth. Now as I said before to a previous question we will see how many cardiomyopathy patients or patients with true cardiomyopathy we have, and report out all the data that we've collected including biomarkers outcome. In terms of the primary functional outcome as you put it, I guess, the most important would be hospitalizations and deaths. But again the study is not orientated towards cardiomyopathy. So I don't know, exactly how many of those events would have occurred but we'll certainly be sharing them in due course.
Great. Does that answer your question?
Yes. Thank you.
Fantastic.
Moving on to our next question from Alethia Young from Cantor Fitzgerald. Please go ahead. Your line is open.
Great. Thanks. This is Emma Nealon on for Alethia. Thanks for taking my question. In light of some of the recent progress on challenges in AAT. We're curious to see how you're thinking about plans going forward with this smart zen for RNAi. And do you think that combination is to [Indiscernible] RNAi has come a long-range goal here? Thanks.
So I'm not sure, I heard you clearly on the first part because Emily, could you repeat what area are you commenting on specifically?
Sir, AAT. In light -- early.
Alpha1-Antitrypsin?
Yes.
Okay. Got it. Absolutely. Yes. Look, I mean, we are excited about the potential for RNAi therapeutics to treat the liver disease associated with Alpha1-Antitrypsin deficiency, and obviously, have advanced a molecule Alpha1 ALN-AAT-02 into development. Now earlier this year, we decided to partner that program together with Dicerna who has their own independent effort as well. And so the combined effort between Alnylam and Dicerna now really is positioned to advance quite nicely and isn't currently going to be -- is in a Phase I/II study, we'll be going into a Phase II/III in due course. So we're definitely excited about the opportunity, the way the partnership with Dicerna works is they will advance the program 100% on their cost. We retained an opt-in right at the end of Phase III. So after all the risk is taken out. It's a free option that we have to commercialize outside the U.S. market. So they'll keep the U.S. and we'll have the rest of the world. So we are encouraging our colleagues at Dicerna to move swiftly with the program. And we do think that it becomes a very competitive opportunity to deal with the liver manifestations.
Yvonne, anything else from your perspective to add as it relates to the Dicerna relationship?
No, John, I think, you've covered it really well.
Right. Emily, does that answer the question?
Yes. Thank you.
We'll now take our next question from Ted Tenthoff from Piper Sandler. Please begin.
Hey thank you very much. Just to congratulate you on continued excellent execution on the commercial side, especially during the difficult time.
Thank you.
Really incredible just how over the years the business come down how you're treating patients so effectively now. My question is related fitusiran, a lot the others were answered. But kind of what's the latest there?
And we haven't really talked about that one as much recently just because there's been such a focus on the success with the other programs. But kind of how have you seen that market change a little bit over the last year? And where do you think that fits for Sanofi and for you guys going forward? Thanks.
Yes. Thanks Ted. Thanks -- first of all, thanks for the comments the congratulatory comments at the beginning. But on fitusiran, specifically, as you know this is partnered and as you mentioned this is partnered with Sanofi. It's an RNAi therapeutic that targets antithrombin with the goal of increasing omnigeneration to improve hemostasis in patients with hemophilia A hemophilia B with and without inhibitors. So, it really is an attractive target product profile that we've constructed for the molecule.
The program is in Phase III. It's being led by Sanofi and we really rely on their continued execution of the program. So, we hope to learn more in the next period. And so that's where it is. But I think for the most part Sanofi really has been the driver of the program and it's ultimately their call in terms of how they advance it. I don't know Akshay or Yvonne anything else to add to that from your perspective?
I think the other thing I'd add is to put the hemophilia landscape continues to need innovation the adoption -- shows that people are keen to find therapies other than multiple times a week intravenous factor replacement. And so I'm very excited about fitusiran hopefully as a growth home for growth in hemophilia A and B with and without inhibitors. But as John said, Sanofi would guide you on further progress with the program.
Yes. Great. Thanks. And can you just remind us your commercial interest there? Thanks guys.
Yes. So, we have a very important point. So, we have reciprocal we have royalties on fitusiran that range from 15% to 30% tiered to sales. So, we have a -- we do have a significant and attractive financial interest in the product success. No question about it.
Great. Thanks so much.
Thanks Ted.
Our next question comes from Anupam Rama from JPMorgan. Please go ahead.
Hi guys. Good morning. This is Tessa on the call John. Thanks for taking our question. So, for the APPOLO-B trial enrolling in ATTR-CM I think you noted that enrollment is expected to complete in 2021. So, when considering a potential for an internal analysis here what are the factors that you're considering?
And then a second quick one. On the ALN-AGT at update next week at AHA can you just give us a quick sense on the size and scope of the data we'll be seeing at the conference there next week? Thanks so much.
Yes. Terrific. Great questions. Let me just first clarify with APOLLO-B which is the patisiran study in both hereditary and muller cardiomyopathy. That's a 12-month study. There is no interim analysis. You certainly are right regarding an interim analysis on HELIOS-B. So, I just want to clarify what trial.
Yes. I'm sorry John I meant HELIOS, I misspoke.
It's okay. I wanted to clarify. Okay. So Akshay do you want to comment on HELIOS-B a little bit an interim analysis? Akshay are you on mute?
The HELIOS-B the interim analysis obviously is going to be very interesting to execute on. We've picked up enrollment very well this year after that slow Q2 with COVID. So, as we further enroll in that study and also importantly completion of the APOLLO-B study which will give important information on how our TTR reducing approaches impact cardiomyopathy that information will be a strategic important I think in design of the interim analysis, which we're busy working on. And we'll share further details with you as enrollment picks up and we get anything from APOLLO-B ultimately as the result we thought.
With respect to your other question Tessa, on ALN-AGT at American Heart next week. Yes, that's the first time we'll be sharing all the base that we have. There will be obviously safety. First and foremost, it's the first human study. We'll also be sharing all the pharmacodynamic based on target knockdown and how that relates to change in blood pressure.
We've reported that there are significant changes in blood pressure, but you'll see all the data in full including dose dependents and the extent of change in systolic and diastolic et cetera. And I think people will come away with the good insight into the frequency of those things and we obviously continue to believe that this will be an infrequently administered therapeutic for hypertension as we further develop it which will give great advantage to this patient population were compliance a huge issue in about half the patients. So that's kind of the thumbnail on what's coming up next week.
Great. Thank you so much both for taking our questions.
Thanks, Tessa.
We'll take our next question from Joel Beatty from Citi. Please go ahead. Your line is open.
Great. Hi and thanks for taking my question. For Alnylam HSD in NASH that recently initiated study. Could you discuss the potential to evaluate any efficacy or biomarker endpoints?
Absolutely. Akshay, do you want to talk about the HSD Phase 1.?
Yes. So that study is ongoing, will progress from healthy volunteers those sending fashion into a subset of patients with NASH itself. The target HSD, it doesn't circulate in the blood. So like a lot of our programs. We don't have direct biomarker data on the target itself, but there are a number of other downstream factors that we're looking at in terms of biomarkers and we believe will be highly informative. We'll share more on that as the program progresses and the study progresses next year. And ultimately I think what goes on in the liver in the NASH patients will be of great importance both biochemically as well as radiological and we'll share that as the study matures.
Yes, I'll just add to that. I'll just add to that that we also have our upcoming R&D Day in December and that will be an opportunity for us to do more of a deep dive on the HSD opportunity and the clinical plans for that program. But it is an exciting program because it is a genetically validated target for NASH. And we think it obviously hold great promise in that important indication.
Thanks, John.
We'll now take our next question from Maury Raycroft from Jefferies. Please go ahead. Your line is open.
Hi, everyone. Good morning. Congrats. And thanks for taking my question. First one is also on the ALN-AGT program for the data next week. I'm just wondering if you're going to have some data from the additional exploratory cohorts including these patients soft control cohort in our combo cohort as well. And if not I guess what's the latest status with those cohorts? How meaningful are they? And then what are next steps with the broker?
Okay. Great questions. I mean the simple answer is you won't see those cohorts next week because they haven't been dosed yet. But Akshay, do you want to comment a little bit on the next steps for those cohorts and just the completion of the Phase 1?
Yes. So Maury obviously, the study did get delayed in part through Q2 with COVID and so forth, which hit that study like so many others. We've picked up steam. We haven't commenced those things as John said, yes, but we are in place now to start those things. Those cohorts and that will be ongoing through the rest of the year. And due course, we'll report where we'll give a further update on the Phase 1 study early next year in terms of scientific meeting where we can bring that information to everybody.
But most importantly next year, I think beyond the clear anti intensity effect which we believe we've established and everyone will share in next week at AHA. The most important thing is to take that observation into the Phase 2 setting and we're very busy aligning on the design of the Phase 2 effort and getting going with that next year. So that's the crucial next goal.
Yes. And I would just add Maury that again our upcoming R&D Day we will do a deep dive on the potential opportunity because we think it is obviously an exciting prospect for new innovation coming from the Alnylam pipeline.
Got it. Thank you very much for taking my questions.
Thank you.
Moving on to our next question coming from Salveen Richter from Goldman Sachs. Please go ahead. Your line is open.
This is Sonia [ph] on for Salveen. So just really a quick question on the progress of your extrahepatic portfolio particularly only with ALN-APP when can you expect First data there?
Yeah. Thanks Sonia. Well, I'm glad to get a question like this, and I'm sure Akshay is as well. Let me just say at the start and remind everybody that one of the exciting breakthroughs that we achieved over the last couple of years is the delivery, the efficient and highly durable delivery of RNAi therapeutics to the CNS and other tissues as well including the eye and more recently to lung.
So we are obviously quite excited about that because it opens up new prospects for our pipeline growth outside of the liver. And in the setting of the CNS itself of course it is really an opportunity to go after the many, many neurodegenerative diseases that are caused by gain of function mutations or being a function expression of proteins in the CNS with a dose regimen that we think intrathecally can be given once every six months if not us frequently.
So it is a great opportunity for the company and we've partnered with Regeneron on a 50-50 basis in that regard. Akshay, do you want to specifically talk about APP and the next steps?
Yes. So speaking of Regeneron at APP, it was great that partner with us will be taking the program we've been into Phase 1 next year. We continue to guide that we'll end to Phase 1 in the middle of next year or so. And further guidance on when we'll actually see data will be given once we've gotten going with that Phase 1 study.
And the other thing is of course, there's a very interesting time with the aducanumab review ongoing and there's a lot of excitement around what those data are showing. So it interesting to see the outcome of that on Friday, but we continue to believe in APP is a very important target for Alzheimer's disease and beyond. And not only can we tackle by the deposits we believe in the extracellular of the space but tackling the target outsource and turning off the tap so to speak and all the intraneuronal effects of a beta will also be impacted. So we think this could have a really significant contribution to play. So excited to get into Phase 1 next year and we'll update on those expectations after that.
Thank you.
And Yvonne do you want to comment a little bit on -- thank you, yes. Yvonne do you want to comment a little bit on how this works within our Regeneron relationship vis-à-vis our lead, et cetera that might be a useful context?
Yes. No, that's great. I mean we were delighted that Regeneron have opted in we're actually going to be leading the program and we're very excited about that. And obviously share the economics with Regeneron, but whether excited to be leading the first CNS program out of our platform.
Okay.
We'll now out take -- our next questions comes from Alan Carr from Needham & Company. Please go ahead.
Hi. Thanks for taking my questions. Can you give a little more detail around the -- your COVID candidate? What exactly -- where things stand? What we can need to do around that? I'm kind of curious about where things stand? And whether you're looking at other candidates two and other targets around COVID-19. Can you give us a more comprehensive update around that program?
Yeah. Happy to Alan. And let me start and then Akshay you can comment as well. We're -- we continue to be committed to advancing our COVID program. Obviously, there's the opportunity of targeting the SARS-CoV-2 genome, which is an RNA genome directly with an RNAi therapeutic is certainly inappropriate.
Thing to do from a technology perspective and our recent advances in lung delivery, obviously, have conscious in time to help us advance this program. We've done some work in the sharing Hamster model, which is an established model for SARS-CoV-2 infection. And we have seen antiviral activity in the model specifically. And we're encouraged by that. But we want to do more model work before, we commit to specific IND timing and specific clinical development plan so that we can understand the best place to position, this molecule in the context of emerging therapies for the treatment of COVID-19.
And we're going to play the long game on this program, as it relates to how it could play into the management of COVID-19 in the future, which we think will be an opportunity longer-term for therapies, just like there is for disease flu. But that's how we're thinking about it and those are the specific results. And we look forward to presenting those at some point in the future. Akshay, anything to add to that?
No, I think you covered it John. Exactly, right.
Great.
All right. Thanks for taking my questions and congratulations.
Thanks, Alan.
We'll now take our next question from Patrick Trucchio from H.C. Wainwright. Please go ahead. Your line is open.
Thank you. Hi. Good morning. With the understanding that the closure in the U.S. election may take some time. I'm wondering, if you can comment how a potential change in the administration could impact health care policy and what impact if any this could have on Alnylam's R&D or commercial execution in the U.S. in 2021 and beyond?
Okay. Great. So yeah, obviously I – we are hoping that there is a completion and clarity on the election here in the coming days or coming weeks. And I think it's great to see our democracy going through the process of counting all the votes, which is the way democracies need to work. And so it's great to see that happening. And we certainly, stand by to sort of see how it emerges overall. But I think that regardless of the outcome whether Trump or Biden get elected. We believe that there's going to be a dialogue and continue to be a dialogue around drug pricing politically. But I think that Alnylam is very well positioned in that dialogue, because of the type of innovation that we consistently deliver from our platform.
And I think the type of medicines that we bring forward, the type of ways that we've engaged with payers around sharing of risk and obviously delivery of value ultimately. These are the types of approaches that we think will bode well for continued success a continued ability to get the value of our innovation recognized by governments and payers around the world. So we do think that we're in a good position to – regardless of the outcome regardless of the policies that emerge. To be able to continue to do what drive for patients first and foremost and obviously deliver on the value of that from our platform.
So we think we're in a good place Patrick on that overall. But we certainly have been active in helping different stakeholders in this discussion and we will remain active as a company in this discussion. But we are generally optimistic and maybe, there will be some changes of the count that occur, but we think we're very well equipped to do well through all of that.
That's helpful. Thank you very much.
Thanks, Patrick.
We'll now take our next question from Leland Gershel from Oppenheimer. Please go ahead.
Hey, good morning. Thanks for taking my question. I like those comments on the solidification. Just a question on the reimbursement of progress with OXLUMO having been through the EDA discussions with others on GIVLAARI recently just want to – if you have any comments on any differences you're seeing in that progress? And if you would expect it to basically be on pace with where you were with GIVLAARI as you'd execute on OXLUMO? Thank you.
Yeah, that's a great question, Leland. Let me just start by saying, how proud I am of our access teams around the world with the great job they've done with ONPATTRO, the great job they're doing right now with GIVLAARI and right now we have over 30 just about -- actually just about 30 value-based agreements that we signed with commercial payers in the U.S. and we continue to work with -- in global markets very effectively with the payer stakeholders.
And we've shown a lot of -- we've demonstrated and brought a lot of innovation forward on these DBAs both the general structure of them and I'll be share risk around performance of the product. But also on some of the new features that we've introduced like the prevalence-based adjustment model that we've introduced on GIVLAARI.
So with that as context, Andy do you want to get more specific on OXLUMO? And obviously, we can't share all the details that we'll share when we launch the product, but maybe you can give some context on how our discussions are going.
Sure, sure. So similar to ONPATTRO and GIVLAARI, we will and are pursuing an aggressive value-based agenda with all payers globally. And feedback from early days on that done has been exceptionally positive. So we expect similar results in terms of open access for OXLUMO as we had with GIVLAARI and ONPATTRO, which are really, really strong. So, we'll continue our industry leadership here.
Yeah. Thanks, Andy.
Perfect. Thank you.
Moving on to our next question comes from Mani Foroohar from SVB Leerink. Please go ahead. Your line is open.
Thanks for taking the question guys. A quick one, I guess starting on for Jeff. Kind a little bit about the increasing compliance as a driver of markets performance. At present some of that is from patient hesitance to come in for their IV during the hype of the pandemic. So, that compliance trend reverse entirely? Are there still a little bit of deduce for next quarter and beyond.
And then for Akshay, there's a lot of talk about what HELIOS-A tells us and HELIOS-B on [Indiscernible] maybe APOLLO-B is the more useful lead forward? Can you give us a little view on how you think about taking the optional HELIOS-B interim? Is the most appropriate approach to wait until you have APOLLO-B data to inform that or do you think that just data that you gather on a blinded basis from HELIOS-B itself as the study proceeds will provide you the information we need to decide if and when to take that in turn.
Okay. Those are great. Those are two great questions. Mani, why don't we start with Jeff, and then we'll have Akshay talk about the Cardi B as we call them collectively strategery and how that relates to the interim. So Jeff, do you want to start first on the compliance question?
Yeah. Sure. So, just to remind you on the results that Andy commented on earlier and I did as well. we grew 21% in Q3 in the U.S. for ONPATTRO versus Q2, 14% of that was demand related and that was a mix of new patients coming on to therapy and the increased compliance that we saw in Q3. And that returned in the U.S. to pre-pandemic levels Mani. So I don't see a sort of a big impact of that on growth going forward.
And just a reminder, outside the U.S. we didn't see the same impact on compliance in Q2 that we saw in the U.S. So outside the U.S. the healthcare systems seem to do a better job of maintaining patients on therapy and compliance wasn't impacted. So again, I don't see a big impact of increased compliance going forward on our growth rates.
And just before I hand it over to Akshay, I would just add that the side of care adjustments that we made in Q2, have I think bolstered any potential downside of pandemic resurgence the third wave that might happen in the U.S. et cetera. So I think that we're very -- we're better sheltered in Q4 and beyond to not if things get much worse. Do not have any significant impact from what we saw like in Q2. Akshay, do you want to now handle the more complicated but interesting question that Mani has asked.
Would love to do. The question Mani focused on APOLLO-B and the read-through to HELIOS-B. And I agree that that's a very important aspect of the work we're doing, and the insights on clean that will be very important for us. I'd also say that continuing work with patients from Apollo itself and the open-label extension study, gives us important insights into long-term outcomes on neuropathy and cardiomyopathy. We've had a number of studies on going out in the field and Dr. Gilmore [ph] from the U.K. group just published a paper in JAK imaging on reversal of amyloid deposition in TTR cardiomyopathy patients of the inherited type. And I think that's just something important.
And then we continue to work with groups like that to understand what they're seeing and the outcomes that they're seeing, both clinically and radiologically. The HELIOS-A, as we discussed earlier, to your point, it's not as richer data to serve for cardiomyopathy, but there could be some important information there.
And then APOLLO-B itself. And I think ultimately we'll just have to see on the timings of all these data points and how they factor in. And as we get greater insight into the APOLLO-B readout, I think we can guide on what the exact HELIOS-B interim will be and use all these points of information to guide that. But I think we're fortunate, because there's so much to teach us about what to expect ultimately on HELIOS-B and that should lead to a very informed structure around the interim.
Yes. Absolutely, agree. Does that answer your question Mani?
Yes. That's great. Thanks, guys. Also cardio would have been a great trial in there, so you could have gotten the way --
Agreed.
Thanks, guys.
Thank you.
We'll now take our next question from Navin Jacob from UBS. Please go ahead.
Hi, everyone. This is Jon on for Navin. Thank you for taking our question. So with respect, you've alluded to the COVID recovery across geographies. And we're curious if COVID has caused any shift in payer mix for your assets GIVLAARI and ONPATTRO. We're also curious as to how -- as to which analogue might be better for -- as we prepare for the OXLUMO launch. Would it be more like GIVLAARI with a bit more Medicaid or perhaps more like ONPATTRO? Any color would be appreciated.
Well, those are great questions. I'm going to hand them right over to Andy to answer.
Thanks. So let's start with the first one. So changes in payer mix. Specifically, in the United States we're seeing little to no changes in payer mix. Remember that ONPATTRO is the vast majority Medicare. And at this point in time GIVLAARI is pretty early days here, but largely commercial and we're not seeing any material changes to those due to COVID.
And then, the second question with OXLUMO, in terms of payer mix analogue, actually neither are perfect, but of the two it's certainly going to be less of a Medicare population, right? We think OXLUMO is more of a commercial and/or Medicaid insurance one. So that I guess a little bit more similar to GIVLAARI, if that helps.
Certainly. Thank you.
Sure.
Thank you.
And moving on to our next question comes from Vincent Chen from Barnstein. Please go ahead. Your line is open.
Great. Thanks for taking the question. So probably a little far out but going over to CNS side of things for a moment. I was really looking out to you for the release data on ALN-HTT in Huntington and how that might offer advantages over competitive programs in the space, most notably Roche, IONIS [Indiscernible].
Are there reasons to expect that ALN-HTT and the siRNA platform and CNS will outperform the Roche IONIS program from a perspective of sort of the degree of knockdown achieved, the graph or the ultimate – ultimately the efficacy?
So, let me hand it over to Akshay. Thanks for the question, Vincent. I'll just start by saying that, obviously, the -- what we've seen with our platform in the CNS has been pretty consistent with what we've seen in the platform with liver. And when you compare an RNAi therapeutic approach in the liver compared to an antisense oligo based approach, what you see is you see deeper better knockdown and much greater durability in the liver.
We've seen that all the way through marketed products. And we see similar profiles in nonhuman primates between antisense oligos and RNAi therapeutics. So by all accounts we expect a deeper knockdown potential with our platform and a much more durable approach that would allow for less frequent intrathecal administration, which of course is an important -- is a burden in the administration of oligos in the CNS.
But there's some more to that -- there's more to the HTT opportunity that will leave to Akshay to comment on specifically on exon 1. Akshay?
Yes. And before I get to exon 1, the other thing I'll add to what you said in terms of pharmacologic attributes shown on potency, durability of course, but also just much better by distribution based on our preclinical findings, we think that the RANi approach is much better than deeper brain structures like the basal ganglia, which is where you need to get to for hunting those predominantly. So those pharmacologic attributes and lenders put the actual target strategy itself. And there's an abundance of literature now or significant literature suggesting that exon 1 itself has a very important role to play in the pathology of the disease and their truncate transfers that come off exon 1 that appears in and of themselves to be neurotoxic. And then they approaching aggregates made what protein aide from the truncated exon 1 transit that aggregates and causes pathology. So going for an exon 1 agnostic approach may not be the strongest and we focused on a exon 1 approach. So we can have the best approach the target of the [Indiscernible] constantly would support and the KOL support and that along with the pharmacologic actually as we've discussed I think really sets us up for a very attractive profile. We look forward to going to the 2020.
Thank you.
Does that answer your question Vincent?
Yes. Thank you very much.
Thank you.
We'll now take our next question comes from Luca Issi from RBC. Please go ahead.
Terrific. Thanks for taking my question and congrats on the commercial execution here. Maybe going back to [Indiscernible] for a second, but maybe with a little bit more of a commercial angle here. Do you think that actually APOLLO-B would be sufficient for doc to change their prescribing habits from VYNDAQEL to ONPATTRO or do you think the most doc will actually need to wait for HELIOS-B. Given that again, APOLLO-B is just power for six minutes whopping or still dealing within the IV drug. Any thoughts there would be helpful. Maybe second question. We've seen a few of your competitors actually going after ENAC for cystic fibrosis. Wondering if one, you have any thoughts on that approach? And two, what's your appetite to potentially enter that race? Thank you.
Okay. Well great questions. I think obviously the first one Andy, I'd like you to answer. I'll just start by reminding everybody that obviously the APOLLO-B study is a study of patisiran, which is a non-branded name for ONPATTRO which is an investigational agent right now and it's being studied in patients with both wild-type and hereditary ATTR amyloidosis with cardiomyopathy. And that study uses the 6-minute walk distance as the primary endpoint of 12 months. And then the HELIOS-B study with vutrisiran uses the -- uses CV hospitalization and mortality as a primary endpoint at 30 months treatment. And so that's an important distinction.
But in general and then Andy you should comment, we do feel very encouraged that if APOLLO-B is positive. And if we're able to get an approval with the FDA based on the study and other regulators that this will be a very attractive alternative for the cardiology community to treat their patients with both hereditary and wild type ATTR. And while the ultimate presentation of a TTR silencer with a quarterly or six monthly subcu approach will be certainly much more exciting in the future. In the meantime, ONPATTRO with this broader label will be an important treatment option for patients. Andy do you want to comment a little bit on our perspective on that more in more detail?
Sure, John. Happy to. So we're very excited about the APOLLO-B potential here and the launch into hereditary and wild-type cardiomyopathy. To note in the United States today, cardiologists are currently having very strong experience with ONPATTRO in treating the polyneuropathy. And upon approval, we do expect a meaningful amount of physicians to choose ATTR SILENCER versus a stabilizer. And furthermore, there also will be physicians who don't decide to choose. And frankly they use both. And so reimbursement will be something we'll be proactively looking to resolve on that front as well.
Perfect. And then Akshay do you -- or maybe Yvonne, do you want to comment a little bit on from a portfolio standpoint how we think about programs and ENAC for example and is that -- and whether or not that's an area that we would consider?
Yes in the short term look, I think what's been incredible about our platform is actually the kind of productivity that we've had. And we're increasingly demonstrating our ability to access tissues in addition to liver, CNS and Ocular. And many of you may be aware that our non-entitled history with lung delivery as well with an RSV program many years ago.
So we have a tremendous amount of opportunity in front of us. And clearly we need to think how we prioritize the best opportunities for us. We have a lot on our plate to move forward from an execution perspective. But we remain open about continuing to explore the broad utility of our platform going forward, but nothing to share specifically on cystic fibrosis at this time. John do you want to add anything?
No. I don't know Akshay anything you want to add to that?
No. I mean you know part of the Alnylam COVID assets. Obviously lung delivery has come front and center. We have that preliminary, David about a year ago now showing we've achieved lung delivery which is very exciting. And just as we've done with many other settings and organs, the idea of genetically validated targets comes into the mix. And we have knowledge of a number of very interesting genetic validation beyond ENAC itself cystic fibrosis. So this really the new investor that's forming before us and it will be exciting to take it on beyond the COVID asset itself.
Great. Thanks guys.
Thanks Luca.
We will now take our next question from Shreeshant Shu [ph]. Please go ahead. Your line is open.
Thank you very much. Good morning. Congrats on the strong quarter here.
Thank you.
Quick question on patisiran, I guess on APOLLO-B. Have you guys looked at any I guess clinical or translational data in terms of the correlation between baseline V severity and the potential response to the drug, six minutes walk or hospitalization. I recall the - stabilize it actually has a different trend when it comes to different patient population? And then second question quickly on AGT program, given the drug will be potentially target a large population -- patient population, have you guys starting think about partnership opportunities there? Thank you.
Right. Well let me start with -- let me just -- Akshay you should take the APOLLO-B very interesting APOLLO-B question. But let me just -- on the AGT comment real quickly. Our intent with the AGT program is to advance to the market. We've certainly are a company that as we bring the medicine like AGT forward, we're going to have an opportunity to -- at that stage of our growth and company to commercialize a medicine like that. If we and at that point in the future choose to bring on a promotional partner. We may do that.
But our key goal is to retain the program and develop it ourselves and that's how we're focused on it. And so that's what we're doing there. But Akshay do you want to answer the APOLLO-B question that was asked?
Sure.
Actually John may be if I can just comment really quickly on the point you made. I think the other thing to remember is was our sort of TTR suite of opportunities. We are actually building up a very robust commercial preference in the cardiovascular arena so that's something else that we can consider as we as we plan for AGT.
Yes. Yes absolutely. I agree completely. Thanks for jumping in on that Yvonne. Akshay do you want to then to...
Yes. Shreeshant good question about APOLLO-B. Now of course is an ongoing blinded study. So we don't sort of look at the currently and that's what it should be to maintain study integrity. I can't comment on relationships thing various parameters. I can tell you that there are very good associations between New Class association stage and 6-minute walk distance. You know that from prior work hours and other people's work. And we know how that relates to biomarkers such as BNP and other imaging biomarkers.
In terms of – the other answer to your question was outcomes with and without tafamidis. And there we can look at older information from APOLLO itself the original study for patisiran ONPATTRO, the Phase III study and what was very clear there actually is whether patients had previously been on a stabilizer whether it was tafamidis sold out to Vyndaqel or had never been on a stabilizer their outcome was equivalent.
And that is on average there on missus seven then your often point improve, the quality of life improved. So that's very encouraging for us that our mechanism of actions seems to be potent and whilst it wasn't a head-to-head study everything pointed to ONPATTRO really having a profound impact and result in improvement of disease in the context of the APOLLO study.
And we believe that's one of the very attractive features of the drug. We know from tafamidis from the Phase III ATTRACT study that whilst clearly there was benefit in terms of hospitalization and mortality. All the curve went down. It's just the curve for tafamidis didn't go down as much as it did for placebo, which is a good thing for patients. But sadly disease progress. It's quite clear whichever end point you look at including 6-minute walk distance and walk distance declined and for time in the active group uses placebo.
So if we can stabilize 6-minute walk distance I think that's great. If we can actually improve 6-minute walk distance even better. The recently published study by Dr. Gilmore and others from the U.K. group in Jack imaging where they took a cohort of cardiomyopathy patients. And they were given patisiran, one year compared to a saw controlled base sort of stabilization of 6-minute walk distance, aggression amyloid something that's needed those and continue with rafamidis.
So we think the fundamental mechanism of action to remove the pathogenic protein to a greater extent outcomes of neuropathy that we know well. And also some of the preliminary evidence emerging around the cardiomyopathy and use of ONPATTRO in most patients. And we also suggest that we look forward to stabilizing disease and hopefully improving outcomes.
Chen, does that answer your question?
Yes. Thanks very much.
Thank you. Thank you.
At this time, I would like to turn the conference back to the company for any additional or closing remarks.
Okay. Thank you and thanks everyone for joining us on this call. Look, Alnylam is at a very exciting stage of the continued growth in development as a leading biotech. We're really pleased with our Q3 results and our execution from our commercial and R&D teams. We look forward to updating you on our continued progress at our R&D Day in December. Until then, I hope you all stay safe and healthy and have a great day. Bye-bye now.