Alnylam Pharmaceuticals Inc (ALNY) 2022 Q3 法說會逐字稿

Thank you for standing by, and welcome to the Alnylam Pharmaceuticals Third Quarter 2020 Financial Results Conference Call. (Operator Instructions) As a reminder, today's conference call is being recorded. I would now like to turn the conference over to the company. Please go ahead.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Akshay Vaishnaw, President; and Jeff Poulton, Chief Financial 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 for website, investors.alnylam.com/events.

During today's call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Akshay will review early pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions.

I'd like to remind you that this call will contain remarks from concerning Alnylam's future expectations, plans, 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 recently quarterly report on file with the SEC.

In addition, any forward-looking statements represent our views as only as the date of this report 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 Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. We're very pleased with the results delivered in the third quarter, both commercially and with our pipeline. Commercially, this is the first full quarter of our AMVUTTRA launched since the U.S. approval back in June, which drove 30% growth in the U.S. for the TTR franchise compared to quarter 2.

Clinically, the TTR franchise is a high life as well. We presented positive results for the APOLLO-B Phase III study of patisiran in patients with ATTR amyloidosis with cardiomyopathy, validating the therapeutic hypothesis that RNAi-mediated silencing of TTR has the potential to result in a disease-modifying impact on the cardiac manifestations of ATTR amyloidosis. We're delighted with the totality of these results and we look forward to submitting a supplemental NDA for ONPATTRO by year-end.

This also gives us increased confidence in the HELIOS-B Phase III outcome study of patisiran in ATTR amyloidosis with cardiomyopathy, which is on track for top line results in early 2024. Our earlier stage programs advance as well with positive results presented from the Phase II study of cemdisiran in patients with IgA nephropathy as well as preliminary data in patients from the ongoing Phase I study of ALN-HSD in development for the treatment of NASH.

In the coming quarters, we expect to have more exciting updates from our pipeline, including results for potential biannual dose regimen for patisiran preliminary Phase I results and healthy volunteers for ARN-XDH an investigational RNAi therapeutic for the treatment of gout.

Completion of enrollment in the KARDIA-2 Phase II study of zilebesiran and initiation of a Phase I healthy volunteer study of ALN-TTRsc04, for which we filed a CTA earlier this month. This execution is in line with our focus on these key drivers for our Alnylams' growth over the next several years. Firstly, the potential near-term expansion of our TTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicines for patients.

Second, our expansion beyond rare diseases and for prevalent diseases. And the third growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, opportunities with extrahepatic delivery and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.

We believe all of this positions us well to deliver on our Alnylam P5x25 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and prevalent diseases for patients around the world, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results.

With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Thanks, Yvonne, and good morning, everyone. Q3 was a strong quarter for our commercial portfolio with 9% quarter-over-quarter growth driven by a strong launch of AMVUTTRA in the U.S., as Yvonne highlighted. While still early, we are encouraged by several signs indicating that AMVUTTRA is expanding the size of the opportunity for our hATTR-PN franchise. I'll have more details to share on this shortly.

The strengthening of the U.S. dollar continues to impact product revenues from our international operations as ONPATTRO, GIVLAARI and OXLUMO Q3 product sales each experienced effects headwinds compared with the prior quarter and prior year period. With initial sales of AMVUTTRA now reflected in our quarterly financial results. Moving forward, we will highlight our results for ONPATTRO and AMVUTTRA on a combined franchise basis. We saw robust growth in our TTR franchise in Q3, achieving $170 million in global net product revenues for ONPATTRO and AMVUTTRA, representing an 11% increase compared with the second quarter and a solid 41% growth compared with Q3 2021. At the end of Q3 over 2,580 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, up from over 2,400 patients at the end of the second quarter, representing a steady 8% quarterly patient growth.

In the U.S., combined sales of ONPATTRO and AMVUTTRA increased a robust 30% versus the second quarter and were primarily impacted by the following: and 19% increase in demand growth, which was driven by the strength of the initial AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO that switched AMVUTTRA. In total for the quarter, 180 patients initiated AMVUTTRA treatment with over 40% representing new patients for Alnylam and the balance representing patients switching from ONPATTRO.

Initial AMVUTTRA launch inventory stocking in the distribution channel increased growth an additional 11% in the quarter. In our international markets, ONPATTRO Q3 product sales decreased 5% versus Q2 '22 despite an increase in patients on therapy as the timing of orders in partner markets and FX headwinds offset the increase. Our global results continue to be challenged by foreign exchange headwinds, with ONPATTRO year-over-year reported growth of 41%, held back 11 percentage points due to the foreign exchange impact of the strengthening U.S. dollar.

Now I'd like to provide you with some additional color on our AMVUTTRA U.S. launch. In the first 4 months of launch, new patient start forms have doubled to an average of 60 start forms per month, excluding switches in comparison to 30 start forms per month for ONPATTRO in the first half of this year, which we believe highlights the strength of the AMVUTTRA launch to date.

Our demand generation has been healthy and balanced between community accounts and centers of excellence, while about 17% of start forms have been generated from new prescribers. We're seeing our patient base broaden to include a variety of newly and previously diagnosed patients starting on AMVUTTRA with significant enthusiasm being expressed for AMVUTTRA product profile, including quarterly subcutaneous dosing.

Meanwhile, on the access front, given our parity pricing to date, we have not faced with any significant access headwinds and have made significant progress with formulary approvals, providing smooth access to patients that are put on AMVUTTRA therapy. Additionally, we are pleased with the average time from receipt of start form to initiation of therapy for AMVUTTRA patients, which is already in line with our ONPATTRO benchmark.

To wrap up with AMVUTTRA, we're also excited about the recent regulatory approvals in the EU and Japan for hATTR and TTR amyloidosis patients with polyneuropathy and are looking forward to launches in Germany and Japan in the fourth quarter.

Moving AMVUTTRA rare disease franchise. First GIVLAARI, we achieved $46 million in global net product revenues in the second quarter, representing a 1% increase compared with Q2 '22 and and 43% growth versus Q3 '21. At the end of Q3, over 460 patients were on commercial GIVLAARI treatment worldwide, up from over 420 at the end of second quarter representing 10% quarterly patient growth.

In the U.S., sales of GIVLAARI increased 5% versus the second quarter primarily due to demand growth of 7% by an increase in patients on therapy, which was modestly offset by changes in inventory, stocking and gross to net sales deductions. In our international markets, GIVLAARI sales decreased 6% compared with the second quarter, with growth in patients on therapy more than offset by lower net pricing and FX headwinds.

Finally, the reported 43% increase in year-over-year global net product revenue growth of GIVLAARI was held back 7 percentage points due to unfavorable movements in foreign exchange rates.

Moving now to our second ultra-rare disease product, OXLUMO. We achieved $16 million in global net product revenues in the third quarter, representing a 10% increase compared with the second quarter. At the end of Q3, over 230 patients were on commercial OXLUMO treatment worldwide, up from over 200 at the end of the second quarter, representing 15% quarterly patient growth.

In the U.S., sales of OXLUMO decreased 10% versus the second quarter as growth in patients on therapy was more than offset by decreased average patient utilization during the quarter, driven by fewer patients on the monthly loading dose portion of their initial treatment. In our international business, sales of OXLUMO increased 29% compared with the second quarter due to an increase in patients on therapy and higher net realized price during the quarter, partially offset by FX headwinds.

Additionally, as with AMVUTTRA and GIVLAARI, changes in foreign exchange rates also negatively impacted OXLUMO Q3 results, with reported year-over-year growth of 10%, held back by 10 percentage points due to the strengthening U.S. dollar.

In conclusion, we're pleased with the growth in revenues and patient demand achieved in Q3 and particularly with early signs of strong performance associated with AMVUTTRA launch, which we believe represents an important therapy option for hATTR amyloidosis patients with polyneuropathy and an accelerated growth opportunity for our TTR franchise.

With that, I will now turn it over to Akshay to review our recent R&D pipeline progress. Akshay?

Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing 2 clinical stage product candidates Patisiran and vutrisiran. Whilst ONPATTRO is currently approved in multiple markets around the world to treat the polyneuropathy associated with ATTR amyloidosis, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients.

At this end, we're excited to have recently presented positive results from the APOLLO-B Phase III study where Patisiran achieved a statistically significant and clinically meaningful improvement relative to placebo in the 6-minute walk test at 12 months, the primary endpoint of the study.

It also achieved a statistically significant and clinically meaningful improvement relative to placebo at 12 months on the Kansas City Cardiomyopathy Questionnaire, the study's first secondary endpoint and a key measure of patient self-reported health status and quality of life. But the more Patisiran demonstrated an acceptable tolerability profile, and we're very encouraged by the overall safety profile of Patisiran.

Collectively, we believe these efficacy results validate the therapeutic hypothesis that RNAi-mediated silencing of TTR has the potential to result in a disease-modifying impact on cardiac manifestations of ATTR amyloidosis. With these results in hand, we remain on track to submit a supplemental NDA filing for review by the FDA by the end of this year with the goal of obtaining regulatory approval in the U.S. making this medicine available to patients with ATTR amyloidosis with cardiomyopathy as rapidly as possibly.

We're also advancing vutrisiran, which is delivered by a quarterly subcutaneous injection, now marked as AMVUTTRA to treat the polyneuropathy of ATTR amyloidosis. AMVUTTRA was approved based on results from the HELIOS-A Phase III study. That study includes an ongoing randomized treatment extension where we're evaluating a biannual dose regimen and we're on track to share results in late 2022.

As with ONPATTRO, year 2, we're committed to expanding the label to include the treatment of cardiomyopathy in hereditary and wild-type ATTR amyloidosis patients. This is being accomplished by the HELIOS-B Phase III study of investigational vutrisiran. HELIOS-B, which is fully enrolled, has an endpoint of all-cause mortality and CV events assessed after at least 30 and up to 36 months, and we're on track to share top line results in early 2024. As was announced this morning, after careful consideration, we've made the decision not to conduct the optional interim analysis for HELIOS-B. Several factors drive us to this decision, including one, the early completion of enrollment of HELIOS-B, which meant that any potential acceleration in the approval based on an interim analysis was minimal relative to waiting until readout from the fully completed study in early 2024. Two, our desire to conclude HELIOS-B with the strongest possible data set, including outcomes data; and three, further enhancement in confidence in HELIOS-B with the recently positive APOLLO-B readout. As such, we look forward to the HELIOS-B readout as scheduled early in 2024.

We've also announced this morning that while we remain very excited about the opportunity for TTR lowering to address Stargardt disease, we do not plan to initiate a Phase III study of vutrisiran this year as previously planned as we evaluate the impact of the inflation reduction act on therapies being developed from more to (inaudible) often disease. We're continuing to consider options for the best path forward in the Stargardt disease as we recognize the significant unmet medical need in this patient population.

Lastly regard to our TTR franchise, we're excited to announce that a clinical trial application has been filed for ALN-TTRsc04, the first clinical program from our IKARIA platform which aims to achieve an annual dosing regimen with highly potent and reversible effects. We expect to initiate a Phase I study in healthy volunteers by year-end. In addition to our late-stage clinical programs, we believe we have also been making great progress with our early and mid-stage programs. Notable highlights this quarter was our announcement of positive results from our Phase II study of zilebesiran, an investigational RNAi therapeutic targeting C5 complement pathway, which is in development in collaboration with Regeneron for the treatment of IgA nephropathy or IgAN.

In the study, at week 32, treatment of cemdisiran results in a 37% mean reduction in baseline in the 24-hour urinary protein to creatinine ratio relative to placebo. The primary readout of the study and an important prognostic marker of disease progression. The results of secondary endpoints were also consistent with the therapeutic benefit of cemdisiran in IgAN. There were no significant drug-related safety signals, and we believe these collective efficacy and safety data support continued clinical development of cemdisiran monotherapy in patients with IgAN. We look forward to gaining alignment with Regeneron to finalize plans for Phase III and sharing those updates with you in due course.

Another exciting highlight recently will be the announcement of the preliminary Phase I data supporting the clinical advancement of ALN-HSD, an investigational RNAi therapeutic targeting HSD17B13 in development for the treatment of nonalcoholic steatohepatitis or NASH. After single-dose evaluation in healthy adult volunteers on A, multiple doses of ALN-HSD are being studied in adult patients with NASH or B, patients in the first 2 part B cohorts namely 200 and 400 milligrams quarterly have completed at least 6 months on the study. The remaining cohorts are exploring a lower dose or a later biopsy time point.

In the first 2 Part B cohorts, ALN-HSD was associated with robust target knockdown and numerically lower liver enzymes and biopsy-derived nonalcoholic fatty liver disease activity score over 6 months in patients receiving ALN-HSD relative to placebo. The study was not powered to achieve statistical significance on these endpoints and the primary outcome measure is frequency of adverse events. ALN-HSD has exhibited an encouraging pace and tolerability profile to date. Based on these results, we plan to initiate a Phase II study in adult patients with NASH in late 2022 in collaboration with Regeneron.

Now turning to our ALN-APP program, which is in the development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. ALN-APP is our first investigational conjugate RNAi therapeutic targeting gene expression in the central nervous system. We continue to make progress enrolling patients with early onset Alzheimer's disease and are progressing through the single ascending dose portion of the Phase I study. As we announced in our press release this morning, we now expect initial clinical data from this study in early 2023, a slight change from our previous guidance of late '22. This change reflects the continued progression through dose escalation cohorts at a measured pace and the rigor with which we are screening for appropriate patients for this study that meet all necessary inclusion/exclusion criteria.

We believe this initial clinical data with ALN-APP is positive, will be an important milestone for our CNS platform to show that RNAi can achieve clinically relevant degrees of target outbound in the CNS with the safety and dosing profile that supports further development. And we look forward to reporting top line results from the study in early 2023. These are just a few highlights from our broad and innovative pipeline driven by our underlying organic product engine that will drive sustainable innovation and represents a key growth driver for Alnylam in the years to come. Representative of the productivity of our engine, we look forward to 2 further CTA or IND filings for the first in human studies before year-end, namely ALN-KHK for the treatment of metabolic liver disease, including diabetes, which is an Alnylam wholly owned program and ALN-PNP for NASH in collaboration with Regeneron. We'll be discussing all this in greater detail at our upcoming R&D Day being held virtually on December 15, and I encourage you to tune it.

With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2022 financial results and an update on our full year guidance. Starting with a summary of our P&L results for Q3 2022. Total product revenues for the quarter were $232 million or 39% growth versus Q3 2021. It is also worth noting that year-over-year growth in combined product revenues was held back by approximately 10% due to the foreign exchange impact of a strengthening U.S. dollar and given that approximately 45% of our product revenues are generated via sales in international markets. Net revenue from collaborations for the third quarter was approximately $29 million, representing a 45% increase compared with Q3 2021, primarily due to an increase in revenue recognized and connection with our collaboration agreement with Regeneron contributed to an increase in reimbursable activities under our research services arrangement in addition to an increase in revenue recognized associated with partnership and clinical trial activities.

Our non-GAAP R&D expenses increased 6% in the third quarter 2022 compared to the same period in 2021, primarily due to increased compensation-related expenses as a result of increased employee headcount and an increase in development expenses, primarily associated with the ramp-up in enrollment in the KARDIA 1 and KARDIA 2 zilebesiran Phase II studies offset by decreased clinical batches manufactured during the quarter.

Our non-GAAP SG&A expenses increased 33% in the third quarter of 2022 compared to the same period in 2021 primarily due to increased headcount and other strategic investments in support of our AMVUTTRA launch and other corporate purposes. Our non-GAAP operating loss for Q2 2022 was $130 million representing an $18 million improvement compared with Q2 2021, driven by strong top line growth, offset by more moderate growth in operating expenses.

Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.3 billion compared to $2.4 billion at the end of 2021 with the decrease primarily due to our year-to-date operating loss in 2022. This decrease was largely offset by approximately $200 million received from employee option award exercises and approximately $135 million received from the issuance of convertible debt net of repayment of our Blackstone credit facility inclusive of prepayment premiums, purchase of cap call transactions and offering expenses.

We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile. Now I'd like to turn to our full year 2022 financial guidance. Starting with net product revenues, we continue to anticipate combined net product revenues for our 4 commercialized products will be between $870 million and $930 million. Additionally, given the continued strengthening of the U.S. dollar since we issued our current guidance in April, we are currently trending towards the lower half of our $870 million to $930 million guidance range. We are reducing our guidance for net revenue from collaborations and royalties from a range of between $175 million and $225 million to a range between $100 million and $150 million primarily due to the timing of reimbursable activities in our collaboration with Regeneron and lower-than-anticipated Leqvio royalties and sales milestones.

And our guidance for combined non-GAAP R&D and SG&A expenses remain unchanged and is a range between $1.390 billion and $1.450 billion. Let me now turn from financials and discuss some key goals and upcoming milestones on deck through the end of 2022. We will continue executing on our global commercialization of ONPATTRO and AMVUTTRA, GIVLAARI and OXLUMO. Next, our TTR franchise will have important updates. With Patisiran, we plan to submit an sNDA for review by the FDA for the treatment of patients with ATTR amyloidosis with cardiomyopathy. With vutrisiran, we plan to report results on a biannual dose regimen from HELIOS-A in hATTR amyloidosis patients with polyneuropathy.

Lastly, for ALN-TTRsc04, we are on track to initiate a Phase I study in healthy volunteers. In our mid- and early-stage portfolio, we are looking forward to milestones that include completion of enrollment in the KARDIA-2 Phase II study of zilebesiran at or around year-end, preliminary results expected from healthy volunteers in the Phase I study of ALN-XDH in development for patients with gout and submission of CTA filings for ALN-KHK for the treatment of metabolic liver disease, including diabetes, and ALN-PNP for NASH. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for your questions. (Operator Instructions).

(Operator Instructions) Our first question comes from Maury Raycroft at Jefferies.

I was wondering if you can talk about whether you've gotten any feedback from FDA on APOLLO-B data and what the NDA package would contain? And also, if you can talk about confidence around your primary endpoint P value and whether FDA has provided any specific comments on this?

Thanks for that question. Maury. I mean, clearly, we were delighted with the results from our APOLLO-B study where we deliver meaningful and significant benefits across the 6-minute walk test and KCCQ, which are important measures actually for patients in terms of how they function and we've got good safety and numerical reduction in test. So we're very confidence with the package of data that we have supporting this indication holistically, particularly given the small size and on short duration of the study, actually, perhaps you can comment on regulatory progress.

Yes. So thanks, Maury, and thanks, Yvonne. I mean, I think you addressed at the high level, the key positives that came out of the study that reinforces that of RNAi therapeutics can have a significant impact, we believe, in ATT amyloidosis, including in the cardiomyopathy. We're proceeding to file the supplemental NDA by the end of the year, as we've said. We're confident in this package, the points that Yvonne outlined as the file goes under review, the FDA was get a safety update, 180-day safety update during review, so we'll be providing that, of course. And we'll be very responsive to any questions they have. And so that's as much as I can say at this point in time. But we've shared the data across 2 meetings at ISA and HFSA, had extremely strong and positive responses from investigates of KOLs and others. And so we're excited for all this (inaudible).

That's great. So moving forward expeditiously.

Our next question comes from Salveen Richter.

Did the outcomes analysis of APOLLO-B impact your thinking on treated or placebo separation here? And how much time do you save?

Actually, I think that's 1 for you.

So would actually repeat the whole question. I think talking about the outcomes analysis, but the line is not brilliant. So we didn't quite catch the second half of your question. Could you repeat first?

Sure. Could you explain the factors you considered when deciding not to conduct the HELIOS-B interim? I'm just wondering whether the outcomes analysis of APOLLO-B impact your thinking on treated placebo separation and how much time you save here?

The question is around thinking behind not progressing the interim analysis.

Yes, I mean, Salveen, as you intimate, the positive data out of APOLLO-B significantly increase our confidence and belief that the design and conduct of HELIOS-B is the right test of our hypothesis that vutrisiran can help patients with ATTR cardiomyopathy. So we feel quite bold after looking at all the detailed data, most of which we've shared already at these international meetings, but there are others. And so that was 1 major factor.

The second was we obviously want to have the best data associated with vutrisiran to make it a best-in-class product, hopefully, for patients with ATTR cardiomyopathy. The best way to do that is to preserve alpha and not mess around with the statistics, which obviously, if you do an interim, then that has a significant downstream consequences on how -- on both the statistics for the final readout in early '24.

And thirdly is just the speed at which everything has moved which we're delighted by. So the fact that HELIOS-B actually overenrolled that it did, means it's such a narrow time frame between any putative interim and any potential approval thereof versus the full readout in early '24 and hopefully getting a great label in serving patients with ATTR cardiomyopathy.

Our next question comes from Tazeen Ahmad of Bank of America.

Maybe, Yvonne can you just clarify whether your team has already met with FDA for your pre-sNDA meeting regarding the APOLLO-B results yet? Or is that still to come? And then secondly, do you have any expectations about whether or not an AdCom would be needed to review this filing. It is the second indication proposed for an already approved drug, but I just wanted to get your latest thoughts on that.

Yes. Thanks, Tazeen. I mean, as you know, we don't comment on regulatory interactions. I think I actually covered this in an earlier question, we're very confident with the package that we have supporting this indication, and we're moving forward as planned with a submission later this year. That's about all I can say on the topic. But thanks for the question.

Our next question comes from Eliana Merle of UBS.

Just another 1 in terms of thinking about HELIOS-B as well as the potential uptake in cardiomyopathy. Could you help us understand how you interpret the data in tafamidis combination? And what this could potentially mean in terms of uptake in, and say, tafamidis progressors or combination use in the real world commercially. And any initial feedback say you're hearing initially? I know it's early, but just curious about your thoughts.

Right. So I think there may be kind of 2 parts of the question. I think 1 actually may be starting off with you perspectives around data and combination with patent and maybe talk to give some perspectives on how you see things in the commercial.

Thank you, vis-a-vis your question Eliana, though its a family subgroup in concomitant with Patisiran. Just to step back, this was a, I think, a large robust study that considered the real-world population out there. The majority of whom don't have any drug right now, about 75% of the study was on placebo and no background therapy. At about 25% of patients had background tafamidis. I refer you to our HFSA output and Dr. Mauer is very eloquent discussion of why it's a little bit of a full there and just to use a phrase to cut into small subgroup analysis that really are not powered and the study was not designed to test so we fool ourselves. And again, Dr. Mauer explained and discussed all this very well. I call it HFSA.

So the overall readout of the study, I think, was robust and excellent impacting patients functionality via the 6-minute walk distance and the quality of life, lots of internal consistency in the data. So this is a strong package and we're delighted with it. I appreciate the interest of subgroups, so that's really now what the study was poured to read out.

Yes, I thought that just generally or factors around how the commercial...

Yes. Just to build on Akshay's point, it would be premature for us to comment anything specific on without the label. But what we can tell you is if you just look at the numbers since the launch of tafamidis, the diagnosis rate went up by 10x and we certainly anticipate that to continue. This is a highly devastating disease. Across the U.S. and ex-U.S., there's about 250,000 to 300,000 patients suffer from this devastating disease. And what we know is those patients that are a lot of untreated patients and those patients who continue to progress on TAF. So we believe our upcoming therapies if they're approved, will be a very attractive option, both for our physicians and obviously for patients.

Thank you. So absolutely lots of medical needs still there for these patients unfortunately.

Our next question comes from Ritu Baral of Cowen.

Yvonne and Akshay, should we be expecting priority review on the sNDA just given what you and your regulatory consultancy as the unmet need in TTR cardiomyopathy. And can you just also remind us when the last interaction you had with FDA was -- in the past, obviously, not forward-looking. And if there's been any significant turnover in the review team or senior members in the review division since then.

Thanks, Ritu. So another question about. The regulatory outlook here actually in terms of expectations with respect to (inaudible)? And another question really just asking us to comment on our progress with regulatory interactions. So I think you've sort of answered the question, but maybe you can reiterate the point.

Yes. I mean, I think it, Ritu, thanks for the question. As you know, we don't discuss the back and forth regulators. I will reiterate what I said earlier, that we're confident in this data package, we're on track to file the supplemental NDA by the end of the year and the priority review, well, that's the FDA's decision, and they have to evaluate the pros and cons of this therapy and the data package we've submitted. And we'll eagerly await their decision, but there's not much more I can fit in there.

And Ritu, so many comment on review team turnover. I think that's what the FDA management should do and we're not really in a position to speak for that.

Our next question comes from Jessica Fye of JPMorgan.

Did you have a pre-NDA meeting yet for the ONPATTRO cardiomyopathy filing? Or if not, do you expect it to?

Yes. Thanks for the question. I mean, again, I think there's lots of interest around this. The most important thing is that we obviously have lots of back and forth regulators across all our programs. And let me just reiterate that we will file the supplemental NDA by the end of the year for this program based on everything we've discussed so far on this call and in many other settings. So thanks for the question.

Our next question comes from David Lebowitz of Citi.

When you look at the ONPATTRO, [excluding] the AMVUTTRA new patient start forms, I noticed that the number of new patients percentage uptick from what was announced in the first quarter of launch, I think we -- from about 1/3 to nearly 50%. Could you comment on what the expectations for new patients to be coming to market is and what that might -- and how that might impact growth of the overall franchise relative to what ONPATTRO would have done without the presence of AMVUTTRA?

Yes. No, that's a great question. I mean, we're particularly pleased with the performance of our TTR franchise, especially the progress of the AMVUTTRA launch in the U.S., and we're seeing a kind of great dynamic. With approximately half of new patients and half switches. And I think you made the point about a TTR franchise, which I'd like to underscore. I think we now really have a TTR franchise, and we expect to be able to grow the PN market encourage earlier treatment given the very effective regimen of AMVUTTRA. But Tolga, do you want to add some more color maybe to how you're seeing the outlook for the TTR franchise?

No, no, absolutely, Yvonne. Look, early signs of U.S. AMVUTTRA launch is a good testament to the overall TTR franchise future. Our TTR franchise grew by 30% versus last quarter, driven mainly by AMVUTTRA. 2/3 of this growth was really demand. In our view, early signs of performance really confirm 3 key beliefs. One is the fine available treatments, there is a significant unmet need and the role of AMVUTTRA in its attractive product profile will continue to increase growth. That's going to be important. And also, we do have the strong foundational capabilities that we build over time across customer-facing capabilities that will allow us to continue expand this growth.

So we're really excited about this. We're still scratching the surface in terms of diagnosis and treatment. There are 10,000 to 15,000 patients in the U.S. that suffer from this condition. We believe AMVUTTRA product profile will be a very nice fit to that treatment regimen.

Our next question comes from the line of Gena Wang of Barclays.

Sorry, I will ask APOLLO-B question again. I think because there are quite some questions who were raised on its approvability since it's only 1 study and then there is no outcome data. So maybe if you could refresh our memory, the history of APOLLO-B study. So basically, how study was designed and was it aligned with the FDA?

Yes, Akshay, clearly for you.

Yes. Thanks, Gena. I think we've discussed much of this on other calls, but let me just reiterate, Gena, that I think this is -- I'm losing track a little bit, (inaudible) Phase III study or Phase III study that we've negotiated with the FDA and other regulators around the world. All our work is in collaboration with guidance from regulators. We have 4 Alnylam products approved based on that excellent set of dialogues and relationships we have and understanding how regulators are trying to guide us this product and this trial was no different from that. And so if any credibility or confidence is derived from our prior performance would I like you to apply it here. Now in the specifics here, when APOLLO was done, and we all remember the conversations, those of you that were involved then, the cardiac data, the cardiac subgroup data from APOLLO were very promising.

And the FDA said, yes, that is the case, and we've discussed that before. And based on that, they guided us that we should do a separate study in a cardiomyopathy population. And with that conversation and collaboration, the design that you see in APOLLO-B resulted. And so this study was done in close collaboration with regulators, and we're grateful for the guidance, and we're very happy with the outcome where clearly, we've shown the impact on patient functionality and quality of life, which are 2 cornerstones of FDA base of approval of drugs. Safety looks very encouraging to us, too. And then finally, on the monetary front, you'll recall that 4 patients [died] on placebo rather on Patisiran and 10 on placebo. So that's encouraging, although it's a small number. So this package, we believe, is rather strong for a trial that was designed in collaboration with regulators. And so we're looking forward to filing the NDA.

Our next question comes from the line of Paul Matteis of Stifel.

I was really interested in your comments in the press release and in the prepared remarks on drug positioning related to the inflation Reduction Act and kind of broader drug pricing risk. And to that point, you just filed a CTA for a once annual TTR knockdown drug. How do you think about positioning that and kind of balancing Stargardt versus this potentially just being a next-gen and TTR cardiomyopathy and also enabling you to maintain premium pricing beyond a decade in that space?

Yes, thank you for the question here. I think Look, the inflation reduction act is a significant shift in Medicare and how the federal government regulates our industry. We are supportive of the new Part D patient out-of-pocket caps, but we have considerable concerns about a couple of other aspects of the legislation. Clearly, the first is around concerns of small molecule, medicines, face negotiated Medicare reimbursement rate only 9 years after approval compared to 13 years for monoclinal antibodies.

I think very pertinent to us in the near term is that while the exemptions in the inflation reduction act from Medicare price negotiation for a drug that has a single orphan drug indication, they're not as incentive to pursuing the approval of drugs that in additional indications. You can look, we're still digesting the legislation. But as you points out, in the meantime, [despite the support of] patisiran and Phase III study and Stargardt disease as we consider options for the best path forward. I'd like to just kind of note 3 points really. One is that we remain excited actually by the opportunity for an RNAi-mediated and TTR lowering method as a potential therapy in patients with Stargardt disease. We think it's an important unmet medical need.

The second, I think you touched on it when you talked about TTRsc04. As a platform company, we really have the opportunity to continuously innovate and bring optionality to how we think about developing our medicines. And I think TTRsc04 is another TTR lowering program that we're moving forward, which we're very excited about. I think the other point that I'd like to make, which I think is quite important and just to remind everybody that vutrisiran actually has orphan disease that we mentioned for TTR amyloidosis, be a phonopathy or cardiomyopathy. So as with many other companies, we're reflecting on the implications that that's relatively new legislation on how we think about our portfolio. But it's a company we actually think we're very well positioned given our platform and our ability to continuously innovate around our medicines.

Our next question comes from the line of Gary Nachman of BMO.

If you end up getting the ONPATTRO or APOLLO-B approval, let's say, end of next year, but then you'll be bumping up against the vutrisiran HELIOS-B data in early '24. How much of an impact do you think that might have on your launch of ONPATTRO in CM when physicians will be anticipating this other important data set. I know it's a bit early thinking about the launches, but given the timing of these, I was curious to get some of your early thoughts on that.

I'll just start off by saying that the reason why we progress ONPATTRO in the cardiomyopathy indication but really just a level of unmet medial needs that are there for patients who continue to progress despite the available therapies. And really, we took the opportunity with ONPATTRO try to bring a near-term solution for these patients, whilst we continue to develop vutrisiran in our HELIOS-B study. And as you pointed out, we'll have those results shortly at the beginning of 2024. So we think that we're able to meet the needs of patients in the near term hopefully with the approval of ONPATTRO and CM. And then as we progress HELIOS-B going forward and even more attractive regimen for these patients shortly afterwards. But maybe Tolga, you can comment on how we're thinking about the launch of ONPATTRO with the opportunity hopefully, of bringing vutrisiran to these patients in the medium term.

Yes. No, I think you summarized perfectly, Yvonne. All I would add is there is a big unmet need. There are patients who are currently on available treatments that are continuing to progress. And to your point, we want to make an alternative treatment available as quickly as possible so we can actually meet those needs and also continue to build our capabilities for the larger indication. We're obviously very pleased with the capabilities that we've built based on what we're actually able to demonstrate with AMVUTTRA (inaudible) launch. And as we continue to expand the indication, we believe our experience with the CM is going to help us to have even a stronger launch with AMVUTTRA and CM, if it's approved.

Thanks, Tolga, that's great. So again, the sort of TTR franchise approach, which we think will be important for patients and our commercial performance going forward.

Our next question comes from Luca Issi of RBC Capital.

Great. Maybe 1 on the pipeline, if I may. So maybe on APP kind of any additional color on why the readout has been pushed out? And maybe bigger picture, can you level set expectations in to date the next year? Reduction in CSF, APP alpha and beta would you consider it meaningful? And maybe what's the earliest we could possibly see functional data for that data set?

Great. Thank you, Luca, for a question on ALN-APP. Look, we're clearly excited about the potential for RNAi therapeutics and addressing CNS diseases. This is the first 1 out of the gate, and we're progressing kind of very well, but thoughtfully as Akshay described in his introductory remarks. But actually, maybe you can speak to the data that we are expecting after the on going study.

Yes. The crucial data, I think, first and foremost, is safety. This is our first candidate in the central nervous system. So that's a keen interest. The study is progressing well. So we are very comfortable so far. Beyond that obviously, there's lots of interest in the biomarker outlook. And so we'll be looking for APP knockdown and the fragments -- the various fragments -- circulated fragments fall from APP changes in those into CSF and in addition to that, there's going to be important PK because, again, it's the first time we've injected that (inaudible), so we'll have to see interest weekly. So those are the key data points in the short term that we'll be looking at and we're looking forward to reporting in early '23.

Absolutely. And as we move forward and on APP, we're able to demonstrate impact on patients with earlier onset Alzheimer's disease. The quarter opens up the opportunity for a whole host of other devastating CNS supporters. So a very important program for us though, we're progressing well.

Our next question comes from Joseph Stringer of Needham & Company.

A question on AMVUTTRA start forms in the percentage sourced from new prescribers. I think this quarter, you have around 17%, that was similar to 20% from your last update. Do you sort of see this continuing and fairly stable in that 15% to 20% range going forward? Or how do you see that going forward?

Tolga, that's clearly a question for you. How do you see the percentage of new prescribers going forward?

Yes. Look, I mean, I'm glad you highlighted that. We're really excited about sort of how we're displaying those strong foundational capabilities that we've been able to build from diagnosis all the way to access support. One of those excitement is we see a healthy balance of physicians, both from academic centers and community specialists, start prescribing this medication. And as you pointed out, another important metric is the new prescribers. We see a steady increase of this new specialist around 20% month after month being added to the prescriber base.

And as a result of that, we also see patients are treated a bit younger, a sign that patients are getting diagnosed and obviously, they're getting the AMVUTTRA treatment. Another important metric that we also see, and we're obviously going to pay a lot of attention to this is our start forms to treatment rates, despite having a temporary (inaudible), it's been similar to ONPATTRO.

And again, thanks to our good access support, VBAs and our price therapy strategy. So because of those elements, we believe we're going to continue to see a good expansion of new prescribers and net new patients for AMVUTTRA that's going to drive the TTR franchise to the next level.

I think we've got time for 1 more question.

Our next question comes from Myles Minter of William Blair.

Just on OXLUMO actually, just with the recent FDA label expansion. Are you expecting like a significant amount of warehouse advanced PH1 patients. And I guess, how are you thinking about growing that franchise moving forward, considering it looks somewhat flat over the past quarters?

Tolga, do you want to take that ? And where we're in (inaudible)

Yeah. Look, PH1 is a devastating disease, and we're very pleased to be able to actually provide important treatment for these ultra-rare disease patients. ILLUMINATE-C has been a great addition,we do see a good addition to our data suite of data that we have. We see a good group of patients, both from pediatric and as adults level as well as various progressive stage of their diseases and ILLUMINATE-C is simply another important element that will allow the prescribers to be able to prescribe this medicine to a broad range of patients that suffer from this ultra-rare disease.

Thanks Tolga. Look, we've had a great quarter. We really are based in our commercial performance, and we're seeing strong growth in patients on therapy across all of our commercial portfolio. So I'm certainly very pleased with our performance.

So look, thank you, everyone, for joining us on this call. Great progress in the third quarter of 2022, talked about our strong commercial results, but also we're pleased with how we're advancing our diverse pipeline programs that are in development. There's a lot of excitement ahead, cashless on deck in the coming months. And we, of course, look forward to updating you along the way as we continue to deliver on our near and long-term goals. So thank you, everybody, and have a great day.

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.