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Alnylam Pharmaceuticals Inc
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Thank you for standing by and welcome to the Alnylam Pharmaceuticals Fourth Quarter 2022 Financial Results Conference Call. 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 am 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; Pushkal Garg, Chief Medical Officer; 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 of our website, investors.alnylam.com/events.
During today’s call, as outlined on Slide 2, Yvonne will provide introductory remarks and general context. Tolga will provide an update on our global commercial progress. Pushkal will review 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 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 periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as the date of this reporting 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. 2022 was an excellent year at Alnylam where we delivered impressive commercial performance and made significant advancements across our broad pipeline of RNAi therapeutics. Commercially, as preannounced in January, we achieved full year 2022 net product revenues of $894 million which represents year-over-year growth of 35% or 43% with constant exchange rates and 13% growth between the third and fourth quarters.
A tailwind to the success was the approval and launch of AMVUTTRA in the U.S., Germany, and Japan for hereditary hATTR amyloidosis patients with polyneuropathy where rapid uptake among physicians and patient reflects an attractive product profile. With our pipeline, notable progress during the year included the exciting results for APOLLO-B, our Phase 3 study of patisiran ATTR amyloidosis patients with cardiomyopathy. The sNDA based on these results has been accepted with a PDUFA date of October the 8th. And we look forward to the FDA's review and potential approval later this year. Pushkal will provide more color on this later in the call.
Among our earlier programs, a highlight for the year was the initiation of the first-in-human study of RNAi therapeutic in the CNS with ALN-APP for Alzheimer's disease. We also completed three CTA filings advancing to the clinic promising programs such as ALN-KHK for type 2 diabetes, ALN-PNP for NASH and ALN-TTRsc04 for ATTR amyloidosis and we are announcing today the dosing has started in a Phase 1 study with this program.
Looking forward to the rest of 2023, we are excited for seven important pipeline milestones, including 10 clinical readouts from Alnylam and partner led programs, such as Phase 1 results from the aforementioned ALN-APP study and Phase 2 results from the KARDIA hypertension studies of zilebesiran. This execution is in line with our focus on the following key drivers for Alnylam's group over the next several years.
First, is the potential near-term expansion of our ATTR franchise opportunity where we aim to become a global leader in delivering impactful and highly differentiated medicines to patients. Second, is our expansion beyond rare diseases to also address more common disease areas. And the third growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, opportunities of 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 tier biotech, developing and commercializing transformative medicines for rare diseases and beyond for patients around the world driven by a high yielding pipeline of firsts and/or best-in-class product candidates from our organic products 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. Our commercial operations had a strong close to 2022 delivering $262 million in combined net product sales in Q4, which represented 13% growth compared with Q3 2022. The strong growth was driven by an increase in patients on commercial therapy across both our TTR and also rare franchises. We remain particularly encouraged by several signs indicating that the ongoing launch of AMVUTTRA for ATTR amyloidosis patients with polyneuropathy both in the U.S. and now also in Germany and Japan, is expanding the size of the opportunity for our TTR franchise.
Now I will turn to our specific results starting with our TTR franchise. We saw robust growth in our TTR franchise in Q4 achieving $191 million in global net product revenues for ONPATTRO and AMVUTTRA representing a 12% increase compared with the first quarter and a solid 38% growth compared with Q4 2021.
The year-over-year growth in Q4 was driven by the strength of the AMVUTTRA launch in the U.S. with the U.S. market delivering an impressive 72% growth compared with Q4 2021. At the end of 2022, over 2,975 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, an increase of nearly 400 patients from the end of Q3, which represents a doubling of the quarterly trend that existed prior to the launch of AMVUTTRA, a clear signal of accelerating TTR franchise growth.
In the U.S. combined sales of ONPATTRO and AMVUTTRA increased 12% versus the third quarter and were primarily impacted by the following. A robust 19% increase in demand growth, which was driven by the strength of the AMVUTTRA patient uptake, which is being driven both by switches from ONPATTRO and more importantly from increases in patients new to therapy. ONPATTRO inventory destocking in the channel during the fourth quarter reduced reported TTR growth by approximately 5%. This was anticipated as demand for ONPATTRO in the U.S. continues to decrease as more patients switched to AMVUTTRA.
In our international markets, combined sales of ONPATTRO and AMVUTTRA also increased 12% versus Q3 2022, primarily driven by the success of initial international AMVUTTRA launches in Germany and Japan with growth favorably impacted both by increased patient demand and initial launch stocking. Finally, our global results continued to be challenged by foreign exchange headwinds with total TTR year-over-year reported growth of 38% deflected the foreign exchange impact of 10 percentage points due to the strengthening U.S. dollar.
Now I would like to provide you with some additional color on our ongoing AMVUTTRA U.S. launch progress as well as an update on initial international launches in Germany and Japan. In the U.S., we've received more than 750 AMVUTTRA start forms in the six plus months since launch with more than 50% of the start forms representing new patients and the balance representing switches from ONPATTRO.
Consistent with what we shared at Q3, the monthly average of new therapy AMVUTTRA start forms remains at 60 per month, which is double the rate of ONPATTRO new to therapy start forms that we were receiving prior to the launch of AMVUTTRA. Furthermore in the U.S. our demand generation has been healthy and balanced between community accounts and centers of excellence and we have and we have seen an approximately 30% increase in our prescriber base since launch, a clear signal that AMVUTTRA is expanding the opportunity for our TTR franchise.
Additionally, our patient base has broadened to include a variety of newly and previously diagnosed patients starting on AMVUTTRA with significant enthusiasm being expressed for AMVUTTRA's product profile including quarterly subcutaneous dozing. Meanwhile, on the access front, given our parity launch pricing, we have not faced any significant access headwinds. We've also made significant progress with formulary approvals supporting smooth access to patients that are prescribed AMVUTTRA.
In our international markets the initial launches of AMVUTTRA in Germany and Japan in Q4 experienced robust demands with new patient starts coming from both switches from ONPATTRO as well as new to therapy patients that were consistent with what we experienced in the U.S. in our initial launch quarters. The new to therapy patients included a healthy mix of naive to therapy and switches from the competition and ONPATTRO. Our next anticipated international launch is expected in the UK in late Q1 2023. To wrap up with AMVUTTRA, we are pleased with our initial launch progress and are encouraged by the early signs that were expanding the market opportunity for our TTR franchise.
Moving to our ultra-rare disease franchise, first GIVLAARI, we achieved $47 million in global net product revenues in fourth quarter representing a 3% increase compared with Q3 2022 and 16% growth versus Q4 2021. At the end of 2022, over 520 patients were on commercial GIVLAARI treatments worldwide, up from over 460 at the end of the third quarter representing 13% quarterly patient growth.
The reported 16% increase in year-over-year global net product revenue growth of GIVLAARI reflected a foreign exchange impact of 6 percentage points due to the strengthening U.S. dollar. In the U.S. sales of GIVLAARI were flat versus the third quarter, primarily due to the demand growth of 3% driven by an increase in patients on therapy, which was offset by changes in inventory stocking during the quarter. In our international markets, GIVLAARI sales increased 10% compared with the third quarter, primarily due to the growth in patients on therapy and the timing of orders in partner markets.
Moving now to our second ultra-rare disease product OXLUMO. We achieved $24 million in global net product revenues in the fourth quarter representing a 45% increase compared with the third quarter. At the end of 2022 over 280 patients were on commercial OXLUMO treatment worldwide, up from over 230 at the end of the third quarter, representing 22% quarterly patient growth. In the U.S. sales of OXLUMO increased 38% versus the third quarter due to a growth in patients on therapy and an increase in average patient utilization during the quarter driven by more patients on the monthly loading dose portion of their initial treatments.
In our international business sales of OXLUMO increased 50% compared with the third quarter due to an increase in patients on therapy and due to the timing of orders in partner markets. Additionally, as with ONPATTRO and GIVLAARI, changes in foreign exchange rates also negatively impacted OXLUMO Q4 2022 results with reported year-over-year growth of 24% reflected a foreign exchange impact of 9 percentage points due to the strengthening U.S. dollar.
In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q4 and particularly with our early signs of strong performance associated with the 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 Pushkal to review our recent R&D and pipeline progress. Pushkal?
Thanks Tolga, and good morning everyone. Let me begin by updating you on our efforts in ATTR amyloidosis, where we are advancing three clinical stage product candidates, patisiran, vutrisiran, and as I'll update in a moment, TTRsc04. First, as you've heard from Yvonne, we are delighted that our supplemental new drug application for patisiran for the cardiomyopathy of ATTR amyloidosis has been accepted by the FDA with a standard review and a PDUFA date of October 8th.
In their file acceptance letter, the FDA stated that they have not identified any review issues. The agency also noted that they are planning to hold an advisory committee meeting to discuss the application. If approved, this will allow us to extend the potential benefits of an RNAi therapeutic to the many patients with wild type and hereditary ATTR amyloidosis with cardiomyopathy. This filing is based on the pivotal APOLLO-B study, which demonstrated improved functional status and quality of life in patients with ATTR cardiomyopathy given patisiran for 12 months relative to placebo.
The efficacy is also supported by an encouraging safety profile and exploratory data indicating that patisiran treatment can favorably impact disease progression. With the sNDA now accepted, I'd also like to share some details on our global filing plans for patisiran in ATTR amyloidosis with cardiomyopathy. We are planning to submit an sNDA in Brazil in early 2023. However, we do not plan to pursue label expansion in other regions. This is a result of the earlier than anticipated enrollment completion of the vutrisiran and HELIOS-B study combined with the timelines for regulatory approval and obtaining market access in these countries. As a result, we will focus our efforts in other regions to submitting an sNDA for vutrisiran assuming positive results from the ongoing HELIOS-B study.
As a reminder, HELIOS-B is studying a similar population as APOLLO-B, but is designed for a primary outcomes endpoint of all-cause mortality and recurrent CV events. We remain on track to share top line results in early 2024. As you know, we have been evaluating a biannual dosing regimen of vutrisiran as part of the HELIOS-A randomized treatment extension or RTE, which was performed after the main portion of the study had completed. Our objective has been to see if we can provide a more convenient dosing regimen versus the already excellent profile of the 25 mg every three months regimen with maintained efficacy.
The primary endpoint of the RTE was non-inferiority of TTR lowering with the 50 mg biannual regimen versus the 25 mg quarterly regimen as well as an acceptable safety profile. Today we are reporting top line results of the randomized treatment extension through month nine. As expected non-inferiority of the 50 mg biannual dosing regimen was indeed established as demonstrated by mean serum TTR reduction over nine months. However, we did note some recovery of serum TTR reduction in the 50 mg arm towards the very end of the dosing interval at six months.
To illustrate this, at month six, 80% of patients on the 25 mg quarterly regimen achieved 80% knockdown or greater, whereas on the 50 mg biannual regimen, 63% of patients achieved that same degree of knockdown. In other words, 37% of patients did not get to 80% TTR knockdown with the biannual regimen. Vutrisiran also continued to demonstrate an acceptable safety profile. No safety signals regarding cardiac, hepatic or renal events were observed.
In the RTE study there were six deaths of which five occurred on the 50 mg biennial arm and one occurred on the 25 mg quarterly arm, after the patient dropped out of the study. None was considered related to the study drug and the majority occurred in patients with notable preexisting cardiomyopathy at baseline in the context of known aggressive mutations.
We're planning to present more details on these results in a scientific congress in early 2023. Despite the supportive efficacy data and safety data from the RTE, we've made the strategic decision not to move forward with regulatory submissions for the 50 mg biannual dosing regimen of vutrisiran as previously planned. Several factors played into that decision.
First, the dynamics of serum TTR recovery observed towards the very end of the biannual dosing interval, which we believe is suboptimal in terms of a product profile where we see clamped pharmacology in order to achieve maximal efficacy for patients. Second, as you heard from Tolga, the very strong initial commercial performance of AMVUTTRA in its first two quarters on the market, given its compelling therapeutic profile with quarterly subcutaneous dosing, along with the extremely positive feedback it has received from patients and physicians, allows us to exercise greater selectivity in advancing an innovative offering.
And finally, we now have a new molecule targeting TTR, TTRsc04 which I'm proud to announce that it has entered the clinic and begun dosing in a Phase 1 study. ALN-TTRsc04 is an investigational RNAi therapeutic based on our IKARIA Platform and offers the potential for more durable and potent TTR silencing with the possibility for annual dosing. As such, we will focus our continued innovation on advancing TTRsc04, which may offer a transformative profile. We expect top line results from the Phase 1 study in late 2023.
In addition to our late stage clinical programs, we believe we have also been making great progress with our early and mid-stage programs. A notable highlight includes zilebesiran, our investigational RNAi therapeutic for hypertension which we believe could transform the treatment of this disease and offer a highly differentiated profile from all existing antihypertensives including RAS inhibitors. We're thrilled to have announced that our KARDIA-1 Phase 2 study was fully enrolled as of December and on track to deliver top line results in mid-2023. We also look forward to KARDIA-2 top line results at or around year end 2023.
We're also working to expand delivery of RNAi therapeutics to tissues beyond the liver. To that end, we are on the cusp of seeing important data from ALN-APP, which is our first investigational RNAi therapeutic directed to the CNS, and in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. ALN-APP has the potential to offer a highly differentiated approach in Alzheimer's disease by targeting APP upstream of where antibodies currently target and has the potential to act both intracellularly and extracellularly to reduce disease-causing peptides.
We believe these initial clinical data with ALN-APP if positive will be an important milestone, not just for this particular program, but for our overall CNS platform to show that RNAi can achieve clinically relevant degrees of target knockdown in the CNS with a safety and dosing profile that supports further development. We remain on track to report top line results from the Phase 1 study in early 2023.
These are just a few highlights from our broad and innovative pipeline, driven by our underlying organic product engine that we expect will deliver sustainable innovation and represents a key growth driver for Alnylam in the years to come. To wrap up these highlights, we're excited to have submitted a CTA filing for ALN-KHK in type 2 diabetes with a Phase 1 start expected imminently. In addition, our partners at Regeneron have begun dosing in a Phase 1 trial of ALN-PNP in NASH.
With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?
Thanks Pushkal, and good morning everyone. I'm pleased to be presenting Alnylam's Q4 in full year 2022 financial results, which underscore Alnylam's strong commercial capabilities and operational excellence. After commenting on our fourth quarter and full year results, I will also provide our financial guidance for 2023.
Turning now to a summary of our full P&L results for the fourth quarter and full year, total product revenues for 2022 were $894 million or 35% growth versus 2021 or 43% on a constant exchange rate basis with growth contributions from all four commercial products. Net revenue from collaborations for the fourth quarter was approximately $71 million, representing an 18% increase compared with Q4 2021, primarily due to increased revenue from our collaboration with Regeneron from increased manufacturing activities in the quarter.
For the full year, net revenue from collaborations was $135 million, representing a 25% decrease compared with 2021 primarily due to a decrease in revenue recognized in connection with our collaboration agreements with Regeneron and Vir, attributed to reduced research and manufacturing activities and timing of reimbursable activities. Our non-GAAP R&D expenses increased 16% in the fourth quarter 2022 compared to the same period in the prior year, primarily due to increases in headcount to support our R&D pipeline and development expenses associated with the KARDIA-1 and KARDIA-2 zilebesiran Phase 2 studies.
Our non-GAAP SG&A expenses increased 15% in the fourth quarter of 2022 compared to the same period in the prior year, primarily due to increased headcount and other investments in support of the global launch of AMVUTTRA and other corporate expenses to support the scaling of our business. Our combined non-GAAP R&D and SG&A expenses were approximately $1.4 billion for the full year 2022, representing 14% growth versus 2021 as we continue to advance our pipeline and deliver strong top line growth while maintaining discipline and how we invest in our operations.
Our non-GAAP operating loss for 2022 was $554 million or approximately flat versus 2021. We do anticipate reducing our non-GAAP operating loss in 2023 as you will hear when I provide our 2023 financial guidance as we remain focused on achieving a self-sustainable financial profile by 2025, aligned with our P5x25 25 goals.
Finally, we ended the year with cash, cash equivalents and marketable securities of $2.2 billion compared to $2.4 billion at the end of 2021 with the decrease primarily due to our operating loss in 2022, which was partially offset by approximately $265 million received from employee option award exercises and approximately $135 million from our convertible debt financing. We continue to believe that our current cash balance will bridge us to financial self-sustainability, an enviable position in today's market environment.
Now turning to our financial guidance for 2023, starting with net product revenues, we are providing combined net product revenue guidance from ONPATTRO, GIVLAARI, OXLUMO, and AMVUTTRA. Our guidance assumes the sNDA for patisiran for ATTR amyloidosis with cardiomyopathy in the U.S. will be approved by the PDUFA date on October 8th, 2023, and also assumes foreign exchange rates as of December 31, 2022.
We anticipate combined net product revenues for these four products will be between $1.2 billion and $1.285 billion with the projected report growth range versus 2022 of 34% to 44%. As you can see, we are also providing constant exchange rate growth guidance for our net product revenues this year with a projected range of 34% to 44%, highlighting no current difference between our reported and constant exchange rate growth guidance.
Our guidance for net revenue from collaborations and royalties is a range between $100 million and $175 million with the midpoint of the range of approximately flat versus 2022. We anticipate the collaboration revenue associated with our partnership with Regeneron and Leqvio royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2023. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.575 billion and $1.65 billion. The midpoint of the guidance range represents a projected 13% increase compared with 2022.
Growth highlights for R&D expense in 2023 include increased investment in zilebesiran as we progress the KARDIA-1 and KARDIA-2 Phase 2 studies, initial investment in TTRsc04, as well as growth in pre-DC and IND enabling efforts across our preclinical portfolio as we continue to invest in creating new organic growth opportunities for the future. Growth Highlights for SG&A expense in 2023 include increased medical and commercial investment as we prepare for the potential launch of patisiran in the U.S. for ATTR amyloidosis with cardiomyopathy.
Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2023. We will, of course, be executing on the global commercialization of our products on ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. We expect to complete enrollment in the KARDIA-2 Phase 2 studies of zilebesiran, topline results from our Phase 1 study of ALN-APP in patients with early onset Alzheimer's disease is on track for early 2023 with our partner program Vir expects additional results from Phase 2 combination trials of ALN-HBV02, and Regeneron plans to initiate a Phase 2 study of ALN-HSD in patients with NASH.
Let me now turn it back to Christine and coordinate our Q&A session. Christine?
Thank you, Jeff. Operator, we will now open the call for your questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.
[Operator Instructions] Our first question comes from the line of Ritu Baral from Cowen. Your line is now open.
Good morning everyone. Thanks for taking the question. Yvonne, I wanted to ask about just the potential topics of the advisory committee meeting. What do you think at this point, what is Alnylam planning on addressing during the Advisory Committee meeting? If no review, I'm sorry, no review issues have yet been identified in the communication are there points during the sNDA review that by law interaction is required between the sponsor and the regulator to help you suss that out? Thanks.
Ritu, thank you very much for that question. I mean, as you know, we were very pleased with the results from the APOLLO-B study and please that the FDA accepted our application. And as you point out, did not identify any review issues to date. You know, whether you have an ADCOM [ph] or not is entirely up to the FDA. We have no indication at this point in time with respect to any specific areas to address as any potential advisory committee. But we look forward to engaging with the FDA through this process and sharing our data. Beyond that there's not a lot else we can say at this point in time.
So no legal interactions required for the sNDA process in the near future with you guys?
Well, we will get information as to more details around the advisory committee actual points in time, but at this stage we have no further information that we can provide. I mean, the only update that we are required to provide the FDA is the 120-day safety update.
Got it. Thank you.
Next question?
One moment for the next question. And your next question comes from the line of David Lebowitz from Citi. Your line is now open.
Thank you very much for taking my question. With respect to the six-month dosing of AMVUTTRA, I'm falling short and being discontinued. What learnings are you taking from that to the IKARIA program and is it changing your strategy with respect to how you're looking at that particular therapy? And then just a little tag on, do you think that the lack of the biannual dose substantially changes anything for the AMVUTTRA's prospects?
Right, so I'll start off and then invite Pushkal to contribute. I think really the first thing to say is that the quarterly regimen of AMVUTTRA has really been a game changer for patients with TTR Polyneuropathy, and we are really pleased with the profile. You've heard from Tolga earlier, you know how well the launch is going. So really the decision to not move forward with a six monthly regimen was a strategic one. We want to be able to focus on the quarterly AMVUTTRA regimen in the near-term.
And then as you've heard, and you've touched on this, progressed TTRsc04 based on our IKARIA platform, where we believe there's a real potential for knockdown, TTR knockdown of close to 90% and potentially annual dosing as well, which we think is then a real step forward for patients. I mean, Pushkal any commentary on the, you know, learnings? I suppose what we've learned is you know, more about the profile of the six monthly regimen. Anything else to add?
Yes, no, I think the only thing that I would add to what you said, Yvonne is, I mean, a it's reaffirmed the potency and the power of the 25 mg quarterly regimen where we saw excellent clamped pharmacology with the quarterly dosing that reaffirms the profile that we saw on the original HELIOS-A study. And I think Dave, to your other point, I think and as Yvonne highlighted, we're really excited that TTRsc04 is now in the clinic and we will get data shortly later this year around what that's looking like in the Phase 1 study. And we're optimistic based on the preclinical data and the power of the IKARIA platform that we will see more potent and more durable knockdown and enabling a possible annual dosing regimen with that. So I think, we're really in a fortunate position that our research engine has been able to bring forward this sc04 molecule that we can bring into the clinic. It allows us to progress innovation for these patients.
Thanks. Thanks Pushkal. May I have the next question?
One moment for the next question. Your next question comes from the line of Tazeen Ahmad from Bank of America. Your line is now open.
Hi, good morning. Thanks for taking my question. Mine is on APP for the expected top line that's due in the beginning of this year, can you just give us some color on what data exactly you're planning on presenting and how we should interpret that data? What would be clinically meaningful? And do you also plan on presenting any plaque [ph] clearance data with that top line? Thanks.
We didn’t actually kind of hear all of the questions. Do you mind perhaps repeating it and maybe focusing on just one question?
Yes. The question is on what you're going to present at the top line? What should we include in that assumption of what you're going to be presenting? So would you be [indiscernible]
Fine, that's really clear, so top line…
Yeah.
Topline data from the ALN-APP study. Pushkal?
Yeah. Thanks, Tazeen. So, yes, we're really excited about the ALN-APP program. It's our first foray into the CNS. We're still on track to have top line data in the first half of this year. As a reminder, this is a study in patients with early onset Alzheimer's disease. We're in the single ascending dose phase of that study. And what we are hoping to report out on will be safety and tolerability, which is the primary endpoint. This is the first time we're giving intrathecal injection with the C16 conjugate, and then looking for target engagement, a knockdown of soluble APP alpha and beta. So we have very good pharmacodynamic markers that can point to target engagement. And we will want to see evidence of target engagement there that we're seeing good pharmacology in the brain. So those are really the key things that we'll be reporting on later in the first half of the year.
Thanks Pushkal. Next question?
One moment for the next question. And your next question comes through the line of Salveen Richter from Goldman Sachs. Your line is now open.
Hi, this is Tommy on for Salveen. Thanks so much for taking our questions. For HELIOS-B can you remind us of the rationale behind using all-cause mortality instead of cardiovascular mortality in the composite primary endpoint? And is there one that's preferred by physicians and regulators? Thank you.
Thanks. And I guess that's a question straight for you, Pushkal.
Yeah. So Salveen I think when we, you know, when we look at, when we designed the HELIOS-B study, we really want to ultimately show the benefit of the drug on the totality of the experience of patients with this disease. And an all-cause mortality and recurrent CV event endpoint really captures, maximizes the number of events that we can capture in the course of the study which aids in the powering of the study and also becomes a very clinically meaningful effect. Certainly there can be analyses that are looked at under that as secondaries or post hocs that look at the various types of mortality events. But that's the basic explanation.
Next question?
One moment for the next question. The next question comes from the line of Maury Raycroft from Jefferies. Your line is now open.
Hi, good morning. Thanks for taking my question. I was wondering if you have a tentative date scheduled for the adcom and you've mentioned adding the 120-day safety data from APOLLO-B open label extension, but I'm wondering if you can discuss possible scenarios where you may be able to supplement the sNDA with additional efficacy or safety data from APOLLO-B, open label extension and or the HELIOS-B study.
Yes, so Maury, maybe a couple questions in there. You know, we don't have a formal date yet. That's something again, we've released what we understand at the moment from the agency's correspondence with us. So we'll look forward to getting additional information on that. And in terms of the 18-month data, look we're in the process of getting and reviewing the APOLLO-B open label extension data. As a reminder, everybody crosses over to active drug at month-12. And we'll certainly share those data at an appropriate scientific meeting. And with regard to the agency, we'll be supplying whatever they need to facilitate their review. And so, we're looking forward to sharing things, the data with them, both from the main study and as they need from the open label extension. The day 120 safety update is primarily focused on safety update data, so that will also be a parallel process.
Understood. Okay, thanks for taking my question.
Sure.
And one moment for the next question. Your next question comes from the line of Paul Matteis with Stifel. Your line is now open.
Hey, thanks so much for taking my question and congrats on the progress. I was, I thought it was really interesting that you included potential sales from ONPATTRO in TTR cardiomyopathy in guidance, given that it's under review, given that there is an adcom, and I guess is it the right interpretation of that decision, that the company continues to have very high conviction that the APOLLO-B data should lead to an approval, and that was enough for you to plan financially and guide around that? Thank you.
Yes, well, I mean, I'll start and then hand it over to Jeff in terms of how we thought about planning. I mean, clearly, we do believe that the APOLLO-B study has delivered actually very impactful results, both in terms of health status and disease progress. We've talked about the efficacy endpoints in some detail. And clearly we are planning for the advisory committee as notified by the FDA. And obviously you know, we will have to await the FDA's determination on our submission. But you know, we believe that we have an efficacy and safety package here that is pretty compelling. Jeff, do you want to speak a little bit to how we thought about ONPATTRO CM revenues?
Yes, I mean, Paul, you're right. I mean, we flagged that in the guidance on the slide that we assumed that. Again, given the timing of that, given that it's in the fourth quarter, the impact of that from a revenue perspective, that this year is going to be relatively modest. And so, not, that doesn't really have a significant impact on the financial guidance we've given for the year as a result, if approved, we would expect more significant impact next year.
Thanks so much.
And one moment for your next question. The next question comes from the line of Gena Wang with Barclays. Your line is now open.
Thank you. I have one question regarding the APP program. What will be the ideal clinical profile regarding percentage of knockdown and the frequency of dosing? Any negative review from vutrisiran by any dosing data regarding frequency of dosing for the APP program?
Yes, Gina, thanks for your question. So I guess a couple things in there. You know, what's the ideal profile? So look, I think this is the, you know, we've said before that we don't have the, from genetic data, we would imagine that we would want get to close to about 50% knockdown of ALN-APP of amyloid precursor protein. We think that's probably around the target range to get to a therapeutic effect, but at the end of the day, no one really knows. And so that's kind of where we're shooting for. But this is again an initial single ascending dose study. We'll be providing some interim data and so we'll be working our way up to get to higher levels of knockdown as the data allow and so that's point one.
In terms of the frequency of dosing, look, the preclinical data that we have suggests that this may be a relatively infrequently dosed molecule. We've seen knockdown lasting over six months in the non-human primate studies that we've done with ALN-APP. So we're very encouraged with the potential that this could be a quarterly or potentially biannually dosed drug in the CNS. But again, the data will inform that. I don't think there's any particular read-through from the increased randomized treatment extension that's a different molecule given to a different space. It's a different conjugate. And as you know, we continue to -- our scientists continue to hone our chemistry all the time, but a lot of that is also molecule and target dependent. So we're very encouraged by the data we have so far non-clinically and really looking forward to the clinical data emerging shortly.
Thank you very much.
Thanks, Gena.
For your next question. Your next question comes from the line of Luca Issi with RBC Capital. Your line is open.
Oh, great. Thanks so much for taking my question, and congrats on the progress. I have a quick one on HELIOS-B. I think there's a few docs out there that are convinced that actually the drug is making an impact for their patients with ATTR cardiomyopathy, but they are just worried that this trial is not long enough to actually show a convincing separation of the curves. Is there a scenario where you can amend the protocol so you don't read out the primary endpoint when the last patients reach the 30-month mark, but rather after a pre-specified number of events? Any thoughts there? I much appreciate it.
Yes, Luca, I think, you know, there's, and first of all, it's great that you're getting that sort of feedback. We're obviously encouraged overall by the profile of vutrisiran and that we're seeing from patients out there. In terms of the study design, I think we've a, I'll just remind you, we have a track record of working in this space for quite a while and executing successful studies. Our teams have gone through and we feel very good about the design of the study and the execution of this study.
As a reminder, we've got variable follow up for 30 to 36 months. And this study builds upon the success and what we've seen in terms of encouraging data coming out of APOLLO-B where we saw positive impacts on functional endpoints, quality of life, evidence of potential delays in disease progression and favorable impacts on echocardiographic parameters, technicians, and there's a lot of positive data there. And HELIOS-B is twice as large and about three times as long. So we feel good about the design and execution of that study, and we're not planning at this point to make any changes.
Yes, spot on Pushkal. I mean, right now we're focused on robust execution and bringing this home and sharing results with you in early 2024.
Got it. Super helpful. Thank you, guys.
Next question,
One moment for your next question. And your next question comes from the line of Jessica Fye with J.P. Morgan. Your line is now open.
Hey, good morning. This is Jail for Jess. So two questions from us on the sNDA of ONPATTRO, in the case that the FDA will request any new data, or in the case that you might want to send more data to the FDA, do you expect any type of PDUFA extension because of the new data submission? And then secondly, we know that the cardiovascular outcome data from [indiscernible] trial will be available in July. So just curious, would you be watching for the data from the [indiscernible] CM and if any thought you can share with us regarding the kind of potential impact on the tribute data on your thinking of the change in patient population and anything along those lines? Thank you very much.
Two questions for you really here, Pushkal. One on the sNDA was on ONPATTRO and requirement for new data and potential extensions, the data and then I think some questions around our perspectives on [indiscernible] cardiomyopathy outcome study.
Yes, thank you. Look, in terms of the impact if we're asked to supply additional data, I really can't speculate. Certainly we will provide whatever data the agency requires to facilitate their review. And we look forward to sharing that data in the course of questions that come from the agency and at the advisory committee. The FDA has declared a PDUFA date of October 8, and I know they'll be striving to achieve that, and we'll update if there's any changes to that based on their requests.
In terms of the [indiscernible] data, look, we look forward to seeing the results. I think it's scheduled for the middle of the year, but I don't think that really changes anything for us in the context of the APOLLO-B sNDA. That study is completed and under review and so we'll certainly be looking for those results, but -- and watching them, but there's, I don't see any really particular impact on the APOLLO-B sNDA.
Yes, so informative for the field, yes. But of no real kind of consequence to our specific programs, correct, yes. Next question?
One moment for the next question and your next question comes from the line of [indiscernible] with Morgan Stanley. Your line is now open.
Good morning and thanks for taking the question. May be just a quick one on AMVUTTRA in polyneuropathy. I noticed you got a J-Code in early January. Just curious what impact you think that could have on the trajectory of the launch and is it potential we could see an inflection there? Thanks.
Yes, that's a nice short question for Tolga, implications of the, our receipts of the J-Code.
Right. Hi Mike. Thanks for the question. We're very pleased with the fact that the J-Code we received the J-Code as a, on the due date. Prior to the J-Code we already had a generic J-Code that allowed us to be able to have access to provide the right access to our patients in the U.S. Therefore, we wouldn't necessarily be expecting any significant change.
Now in terms of the outtake is already itself has been, as Yvonne put it, has been a game changer. We have doubled the number of start forms that we would normally receive in a steady state of ONPATTRO. Therefore, we're very pleased with the accelerated growth that our parity pricing at launch, as well as our good value based access strategies that we were able to establish prior to the launch, that's really allowing us to have a smooth sailing in terms of the access front, and the growth is really coming from thanks to the profile of the product as well as our efforts in expanding the prescriber base for the polyneuropathy across the U.S. as well as now in Japan and Germany.
Got it. Thank you.
Thanks, Tolga. Next question, please?
One moment for the next question and your next question comes from the line of Myles Minter with William Blair. Your line is now open.
Hi, thanks for taking the question. Just on the HELIOS extension and the 50 mg biannual dosing, did the five patients that passed away in that arm all achieve the 80% TTR knockdown, or did they not? And did they all die from cardiomyopathy? There just again seems to be an imbalance between mortality on the 25 mg every quarter and the 50 mg biannual. And we know that the 25 mg quarterly is efficacious. So just clarifying that would be helpful.
Thanks, miles. Maybe I can just give you a little bit of context of the death events that happened in this study. I mean, just taking a step back, the overall safety in terms of adverse events, serious adverse events, cardiac, renal, hepatic events, laboratory, that was all really quite balanced between the arms. We did see this numerical difference in terms of deaths. They were all unrelated as deemed by the investigator. They had multiple risk factors for poor prognosis in terms of advanced NYHA Class, elevated BNP or aggressive mutations.
As an example, three out of the five patients in the 50 mg biannual regimen who passed away had glue 89 glen [ph] and Serine 77 [indiscernible] mutations, which are particularly aggressive, so make the causes too, some CB, but some were non-CB. As an example, one of the patients who passed away in the biannual regimen was diagnosed with acute myeloid leukemia and died after chemotherapy. And then we looked you know, there was no relationship to pharmacokinetics or as you were asking pharmacodynamics a knocked down that we observed. So we'll provide more details in upcoming scientific meetings. But we're very reassured from the detailed safety analysis, which did not, did not to our minds seem to be any relationship to the drug.
Right. Thanks.
One moment for the next question, and your next question comes from the line of Joseph Stringer from Needham and Co. Your line is now open.
Good morning. This is Barbara on for Joey, and our question is about the big picture. Can you give us a sense of what you think ONPATTRO and AMVUTTRA's combined market penetration of the TTR polyneuropathy and mixed phenotypes is at this time?
Yes, I think, I think just kind of taking a step back and thinking about the TTR market as a whole, I mean, there's no doubt that it's a rapidly growing market with increased physician awareness, increased diagnosis of patients, and obviously that's translating into increased treatment of patients. So we are very excited that we have two RNAi therapeutics participating and helping patients who have ATTR Amyloidosis at the moment with polyneuropathy, and then of course, hoping to extend the label to patients who also have cardiomyopathy. We think it's a market that also has room for multiple players. It really is all about kind of market growth rather than market share.
And I think what's particularly pertinent with respect to our portfolio is, we really see our portfolio driving growth overall going forward for Alnylam. So, you know, we're very pleased with our progress thus far. And you know, we look to continue helping physicians, treat patients as appropriate with both ONPATTRO and AMVUTTRA. I mean, Tolga is there anything you want to add in terms of just stepping back and thinking about the TTR market?
Yes, I mean, along the same lines we're very pleased to be able to provide now we do have a franchise. We have two products that are available in the US? and soon for the rest of the world in polyneuropathy. And what we know is despite the fact that it's a rare disease, there is still significant unmet need, it's a devastating disease. If the patients are not treated, they do end up with mortality care mobility in a timeframe of five to seven years. And despite that, diagnosis and treatment is still relatively low numbers. And what AMVUTTRA launch has demonstrated to us is the fact that having a very compelling product profile and with the convenience of subcutaneous injectable every quarter really does change the game in terms of how it allows us to be able to reach more patients through by actually finding more, more physicians.
So we do have this prevalence number that's anywhere between 40,000 to 50,000 across the world, including the mixed genocide patients. We're still scratching the surface and as Yvonne indicated with these products coming into the market will allow us to actually increase the awareness, both on the physician side as well as on the patient's side. And the most recent launch of AMVUTTRA clearly demonstrates that.
Thanks, Tolga. So we've got time for one last question.
One moment for the last question, and your last question comes from the line of Eliana Merle with UBS. Your line is now open.
Hey guys, thanks for taking the question. Just on the ONPATTRO ADCOM, I guess just from the interactions and feedback from the FDA so far, do you get the sense that this ADCOM is more specific to the APOLLO-B data, such as being at 12 months, or do you think it sort of is more broadly about the ATTR landscape in cardiomyopathy and the clinical significance in different subgroups? I mean, I guess like in other words, how much do you think the ADCOM would impact AMVUTTRA potential labeling discussion versus this being more of an APOLLO-B specific related discussion at the ADCOM? Thanks.
Thanks Ellie for your question. Again, as we've said at the beginning, we don't have any particular feedback from the agency on the specifics of what the ADCOM will be or the questions there. And we'll certainly look forward to hearing more from the agency. We're committed to supporting their review in any way we can. I do expect that the ADCOM is going to be focused on the APOLLO-B data however. That's the sNDA that we filed and that would be the subject of the review. Those would be the data that we'd be sharing and talking about in the context of that -- the review and the advisory committee as well. But again, we'll look forward to seeing more from the agency when they get back to us with details.
Yes, and again, I think just to underscore that we believe the APOLLO-B data actually, you know has demonstrated the hypothesis that RNAi therapeutics can have a meaningful impact on patients with TTR amyloidosis with cardiomyopathy.
So we shall stop there. Thank you everybody for joining the call. We're really happy with the progress that we've made in the fourth quarter and the full year 2022. We've had strong commercial results. We've continued to advance our diverse pipeline of programs and developments, and we've also got a number of exciting catalysts on deck in 2023. So we look forward to updating you along the way as we continue to deliver on these goals. So thank you everybody, and have a great day.
Goodbye.