Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss the FDA approval of AMVUTTRA. There will be a question and answer session to follow. Please be advised that this call is being taped at the company's request. I would now like to turn the call over to the company.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer, Akshay Vaishnaw, President, Pushkal Garg, Chief Medical Officer, and Tolga Tanguler, Chief Commercial Officer. Also joining us and available for Q&A are Jeff Poulton, Chief Financial Officer, and Rena Denoncourt, Vice President, TTR Franchise Lead, with John Vest, Vice President, Clinical Research. For those of you joining us via conference call, the slides have been made available via webcast and can also be accessed by going to the investor page of our website, www.alnylam.com/events. Now, turning to today's call, as outlined in slide two, Yvonne and Akshay will provide some introductory remarks and offer context around today's FDA approval of AMVUTTRA, the trade name of vutrisiran.
Pushkal will review the label and the data to support the approval of AMVUTTRA, and Tolga will discuss our commercial plans for AMVUTTRA before opening up the call for your questions. Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report, quarterly report, and 8-K current reports on file with the SEC. In addition, any forward-looking statements represent our views only as of the day of this recording and should not be relied upon as representing our views as of any subsequent date.
We specifically disclaim any obligations to update such statements. With that, I'd like to turn the call over to Yvonne. Yvonne?
Thanks, Christine, and thanks everyone for joining the call. Today happens to be the 20th anniversary of Alnylam, and I couldn't think of a more fitting anniversary gift to help us acknowledge this day. Yesterday evening, the U.S. Food and Drug Administration approved AMVUTTRA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. With this approval, AMVUTTRA now becomes the fifth RNAi therapeutic invented by Alnylam to be approved by the FDA in less than four years. It also represents what we believe to be a major step forward for patients living with a polyneuropathy of hATTR amyloidosis, a rare, inherited, rapidly progressive, and fatal disease. With today's regulatory decision, AMVUTTRA becomes the first and only medicine approved for the treatment of the polyneuropathy of hATTR amyloidosis that is administered by subcutaneous injection once every three months, offering the potential for reversal of neuropathy impairment.
We believe the efficacy and safety profile that Pushkal will review, along with the infrequent dosing every three months, creates an attractive therapeutic option for patients and their families. In addition, AMVUTTRA now becomes our second RNAi therapeutic for the treatment of the polyneuropathy of hATTR amyloidosis, joining ONPATTRO to create a multi-product commercial TTR franchise. We believe the launch of AMVUTTRA has the potential to drive significant growth of our hATTR amyloidosis with polyneuropathy opportunity beginning this year, and as you know, both ONPATTRO and AMVUTTRA, AMVUTTRA is currently also being evaluated in phase 3 clinical studies in patients with hATTR amyloidosis with cardiomyopathy, with the potential to address many more patients in the future and to further expand the franchise into what we believe could represent a multi-billion dollar opportunity for Alnylam over time.
We're pleased that the FDA was able to act swiftly in approving AMVUTTRA in light of the recent PDUFA extension following our submission of an amendment to utilize a new third-party secondary packaging and labeling facility. With a decision by the European Commission expected later this year and similar timing of expected approvals in Brazil and Japan, we plan to shortly be making AMVUTTRA available in multiple regions around the world. We're proud of today's milestone and ready to soon deliver this important new medicine to adult patients diagnosed with a polyneuropathy of hATTR amyloidosis and their families. Of course, as you know, regulatory approval is just the first step in making AMVUTTRA available to patients. As Tolga will elaborate further, we're in the midst of proactive discussions with payers in the U.S. to help ensure that those who benefit from AMVUTTRA will have access to it.
This approach continues to leverage our innovative value-based agreements, or VBAs, and is consistent with our patient access philosophy and the access track record we've achieved for our three previously launched commercial products. The approval of AMVUTTRA moves us further along our path towards achieving our Alnylam P5x25 goals. Alnylam P5x25 is aimed at bringing transformative medicines for rare and prevalent diseases to patients around the world while advancing a robust and high-yielding pipeline of first and/or best-in-class clinical programs from our organic product engine, as well as delivering exceptional financial performance. I'd like to take a moment to express our deepest gratitude to the patients, clinical investigators, and study staff that have participated in the AMVUTTRA clinical trials. Without your participation and tireless efforts over the years, we could not have generated the evidence needed to seek approval for this medicine.
In addition, I'd also like to acknowledge all the patients, families, caregivers, and physicians that comprise the hATTR amyloidosis community. For more than a decade now, you have encouraged us, supported us, and inspired us as we have worked to bring our medicines to all of you. With that, I will now turn it over to Akshay to provide some additional context on today's approval. Akshay?
Thanks, Yvonne, and hello, everyone. I certainly echo Yvonne's sentiments regarding the sense of pride and gratitude among all of us here at Alnylam for having the privilege to be able to bring this innovative therapy to patients as well as their families and healthcare teams. As most of you are aware, hereditary ATTR amyloidosis is a multi-system orphan disease caused by mutations in the transthyretin, or TTR, gene that leads to aggregation of misfolded TTR monomers into amyloid fibrils that deposit in multiple tissues, including nerves, heart, and the gastrointestinal tract. This pathogenic process results in a multi-system disease that manifests typically as a polyneuropathy due to amyloid deposition in the nerves or cardiomyopathy due to deposition in the heart, although most patients exhibit a mixed phenotype, including both polyneuropathy and cardiomyopathy.
As indicated by its name, the polyneuropathy involves all classes of nerves, leading to disabling sensory, motor, and autonomic symptoms. Regardless of the clinical presentation, hATTR amyloidosis is a rapidly progressive, debilitating disease that is often fatal. ATTR amyloidosis has a common pathogenic mechanism related to wild-type or variant TTR production and deposition as amyloid in a range of tissues. This is a single disease caused by TTR that results in a spectrum of clinical manifestations. Alnylam's RNAi therapeutics reduce the production of the disease-causing TTR protein in the liver, thereby reducing continued amyloid deposition and thus halting or improving the manifestations of disease. This concept was first demonstrated in the polyneuropathy of the disease with ONPATTRO or vutrisiran, then later shown with vutrisiran 9 and 18 months, with the vutrisiran 9 and 18 month results from HELIOS-A.
As you know, we have three RNAi therapeutics in development for the treatment of ATTR amyloidosis. On the left, you see ONPATTRO, which was the first ever approved RNAi therapeutic. It is administered every three weeks by IV infusion and is now being marketed around the world for the treatment of hATTR amyloidosis with polyneuropathy. Vutrisiran is also currently in further clinical development in our APOLLO-B phase 3 study. Next, AMVUTTRA or vutrisiran, which is the focus of today's call, is an RNAi therapeutic which we believe has a very compelling product profile given its efficacy and safety, as well as its subcutaneous administration of a 25 milligram dose once every three months. In addition to the HELIOS-A study, vutrisiran is also being evaluated in the HELIOS-B phase 3 outcome studies in ATTR amyloidosis with cardiomyopathy. Finally, ALN-TTRsc04 is the newest program within our franchise.
It utilizes our new IKARIA platform chemistry in its design and we believe has the potential for once-annual dosing and greater than 90% serum TTR reduction. Collectively, it is our belief that these three programs will support Alnylam's development of the leading ATTR amyloidosis franchise for years to come. And with that, I'll now turn over the call to Pushkal to review the label and the data that supported the label. Pushkal?
Thanks, Akshay, and good morning to everybody. It's a privilege to be here on this momentous occasion. Let me begin by turning to the pivotal HELIOS-A phase 3 study that formed the basis for yesterday's FDA approval. HELIOS-A was a randomized open-label study in patients with hereditary ATTR amyloidosis with polyneuropathy.
The study enrolled 164 patients who were randomized three to one to receive AMVUTTRA at a dose of 25 milligrams administered subcutaneously once every three months, or patisiran administered intravenously once every three weeks at a dose of 0.3 milligrams per kilogram as a reference comparator. The study compared AMVUTTRA to the placebo arm of the APOLLO phase 3 study as an external control for the primary and most secondary endpoints. The primary endpoint was measured at nine months and was a change from baseline in the modified neuropathy impairment score, or mNIS+7, as compared to the external placebo. The study was designed to continue patient dosing past the nine-month mark, and a series of secondary endpoints were evaluated at 18 months to evaluate the impact of patisiran on polyneuropathy manifestations of disease, as well as serum TTR reduction.
The study also included exploratory endpoints to better understand the potential impact of vutrisiran on cardiac manifestations of the disease, including the cardiac biomarker NT-proBNP, echocardiographic parameters, and cardiac amyloid burden through the use of technetium scans. Let's now turn to the clinical efficacy results, and I'll start with the impact on neuropathy impairment and quality of life. On the primary endpoint of change in mNIS+7 from baseline at nine months, AMVUTTRA treatment resulted in a 17-point mean treatment benefit relative to the external placebo. This effect was highly significant, indicating robustness of the treatment effect. Also, the mean change from baseline in mNIS+7 at nine months was a negative value, indicating improvement, providing evidence that, like vutrisiran, AMVUTTRA not only halts neuropathy progression, but it also achieved reversal of neuropathy impairment in 50% of patients relative to baseline.
As to the key secondary endpoint, change in the Norfolk Quality of Life score relative to baseline, AMVUTTRA-treated patients demonstrated a mean 16-point improvement in quality of life relative to the external placebo arm at nine months. The AMVUTTRA results were largely maintained when mNIS+7, Norfolk, and gait speed were assessed again at 18 months, and significant effects on nutritional status and activities of daily living were also observed in AMVUTTRA-treated patients relative to the external placebo at 18 months. The results of the HELIOS-A study also highlighted the encouraging safety profile of AMVUTTRA. The frequency of adverse events and serious adverse events were generally similar in AMVUTTRA and placebo-treated patients. There were no drug-related discontinuations or deaths. There were two serious adverse events deemed related to AMVUTTRA by the study investigator, consisting of dyslipidemia and urinary tract infection.
Treatment-emergent adverse events occurring in 10% or more of the patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia, and dizziness. With the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with external placebo. Injection site reactions were reported in five patients (4.1%) and were all mild and transient. Of note, patients who completed the HELIOS-A trial rolled over into the randomized treatment extension period, in which they were re-randomized to receive AMVUTTRA at either 25 milligrams every three months or 50 milligrams every six months. Data on the 50 milligram every six-month regimen will be available later this year, and if positive, will form the basis of an sNDA for AMVUTTRA. Let's move on to the AMVUTTRA label and review some of the prescribing information.
AMVUTTRA has been approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Drug is administered by a healthcare professional via subcutaneous injection once every three months at a fixed dose of 25 milligrams. There's a warning and precaution about AMVUTTRA treatment leading to a decrease in serum vitamin A levels, which is expected given the mechanism of action. To mitigate this, supplementation at the recommended daily allowance of vitamin A is advised for patients taking AMVUTTRA, with referral to an ophthalmologist if ocular symptoms of vitamin A deficiency occur. The label lists adverse reactions that occurred in at least 5% of patients treated with AMVUTTRA, which were arthralgia, dyspnea, and decreased vitamin A. Importantly, for patients, there is no required laboratory monitor.
Of course, we believe that this is just the start for vutrisiran, and we're also conducting another phase three study, HELIOS-B, which is our ongoing phase three cardiac outcome study with vutrisiran and hereditary and wild-type ATTR amyloidosis with cardiomyopathy. HELIOS-B, which is fully enrolled as an endpoint of all-cause mortality and CV events with a 30-36-month duration of follow-up, and we expect the full results in early 2024. Let me now turn the call over to Tolga, who will walk you through our commercialization plans for AMVUTTRA. Tolga?
Thank you, Pushkal, and hello, everyone. I'm thrilled to be here to discuss the approval of the fifth RNAi therapy developed by Alnylam in less than four years, and our second RNAi therapeutics approved in the TTR space. We are in a position of strength to leverage the learnings and infrastructure we built for ONPATTRO to help successfully commercialize AMVUTTRA. We believe AMVUTTRA has the potential to be a very meaningful treatment option for patients. In terms of the overall opportunity, we believe that AMVUTTRA is an important therapeutic option for the 20-30,000 hATTR amyloidosis patients with polyneuropathy worldwide. We've been working hard since before the launch of ONPATTRO in 2018 to educate the healthcare community since early and proper diagnosis is the biggest challenge in this rare disease. However, there is still more work to be done.
Today, we estimate that fewer than 3,000 adult patients in the United States have been diagnosed with hATTR amyloidosis with polyneuropathy. We believe that AMVUTTRA has the potential to expand Alnylam's overall share of the hATTR amyloidosis with polyneuropathy market in multiple ways as it grows our TTR franchise and provides a new RNAi therapeutic option for patients. AMVUTTRA has the potential to be a key treatment option for those patients who may have otherwise been in a watch and wait holding pattern before committing to treatment, or other patients who wish to switch therapies. We also anticipate. In short, we believe the totality of the HELIOS-A data, the AMVUTTRA label, and its product profile will now provide a very attractive option for patients and their healthcare professionals. Let's now discuss pricing.
Consistent with Alnylam's patient access philosophy, we price our therapies based on the value delivered to patients and the ability to continuously innovate for the benefit of patients. Our overarching patient access philosophy is grounded in helping patients deliver value and being proactive. It includes a commitment to refrain from increasing the price of our medicines by more than the annual consumer price index for urban consumers, CPI-U, and measure of inflation unless there is new innovation delivering value to patients. It also includes a commitment to proactive engagement with payers to identify innovative approaches for access, such as value-based agreements or VBAs. We're very proud that across our portfolio, we've now executed over 40 VBAs. We aim to demonstrate the value of our medicines objectively and transparently and to be market leaders in this regard. Let's now turn to the specifics on pricing for AMVUTTRA in the U.S.
The average annual list price for AMVUTTRA before gross-to-net sales deductions will be $463,500 per patient per year. This is consistent with the current ONPATTRO list price. Patient affordability is a key focus for us, similar to the patient experience with all our products. For most commercially insured people whose plans cover AMVUTTRA and are enrolled in Alnylam's commercial copay program, their out-of-pocket costs will be zero. In addition, Alnylam's patient assistance program provides AMVUTTRA at no cost to eligible patients, primarily the uninsured, who met specific financial criteria. We evaluated the following five factors when considering the value that AMVUTTRA will provide to patients, their families, insurers, and physicians. First, continued innovation in RNAi therapeutics for TTR. AMVUTTRA represents Alnylam's continuous innovation in the field, which underscores the company's commitment to developing a TTR franchise of transformative RNAi therapeutics. Second, established efficacy and impact of AMVUTTRA treatment.
As we've discussed today in HELIOS-A, AMVUTTRA demonstrated the potential to reverse neuropathy impairment and improve other measures of disease burden. Third, the established safety. The HELIOS-A study also demonstrated the acceptable safety and tolerability profile of AMVUTTRA. Fourth, quarterly dosing and route of administration. AMVUTTRA gives patients and providers a new and highly differentiated dosing regimen, consisting of a 25 milligram subcutaneous injection once every three months. It is HCP administered with no pre-medications or laboratory monitoring. And finally, building on the existing value delivered, Alnylam has a proven reputation for innovative contracting, including successful value-based contracts based on established VBA frameworks. With AMVUTTRA now approved in the U.S., we are in a position to make the drug commercially available over the following weeks, with first U.S. commercial sales expected in early July. We expect to leverage the existing commercial infrastructure that we've already built for ONPATTRO.
This includes our amazing team in customer-facing roles, including sales, marketing, patient support services, coverage and reimbursement, and our market access. Our U.S. team is on board and ready to go. We're also improving education of healthcare providers and patients with targeted websites aimed at providing education and resources for disease awareness, accurate diagnosis, and patient care. Furthermore, we plan to rely on our patient support services program, Alnylam Assist, to guide patients through treatment. Alnylam Assist provides a range of personalized services that include access to in-house case managers and field-based patient education liaisons who will assist with prompt initiation of treatment through comprehensive verification of insurance benefits within 24 to 48 hours of receiving the Alnylam Assist start form, financial support for eligible patients, and education on their disease and treatment with AMVUTTRA. The final piece is our continued proactive engagement with payers to ensure broad access.
We recognize that our efforts in advancing AMVUTTRA toward the market will only be successful if patients who may benefit from this new medicine have access to it. To that end, we have made significant progress toward negotiating value-based agreements with several leading health insurers. We intend through these agreements to ensure that patients will receive swift access to AMVUTTRA following diagnosis by a treating physician and the physician's prescription of AMVUTTRA, and insurers can qualify for a significant rebate if treatment outcomes are suboptimal. As such, these agreements help provide more certainty to payers for their investment and help accelerate coverage decisions for patients. In addition, we have our manufacturing and supply chain in place and are prepared to meet the demands of this underserved community.
In closing, I'd like to thank the patients, caregivers, and patient advocates, and study investigators and staff that continue to work extraordinarily hard for the ATTR amyloidosis community. I will now turn the call back to Christine to coordinate Q&A. Christine?
Thanks, Tolga. Operator, we will now open the call for questions. As a reminder to those dialed in, we will be strictly adhering to the one-question rule and ask that you limit your question to one each and then get back in the queue for any additional questions.
Thank you. To ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Tazeen Ahmad with Bank of America. Your line is open.
Hi, good morning, guys. Congrats on getting this approved. It's a relief for all of us, I'm sure. Just wanted to clarify some language in the label. Inside the label, it does list two serious adverse reactions of AV heart block at 1.6%, and that occurred in patients treated with the drug, including one case of complete AV block. How are you thinking about this particular side effect? I guess more importantly, as it relates to the upcoming data for vutrisiran in cardiomyopathy, anything to read through from that? Because I'm sure we're going to probably get questions on that.
Thanks, Tazeen, and we're very excited, obviously, about the approval of AMVUTTRA. I think that's a question for Pushkal, so Pushkal, do you want to give our perspectives on the AV block and potentially how you're thinking about that with respect to the upcoming cardiomyopathy study results?
Yeah, absolutely. Thanks for your question, Tazeen. We're joined by John Vest, who's the clinical lead for our TTR franchise. So maybe, John, if you want to speak to it.
Yeah, certainly. Thanks so much for the question. As you pointed out, the label does reflect two serious adverse events that were related to AV block. But I think it's important to think about these events in context. These events both occurred in patients who had underlying cardiac amyloidosis at baseline coming into the study, one of whom had substantial conduction system disease. Neither of the events was considered related to vutrisiran by the investigator, and both of the patients continued on vutrisiran in the study. Nonetheless, in consultation with the FDA, it was decided that these would be reflected in the label. With regard to your question about read-through to the other studies, we'll look at the results of that study when it reads out. But I don't see it as any cause for concern with regard to the readout of APOLLO-B.
Yeah. And, Tazeen, I'll just add to all that John said by just reminding you that ONPATTRO has been on the market now for four years. There's been periodic safety reviews of that, as well as both our HELIOS-B studies are under frequent review by the Data Monitoring Committee, and those studies have proceeded on without any change. So we remain very confident about the overall safety profile of both ONPATTRO and vutrisiran.
Okay. Thank you.
Thanks, Pushkal. Next question, please.
Our next question comes from Gena Wang with Barclays. Your line is open.
Thank you for taking my questions. Also, congrats on the earlier approval. I just have one question regarding the Apollo B. I just wanted to confirm that the tafamidis dropout rate maintained at the low single digit, and also, what is the definition of tafamidis progressors?
Thanks, Gena, for that question. I'm happy to answer the question, and Pushkal, I'll be passing that on to you to answer. But I just wanted to highlight that, given the sort of intense investor interest in the APOLLO-B study and the fact that we've actually shared everything that we're able to share about the study at this point, we will be entering a quiet period in early July. So I just wanted to make everybody aware of that. But, Pushkal, perhaps you could answer the specific questions quite straightforward about confirmed drop-in rates. Go ahead.
Yeah, absolutely, Yvonne. Thanks, Gena. So, yes, we obviously have been very careful about both background TTR rate and drop-in rates, and I can confirm that the TTR/drop-in rates remain quite low in the study. And again, we're eagerly anticipating the results that will be coming forward from the Apollo B study shortly.
Thank you, Gena. Next question, please.
Our next question comes from David Lebowitz with Citi. Your line is open.
Thank you very much for taking my question, and congratulations on the approval. Given that the royalty structures for ONPATTRO and vutrisiran are different, how do we expect the sales to ramp throughout the year as vutrisiran launches, I guess, between naive patients and experienced patients who are on ONPATTRO switches? How might that affect the general progression cadence?
Yes, just to remind everybody that we do have royalties due to Sanofi tiered royalties of 15%-30%. So there is an additional royalty burden with respect to vutrisiran. I mean, given the increased opportunity ahead of us with vutrisiran, we don't see this being a factor affecting switches. But perhaps, Jeff, if you've got anything to add, and then Tolga, if you feel that Jeff's follow-up would be helped by additional perspective. So, Jeff, do you want to make a few comments? And then perhaps we'll pass it over to Tolga.
Yeah, just a few comments on the economics. I think you got it right. There's a higher royalty burden on vutrisiran than there is on ONPATTRO. There is an offset, a partial offset to that in terms of cost of goods sold that will be lower on vutrisiran. But overall, the gross margins as a percentage of revenue will be lower on vutrisiran than ONPATTRO. But I'll pass it over to Tolga to talk about the cadence of sort of the ramp-up of vutrisiran that we expect.
Yeah, good morning. Look, I mean, the way we really see this market is this AMVUTTRA will enable us to actually accelerate our growth in the TTRPN franchise. Therefore, we do anticipate new patients coming in, especially those that may have been early diagnosed but not yet on the treatment, as well as switches from competition. Obviously, we will start seeing some switches from ONPATTRO, those patients who may prefer. We won't be actively targeting those patients, but we would anticipate, given the very attractive profile of AMVUTTRA, we would anticipate the majority of our business ends up with AMVUTTRA over time. The timing of that is not something we've guided at this stage.
This is Rena Denoncourt. I would just add that the royalty dynamic is not connected to the patient or physician choice of ONPATTRO or vutrisiran. We have the two options available, and the patients and physicians would choose the option that best suits their needs.
Thank you. We need help for additional color. Thank you. Next question.
Our next question comes from Ritu Baral with Cowen. Your line is open.
Good morning, guys. Thanks for taking the question. Just as a follow-up to that, Tolga, Jeff, I guess, what will you be telling us as far as metrics and forward quarters on AMVUTTRA? Will you be giving us sort of NRx's representing expanded patients and switches, whether they're from ONPATTRO or competitive therapy?
Thanks, Ritu. Let's start with, sorry. Okay, Tolga, you go ahead.
No, no, no. No, Yvonne. I just couldn't hear the full question here.
Okay. It's about what metrics, sorry, Ritu. I think it's about the metrics that we're planning to share with respect to AMVUTTRA. Maybe, Jeff, we can start with you. There's a lot of background noise, Ritu. I don't know if that's on your line.
I apologize. It's on my line.
Yeah, I think I understood the question from Ritu. She was asking about the level of detail that we'll be providing on patients that are initiating therapy on AMVUTTRA. We expect—or AMVUTTRA, I should say—we expect to provide the same level of detail on AMVUTTRA that we provide on our other three products in terms of the number of patients that are on commercial therapy on a quarterly basis. I think for the franchise now, the best way to look at this in terms of understanding growth of the franchise is going to be to look at the combined patients on therapy, both on ONPATTRO and on AMVUTTRA. Again, we'll give the individual product details so you can see how things are trending for each product. But on a total franchise basis, will be the best way to look at the progression of patient adds over time.
Tolga, I don't know if there's anything you want to add to that.
No, Jeff, I think you captured it perfectly.
So no specific metrics that'll indicate the cost of the switches, correct?
Yeah, we won't have full detail on that, Ritu, so we won't be able to provide that in specific great detail.
Great. Thank you so much.
Thank you, Ritu.
Our next question comes from Eliana Merle with UBS. Your line is open.
Hey, guys. Congrats on the approval, and thanks so much for taking the question. Maybe just from your, I guess, commercial conversations with physicians and patients, how are you thinking about how much sort of the sub-Q and added convenience could accelerate uptake and growth, particularly in sort of the mixed phenotype with cardiomyopathy segment? Anything you're hearing in terms of feedback, as well as how you're thinking about focus in the commercialization strategy, just in how you're targeting neurologists versus cardiologists?
That's a great question, Ellie. So I think it's one for Tolga. And, Tolga, it's about how we're thinking about the impact of the sub-Q and the convenient regimen of AMVUTTRA on the uptake of AMVUTTRA, particularly in those patients that have the mixed phenotype, and also how we're thinking about targeting neurologists and cardiologists. So, Tolga, that's one for you.
Thank you, Yvonne. Thanks for repeating the question. Look, we have an experienced and knowledgeable organization, and we've obviously learned a lot in terms of data and understanding of how patients are getting diagnosed. Our efforts have been, over the years, also getting those patients diagnosed early, and what we have seen so far is patients are getting early diagnosed, but not all of them, given the infusion and the pre-medication regimen of ONPATTRO, not all those patients are immediately on treatment. So that's, I think, one of the major growth drivers that we'll see, those patients that are being waited and see if their disease is progressing. We know that doctors, regardless whether they're neurologists or cardiologists, they would like to make sure that those patients that are diagnosed with polyneuropathy are being put on treatment. We do anticipate some growth and acceleration.
The other important part of this is, in the U.S., we anticipate 10,000 to 15,000 patients that are currently diagnosed, but only less than 3,000 of those are being treated. We certainly anticipate an accelerated growth, whether you are polyneuropathy or with mixed phenotype and manifesting polyneuropathy symptoms. So we certainly anticipate an accelerated growth in those two fields. I don't know, Rena, if you want to add anything.
That covers it. Thanks.
Our next question comes from Gary Nachman with BMO Capital Markets. Your line is open.
Thanks. And my congrats as well. How would you characterize what the access for ONPATTRO has been, your experience there so far? And would you expect AMVUTTRA to be similar or maybe even better, given the profile of the drug that you highlighted? And will there be good access for both the PN and the mixed patients, as you're highlighting them? And then, I guess, with all the patient assistance, what do you expect the gross to net to be in the early phases of the launch? Thank you.
Thank you, Gary. I think we'll answer your questions with respect to access. We're trying to sort of limit the number of multi-part questions that we get so that all analysts get a chance to participate. So we should focus on access. I think the first thing that I'd just like to underscore, and Tolga captured in his remarks, but how successful our approach to access has been with our value-based agreements, and we really had no headwinds for ONPATTRO. But Tolga, I think this is a question for you. How would you characterize what access has been like for ONPATTRO? And do we think that access will be similar or better for AMVUTTRA? And then a final access question on how we're thinking about access for patients with polyneuropathy compared to patients with a mixed phenotype. So Tolga, I think those are over to you.
Yeah, thank you, Yvonne. Look, as you alluded to, the headline here is we're really not anticipating any access headwinds. ONPATTRO's access has been rather smooth, thanks to our innovative value-based agreements that we have proactively engaged our payers. And we've been able to not only provide access to these patients, but also maintain access over the course of four years. We're very proud of that. We've also, obviously, had the opportunity to engage on a very preliminary level with payers for AMVUTTRA. And I'm pleased to see that so far, we haven't really had any pushback in regards to our ability to provide these medicines as well. Now, when it comes to mixed phenotype patients and polyneuropathy patients, at the end of the day, these patients are diagnosed with polyneuropathy.
We do know that if they're on a concomitant treatment, they need to go through their benefit verification and approval also through the polyneuropathy. We are the product if we are the product of choice, we see similar outcomes as we see with all of our patients. They go through the benefit verification. We have a great support system that enables them to get through that. We haven't had any issues with ONPATTRO so far. We would anticipate a similar trend also with AMVUTTRA.
Okay. Thank you.
Our next question. Paul Matteis with Stifel. Your line is open.
Hi. Thanks for taking our question. This is Alex on for Paul. I was wondering if you could comment on expectations for 18-month data in the label and whether you expect any of the exploratory cardiac endpoints could be included? Thanks.
Thank you very much. Pushkal, I think that's the one for you, expectations for 18-month data in the label as well as exploratory cardiac endpoints.
Yeah. Thanks for the question. So the primary endpoint for the study was at nine months, and the FDA considered that sort of the primary data package that they reviewed. So at the time being, I think this is the label that's come out. We're very pleased with all that's contained therein. As you know, the 18-month data are available for prescribers, etc., to see it's out in the public domain as they wish to. And, of course, we're looking forward to seeing more cardiac data coming out of the APOLLO-B and ultimately HELIOS-B studies this year and early 2024, so.
Okay. Thanks.
Thank you.
Our next question comes from Ross with Jefferies. Your line is open.
Hi. Good morning. Congrats on the update, and thanks for taking my question. Just wondering if you expect any bolus of current ONPATTRO-treated patients to switch over to AMVUTTRA, and what are your latest thoughts on the types of patients who are more suitable for ONPATTRO every three week infusion-based dosing?
Great question. I think, again, one for Tolga. How are we thinking about whether there'll be a bolus of ONPATTRO patients switching to AMVUTTRA? Maybe you can start off answering that question.
Yeah. Thank you, Yvonne. And thank you for the question. Look, ONPATTRO is an effective treatment. It's safe. And we built a following. Those patients who have had no choice before now have been treated successfully over the four years. So we certainly believe some of these patients, especially what we see in ultra-rare diseases, these patients wanted to—they're comfortable with their treatment, and they don't want to really rock the boat. There will be some of those patients. Now, eventually, what we believe, given the attractiveness of AMVUTTRA and similar safety and efficacy profile, we would really anticipate a large portion of our patients end up choosing—end up staying on AMVUTTRA. That's for sure. But we do anticipate some of these patients that are very comfortable and change-averse will remain on ONPATTRO.
The majority of new patients going on to treatment for the first time will likely be for AMVUTTRA.
Thanks, Rena. I think maybe just also to add how remarkable the adherence that we're seeing on ONPATTRO to date. I mean, over 90%, which for a three-weekly infusion is incredibly impressive, and I think just as a testament to the fact that, obviously, patients are experiencing benefits on ONPATTRO. So we imagine that many patients on ONPATTRO will stay on ONPATTRO, but obviously, as new patients get diagnosed, many of them may prefer the profile of AMVUTTRA. Next question, please.
Our next question comes from Matthew Harrison with Morgan Stanley. Your line is open.
Hi. Thanks for taking the question. This is Charlie Young for Matthew, and apologies if I missed this earlier, but can you just talk about the gross to net expectations and how this compared to ONPATTRO? Thank you.
Of course, Charlie. Yes, the question was asked, but we didn't cover it as it was in a sort of long multi-part question. So the question's around gross to net expectations. Maybe Jeff, you could speak to that one.
Yeah. I think this is a quick answer. We do expect gross to net on AMVUTTRA to be very similar to ONPATTRO in the U.S., given the fact that the payer mix for the two products will likely be very similar, and that's the biggest driver of gross to net. So absolutely, we expect similar gross to nets in the U.S. for AMVUTTRA compared with ONPATTRO. Thank you.
Thank you, Jeff. Thanks, Charlie.
Next question comes from Luca Issi with RBC Capital. Your line is open.
Oh, great. Thanks so much for taking my question. Congrats on the approval. Obviously, the label reports 83% TTR knockdown. Obviously, Intellia has shown 93% knockdown with a one-and-done gene editing approach. Do you think that the incremental 10% knockdown will drive better outcome for patients, particularly for cardiomyopathy? And maybe more broadly, what's the latest thinking on the competitive landscape? Thanks so much.
Yeah. That's a great question, Luca. Thank you. And I think it's one that I'm going to start off with, actually. So actually, what are your perspectives with respect to the knockdown that Intellia is seeing with its approach in terms of that leading to outcomes for patients? And then just your general perspectives on the competitor landscape and TTR. So actually, maybe you could start with answering that question.
Yeah. The Intellia approach, obviously, has been interesting to look at. The latest round of data, if I'm not mistaken, showed, and that only goes to show that with any technology, as you dose a large number of patients, you're going to see variability. And so I don't think that at the current time, we believe every single patient will get more than 90% knockdown, even based on these preliminary data. And I think that's important to keep in mind. Beyond that, in terms of the competitive landscape, I think the important thing is that we're building the leading TTR franchise.
This is terrific news today about the approval of AMVUTTRA. We're very confident about the cardiac benefits and what we can achieve both with the patisiran and AMVUTTRA in that space in the cardiomyopathy setting. And ultimately, we have drugs that will develop even beyond that, including ALN-TTRsc04, of course. With ALN-TTRsc04, we're fully confident of achieving more than 90% knockdown. I think great day today for patients. This is an exciting development with AMVUTTRA. Intellia will have to continue to do their work and define more precisely the extent of knockdown and the variability. Thanks.
Got it. Thanks so much. Yeah.
Yvonne, if I may add one quick point also. The more competition, the better at this stage, given the fact that we still have a highly undiagnosed and a highly untreated patient population. What we've seen in similar categories like MS, where the number of options for the patients that come in actually accelerates the patient diagnosis. So I think it would be a welcome opportunity.
No, thanks, Paul. And I think we also need to reflect on some of the development challenges and potentially access challenges that some of these one-and-done approaches might have. So I think actually summarized it really well. I mean, we have a proven platform here. We have best-in-class regimens to provide patients. And particularly given the patient population that experienced TTR amyloidosis, we actually think that the RNAi approach is likely to be the preferred approach over time. So next question, please.
Our next question comes from Patrick Trucchio with H.C. Wainwright. Your line is open.
Hi. Good morning. And congrats on the approval. Just a question around COVID-19, where we've seen in recent weeks an uptick in some parts of the U.S., though in other areas, the rates are decreasing. So I'm wondering what learnings you've taken from the pandemic forward to the launch of AMVUTTRA and what, if any, impact this most recent wave or maybe potential future waves of COVID-19 could have on this.
As we go into the launch of AMVUTTRA, particularly if there's an experience of further waves of COVID over the next period. So Tolga, one for you.
Thanks. Two years, we've learned a lot. One of the things is we have an experienced and very knowledgeable team in this particular category, from diagnosis all the way to treatment and patient services. Throughout the pandemic, we've been able to actually upgrade and shift some of our capabilities. One perfect example was for the infusion. We've obviously provided site-of-care services and home infusion services. One of the great benefits, obviously, of AMVUTTRA is it's a subcutaneous injection, and some of these services will be a lot smoother, a lot easier. We've also invested quite heavily on data and our ability to be able to actually reach out to healthcare providers to be able to communicate, inform them a lot more effectively than I would say two, three years ago.
So a combination of our market knowledge and understanding how we were able to commercialize ONPATTRO and with the attractive profile of AMVUTTRA, with the additional learnings from the pandemic, we believe we have the right capabilities and the right organization to be able to address the pandemic challenges. Look, we've had a Q1 that we've also had a bit of a slowdown. We continue to learn from that, and we don't see a similar dynamic when it comes to the ability to access physicians in Q2. But we will obviously be on the lookout and continue to learn from the challenges.
Thanks, Tolga. And thanks for the question, Patrick.
Our next question comes from Anupam Rama with J.P. Morgan. Your line is open.
Hey, guys. Thanks for taking the question, and congrats on the approval. Maybe I'll just follow up on some of the switch dynamics here. But as you were doing your market research, are there disease or drug sort of indication comps out there that we should be considering when thinking about the ONPATTRO and AMVUTTRA sort of switch dynamic? Thanks so much.
Great question. So I think it's one for Tolga. So any disease or indication comps that would help inform how we think about the ONPATTRO and AMVUTTRA switch dynamics? Tolga?
Thank you. Look, I mean, at the end of the day, every category is very different and very unique, especially in this particular rare disease. We believe it's going to present itself. It's your own unique dynamics. As Jeff indicated, we will update, provide guidance, and share information every quarter, specifically like we do with all of our products, and perhaps I will keep it there in terms of how much right now we share in terms of our switch dynamics.
Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Hi. Thanks for taking our question. This is Tommy Young for Salveen, and congratulations on the approval. Our question is about pricing, so as we look further down the road, could you anticipate that there might be changes to pricing if ONPATTRO or AMVUTTRA's label potentially expands to include cardiomyopathy? Thank you.
That's a great question. Tolga, how are we thinking about pricing over the medium and long term, particularly with the potential expansion of the labels for both ONPATTRO and AMVUTTRA?
Yeah. No, great question. At the end of the day, like any learning organization, we look at the price prevalence ratios and ensure that we set the right price for the right prevalence. So in regards to our anticipation for cardiomyopathy, it's obviously a larger patient population, and we would certainly look for an appropriate pricing for that larger category.
Great. Thank you.
Our next question is from Leland Gershell with Oppenheimer. Your line is open.
Hi, Eliana. Congratulations as well on the early approval. Just a question. Tolga, you had touched on the VBA, and you've been proactively speaking with payers. Just wondering if the VBA process may be accelerated given prior experience with ONPATTRO. If you could comment on any potential differences or maybe on metrics that may cause rebates given patients perhaps not having the efficacy that they should have. Thank you.
Tolga, straight to you.
Yeah. Look, we know a lot more in access and value-based agreements than we did four years ago. So in our ability to actually approach payers, mainly larger ones, we've had great interactions with them. And our ability to actually build individualized VBA is very important. Therefore, it would be difficult for me to characterize sort of what specifically would include in every single VBA. But what I can share is we're very pleased with the progress that we made. Our preliminary discussions with those payers who are familiar with how we manage that, it's been very welcomed. Like any VBA, there are a number of criteria, including performance and metrics and access metrics. And we will be continuing to pursue them. And based on our knowledge and understanding, obviously, we would anticipate a little more accelerated ability to provide access to these patients.
Thank you.
Our next question is from Myles Minter with William Blair. Your line is open.
Hi. Just to follow up to that question, are we expecting for the value-based agreement that efficacy would have to look something like what we're seeing in the prescribing label, or is it more that a clinician global improvement scale or something like that is communicated to the payer? Just wondering if there's any sort of key specific aspects of AMVUTTRA's risk-benefit that need to be communicated to that payer to achieve maximal reimbursement here. Thanks.
Tolga.
Yeah. I mean, I just want to make it clear. We wouldn't go beyond our label. Our label is what we're approved for. That's the treatment of polyneuropathy and hATTR. And we would obviously stick to that.
Hello?
Yes.
Okay. Great.
That was the answer.
Thank you. I was just checking if there's any more to come. So where are we with respect to questions?
Thank you. I would now like to hand the call back over to the company for any closing remarks.
That's great. Thank you. And look, I'd just like to close by thanking everyone again for joining us today. We're absolutely delighted to be bringing our fifth RNAi therapeutic to patients in less than four years. And also excited by the tremendous work now is to make AMVUTTRA available to patients with polyneuropathy of hATTR amyloidosis. So thank you, everybody, and have a great day.
This concludes today's conference call. Goodbye. Thank you for participating. You may now disconnect.