Alnylam Pharmaceuticals, Inc. Q2 FY2022 Earnings Call

Hello, thank you for standing by. And welcome to the Alnylam Pharmaceuticals Second Quarter 2022 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. Please be advised that today’s conference may be recorded. I would now like to hand the conference over to the company. Please go ahead.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Akshay Vaishnaw, President; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website. During today’s call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Akshay will review recent clinical and preclinical updates. And Jeff will review our financials and guidance, followed by a summary of our upcoming milestones before we open the call for your questions. Please note we are in a quiet period with regards to the upcoming APOLLO-B results and therefore will not be addressing any questions on that matter. 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 recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will now turn the call over to Yvonne. Yvonne?

Thanks, Christine. And thank you, everyone, for joining the call today. We are very pleased with our second quarter results and the progress we've made towards our near- and long-term goals. Commercially, we achieved 14% product sales growth compared with the first quarter as we continue to drive a steady increase in patients on therapy across our portfolio of marketed products, including ONPATTRO, GIVLAARI, and OXLUMO. And we're excited to have expanded that portfolio with a recent U.S. approval and positive CHMP opinion for ONPATTRO for hATTR amyloidosis patients with polyneuropathy. And we are looking forward to executing ONPATTRO’s launch and the potential for further global expansion. Five RNAi therapeutics from our organic platform have been approved in under four years, which is truly remarkable. In addition to our growing commercial portfolio, we continue to make great strides with our RNAi therapeutic pipeline programs. This includes our progress in establishing our TTR franchise, where we are tracking towards our plan and are on the cusp of seeing results from the APOLLO-B Phase 3 study of patisiran in patients with ATTR amyloidosis, with cardiomyopathy. We've announced the date that we expect to share top line data within the next three weeks, with full data to be released thereafter at the medical congress. In addition to these highly anticipated results, we continue to make exciting progress across numerous other developments within our pipeline. We have reported positive top line Phase 2 results in patients with IgA nephropathy, a kidney disease with significant unmet medical need. We're now working with Regeneron to finalize Phase 3 plans and potentially initiate the program by the end of this year. We're also excited to see positive data presented by Sanofi from the Phase 3 ATLAS-PPX study of fitusiran in patients with hemophilia, which met its primary endpoint and demonstrated that fitusiran prophylaxis significantly reduces bleeding episodes compared to prior factor bypassing agent prophylaxis. Looking ahead to the end of this year, we expect to have updates across our pipeline, including the potential for top line results from early studies of AI and HSV in NASH, AI and XVH in Gout, and AI and ATP in early onset Alzheimer's disease, which is our first CNS endeavor. Together, this all highlights our focus on three key drivers for Alnylam’s growth in the next several years. First, the potential near-term expansion of our TTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicine to patients. The second key growth driver is our expansion beyond rare diseases into prevalent diseases. The third growth driver comes from our sustainable innovation engine, comprised of new platform enhancements, opportunities for extrahepatic delivery, and our ability to find new genetically validated targets for further pipeline expansion through 2025 and beyond. We believe all of this positions us well to deliver on our Alnylam P5x25 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and common diseases worldwide, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, while delivering exceptional financial results. With that, let me now turn the call over to Tolga, to review our commercial performance. Tolga?

Thanks Yvonne. And good morning, everyone. Q2 was a strong quarter for our commercial portfolio with 14% quarter-over-quarter growth as Yvonne highlighted. We're also excited about the FDA approval and launch of AMVUTTRA in June, and we are encouraged by early promising signs. I have more detail to share on that shortly. As anticipated, we are also experiencing improved market conditions following COVID, impacting Q1, as we saw increased promotional activities, improved patient flows, healthy demand, and improved patient compliance across our portfolio. I'll now provide details on the performance of each of our products. We continue to see growth for ONPATTRO, achieving $153 million in global net product revenues in the second quarter, representing a 12% increase compared with the first quarter and 35% growth compared with Q2 2021. At the end of Q2, over 2,400 patients were on commercial ONPATTRO treatment worldwide, up from over 2,200 patients at the end of the first quarter, representing steady 9% quarterly patient growth. In the U.S., sales of ONPATTRO increased 14% versus the first quarter and were primarily impacted by an increase in patients on therapy and improved patient compliance following Q1, which was negatively impacted by COVID. In our international markets, ONPATTRO Q2 product sales increased 10% versus Q1 2022, primarily due to an increase in patients on therapy and timely orders in distributor and partner markets. It's important to note our global results continue to be challenged by foreign exchange headwinds, with ONPATTRO year-over-year reported growth of 35% being held back by seven percentage points due to the strengthening U.S. dollar. As you are aware, we received U.S. approval for AMVUTTRA at the end of the second quarter, and we're very pleased with the initial launch so far as our teams continue to execute in line with our expectations. We received 133 start forms from launch through July 22, keeping demand generation on track, with approximately one-third of start forms generated from patients new to Alnylam and two-thirds from switches from ONPATTRO. Over 20% of those start forms came from new prescribers, which we believe is an encouraging early sign of potential market growth. We hit the ground running, reaching over 61,000 key stakeholders within 48 hours of launch, serving as a catalyst for field engagement. We have also been engaging with health systems and the formulary processes and have started in over 60% of the priority delivery networks. Furthermore, from an access standpoint, our teams have been engaged and feedback has been positive to date. In fact, there is one national policy published with a large national payer covering 24 million lives. The first AMVUTTRA patient has also been treated, and we're looking forward to continuing this rollout and updating you further on our Q3 call. Moving to our ultra-rare disease franchise, first with GIVLAARI, we achieved $45 million in global net product revenues in the second quarter, representing a 28% increase compared with Q1 2022 and 47% growth versus Q2 2021. At the end of Q2, over 420 patients were on commercial GIVLAARI treatment worldwide, up from over 400 at the end of the first quarter, representing a 5% quarterly patient growth. In the U.S., sales of GIVLAARI increased 25% versus the first quarter, primarily as a result of healthy demand growth of 12%, driven by an increase in patients on therapy and improved patient compliance following a soft Q1, impacted by COVID. Inventory stocking dynamics also favorably impacted reported growth. In our international markets, GIVLAARI delivered 34% growth compared with the first quarter, driven primarily by new patient adds, including a strong launch in the UK and favorable growth net deductions. Finally, global GIVLAARI year-over-year reported growth of 47% was also held back by six percentage points due to unfavorable foreign exchange rates. Moving now to our second ultra-rare disease product OXLUMO. We achieved $15 million in global net product revenues in the second quarter, representing a 2% increase compared with the first quarter. At the end of Q2, over 200 patients were on commercial OXLUMO treatment worldwide, up from over 160 at the end of the first quarter, representing 25% quarterly patient growth. In the U.S., sales of OXLUMO increased 32% versus the first quarter and were primarily impacted by an increase in patient demand as well as inventory stocking dynamics and a decrease in growth to net deductions during the quarter. In our international business, despite an increase in patients on therapy during the quarter, Q2 OXLUMO sales decreased by 15% compared with Q1, primarily due to an increase in net deductions during the quarter and timing of orders in our distributor and partner markets. On a year-over-year basis, global OXLUMO sales decreased 9% despite an approximately doubling of patients on therapy. The decrease was primarily due to a higher proportion of patients on the monthly loading dose portion of their treatments as well as lower net pricing in our international markets in Q2 2022. Additionally, as with ONPATTRO and GIVLAARI, changes in foreign exchange rates also negatively impacted OXLUMO Q2 2022 results, holding back reported year-over-year growth of minus 9% due to five percentage points from the strengthening U.S. dollar. In conclusion, we are pleased with the growth in revenues and patient demand and look forward to our Q3 results, which will include the first full quarter of AMVUTTRA's launch. With that, I will now turn it over to Akshay to review our recent IND and pipeline progress. Akshay?

Thanks, Tolga, and good morning, everyone. I'll start with our efforts in AT amyloidosis diseases where we are advancing two clinical-stage product candidates: Patisiran and Vutrisiran. Patisiran is currently approved in multiple markets around the world to treat polyneuropathy associated with hereditary AT amyloidosis diseases. We are committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type AT amyloidosis patients. To this end we're conducting the APOLLO-B Phase 3 study and as announced this morning, we expect to report top line results within the next three weeks. We're also advancing Vutrisiran, which is delivered by quarterly subcutaneous injection and was recently approved in the U.S. under the brand name AMVUTTRA to treat the polyneuropathy of hATTR amyloidosis, in addition to receiving the positive CHMP opinion in the EU. Here too, we are committed to expanding the label for the treatment of cardiomyopathy in hereditary and wild-type patients. Vutrisiran is also in development for Stargardt Disease. HELIOS-A evaluating Vutrisiran in hATTR amyloidosis patients with polyneuropathy formed the basis for regulatory submissions and for the recent U.S. approval of AMVUTTRA. In April 2021 we presented positive results from the study at the AAN meeting, which showed that the study met its primary and secondary endpoints at nine months. We continue to report results from the study and recently presented new 18-month results from exploratory cardiac endpoints at the ESC HF meeting. These findings show that in a pre-defined cardiac sub-population of hATTR amyloidosis patients with polyneuropathy, treatment with Vutrisiran was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of NT-proBNP and a trend towards improvement in echocardiographic parameters. These findings in the cardiac subpopulation were consistent with the previously reported results in the mITT population. Additionally, in a planned cohort of patients from the mITT population, Vutrisiran treatment reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline in the majority of accessible patients, including those with the highest levels of cardiac amyloid burden, suggesting that patients with the highest degrees of burden may benefit from RNAi therapeutics. Vutrisiran also continues to demonstrate an encouraging safety and tolerability profile. As mentioned, this is just the start for Vutrisiran, as it is also being evaluated in the HELIOS-B Phase 3 study for the treatment of patients with AT amyloidosis with cardiomyopathy, including both hereditary and wild-type AT amyloidosis. HELIOS-B, which is fully enrolled, has a 30-month endpoint of all-cause mortality and cardiovascular events, with many patients followed up to 36 months, and we expect the full results in early 2024. The study design includes the potential for an interim analysis, and we will consider this following results from APOLLO-B and engagement with regulatory authorities. In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. Notable highlights in the second quarter were our announcement of positive top line results from our Phase 2 study of Cemdisiran, an investigational RNAi therapeutic targeting the C5 component of the complement pathway and is in development in collaboration with Regeneron for the treatment of IgA nephropathy. In this study at week 32, treatment with Cemdisiran resulted in a 37% mean reduction from baseline in the 24-hour urine protein-to-creatinine ratio, relative to placebo. This was the primary endpoint of the study and an important prognostic marker of disease progression. The results of secondary endpoints were also consistent with the therapeutic benefit of Cemdisiran in IgAN. There were no significant drug-related safety signals, and we believe these collective efficacy and safety data support continued clinical development of Cemdisiran monotherapy in patients with IgAN. We look forward to aligning with Regeneron to finalize plans for Phase 3 and hope to initiate a program by the end of this year, pending regulatory agency feedback. Moving on, a key growth driver for Alnylam in the coming years will be our organic product engine driving sustainable innovation. The second quarter featured a new highlight in this regard. In Nature Biotechnology, we published data from preclinical research on the delivery of lipophilic siRNA conjugates to extrahepatic tissues including the CNS. This data provides early evidence of a potential role for 2'-O-hexadecyl C16 conjugate siRNA in treating diseases of the CNS, eye and lung, with further exploration for lipid conjugates to help achieve delivery to other organs. In another publication in Nature Communications, we published research findings identifying mutations in the INHBE gene associated with protection against abdominal obesity and metabolic syndrome, a condition impacting more than 20% of adults. These findings support the potential of INHBE, which was previously referred to as Gen X, to be evaluated as a novel therapeutic treatment for cardio-metabolic diseases, since INHBE loss of function improves waist-to-hip ratio and is associated with an improved lipid profile. We plan to pursue a development candidate for INHBE leveraging our IKARIA platform. As you can appreciate, we have an incredibly broad and innovative platform that continues to advance, and these are just a few recent highlights. We look forward to updating you on a number of these programs in the coming months. With that, let me now turn the call over to Jeff to review our financials and upcoming milestones. Jeff?

Thanks, Akshay, and good morning everyone. I'm pleased to present a summary of Alnylam's Q2 2022 financial results and an update on our full-year guidance. Starting with a summary of our P&L results for Q2 2022. Total product revenues for the quarter were $214 million, or 33% growth versus Q2 2021. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately 7% due to the foreign exchange impact of a strengthening U.S. dollar, which reached a 20-year high recently. Given that approximately 50% of our product revenues are generated via sales in international markets, net revenue from collaborations for the second quarter was approximately $9 million, representing an 85% decrease compared with Q2 2021, primarily due to a reduction in revenue from our Regeneron collaboration, which is subject to quarter-to-quarter variability dependent on a variety of factors including the level of work completed during the quarter, which is reimbursed by Regeneron. We do expect an increase in collaboration revenue and royalties in the second half of the year, primarily driven by increased activity across our Regeneron programs, as well as from an increase associated with Leqvio royalties and sales milestones as Novartis’s U.S. launch progresses. Our non-GAAP R&D expenses increased 15% in the second quarter compared to the same period in 2021, primarily due to increased spend on early development activities and increased headcount to support the growth of our pipeline. Our non-GAAP SG&A expenses increased 19% in the second quarter compared to the same period in 2021, primarily due to increased headcount and other expenses to support the growth of our commercial portfolio. Our non-GAAP operating loss for Q2 2022 was $161 million, representing a $47 million higher loss compared with Q2 2021, which was primarily impacted by the reduction in collaboration revenue during the quarter. Finally, at the end of the quarter, we had cash, cash equivalents, and marketable securities of $2.1 billion compared to $2.4 billion at the end of 2021. We continue to believe our current cash balance is sufficient to bridge to a self-sustainable financial profile. Now I'd like to turn to our full-year 2022 financial guidance. Following the strength of our operating results in Q2, we are reiterating the financial guidance we provided on our Q1 results call in April. Starting with net product revenues, we anticipate combined net product revenues for our four commercialized products will be between $870 million and $930 million. However, given the continued strength of the U.S. dollar since we issued our guidance in April and the fact that approximately 50% of our global product sales are generated in international markets, we are currently trending towards the lower half of our $870 million to $930 million guidance range. Our guidance for net revenue from collaborations and royalties is in the range of $175 million and $225 million, and our guidance for combined non-GAAP R&D and SG&A expenses is in the range of $1,390 million and $1,450 million. Let me now turn from financials and discuss some key goals and upcoming milestones on deck through the end of 2022. We'll continue executing on our global commercialization of ONPATTRO, GIVLAARI, and OXLUMO as well as the launch of AMVUTTRA. Next, our TTR franchise will have important updates with Patisiran’s top line results from the APOLLO Phase 3 study expected in the next three weeks. With Vutrisiran, we plan to report results on a biannual dose regimen and initiate a Phase 3 study in Stargardt Disease, both in late 2022. Lastly, we plan to file an IND and initiate a Phase 1 study for ALN-TTRsc04 in healthy volunteers by the end of the year. In our mid-stage portfolio, we are looking forward to milestones that include the completion of enrollment in the Phase 2 study of Lumasiran in patients with recurrent renal stones by year-end, completion of enrollment in our Phase 2 KARDIA-2 study of Zilebesiran by year-end, and results from the Phase 2 study of ALN-HBV02 in combination with monoclonal antibody VIR-3434, partner, which we expect to report later this year. Wrapping up, we have a few early-stage readouts coming as well. These include top line results from Part B of the Phase 1 study of ALN-HSD in patients with NASH expected in mid-2022, preliminary top line results from the Phase 1 study of ALN-APP in patients with early onset Alzheimer's disease expected in late 2022, and preliminary top line results from the Phase 1 study of ALN-XDH in patients with gout also expected for late 2022. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we'd like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions. Also, as a reminder, we are in a quiet period with regard to our APOLLO-B study and will not be responding to questions on that topic.

Thank you. Our first question comes from Paul Matteis with Stifel. You may proceed.

Hey good morning. Thanks much for taking my question. Just on Vutrisiran, just a two-part question: the commercial dynamics, I guess one, can you talk about the initial prescribing for patients new to and how much of that is coming from cardiologists? And then just curious on the economics of in-office dosing for Patisiran and how does that compare for a physician versus ONPATTRO as an infusion? Thank you.

Thanks Paul for that question. I just like to start off by saying that we really are delighted to have AMVUTTRA and it's great to have additional ONPATTRO for patients here. The initial signs are very encouraging. Tolga, I'd like to hand over this question to you. So it's around the commercial dynamics with respect to the initial launch, how much in cardiology, and then any commentary on the economics with respect to ONPATTRO compared to fitusiran from a physician perspective? Thanks Tolga.

Absolutely. Hi Paul. This is a really exciting time. We launched the product and are reporting the information that's available to us within the five weeks. In that five weeks, we were able to receive over 130 start forms, and of those, one-third were actually naive patients who are new to Alnylam. That's actually a very good robust number early for us, and these are only start forms. Patients need to go through the system and make sure that they get the product in, but as an early sign, one-third as new naive patient dynamic is very encouraging. In terms of the economics, essentially the product is Part B; therefore, it is still a buy-and-bill, and those patients that are going to be looking at a very similar dynamics as we see in ONPATTRO. What we're also excited about is that, frankly, 20% of our prescribers, in this very short period, are new prescribers of TTR and new prescribers of ONPATTRO. So that's also a very exciting dynamic that I'd like to underline.

Thanks, Tolga. And thanks, Paul. Next question, please.

Thank you. Our next question comes from David Lebowitz with Citi. You may proceed.

Thank you very much for taking my question. First on Vutrisiran, this is not with respect to any details on the data. I just want to confirm that we would likely see P-values certainly on the primary endpoint, but also the secondary endpoints as well. And one little add-on here, as far as pricing goes, can you at least give us perspective on what type of shift we might see once cardiomyopathy gets added to the label?

Great. David, thanks for that question. I think the first one, Akshay, is for you.

Yes. Just clarifying, Dave, that you said Vutrisiran, but I suspect you meant Patisiran with respect to the APOLLO-B results, am I correct?

Indeed, of course.

Yes. And you are right, we'll present top line results in the form of the PR with P-values as we test the primary and secondaries in a hierarchical order. So that's as much as I can present at this time.

Thanks, Akshay. And maybe Tolga, you could take the second question, respect to pricing and any shift as we hopefully enter the cardiomyopathy?

Look, we're excited about the possibility of serving cardiomyopathy patients, but as you could appreciate, it's a little too soon for us to share any information because it's too soon, but we'll obviously update appropriately when we make those decisions.

Alright. Thanks, David. Next question, please.

Thank you. Our next question comes from Salveen Richter with Goldman Sachs. You may proceed.

Good morning. Thanks for taking my question. Could you just speak to the dynamics with regard to switching and combination that's playing out between your TTR franchise and Pfizer’s tafamidis? Thank you.

I think Tolga that that question is straight over to you.

Yes. I mean, switching-wise, obviously in the U.S., we're indicated for polyneuropathy and tafamidis is indicated for cardiomyopathy; therefore, we do not see any switching dynamics. In terms of common use, we see similar rates that we've seen in the past, it's about anywhere between 15% to 20%. What we see, what we're excited about switching dynamics is in ex-U.S., particularly in Europe and Japan where both of those products are available for polyneuropathy. We've seen a significant portion of our business is really built by the switches. Obviously, we continue to add new naive patients both in Europe and Japan, but early on we've seen a good, strong dynamic, which suggests to us that the physicians believe that there is actually probably more opportunity to use ONPATTRO as a silencer in the earlier part of the disease to get adequate treatment.

Thanks, Tolga. Next question.

Thank you. Our next question comes from Ritu Baral with Cowen. You may proceed.

Good morning, guys. Thanks for taking the question. I was hoping for just a follow-up to Paul and Salveen's just a little more detail on the new patients. Tolga, you mentioned the prescribers, but are you seeing less severe patients? Are you seeing more mixed phenotype patients? And does this sort of bolus imply that there's some warehoused patients to work through as we look at the new patient question for AMVUTTRA?

Yes. It's a great question. Thank you. If I indicated before, it's a little too soon for us to really give a lot of specific dynamics. It's an area where we're obviously closely monitoring. What we're encouraged about is the early signs indicate that we do see some younger patients, but again, it's difficult to generalize at this point. We're only five weeks into the launch. What we're again excited about is the fact that we are seeing a broad range of patients quickly getting either switched or not even being treated. Part of it, I'm sure is going to be a little bit of the warehousing, but it's important to highlight that in Q1, we had a great strong robust ONPATTRO growth. With what we originally thought was probably the patients, the physicians would be waiting and warehousing some of those patients for AMVUTTRA, that didn't exactly happen. But I'm certain that part of the uptake that we see in the first five weeks might be contributed to that warehousing dynamic.

Yes. Thanks, Tolga. It really does look like the introduction of AMVUTTRA is helping us grow the overall TTR franchise going forward, which I think is very encouraging. Thanks, Ritu. Next question.

Thank you. Our next question comes from Tazeen Ahmad with Bank of America. You may proceed.

Hi. Good morning. Thank you for taking my question. Mine's on HELIOS-B, so you've reiterated your confidence that the early 2024 target for data readout is something that you feel confident about. I'm just wondering, is there at all a scenario in which you would opt to extend the observation period though to allow for a higher chance of seeing a significant improvement in mortality benefit?

Maybe I'll start by retracing our confidence in an early 2024 data readout from HELIOS-B and Akshay any perspective on how we might think about that study going forward.

Yes. We've revisited the study designs and thoroughly assessed how robust the study is and is it structured and powered in a way to help us meet the primary endpoint and the secondary endpoint. We are comfortable with the study design. The study design is unaltered; the only thing we'll consider is the interim analysis, of course, in due course. Additionally, as you know, patients come in over a long period in a large study like that, so many of them will have gone to 36 months, and that provides additional coverage in terms of the robustness of the study. So we're comfortable and we'd reiterate early 2024 and looking forward to positive results.

Thanks, Akshay. Next question please.

Thank you. Our next question comes from Joseph Stringer with Needham. You may proceed.

Hi, thank you for taking our question. Our question was for AMVUTTRA. I know it's early days, but how do you anticipate the time from start form to getting patients on drug? How do you think this compares relative to your experience with ONPATTRO? Thank you.

Yes. That's a great question, and clearly with AMVUTTRA being our second product in the TTR franchise, we're really building on what's a very robust commercial operation that we have under Tolga's leadership. Tolga, perhaps you could talk a little bit about that?

Thanks, Yvonne. Obviously, we're very well positioned to maximize the opportunity for AMVUTTRA, given our experiences with ONPATTRO. AMVUTTRA’s really attractive profiles will offer subcutaneous injections every month. In regards to the time from start form to getting patients on drug: at the end of the day, we have the right capabilities, patient services, benefit verification, and so forth already in place within this category. What we've so far done is work very closely with major national and regional payers, integrated delivery networks and other health providers to ensure that formularies are in place. Given the fact that we set the price, despite its very attractive profile, its parity with ONPATTRO, we have not seen any significant headwind so far. Nevertheless, like any new product, it does take time for the healthcare system to absorb and to make sure the PNT committees are in place to get the product approved. We're very pleased with the early signs of what we've done and how the healthcare systems are reacting, but I'm sure we're going to see some delays early on, then eventually get to a place where I think it's going to be at parity with ONPATTRO or maybe even a little faster approval dynamic, but it's a little too soon for us to share where we are right now with that.

Thanks, Tolga. I think good progress thus far and we're very pleased. So next question, please.

Thank you. Our next question comes from Maury Raycroft with Jefferies. You may proceed.

Hi, good morning and thanks for taking my questions. I was going to ask a question on Givosiran for hypertension. Just wondering if you can elaborate on steps you've taken to streamline the protocol to speed up enrollment and what the status is on that?

Yes. Just as a reminder, we unfortunately experienced delays with our KARDIA-1 study with zilebesiran primarily due to the fact that we selected sites in Ukraine and obviously with the ongoing war, those sites were unable to move forward. We've expanded our site footprint in a significant way. We also took the opportunity to refine the protocol to make it easier to execute. I don't know, Akshay, do you want to add any?

No, I think you covered it, Yvonne. The only other thing more specifically on the streamlining is we may have to remove some assessments in these protocols, without taking away from the core hypertensive effects and safety, while maintaining two large robust protocols: one in monotherapy and one in combination therapy. So between the site expansion and these decisions, we are optimistic about readouts next year.

Great. And just to add that we're expecting to complete enrollment in KARDIA-2 at the end of this year.

That's right.

So we're looking forward to that. Thank you. Next question, please.

Thank you. Our next question comes from Luca Issi with RBC Capital. You may proceed.

Great. Thanks so much for taking my question. Congrats on the quarter. Maybe one on TTR polyneuropathy, how are you thinking about the competitive landscape here? Obviously, Ionis have reported successful Phase 3 and seem very confident they can compete commercially given the AstraZeneca global footprint. I know we don't have the full data at this point, but how are you thinking about implications of that launch for your franchise? Thanks so much.

Thanks. Yes, look, I think that was primarily a question about how we believe that we're going to compete in the TTR polyneuropathy space, particularly with potential new competitors coming on stream with AstraZeneca.

Yes, thank you, Yvonne. First of all, we are always excited to bring new modes of medication and alternative treatments to patients because there's plenty of opportunities in TTR polyneuropathy prevalence and for patients that are currently being treated. We anticipate the prevalence numbers around 25,000 to 30,000 patients worldwide, and we are a very small fraction of that we've been able to deliver. So what we've seen in similar categories is a good expansion of diagnosis and treatment rates going on. Regarding our position in the market, we have established ourselves in the last four years as the major driver, including in Europe and Japan, against tafamidis, which is also being promoted by an important company. One of the important drivers of our growth is going to be the availability of AMVUTTRA worldwide. We are already well-positioned to achieve that as we have Europe and Japan as geographic footprints and are available in over 50 markets through other partners and distributors. Given that we're going to be a year ahead, we are offsetting competition and have a very attractive profile that AMVUTTRA offers for patients with subcutaneous injection every three months and soon with six-month if those trials succeed. We really like our chances in terms of being able to make this product available and continue to be a portfolio leader. That said, I just want to reiterate that having new products available is good for patients, and we're excited about that.

Thanks. So Akshay, do you want to say anything about the effective profile?

Yes, no, I'll just add to what Tolga said which was makes a lot of sense, but in terms of the data themselves, I think, we've got a very comprehensive data package associated with Vutrisiran around AMVUTTRA in hATTR, and of course the primary showing improvement in neuropathy is exciting. And in terms of the other endpoints for the secondary, but not just those exploratory cardiac endpoint, the impact on the heart, and the respiratory endpoints are still notable, particularly with the new observation of the reducing technetium scan uptake that’s quite exciting for patients and physicians. So, along with the convenience of Q3 injection, and then hopefully soon Q6 monthly dosing, this is a very differentiated product in the market that Tolga explained. We've been leaders in and ultimately, I'll add that patients need good options in this space will want to see the full data package associated with frontiersin, recalling that the first time around with inotersen there were some safety issues of note including renal effects, injection site reactions, and platelet effects. And I'm sure they, and everybody is keen to know that the safety is good. So let's see, but I think we're off to a great start with AMVUTTRA.

Sure, very helpful. Thank you. Next question, please.

Thank you. Our last question comes from Olivia Brayer with Cantor. You may proceed.

Hey, good morning guys. Thanks for the question. I know you are in a quiet period with respect to APOLLO-B, but I wanted to ask if there are any monitoring requirements after patients reach that 12-month mark that are built in this study? And then I've got a follow-up on sequencing from mixed phenotype patients. Is there anything you can do to improve access for patients that could move on ONPATTRO or AMVUTTRA after?

So I just want to say, you pointed out we are in a quiet period, so we're not going to be taking any questions on APOLLO-B, but I didn't actually quite catch your second question. I think it was something to do with AMVUTTRA, but I didn't hear it properly. Could you repeat the question, the second part of the question?

Yes, sure. It's just about mixed phenotype patients, right? And whether there is anything you guys can do to improve payer access there for patients that could sequence onto ONPATTRO or AMVUTTRA after?

You mean plug neuropathy and mixed phenotype patients?

Yes, I mean, look, we certainly have the right capabilities to support those patients. The fact that we've been able to position this at parity pricing certainly should help increase access. So far we haven't heard any headwinds around the access piece. But we are indicated for polyneuropathy and in the U.S., tafamidis is indicated for cardiomyopathy. So in terms of providing any brief strategy for access, that would not be something we would consider. Like any of our new patients, we have great support of benefit verification and patient access support, which those patients would certainly be eligible for if they go through our patient service program.

Thanks, Tolga.

Okay. So thank you everyone for joining us on this call. We're very happy with the progress that we've made in the second quarter and first half of 2022. We've delivered strong commercial results. We've advanced our diversified pipeline programs and development, and we've got a number of exciting catalysts on deck in the coming months. So we look forward to updating you along the way while we continue to deliver on our near and long goals. Thanks everyone, and have a great day.

Goodbye.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.