Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Good morning, everyone. Thank you for joining us for this RNAi roundtable. Today, we'll be discussing our growing ATTR amyloidosis franchise, which includes patisiran and Vutrisiran as well as our newest addition to the franchise, our preclinical program, ALN-TTRsc04. I'm Josh Brodsky, Senior Director of Investor Relations and Corporate Communications at Alnylam. With me today are Rena Denoncourt, Vice President, ATTR franchise lead; John Vest, Vice President of Clinical Research and Clinical Lead for the ATTR amyloidosis franchise; Rebecca Shilling, Director of Clinical Research and Clinical Lead for the HELIOS-A study; Patrick Jay, Director of Clinical Research and Clinical Lead for the Post OLT study; and Dr. Mat Maurer, the Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Medical Center and the key opinion leader in the treatment of ATTR amyloidosis. Today's RNAi roundtable is the second in a series of roundtable webinars that we'll be hosting over the next few months to review progress across our various programs. Today's event is expected to run approximately 75 minutes. Rena will moderate a Q&A session at the conclusion of the presentations. [Operator Instructions] Finally, as a reminder, we will be making forward-looking statements during this webinar, and we encourage you to read our most recent SEC filings for a more complete discussion of risk factors. And with that, I'll now turn it over to Rena.

Thank you, Josh, and thank you, everyone, for joining us today to hear about our ATTR amyloidosis franchise. We are so pleased to have Dr. Maurer join us today as well to present his experience with treating patients with ATTR amyloidosis. Alnylam is the leading RNAi therapeutics company, committed to advancing a whole new class of medicines for the treatment of a wide range of diseases. Based on Nobel Prize-winning technology, we can essentially silence any gene in the human genome. With this elegant and natural mechanism, we can significantly reduce the production of disease-causing proteins or toxic metabolites that contribute to the clinical manifestations of various conditions. At Alnylam, we have successfully harnessed the RNAi mechanism to build our organic product engine to deliver sustainable innovation and to bring medicines to patients with high unmet medical need around the globe. We truly believe this underscores the transformational potential of this modality as a whole new class of medicines. Earlier this year, we announced a bold new plan to guide Alnylam forward over the coming 5 years called Alnylam P5x25. Alnylam P5x25 is aimed at bringing transformative medicines 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, and delivering exceptional financial performance. Our ATTR amyloidosis franchise is poised with the potential to make a major contribution to this vision. One of the P5x25 goals is to achieve 6 or more marketed products by the end of 2025. We presently have 4 approved products: ONPATTRO, GIVLAARI, OXLUMO and with our partner, Novartis, Leqvio. Of course, Vutrisiran is potentially the next in line as it is currently under review with the FDA. The acceptance of our NDA was announced last month, and our PDUFA date is slated for April 14, 2022. Turning to Alnylam's full clinical development pipeline, you will see that we have over a dozen programs in the clinic spanning Phase I to Phase IV studies. We are proud of this pipeline that we've built organically, and we look forward to advancing these programs and bringing potentially transformative medicines to patients in the future. Today, we will focus on our ATTR amyloidosis franchise and the key activities for the programs highlighted here. Let me begin with background on the disease. ATTR amyloidosis is a rare progressively debilitating disease caused by misfolded TTR protein that accumulates as amyloid deposits in multiple tissues, including the heart, nerves and GI tract. Both the hereditary and wild-type forms of the disease may present in adults with multisystem involvement and a high burden of disease that is fatal. As with most rare diseases, the true prevalence is difficult to know but we believe there are approximately 50,000 patients worldwide with the hereditary form of the disease where the patient carries a TTR gene variant. Patients without a TTR variant can also accumulate misfolded TTR protein in tissues, and this leads to wild-type ATTR amyloidosis. Prevalence estimates for this patient segment are significantly larger, perhaps 200,000 to 300,000 patients worldwide, so some estimates are much higher. In both cases, patients can present with a variety of symptoms, as shown here. To further describe the burden this disease has on patients, I'll now share a brief video with Dawn, a caregiver and hATTR amyloidosis patients. [Presentation]

Thank you. As you heard, the burden of this disease is quite significant for these patients. Thank you, Dawn, for sharing your story with us. Turning to our therapeutic hypothesis, it has remained consistent since we first started studying potential treatments for this disease over 10 years ago. It starts with an RNAi therapeutic reducing the production of the disease-causing TTR protein in the liver. This reduces continued amyloid deposition and allows the body to potentially remove existing deposits, which ultimately halts or improves the manifestations of disease. This hypothesis follows logically from the historical treatment intervention, a liver transplant, which removes the production of the variant TTR protein but replaces it with the continued production of wild-type TTR protein from the new liver. Other treatment modalities attempts to interfere with the disease cascade at later points well after the TTR protein has been made and is circulating throughout the body. We believe that suppressing the production of both variant and wild-type TTR protein in a highly potent and reversible manner is a compelling approach to treating this disease, and we have designed our TTR targeting RNAi therapeutics to do just that. We now have 3 RNAi therapeutic programs within our ATTR amyloidosis franchise. On the left, you see ONPATTRO or patisiran, which was the first-ever approved RNAi therapeutic with the U.S. approval in August 2018 for the treatment of the polyneuropathy of hATTR amyloidosis, based on the landmark APOLLO Phase III study. Patisiran is also currently in further clinical development in our APOLLO-B Phase III study. Vutrisiran, an investigational RNAi therapeutic utilizing the ESC GalNAc conjugate chemistry is in clinical development in our HELIOS clinical development program, which currently includes the HELIOS-A and HELIOS-B Phase III studies. Vutrisiran has a compelling product profile with subcutaneous administration of a 25 mg dose once every 3 months. We are also evaluating an additional dosing regimen of 50 mg once every 6 months. And finally, ALN-TTRsc04 is the newest program within our franchise. Like our other programs, this RNAi therapeutic also specifically targets the TTR gene. We are utilizing our advanced IKARIA platform chemistry in its design. Based on preclinical studies and our modeling work, we are exploring the potential for once annual dosing and greater than 90% CRM TTR reduction with ALN-TTRsc04, and we plan to file an IND at or around year-end 2022. And importantly, from a business perspective, we have no third-party royalty payments due in connection with this program. We also anticipate patent protection covering us from a loss of exclusivity perspective, extending beyond 2040. Selectively, it is our belief that these 3 programs will support Alnylam's vision to be the leading ATTR amyloidosis franchise in this space and position us for sustained market leadership in long term as well. And with that, I'll turn it over to Rebecca Shilling to review some highlights from our recently presented clinical development activity.

Thanks, Rena, and good morning, everyone. Let me turn specifically to the HELIOS-A study and begin by reviewing the study design. The design was discussed with global regulators before we started the study in 2018. HELIOS-A is a randomized open-label study in patients with hereditary ATTR amyloidosis with polyneuropathy. We enrolled 164 patients who were randomized 3:1 to receive Vutrisiran at a dose of 25 milligrams administered subcutaneously once every 3 months. Our patisiran administered intravenously once every 3 weeks at a dose of 0.3 milligrams per kilogram. The study has an innovative design where the efficacy result in Vutrisiran-treated patients at 9 months have been compared to an external control book group which is the placebo arm from the APOLLO trial of patisiran in a similar patient population. Small patisiran arm included in HELIOS-A as a -- is included as a reference comparator but not for formal statistical comparison at month 9. The primary endpoint is the change from baseline in the modified neuropathy impairment score or mNIS+7. This is a 304-point score, where 0 indicates absence of disease and 304 points corresponds to end-stage disease. The mNIS+7 score assesses sensory, motor and autonomic function. In addition, we included 2 secondary endpoints at month 9, encompassing clinically meaningful readouts to further assess the impact of Vutrisiran on disease symptoms. These secondary endpoints were the Norfolk Quality of Life-Diabetic Neuropathy questionnaire, which is a validated instrument to measure quality of life and the 10-meter walk test, which assesses gates B. The patient population enrolled in HELIOS-A included a wide range of disease severity and was representative of the global population with the disease, with patients enrolled from 57 sites in 22 countries. Baseline characteristics were generally similar between the Vutrisiran and patisiran reference arm in HELIOS-A and with the placebo arm from APOLLO, and the populations were clinically comparable. Further, just as we did with APOLLO, we predefined a cardiac subpopulation and so with patients with thickened heart wall and without a history of hypertension or aortic valve disease. This cohort provides an enriched population in which to examine potential cardiac effects, which may warrant further investigation. Let's now turn to the clinical efficacy results reported in the study, and I'll start with the results on the primary endpoint, namely the change in mNIS+7 from baseline at 9 months. As shown here, Vutrisiran treatment resulted in a 17-point mean treatment benefit relative to the external placebo group at 9 months. This effect was highly significant with a p-value of 3.4x10 to the minus 12, indicating the robustness of the treatment effect. In contrast to the external placebo group that demonstrated rapid and marked worsening in neuropathy as shown here, the mean change in mNIS+7 relative to baseline for Vutrisiran treated patients with a negative value, indicating an improvement in the overall score on average. Improvements were seen across all components of the mNIS+7 score and also across all our prespecified subgroups such as age, sex, race, geography and prior TTR stabilizer use as well. Let's now turn to the key secondary endpoint in HELIOS-A, which was the change from baseline in the Norfolk Quality of Life score at 9 months. Vutrisiran treated patients demonstrated a mean improvement in quality of life compared to the external placebo group. Specifically, Vutrisiran treatment resulted in a negative 3.3 point mean change, again, indicating that patients on average experience improvement as compared to a 12.9 point mean increase or worsening observed in the external placebo group, resulting in a 16.2 point mean treatment benefit for Vutrisiran treated patients compared to placebo. This result was also highly significant with a p-value of 5.43x7 the negative 9. Improvements were observed across all domains of the Norfolk Quality of Life Questionnaire and all our prespecified patient subgroup. And next, we see the results of another secondary endpoint, the 10-meter walk test, which measures gate speed. Gate speed is an important and clinically meaningful measure of patient functions. In contrast to the placebo group that demonstrated worsening in gate speed at month 9, the Vutrisiran-treated patients remain stable. This result was also highly significant with a p-value of 3.10x10 to the negative 5. On this slide, we present a side-by-side post-hoc comparison of the results at 9 months with Vutrisiran in HELIOS-A and with patisiran in the APOLLO study. On the primary and 2 secondary endpoints, Vutrisiran demonstrated treatment effects that are highly consistent with those seen with patisiran in APOLLO, notably, the effects of Vutrisiran on the mNIS+7 primary endpoint are very similar to those seen for patisiran and APOLLO with a minus 2.2% and a minus 2.0 lease square mean difference from baseline, respectively. Additionally, the cross-study comparison shows similar effects on Norfolk Quality of Life and gate speed measures with overlapping 95% confidence overall. Also, while not a formal comparison, I do want to note that the efficacy observed with patisiran in the small reference arm in HELIOS-A, which is generally similar to that seen in the original APOLLO trial, which speaks to the robustness of the study design and execution and patisiran's consistent efficacy profile. Please note that the efficacy data shown for the HELIOS-A Patisiran reference arm are mean changes as specified in our statistical analysis plan and not least square mean changes. Now to further understand the Vutrisiran treatment effect, we conducted binary analysis to evaluate the proportion of patients who show improvement in neuropathy impairment and quality of life relative to baseline. As you see here, the majority of patients, 50.4% showed improvement in neuropathy impairment relative to baseline by 9 months. Additionally, the majority of Vutrisiran-treated patients, 53.4%, show improvement in Norfolk Quality of Life relative to baseline. These analyses provide evidence that like patisiran and APOLLO, Vutrisiran and HELIOS-A may not only halt neuropathy progression, but could achieve reversal of neurological impairment and its clinical sequela in the majority of hATTR amyloidosis patients with polyneuropathy. In addition, at 9 months, as shown here, we analyzed the exploratory endpoint of NT-proBNP, which is a marker of cardiac stress. On this end point, higher values indicate a greater level of cardiac stress. In both the overall study population shown on the left and in the cardiac subpopulation shown on the right, Vutrisiran treatment led to improvement relative to placebo on this endpoint as well. Specifically, while the external placebo group shown an average increase or worsening NT-proBNP levels over 9 months, levels in the Vutrisiran group remain stable. We're very pleased with this result as it supports further evaluation of Vutrisiran effects on cardiomyopathy manifestations of disease, which we're currently studying in the HELIOS-B trial. And finally, knockdown of serum TTR levels in the Vutrisiran group was rapid and sustained over a period of 9 months and similar to that observed in the patisiran reference arm. Specifically, once quarterly Vutrisiran achieved a mean steady state serum TTR reduction from baseline of 83% at 9 months, with MAX observed reduction of 98%. We're also very pleased to see clamped TTR suppression with a peak to trough fluctuation and interpatient variability was low with the TTR knockdown effect over time with our proposed 25-milligram quarterly regimen. Importantly, Vutrisiran demonstrated an acceptable safety and tolerability profile. There were 2 study discontinuations due to adverse events that both led to death in the Vutrisiran arm by month 9, neither of which was considered related to study drug. One death was due to COVID-19 and one was due to an iliac artery occlusion during a hospitalization for pneumonia in a patient with preexisting congestive heart failure. There were 2 serious adverse events deemed related to Vutrisiran by the study investigator consisting of dyslipidemia and E. coli urinary tract infection. Treatment emergent adverse events occurring in 10% or more of patients receiving Vutrisiran included diarrhea, pain in extremity, fall and urinary tract infections. These events are common in the disease itself and occurred at a similar or lower rate than observed in the external placebo group. Injection site reactions were reported in 5 Vutrisiran patients, which is 4.1% of patients and were all mild and transient. There were no clinically significant changes in liver function tests, hematology or renal function related to Vutrisiran. We plan to report the top line results from the HELIOS-A 18-month analysis in late 2021, which will provide longer-term evaluation of a number of important neuropathy focused endpoints, such as NIS+7, Norfolk Quality of Life and others. In addition, we will look at a number of exploratory endpoints intended to further characterize Vutrisiran's potential impact on the cardiac manifestations of disease, including the cardiac biomarker NT-proBNP, echocardiographic parameters, such as left ventricular wall thickness and longitudinal strain and cardiac amyloid burden through the use of technetium scans. As we have previously announced, we are also very excited about the potential opportunity for a biannual dosing regimen with Vutrisiran, which could further differentiate Vutrisiran from other products and provide yet another dosing regimen option for patients. In the left-hand panel of this slide, you see the robust and sustained TTR reduction data from the Phase I single-dose study of Vutrisiran in healthy volunteers. Here, we note TTR reduction of greater than 80% following single doses of 25 milligrams or greater. In the right-hand panel of this slide, you see the pharmacodynamic modeling results, which illustrate the anticipated TTR reduction of multiple doses of Vutrisiran. While we remain very confident in the 25-milligram once every 3-month dosing regimen, we believe that the pharmacodynamic profile of Vutrisiran also supports even less frequent dosing, such as 50 milligrams once every 6 months. Vutrisiran administered with a regimen of 50 milligrams every 6 months is predicted to achieve TTR reduction that is similar to that achieved with patisiran at its clinical dose of 0.3 mg per kg every 3 weeks. And importantly, average TTR reduction of patisiran at 50 milligrams every 6 months is anticipated to be comparable to what is achieved with 25 milligrams every 3 months at steady state. Accordingly, based on the data I've just shown you, we are now generating the clinical data to advance this additional 50-milligram biannual dosing schedule for Vutrisiran. Specifically, on the far right-hand side of this slide, you can see that we've revised the open-label extension period of the HELIOS-A study now include a randomized treatment extension where the hATTR amyloid dosed patients with polyneuropathy from the HELIOS-A study will be randomized to receive Vutrisiran at a dose of either 25 milligrams every 3 months or 50 milligrams biannually. These data intended to demonstrate the safety and efficacy of the 50-milligram biannual regimen are expected in 2022. We believe that advancing this alternative regimen has the potential to further reduce the burden of care on patients and the health care system and provide additional optionality for patients and physicians. Now to briefly recap the exciting milestones ahead, additional regulatory submissions are planned for Vutrisiran in hATTR amyloidosis with polyneuropathy in the EU, Brazil and Japan later this year. Notably, we have updated the anticipated timing of our European submission following a favorable interaction with the European regulators in which they supported a submission based on the HELIOS-A 9-month data package instead of the previously planned 18-month data package. We also expect to share top line 18 months results from HELIOS-A in late 2021. And our U.S. launch for Vutrisiran is planned for early 2022, subject to regulatory approval by the PDUFA date and in late 2022. We intend to share the data readout on the Vutrisiran 50-milligram biannual dosing regimen from the ongoing extension study. And now with that, I'll turn it over to Patrick Jay to review recent data from the patisiran study in patients with orthotopic liver transplant.

Thanks, Rebecca, and hello, everyone. First, to briefly summarize the post OLT study design. This was a Phase IIIb open-label study conducted across several countries in Europe, which enrolled adult patients with hATTR amyloidosis,; also known as ATTRV with worsening polyneuropathy disability or PND scores after liver transplant to receive open-label patisiran treatment for 12 months. The objective of the study was to describe the 12-month efficacy and safety of patisiran in patients with hATTR amyloidosis who experienced polyneuropathy progression after liver transplantation. The primary endpoint was the average 0 TTR percent reduction over month 6 and 12, while secondary endpoints included the changes from baseline at month 12 in clinical endpoints of neuropathy impairment [ of this ], quality of life with the Norfolk questionnaire, autonomic symptoms with the COMPASS-31 test, disability with the R-OD score and nutritional status with modified BMI. As shown in this slide, 23 patients enrolled in the study and received patisiran. Their baseline demographics and disease characteristics listed in the table on the left. Patients were on average 58 years old, the majority of them were male and had the V30M variant. Of note, patients received their transplant an average of 3.7 years after their first diagnosis. On average, patients received their first patisiran dose 9.4 years after their transplant. The majority of patients had previously received a TTR stabilizer. At baseline, the majority had a PND score of 3A or 3B. Prior to study enrollment and receiving patisiran, about 70% of the patients experienced a 1 unit increase from the first documented PND score to study baseline or about 30% of patients experienced a 2 or 3 unit increase. Here, we are showing data from the primary endpoint of TTR reduction. As you can see, there was a rapid and sustained reduction in serum TTR levels with patisiran treatment. The median TTR reduction from baseline was 91%, which is consistent with that observed in the APOLLO study. As shown on this slide and month 12, there was an improvement in neuropathy as assessed by the decrease in the mean miss from baseline, which was the secondary endpoint of the study. Similarly, in data not shown in this presentation, there was improvement or stability in all of the secondary endpoints of quality of life, autonomic symptoms, disability and nutritional status. Overall, patisiran exhibited an acceptable safety profile in this study as the majority of adverse events were mild or moderate, and the common AEs were consistent with those seen in the APOLLO study. There are new safety signals in this population are important. The most common AEs in this study were diarrhea and infusion-related reactions. 13 serious AEs were reported but only 1 was related to patisiran -- considered related to patisiran. There were no discontinuations due to AEs, and there were no deaths that occurred on study. All patients completed the study. There was one case of liver transplant rejection deemed by the investigator to be unrelated to patisiran and was likely due to inadequate immunosuppression. The patient was able to remain on patisiran and completed the study. Additionally, LFTs were normal in the majority of patients and no cases of thrombocytopenia occurred. In summary, this is the first prospective clinical trial for a therapeutic agent for patients with hATTR amyloidosis experiencing impolyeuropathy progression post OLT. In this study, patisiran showed a rapid and sustained reduction of serum TTR from baseline through month -- through 12 months of treatment, improving our stability on all secondary endpoints and an acceptable safety profile with no new safety concerns identified in this post-transplant patient population. Overall, we believe these results support the benefit risk of patisiran treatment in improving or stabilizing measures of disease impairment in patients with hATTR amyloidosis with polyneuropathy progression post OLT. I'd also briefly mention another ongoing study with patisiran, our Phase IV observational study. This is a multicenter observational study who value the effectiveness of participants in patients with the polyneuropathy of hATTR amyloidosis with a V122I or T60a variant. The patient population will be receiving commercial patisiran that will be categorized in 1 of 3 cohorts, a prospective cohort where patients are naive to participant at the time of enrollment but intend to soon initiate therapy. The mixed cohort where patients have been receiving commercially available patisiran for less than 12 months at the time of enrollment or the retrospective cohort, which includes patients who received mostly available patisiran for more than 12 months. The primary endpoint of this study is the proportion of patients with stable or improved PMD score at 12 months relative to baseline. A robust set of secondary endpoints will also be evaluated, including Norfolk, COMPASS, BMI, NT-proBNP and the Kansas City Cardiomyopathy Questionnaire, or KCCQ, a measure of quality of life. This study completed enrollment in June 2021 with a total of 67 patients. We look forward to the top line readout in 2022. These data are intended to complement the results of the APOLLO study as they will further expand our understanding of the potential benefits of patisiran in hATTR amyloidosis with polyneuropathy due to these genetic variants. where limited to data or otherwise unavailable. And with that, I'd like to introduce Dr. Matthew Maurer, today's guest speaker. Dr. Maurer is a cardiologist at the Columbia University Medical Center and the Arnold and Arlene Goldstein Professor of Cardiology. He will share his perspective on treating ATTR amyloidosis patients today. Welcome, Dr. Maurer.

Thank you. And I'd like to thank Alnylam for having me. It's truly a really exciting time for patients with transthyretin amyloidosis field is moving rapidly. Thanks to efforts of your company and others. Here are my disclosures. And we'll start off with just the realization that for practicing cardiologists, one of the key things to do is to differentiate 2 very disparate forms of cardiac amyloidosis. A majority of patients that we see, more than 95% have either AL amyloidosis, which is caused by a precursor protein produced by the plasma cell, resulting in misfolded light chains that aggregate in the heart or as we're talking about today, transthyretin amyloid. And this distinction is terribly important because obviously, the biology is very different. The natural history of the disease, hence, the prognosis differs, as we heard from the elegant statements of the patient who spoke genetics or preeminent importance in transthyretin amyloidosis. Of course, treatment differs across the spectrum of these 2 very disparate disorders that present phenotypically quite similarly. The challenge for cardiologists is to distinguish these and there is a wealth of epidemiological evidence shown here that individuals with AL are often slightly younger than those certainly with wild-type disease. Wild-type disease is the disorder at least to date and referral centers predominantly of older adult men, though it's probably misdiagnosed in women as well or underdiagnosed as is all cardiovascular conditions. And hereditary TTR has a very wide spectrum of age that it affects with a slight male predominance, and that's in part due to the heterogeneity of the over 100 mutations in the TTR gene. Cardiac involvement is universal in wild-type disease, along with some other orthopedic manifestations that are clinical clues. Obviously, in hereditary disease, there's not only cardiac involvement, as we heard, peripheral and autonomic neuropathy. The outcomes of patients is highly dependent upon how early they're diagnosed, and there are tremendous efforts, all forms of cardiac amyloidosis to reduce the delay and the time span, initial presentation to diagnosis. Obviously, as we talked about, the treatments differ considerably. There is a revolutionary new treatment for AL amyloidosis. So that is daratumumab, a clonal antibody against CD38. And there are emerging revolutionary treatments, both for hereditary, wild-type TTR, though currently stabilizers are the only approved therapy wild-type disease. As you're probably well aware, as shown on this slide, amyloid is a multi-systemic disease. And given the multitude of symptoms and their nonspecificity, unfortunately, clinicians at the forefront of making a diagnosis really have significant challenges. As is highlighted in the slide, both AL and TTR have similar overlapping symptoms. Most importantly, though, disorders like periorbital purpura macroglossia, which are not very common, but are almost only seeing AL amyloidosis. Cardiac involvement, which is what I focus in is quite common in AL, but as I mentioned, is nearly universal, certainly in wild-type TTR, quite common in the United States, at least, given the mutations that we frequently see in the heart as well. Unfortunately, patients often have this journey to make a diagnosis that's been highlighted by excellent data Isabelle Lousada, the Amyloid Research Consortium in which many patients wait a long time, need to see many doctors often. Unfortunately, cardiologists are at the forefront of making a misdiagnosis, often attributing thick wall heart in an older adult to hypertrophic cardiomyopathy when the amyloid is the correct diagnosis. The next slide, we demonstrate here, I think, a very important use of multimodal imaging. Certainly in the phases of a work of a patient when you're suspecting the disease through early and definitive diagnosis to when you're trying to prognosticate or determine response to therapy, different imaging techniques play a differential role. Just to highlight, the suspicion usually begins with images on Echo or MRI. A definitive diagnosis can be established as we've all shown, finding scintigraphy with assessment of monoclonal proteins to establish a TTR cardiac amyloid without a biopsy that has really shortened the time to diagnosis led to patients being diagnosed earlier in the course of their illness. As you can see, we have some techniques to prognosticate, but most importantly, those are the cardiac biomarkers that also are at this point, really important in assessing response to therapy. So there is quite a bit of hope for merging MRI techniques or maybe even PET scans. The next slide, I just again highlight some of the advantages and limitations of multimodal imaging. Obviously, Echo is very widely available. There's an emerging role for strain-based imaging for both diagnosis, the so-called apical sparing pattern and for establishing prognosis. But there are lots of limitations. Certainly, Echo cannot distinguish, if you will, AL and TTR amyloidosis. And as well, a lot of the specialized imaging techniques are not very widely available. As I mentioned, nuclear imaging has come to the forefront, highly-sensitive been specific for identifying TTR amyloid, especially when combined with monoclonal protein assessment ironically, these isotopes are not FDA approved. For this particular indication, thankfully, that has not hindered their application in clinical medicine. And cytography has not shown to be quite useful at actually following patients over time. It's more of a diagnostic approach. And MRI has, as we all know, very high spatial and tempo resolution. Really identify extracellular volume, which is the surrogate for amyloid deposition and event. And there's quite a bit of evidence to suggest that's emerging that following MRI longitudinally will provide important insights into the characteristics of the myocardium, whether there is an ability to actually regress alloy deposits. On the next slide, I highlight what I think is the most underutilized basic test to identify patients with cardiac amyloidosis and that is the classic discordance between the voltage seen on an EKG and the wall thickness determined on an echocardiogram. And almost all patients who have cardiac amyloid have undergone an EKG and an echocardiogram. And as we know from the seminal data from [ Cristina Quarta ], you can see that low voltage QRS abbreviated LQV is highly specific. So when you see low voltage, you should think about amyloid. But unfortunately, it's not very sensitive, and it's quite of a late-phase phenomenon. That is not the point in time where we want to diagnose every patient with amyloid when they have low voltage on an EKG. And that's true for males and females. Obviously, increase in wall thickness is highly sensitive for amyloid, but it could be lots of other things, hypertensive heart disease, hypertrophic cardiomyopathy, as we mentioned. But the key is if you're able to combine the wall thickness cardiogram and the voltage on an EKG, you can arrive at sensitivity and specificities and likelihood ratios that are quite high for identifying individuals with amyloid. And as shown on the next slide, we've been using this very basic approach with kind of neural networks and machine learning to facilitate the diagnosis of cardiac amyloid on a population level. And I just highlight here, these AUC curves from my colleagues that were recently presented at the ACC demonstrating that you can get AUCs of almost 0.95 using machine learning techniques to analyze EKGs and utilize the simple wall thickness on the echocardiogram. This is not even using more sophisticated measures on the Echo, which would only, I believe, improve the diagnostic ability. This approach, I think, using artificial intelligence, machine learning is ripe for future investigation and identification of patients who suffer from amyloid early in the course of their illness. The excitement, obviously, in the field results not only from the realization that the disease was underdiagnosed in the past but that we now have therapies that can be brought to bear. Those therapies have emerged from an understanding of the pathogenesis of this disorder, which, as shown here, is related to misfolded monomers or oligomers of the transthyretin protein that usually exists as a home or tetramer or 4 leaf clover composed of 4 individual monomers, each one, which is 127 amino acids. For better or worse, we've characterized the disease and to those who have "cardiomyopathy" and those who have polyneuropathy, depending upon the post-mitotic organ, which the amyloid deposits up in the heart or the nerves. But I would assure you, I think this is probably a result of clinical experience, the regulatory issues, but an oversimplification. And many patients have both manifestations of cardiomyopathy and neuropathy. From the biology, on the next slide, we've learned that as the liver produces this protein and it misaggregates and forms amyloid fibrils, there are essentially 3 emerging areas for targeting the biology of the disease. Most importantly is the concept of TTR silencing a knockdown using either antisense, TTR RNA or RSP-based therapies. And most of us in the field, at least looking at the biology, if you will, of AL amyloid or AA amyloid believe that silencing is going to afford us a significant efficacy because when you're able to knock down or eliminate the precursor protein in diseases that are analogous such as AL amyloid where anti-plasma cell therapy is utilized to reduce the plasma clone in the light chains as low as possible, clinical benefits accrue such patients. So TTR silencing and knockdown is something that the cardiology community is very enthusiastic about. Currently, we do have stabilizers, which are quite effective. They favor the kinetics towards stable tetramer as opposed to the oligomers or monomers and those include tafamidis, which is FDA approved and diflunisal and then AG10, which is in late phase clinical development. And there is obviously a great interest in anti-amyloid therapies for those poor patients who are diagnosed late in the course and there are a whole host of antibodies that have been developed and are in early phase clinical investigation, some in later phase to target the preformed amyloid fibrils in the various organs, including the heart. So as I mentioned, tafamidis is the only FDA currently approved therapy for transtyrid in cardiac amyloidosis in that came about as the result of the landmark ATTR-ACT trial, which I had the privilege with Claudio Rapezzi co-chairing on the steering committee and tafamidis, as you know, resulted in a significant reduction in overall mortality, with a pretty large number in the absolute difference in mortality that was 13%. But it's far from a panacea, patients with this particular condition, as you can see, continue to progress despite the reduction in overall mortality or hospitalizations, there's still, I think, an important unmet need as a significant portion, for example, of tafamidis-treated patients still die to 30 months. And even those who are taking tafamidis still have hospitalizations. Additionally, we showed in the trial regarding secondary endpoints that tafamidis reduced the decline in both functional capacity as measured by the 6-minute hall walk and reduce the decline in KCCQ. However, patients are not looking for a reduction in decline. They're looking for ideally improvements or minimally stabilization. So again, widely effective therapy, one that I think will highlight a significant unmet need for patients with this particular condition related to important endpoints that really matter that is functional capacity and quality of life. We've learned from analysis of the ATTR Act trial shown here that stabilization at least is much more effective as a therapy when administered early in the course of the illness. While the confidence intervals around these point estimates are wide, I think the trend is clear that the rare patient in ATTR Act, that was 37 out of 441 who had NYJ Class I symptoms had a significantly lower mortality than patients, for example, who had Class III symptoms where it was even debatable about the efficacy of therapy. So the field has really moved toward leveraging genetic testing, cyntigraphy and early identification of patients. There's been a great need now that we've identified patients who we're caring for to assess how we should monitor the disease, and this is an expert consensus document, well written, that was recently published by colleagues, demonstrating clinical and functional variables, biomarkers and imaging parameters that they recommend following. Usually, as you can see in the far right, every 6 months, those include, obviously, into current clinical events such as cardiovascular hospitalizations, NYJ class, and measures both of disease-specific and nondisease-specific quality of life as well as a 6-minute hall walk. Biomarkers are quite important. They form a mainstay of staging systems and patients fortunately do progress through stages. So they're quite useful. And then, as I mentioned, Echo and EKG and Holter monitoring quite important. The prevalence of atrial filtration in patients with amyloid is a very, very high. They're increased risk for thromboembolism and active surveillance for atrial fibrillation is incredibly important. So on this slide here, they summarize that, again, clinicians should be moving toward a state in which when they're following the patients over time, they're looking at clinical and functional measures signed with laboratory or biomarker and imaging and ease. They define, I think, appropriately cut points for stabilization and/or progression of disease, including, God forbid, hospitalization, rising your class or a decline in your KCCQ or EQ5D or about a 30- to 40-meter decline in 6-minute hall walk usually measured every 6 months. Biomarker cut points are shown here, including increases in troponin and BNP as well as advances in various staging systems. There are also imaging in ECG abnormalities. Most importantly, it looks like a reduction in global longitudinal strain of 1% or 1.5% is associated with a pretty significant decline, cardiac function along with declines in stroke volume. So as I mentioned at the beginning, it's really exciting times for clinicians in this field and most importantly, for the patients that we take care of. Certainly, our basic science and translational colleagues have demonstrated that when we understand the biology of the disease, we can then develop important emerging therapeutic. Unfortunately, a large portion of the patients with this particular condition remain undiagnosed and continue to be diagnosed at late stages and we need as a community to do something about that. But I do think someday, in the near future, we will all be that is patients, doctors, they're family members being an enviable position of having several different therapies across the spectrum of this disorder, choosing which one and when they're administered, in what order, will be something that we need more data on will require a process of, I think, shared decision-making. So again, thanks for your time and attention.

Thank you, Dr. Maurer. That was really a great summary of the status of the field today and the challenges that continue to exist for patients. And hello, everyone. I'm John Vest, Vice President of Clinical Research and the clinical lead for the ATTR franchise at Alnylam. We feel extremely well positioned and able to move forward with confidence in our ongoing efforts to develop Vutrisiran and patisiran in ATTR cardiomyopathy based first and foremost on our understanding of the pathophysiology of the disease and our ability to directly address the underlying cause of ATTR amyloidosis, by specifically reducing the pathogenic amyloid-forming TTR protein. As we have presented and published before, our initial confidence for developing RNAi therapeutics and ATTR cardiomyopathy came from the APOLLO study, which, as you know, is the pivotal Phase III study that was the basis of approval for ONPATTRO for the treatment of the polyneuropathy of ATTR amyloidosis. Importantly that study included a spectrum of prespecified exploratory cardiac endpoints that were assessed in the study participants with prespecified evidence of cardiac amyloid involvement referred to as the cardiac subpopulation. We believe what was most compelling about the data on these exploratory endpoints was the consistency across a variety of complementary assessments, which included improvement compared to placebo and assessments of cardiac structure, evidenced by a decrease in LV wall thickness; cardiac function, evidenced by a decrease in longitudinal strain; a decrease in the important cardiac biomarker, NT-proBNP; and an improvement in 10-meter walk test. The significance of these improvements in cardiac assessments was supported by a post hoc analysis of safety data from the APOLLO study looking at the impact of patisiran treatment on mortality and hospitalizations across all patients in this study. As shown on the left, you can see that for the composite of all-cause mortality and hospitalizations, we saw roughly a halving of these event rates over the course of this 18-month randomized controlled study. Importantly, as we have previously published, patisiran demonstrated an acceptable safety profile based on an in-depth analysis of cardiac events in both the overall study population and the cardiac subpopulation. These initial data from the APOLLO study have now been complemented by data published by Julian Gillmore and colleagues at the National Amyloidosis Center in London, from 32 patients with hereditary ATTR amyloidosis with cardiomyopathy. 16 patients received treatment with patisiran, a majority of whom also received diflunisal and 16 control subjects did not receive any disease-modifying treatment. At 1 year, there was a substantial reduction in amyloid burden, which the authors characterized as "in keeping with amyloid regression" in 45% of patients who received patisiran. Overall, the patisiran treated patients demonstrated a decrease in cardiac MRI assessment of extracellular volume, which is the area occupied by amyloid in this disease as compared to an increase in extracellular volume in the control group. The patisiran treated patients also demonstrated a substantial improvement in change in 6-minute walk test compared to the control group at 1 year. This is a very encouraging finding for us given that this is the primary endpoint of the APOLLO-B study and an important secondary endpoint in HELIOS-B. The patisiran treated patients also demonstrated a substantial improvement in NT-proBNP compared to the control group at 1 year. The authors described these data as demonstrating "compelling evidence of substantial amyloid regression." It is important to note that patisiran is not currently indicated for the treatment of ATTR cardiomyopathy and Vutrisiran is not yet approved for any indication. These are exploratory and post hoc analyses and thus need to be confirmed in ongoing trials, but you can start to see a consistency of findings across a wide spectrum of parameters that we believe all support the hypothesis that we're pursuing in the ongoing APOLLO-B and HELIOS-B studies to establish the role of patisiran and Vutrisiran in the treatment of patients with ATTR amyloidosis with cardiomyopathy. On the next slide, you can see the high-level overview of our ongoing APOLLO-B study of patisiran in ATTR amyloidosis with cardiomyopathy, which was initiated in late 2019. The study was designed to enroll approximately 300 patients with ATTR amyloidosis, either wild type or hereditary who've demonstrated evidence of cardiac involvement. Patients are required to have symptomatic heart failure. A portion of the patients were progressing while on a TTR stabilizer prior to study entry, and they were to remain on that stabilizer for the duration of the study. The other patients were not on a TTR stabilizer at study entry. Patients were randomized 1:1 patisiran or placebo, and the primary endpoint is change versus baseline in 6-minute walk test at 12 months. We selected 6-minute walk test as a recognized measure of clinical benefit in heart failure, and we identified this as an endpoint that will allow us to bring patisiran in the potential benefits of this therapy to this population as rapidly as possible. We will, of course, look at a variety of secondary endpoints, including outcomes of death and hospitalization as well as exploratory endpoints, such as cardiac biomarkers and cardiac imaging. We are extremely pleased with the progression of the study, which completed enrollment in early 2021. We expect to report top line results in mid-2022. If positive, we would expect to file an sNDA in late 2022 in support of a potential FDA approval in mid-2023. In addition to APOLLO-B, we are also very excited about HELIOS-B, which is our ongoing Phase III cardiac outcome study with Vutrisiran in ATTR amyloidosis with cardiomyopathy. HELIOS-B is a 600-patient randomized controlled trial also in patients with hereditary or wild-type ATTR amyloidosis. Like APOLLO-B, all patients will have confirmed ATTR amyloidosis with cardiomyopathy at baseline and symptomatic heart failure. This study will include both patients on a TTR stabilizer at baseline as well as TTR stabilizer naive patients. Patients are randomized 1:1 to Vutrisiran 25 milligrams quarterly or to placebo. The primary endpoint is a composite of mortality and CV events be analyzed when the final patient completes month 30. However, as we will discuss on the following slide, the study includes an option to perform an interim analysis with the potential for an earlier data readout. There is also a robust package of secondary endpoints, including 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire that will allow us to fully elucidate the treatment effect of this therapy across a broad spectrum of disease manifestations. We anticipate completion of enrollment in HELIOS-B in late 2021, earlier than originally expected. Enrollment today is going extremely well. As noted previously, the HELIOS-B study includes an optional interim analysis, providing the potential for an earlier data readout. We are engaging with regulators to align on the details of a potential approach. Importantly, the analysis would be staged such that the results from APOLLO-B can inform our final strategy, and allow us to achieve the optimal balance between speed and the desired label expansion for Vutrisiran in ATTR amyloidosis with cardiomyopathy. Therefore, we expect that we will only be in a position to share further information on our thinking after the APOLLO B study data are available. And with that, I'll turn it back over to Rena for final thoughts on the future of the franchise.

Thank you, John. Now let's turn to our thoughts on the emerging ATTR amyloidosis franchise opportunity. Focusing initially on the potential launch of Vutrisiran in the U.S. in early '22, we believe that Vutrisiran, based on HELIOS-A alone has the potential, if approved, to expand Alnylam's overall share of the hATTR amyloidosis with polyneuropathy market in multiple ways. First, similar to what we've forged with ONPATTRO, we aim to secure broad patient access across the globe for Vutrisiran with proactive and innovative market access approaches. We also expect that with the infrequent subcutaneous dosing, Vutrisiran has the potential to be a particularly well-suited treatment option for those patients who may otherwise have been in a watch-and-wait holding pattern before committing to treatment, or other patients who wish to switch therapy. We also anticipate increased use by HCPs to treat hATTR amyloidosis patients with a mixed phenotype given the simplicity of this dosing regimen. Importantly, Vutrisiran, if approved, would provide greater patient choice with the availability of 2 RNAi therapeutic treatment option. In short, we believe the HELIOS-A study results and safety at 9 months will make Vutrisiran, if approved, a very attractive option for patients and their HCPs. Let's also talk a little more about our latest addition to the ATTR amyloidosis franchise we aim to build, the new Alnylam development candidate called ALN-TTRsc04. Our organic research and discovery engine continues to drive innovation forward in new ways and such advances can be applied to the TTR space. With our IKARIA platform chemistry applied to a new TTR targeting siRNA, our preclinical studies suggest the potential for an extended duration of action, which would enable a once annual dosing regimen. Importantly, highly potent target knockdown, potentially greater than 90% could also be achieved. On the right-hand side of the slide, you see our multi-dose modeling of an annual dosing regimen with ALN-TTRsc04 after 3 annual dose administration. We intend to share more details on the IKARIA platform and our preclinical work at an upcoming scientific meeting in mid-2021. Now pulling it all together. Here, you can see how we intend to build the ATTR amyloidosis franchise over time. ONPATTRO has been the foundation of our franchise for nearly 3 years now. With the 2022 to 2024 time frame, we expect to launch the franchise commercially with the anticipated approval of Vutrisiran in the U.S. in early 2022 and in other major markets around the globe thereafter. Notably, we aim to enter into the larger ATTR amyloidosis market with a potential label expansion of ONPATTRO and of course, pending positive APOLLO-B data and positive regulatory review. Notwithstanding the work ahead, patisiran has the potential to be the first RNAi therapeutic option approved for ATTR amyloidosis with cardiomyopathy and the first treatment across the whole gene silencing category available for this population. Then in 2024 and beyond, we expect continued expansion of the franchise, most notably following the readout from the HELIOS-B study. If positive and subject to regulatory approval, this is expected to carry Vutrisiran forward into the ATTR amyloidosis with cardiomyopathy patient population as well. And finally, also in that 2024 and beyond time frame, there is the potential for the once annual ALN-TTRsc04 as our third RNAi therapeutic for patients with ATTR amyloidosis. And again, Alnylam intends to establish the leading ATTR amyloidosis franchise. We aim to do this by building on a strong ONPATTRO foundation and all we have learned through over a decade of research, development and commercialization in this field. Leveraging this depth of knowledge and understanding, we are well positioned to maximize the potential for Vutrisiran to swiftly achieve and sustain a leading position in the market, pending the upcoming global regulatory reviews and approvals. In closing and as an important acknowledgment, ATTR amyloidosis patients are why we do what we do. Thank you to the patients, caregivers, patient advocacy groups and study investigators and staff who continue to work extraordinarily hard for the ATTR amyloidosis community, especially during what continues to be a challenging time globally. Your contributions have been critical to our ability to move these potential treatments closer to the patients who need them. Now let's turn to address some of your questions that have come in from our participants.

[Operator Instructions] All right. Let's first start with a question for Dr. Maurer. Dr. Maurer, are, are you seeing any kind of shift in how patient diagnosis has been evolving in recent years?

Thankfully, yes. I think societal guidelines, the increasing awareness of the utility of scintigraphy has led to an explosion, to be honest, in the number of patients that we're seeing, at least at our center and my colleagues say at other amyloid centers. Part of the concern there is the wait times could get exceedingly long because some providers are limited in how many patients they can handle them. I think so scintigraphy has definitely led to an increased awareness of the condition, along with the potential therapies. The only concern I would say is that providers still don't seem to know exactly in the real world, how to leverage scintigraphy appropriately. They're often employing it without the assessment for light chains, and so that leads to misdiagnosis. And we are seeing an increasing use of scintigraphy in populations where I think the clinical suspicion is probably too low. And as we know from important seminal studies in cardiology over decades, including, for example, in coronary disease, certain tests look really great when you have a very high prevalence of disease in the population you're studying. But when the prevalence drops considerably, the positive predictive value can decline. So scintigraphy, I think, is a 2-edged sword. It helps us identify people earlier, but needs to be employed in the right person at the right time.

Thank you. And we also have another one regarding how treatment today might be different between the community cardiologists and the amyloid centers of excellence, for example. Are there key differences that you could elaborate on regarding those setting?

Yes. So actually getting access to some of the approved therapies is still a challenge for certain patients. The costs are high and many providers in the community, I don't think, have the bandwidth or the capacity. They're not equipped, for example, with specialty pharmacies as part of large institutions to rapidly garner access to tafamidis, for example. And so many patients are referred to centers of excellence for that particular reason. I think the big distinguishing features, however, are in the day-to-day care of patients, those of us who provide care to a large collection of amyloid patients, I think, have quite a bit of experience in the nuances of management and what's appropriate with regard to general medical care. And then the important thing to highlight, as I think Dr. Vest was noting, is that at amyloid centers patients have access to these emerging therapies. And as he noted, this is a population of well educated patients that have tremendous support from their caregivers. And enrollment in these trials is faster than anyone ever anticipated and always happens that way. So that's quite encouraging. That's the big distinction between going to a center of excellence where you can get access to what are exciting and emerging new therapies.

Great. Thank you so much for that color. We have a number of questions coming in around the concept of the HELIOS-B interim analysis plan and how the APOLLO-B study will be informing what we do there. So I'd like to turn to John to elaborate on our plans there.

Yes. Thanks, Rena, and thanks for these questions. We are certainly very excited about the potential and the option that we have to conduct an interim analysis in the HELIOS-B study. And as noted, this is -- provides us with the possibility of an earlier data readout. We are initially certainly very encouraged by the Vutrisiran data that is coming out of HELIOS-A first with our month 9 readout, and we're eagerly anticipating readout of the 18 months data later this year, which will give us further insights into the potential impact of Vutrisiran on cardiac manifestations of the disease, which will provide us with further confidence about our ongoing cardiac studies. I think really importantly and we are actively thinking through and working with regulators to understand what the interim analysis in HELIOS-B might look like. I think as been alluded to, very importantly, we will have the opportunity to see the APOLLO data, which will, of course, provide us with the potential to see confirmation of our therapeutic hypothesis of the impact of TTR silencing in a cardiac population, which will give us the information we need to confidently design and put the details on what that interim analysis might look like.

Great. Thank you for that additional color there. Let's also turn to another Vutrisiran question here, regarding the changes that we've recently talked about regarding the regulatory submission timing for Vutrisiran regarding HELIOS-A outside of the U.S. So Rebecca, would you like to just recap again our submission plans are for -- on the horizon?

Yes, let me do that. So we recently engaged with the European regulators, again, following the availability of our HELIOS-A 9-month data. And we now plan to file the EMA based on the HELIOS-A, 9-month results instead of waiting for the 18-month data package as we had previously planned. So we are targeting late 2021 for our -- later this year for our EU MAA submission. And then the Brazil and Japan regulatory submissions are also anticipated to be by year-end of this year.

Exactly. Great. Thank you so much. Next, we have another question about our OLT study, actually, the patisiran study here. So I'll tee that up for Pat. There's a question about the context of the importance of these OLT results and what our next steps would be for regulatory plans with that study. Pat, would you like to elaborate there for us?

Sure. That's a great question. So orthotopic liver transplantation has been utilized around the world to treat patients with an hATTR amyloidosis. And there are a good number of patients who've had transplants who have since progressed because the transplant doesn't get rid of the wild-type TTR. So the OLT study goes towards demonstrating the efficacy and safety in this population with a significant unmet need. Our plan is to submit this study to European regulators by the end of this year.

Great. Thank you, Pat. Thank you so much. There are also a number of questions coming in about the concept of gene editing technology and what that means for the TTR space. Let me take a first pass at answering that. Certainly, the Intellia data that has recently come out was impressive, and it was an important milestone for the gene editing technology. We do also consider this to still be early in the development of this new technology, and there's still pending outstanding questions related to the safety of gene editing as well as hurdles that might be part of the clinical development plan and the commercial approach. So it is still early days for the technology. Like all competitive landscape factors, we are monitoring them and the whole competitive landscape accordingly. But what is important, in our view, is that we love the TTR -- the Vutrisiran target product profile itself, and we believe that it will be very competitive for the near term and the long term in the TTR space. In general, Vutrisiran leverages RNA interference as that mechanism, and we have a great amount of confidence in the mechanism itself, given that it has been a proven approach across a number of therapeutic indications for a number of years now. And there's that extensive human experience in both the clinic and the real world in TTR and in other indications. When we think about what the target product profile for Vutrisiran has to offer, it leverages that RNAi mechanism, but also brings forth that once quarterly administration, the subcutaneous administration and that highly potent and reversible TTR knockdown. So assume pending regulatory approval, of course, we do believe that this will be a very competitive therapeutic treatment option for patients. Another question that we have coming in is around the clinical development plan for SC04, ALN-TTRsc04 and what our early thoughts are there around the potential launch timing for that product? John, would you like to take that one?

Yes. Thanks, Rena. We are certainly very excited about TTRsc04 in the IKARIA platform and the potential that this has to allow for even less frequent dosing, annual dosing. And we will be releasing at a scientific meeting in mid-2021 further preclinical data on TTRsc04 and the IKARIA platform. which we hope will be informative. With regard to the development program for TTRsc04, it's too early to say exactly what that would look like. However, we do intend to file an IND at or around year-end of 2022.

Great. Thank you. We have another question on the concept of potential labels that would be part of the expanded label indications for patisiran and Vutrisiran following the APOLLO-B and HELIOS-B studies, respectively. And the question is particularly around the use with tafamidis as a background therapy there. So I'll pass this over to Pat in a minute, but I think I'll just start by saying that certainly, this is pending the results of the APOLLO-B and HELIOS-B studies, pending positive results and regulatory review. But certainly, regulators will be the one to decide what is in those expanded labels, and we do not wish to kind of predict what would be in those labels. But we can provide more clarity on, again, the tafamidis use in these -- in the cardiac APOLLO-B and HELIOS-B studies. So let me pass that over to Pat to again articulate the role of tafamidis in these studies today.

Yes. So in both APOLLO-B and HELIOS-B, a portion of patients in each study are on tafamidis and the remainder of the patients are not on tafamidis or any other stabilizer. And in both of these studies, we do expect to get meaningful data from patients who are on tafamidis or not.

Great. Thank you. And we have just 2 last questions here, and then we'll be wrapping up. One is regarding the randomized treatment extension in HELIOS-A and a question around the efficacy assessments that are part of the randomized treatment extension and the anticipated timing of the biannual dosing being available on the market. Rebecca, would you like to take that one?

Yes. So we are evaluating efficacy in the randomized treatment extension with the 25-milligram compared to the 50-milligram q6M dosing. And we will be looking at CRM TTR reduction and safety are key measures across both the dosing regimens as well as the efficacy parameters of mNIS+7, Norfolk Quality of Life and other measures of long-term clinical efficacy. We do expect to have data next year. And based on that data, then we would plan to file the sNDA with the U.S. FDA shortly thereafter. But we cannot speculate exactly on approval timing at this point.

Great. Thank you. And finally, one last Vutrisiran question. It's really tied to the market dynamics and how will switch from patisiran to Vutrisiran take place once Vutrisiran reaches the market. So again, pending regulatory approval, we do have some thoughts on that, and I can share kind of what we have been learning from the field so far. Anecdotally, we certainly hear stories of patients who are on ONPATTRO who have had good response to treatment. And we do think that they would like to stay on ONPATTRO commercially, and that is perfectly acceptable. And then there will be a new group of patients, those who may prefer Vutrisiran. If they are switching therapies or if they're newly diagnosed patients, we do think they would be potentially, again, if approved, interested in selecting Vutrisiran as a treatment choice. Importantly, the way we think about it is it's not a zero-sum game. The addition of Vutrisiran into the space will be anticipated to grow the patient share of hATTR amyloidosis patients with polyneuropathy on a treatment that is an RNAi therapeutic-based treatment and Vutrisiran's target product profile would potentially be attractive for a variety of reasons, allowing, as I kind of indicated before, some new patients and new physicians to select an RNAi therapeutic as a treatment option. So beyond the footprint that we currently see with ONPATTRO, for example. Again, pending Vutrisiran regulatory approval, that is what we believe about the dynamics in the market at this point. So I think that touches upon all of our significant questions, and I can thank you for submitting those engaging questions and wrap up the roundtable. So thank you again, Dr. Maurer for joining us here today and sharing your thoughts. And as we conclude the roundtable, I'll also just highlight that our next RNAi roundtable topic is givosiran for the treatment of acute hepatic porphyria that will be taking place on Wednesday, August 4, at 1:30 p.m. Eastern Time. So please go to the Alnylam website for more information on that. Thank you all again for joining us, and have a great day.