Good morning and welcome to day one of our virtual Alnylam R&D Day event. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Executive Officer, who will provide some opening remarks and general context. Yvonne Greenstreet, President and Chief Operating Officer, will share an overview of our commercial progress. Akshay Vaishnaw, President of R&D, will discuss our approach to sustainable innovation before we take two deep dives, the first being on our Alnylam TTR franchise. In that session, we are pleased to have Dr. Philip Hawkins of the National Amyloidosis Centre, Royal Free Hospital, and University College London join us alongside John Vest, Vice President of Clinical Research at Alnylam.
Additionally, we are excited to have Dr. Akshay Desai, Director, Cardiomyopathy and Heart Failure Program, Cardiovascular Division of Brigham and Women's Hospital, and Associate Professor of Medicine at Harvard Medical School, and Lauren Melton, Senior Director of the ALN-AGT program, discussed reimagining the treatment of hypertension with ALN-AGT. Before I hand it over to John, I'll start with a few brief comments. Today's event is expected to run until about noon Eastern Standard Time. John will moderate a Q&A session at the conclusion of the presentations. If you'd like to submit a question, you could do so at any time during this event by typing your question in the Ask a Question field. Finally, a replay of this event will be available on the Investors page of our website in the Capella section later today.
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 our risk factors, and with that, I'd like to turn the session over to John.
Thanks, Christine. Good morning, everyone. It's great to be here. Welcome to Alnylam's 2020 R&D Day. While 2020 was almost certainly the most difficult year in our lives, it was nevertheless a defining year for Alnylam's transition toward becoming a top five biopharma. Last year, I quoted Justin Timberlake about RNAi therapeutics getting their sexy back, and now, in one year's time, we're seeing a remarkable democratization of RNA therapies in a way I could never have expected. As all of you know, Alnylam is the RNAi therapeutics company. We are proud to have pioneered RNAi therapeutics as a whole new class of medicines. The data speak for themselves. RNAi therapeutics are indeed transformative for patients, and while we are entering our 19th year since founding, we're really just at the beginning stages of realizing the impact of RNAi therapeutics in human health.
Today, Alnylam is advancing the most robust and comprehensive pipeline of RNAi therapeutics. This includes over a dozen programs in clinical development across as many clinical indications. Without a doubt, our pipeline of innovative medicines is one of the strongest in the entire biotech industry. We're very proud to have brought the first RNAi therapeutic to market in 2018, just over two years ago. ONPATTRO is now approved by seven regulatory agencies around the world. Today, ONPATTRO is the market-leading medicine for the treatment of the polyneuropathy associated with hATTR amyloidosis. Just over a year ago, we brought the second RNAi therapeutic to market. GIVLAARI is the first GalNAc conjugate ever approved, a major milestone for Alnylam innovation. And it's the first treatment ever for patients with acute hepatic porphyria, a devastating disease.
Just last month, we brought the third RNAi therapeutic to market with the approval of OXLUMO, first in the EU and then in the U.S. OXLUMO is the first RNAi therapeutic approved for a pediatric indication, and it's the first-ever treatment for primary hyperoxaluria type 1, another devastating disease. There's more. Just last week, Leqvio was approved in the EU, and we expect an approval in the U.S. by Christmas. As you know, Leqvio is being commercialized by our partner, Novartis. This is now the fourth RNAi therapeutic to reach the market. And very importantly, Leqvio is the first to ever treat a highly prevalent disease affecting millions of people around the world. Back in 2015, we boldly put forward our Alnylam 2020 goals of being a global, multi-product commercial company with a significant clinical pipeline and a robust product engine delivering sustainable innovation.
I'm proud to say today that we have exceeded those lofty goals. So we've accomplished a lot with four approvals in just over two years, but we have our sights on much bigger goals. In particular, we believe Alnylam is positioned to lead the industry in the advancement of transformative medicines for patients. And we believe that Alnylam is well positioned to build a top five biotech over the next five years. So let's start with the next one to two years. In the very near term, we have an exciting 2021 in front of us. And we shared our specific 2021 protocols in our PR this morning. So I really encourage you to take a close look. In sum, 2021 will certainly be a milestone-rich year for Alnylam. This includes commercial execution on four brands. It includes one new NDA filing, two new Phase III data readouts.
We also have important Phase II programs such as the KARDIA trials for ALN-AGT and hypertension, and there are other notable highlights. We're especially excited about the growth opportunity for our commercial profile. In addition to our four marketed products, we can expect two additional product launches over the next 18-24 months, meaningfully increasing the number of revenue-generating Alnylam assets, all of which are in a growth phase for the foreseeable future. Frankly, we believe this profile of organic growth and generating commercial products is nearly unprecedented in biotech history. Beyond the next 12-24 months, the key ingredients are in place for Alnylam to build a top five biopharma. Our first ingredient is continued commercial execution and revenue growth, leveraging the global commercial infrastructure we built over the last two years.
The second ingredient is the expansion of our ATTR franchise into what we believe represents a multi-billion-dollar opportunity for Alnylam. With HELIOS about to read out and with APOLLO-B reading out at mid-2022, our continued leadership in ATTR amyloidosis will be further cemented. HELIOS in the near term is a very important study for Alnylam, so stay tuned. As we build out ATTR, we're also advancing our early and mid-stage clinical pipeline. You'll hear today more data from our AGT hypertension program that highlights our opportunity to reimagine the management of this highly prevalent disease. You'll also hear tomorrow about our genetically driven approach for NASH, another area of enormous unmet need. Alnylam's transition from rare diseases to special disease markets and then to prevalent disease opportunities is, without a doubt, an exciting part of our future.
We believe that RNAi therapeutics have characteristics such as durability and clamp pharmacology that can address the major adherence challenges in these prevalent diseases and can also improve outcomes. We also believe that these same characteristics will help overcome some of the access barriers that have recently plagued the blockbuster potential of medicines for prevalent disease indications. Our fifth key ingredient is what brought us to this exciting stage to begin with during the course of our company's evolution, namely our organic product engine. We are truly flush with new RNAi therapeutic opportunities at Alnylam across our liver, CNS, ocular, and now pulmonary programs. We have well over 20 active preclinical programs that are going to fuel two to four new INDs per year for the foreseeable future. Now, the final ingredient for building a top five biotech is achieving a self-sustainable financial profile as we transition to profitability.
Of note, with the Blackstone strategic financing we completed earlier this year, we are confident that Alnylam will never need to go to the equity markets, sparing our investors future equity dilution, bolstering share price appreciation as we build value. So as we now look at the next five years, we've seen exciting future ahead. Alnylam will be a company in both rare and common diseases with six or more approved products across multiple indications and with an industry-leading pipeline of transformational medicines. We believe we can build this type of great company with a commitment at the same time to patients, innovation, responsibility, and excellence. Of course, as we continue our journey, we will never, ever lose sight of our North Star, namely the patients that we serve. At the end of the day, patients matter most, bar none.
So now I'd like to hand it over to our President and COO, Yvonne Greenstreet. Yvonne, take it away.
Thanks, John. Good morning, everyone. I'm Yvonne Greenstreet, President and Chief Operating Officer at Alnylam. Today, I'm excited to provide you with an overview of our commercial platform and our progress bringing RNAi therapeutics to patients around the world. In mid-2018, the approval and launch of ONPATTRO, the first-ever commercial RNAi therapeutic, brought about the advent of a new transformative class of medicines. Indicated for the treatment of polyneuropathy in patients with hATTR amyloidosis, ONPATTRO's approval was a landmark event for us and indeed for the industry. Since that time, we've steadily advanced our late-stage pipeline and have now launched two additional RNAi therapeutics: GIVLAARI for the treatment of acute hepatic porphyria in late 2019 and OXLUMO for the treatment of primary hyperoxaluria type 1 just a few weeks ago. We're very proud of these achievements.
Of course, it goes without saying that successive product launches such as these are rare in biotech. These multiple product launches not only demonstrate the strength of our organic pipeline engine, but also the leverageable nature of the commercial platform we've built over the past two years. Let me now briefly review the progress we've made building our commercial programs and operations. First, ATTR and ONPATTRO. As a reminder, ATTR amyloidosis is a debilitating, progressive, and often fatal multisystemic disease caused by misfolded transthyretin protein, which accumulates in a number of tissues, including nerves, the heart, and the gut. ONPATTRO is indicated for the treatment of the polyneuropathy caused by hATTR amyloidosis. We achieved $82.5 million in ONPATTRO global net product revenue in Q3 2020. As of September 30th, over 1,150 patients worldwide were on commercial ONPATTRO treatment.
Our second product, GIVLAARI, was approved for the treatment of acute hepatic porphyria, or AHP. AHP is an orphan, ultra-rare disease with an enormous disease burden. Patients endure frequent and potentially life-threatening attacks that can be accompanied by seizures and paralysis. GIVLAARI reduces the frequency of these attacks and associated hospitalizations. In Q3, we achieved $16.7 million in GIVLAARI global net product revenues with over 150 patients on commercial drug. In addition to our efforts in ATTR amyloidosis and acute hepatic porphyria, we're also working to address primary hyperoxaluria, or PH1. PH1 is an ultra-rare progressive disease caused by an overproduction of oxalates in the liver that can lead to recurrent kidney stones, end-stage renal disease, and systemic complications. Disease onset is typically seen in childhood, including infancy, but patients can present with symptoms later in life due to the significant variability in disease manifestations.
Just a few weeks ago, we announced that the FDA and European Commission approved OXLUMO for the treatment of PH1. With no other approved therapeutic options available, OXLUMO's approval was a historic event for PH1 patients and their families. Furthermore, OXLUMO is now the first-ever RNAi therapeutic approved for a pediatric patient population, and this is a significant milestone for our platform as it further demonstrates the broad transformational potential RNAi medicines can bring. Now, as you can see on the map on this slide, we're commercializing our products on a global scale. More specifically, we're leveraging the infrastructure we built around the world both to support ONPATTRO's growth as well as driving GIVLAARI and OXLUMO's uptake across multiple regions. With a direct presence in 24 countries and distribution partnerships accessing an additional 34 countries, our commercial footprint positions us well for success.
Of course, this commercial success wouldn't be possible without an effective medical affairs and commercialization strategy systematically executed through this global infrastructure. Taking away learnings from ONPATTRO's launch and geographic expansion, we've optimized our medical affairs and commercial platform to develop a roadmap supportive of successive product launches at a global scale. Let me now walk through the key components of this roadmap and our broader commercial strategy. As one might expect, success begins with a strong product profile. Indeed, as shown by the APOLLO Phase III trial, ONPATTRO is able to reverse the polyneuropathy manifestations of hATTR amyloidosis. This is a key point of differentiation in the hATTR market, as other therapeutic options have only shown an ability to slow disease progression.
With GIVLAARI, treatment in the ENVISION Phase III trial was shown to significantly reduce the frequency of porphyria attacks, easing the heavy disease burden associated with AHP to an extent not previously seen, and a number of patients have experienced extended attack-free periods, which has essentially given them control over their disease for the first time. The ILLUMINATE-A Phase III results have demonstrated OXLUMO's robust efficacy, with treatment leading to significant reductions in urinary oxalates not observed with current standard of care. It's clear that our RNAi therapeutics carry the potential for transformative change across a broad range of diseases, and we expect our mid to early stage pipeline assets to also exhibit a similar potential for strong product profiles, paving the way for the continued growth of our Alnylam. Engagement and advocacy play crucial roles on our roadmap.
Often, the manifestations and symptoms of orphan and ultra-rare diseases are not fully characterized or understood, and while there are important insights to be had from natural history and case studies, engagement with patients, caregivers, treating physicians, and broader advocacy groups provide a two-way dialogue with first-hand learnings, and we've been able to integrate some of these learnings in our development processes as well as driving increased awareness and education with patient communities and advocacy groups. And GIVLAARI's development provides a great example of this patient-centric approach. Through interactions with patients as well as their caregivers and healthcare providers, we recognize the role chronic symptoms play in AHP's significant disease burden, and in order to characterize GIVLAARI's potential effect across the spectrum of AHP disease manifestations, we included measures of chronic symptoms in the ENVISION Phase III trial and subsequent open-label extension.
In this way, the patient voice informs our clinical development plan for the benefit of the AHP community as well as effectively advancing and positioning GIVLAARI in the AHP market. We focus on educating patients about their disease and on promoting awareness with caregivers and healthcare providers using multi-channel awareness approaches across all of our therapy areas, including virtual and in-person forums, to ensure we reach the target audiences. Our PH1 education campaigns exemplify this approach, with virtual content developed specifically for healthcare providers, caregivers, and patients. Importantly, the reach of these campaigns that can be achieved is quite extensive. In fact, for PH1, there have been over 3,000 sign-ups to date across multiple digital platforms. Ultimately, increased awareness benefits everyone as it carries the potential to boost patient identification rates in the hopes of saving and extending lives to earlier and more accurate diagnosis.
Another key tenet of our medical affairs and commercialization strategy includes improving diagnostic efforts through genetic testing and direct-to-consumer tests. Programs such as our Alnylam Act, which provides free genetic testing, are particularly important in rare diseases where growth is driven by patient identification. Our Alnylam Act is currently available in the United States and Canada for hATTR amyloidosis, acute hepatic porphyria, and primary hyperoxaluria type 1. It's also available in Brazil for hATTR amyloidosis. Thus far, we've seen encouraging progress with our TTR program now running at roughly 3,000 tests per quarter. With regard to direct-to-consumer tests, we formed a partnership with 23andMe last year.
This is where eligible 23andMe customers in the United States and select European countries who opt into an hATTR amyloidosis genetic health risk report are notified if they're a carrier of a V122I, V30M, or T60A mutation, the three more common TTR variants in the U.S. Encouragingly, we've shipped over 1,160 kits since the inception of this program in July 2019. We're also improving diagnosis through evidence generation. For hATTR amyloidosis, we've conducted genetic analyses to characterize and better understand disease manifestations across a number of common TTR variants, including those predominantly associated with cardiomyopathy. Results from this work and other studies suggest that greater than 50% of hATTR amyloidosis patients with confirmed cardiomyopathy exhibit polyneuropathy symptoms or a mixed phenotype.
This information has helped drive the improved treatment of polyneuropathy in hATTR amyloidosis patients initially diagnosed with cardiomyopathy through PYP scans, a diagnostic tool that's being increasingly used for cardiac hATTR amyloidosis. Improving disease awareness, whether through targeted education campaigns or evidence generation, has led to clear signs of growth in the diagnosis of hATTR amyloidosis. Excluding dips caused by the pandemic, the quarterly volume of PYP scans and TTR samples submitted to our Alnylam Act for genetic testing has significantly increased over time. While this dynamic is direct evidence of success in hATTR amyloidosis, this approach is applicable across our programs. Of course, diagnosis needs to come hand in hand with access. At Alnylam, we feel it's important to bring innovative solutions to bear to ensure our patients have access to the therapeutics they desperately need.
We've been successful in negotiating value-based agreements, or VBAs, that link payment to real-world outcomes. And we've introduced prevalence-based and patient need adjustments within the framework of our VBAs for GIVLAARI and OXLUMO to mitigate the risk of escalating or variable costs for payers. In doing so, not only are we able to help payers embrace our value proposition, but we're also able to ensure reimbursement is conducted according to label without modifications such as step edits. And since we've introduced these principles in the U.S., we've successfully negotiated nearly 30 value-based agreements and have realized greater than 98% and 93% coverage for ONPATTRO and GIVLAARI, respectively, across U.S. commercial, Medicare, Medicaid, and other government payer categories. Importantly, we've worked to maintain low out-of-pocket costs for patients and reports that 75% of commercially insured U.S. ONPATTRO patients and 87% of commercially insured U.S. GIVLAARI patients had zero copay.
We intend to continue to grow our Alnylam through sustained innovation and have not taken any price increases. We've also seen the success translate globally, particularly in the European Union. Utilizing ONPATTRO as an example, we can see our value-based approach has been received extremely well by government payers in Europe. Indeed, our value-orientated philosophy has facilitated the successful and prompt P&R negotiations, with ONPATTRO achieving reimbursements in major EU countries faster than the average of all EMA-approved and reimbursed orphan drugs. This is an impressive feat that reflects our maturing commercial prowess and global reach, as well as the benefits of our innovation-focused ethos. We're proud to have received widespread recognition for our value-based philosophy, as reflected in this Wall Street Journal article, and we see the opportunity for continued innovation in this regard in the years to come.
We've also built our own bespoke patient assistant hub, Alnylam Assist, to guide and support U.S. patients throughout their treatment. Using our Alnylam Assist, patients can be connected with dedicated case managers who provide supportive services, including benefit verification and coverage explanation. Given the complexities of the U.S. healthcare system, this level of individual personalized support can make a world of difference for patients seeking or undergoing treatment with our Alnylam products. Importantly, our Alnylam Assist will be applied as a capability to every drug we launch going forward. As you can imagine, patient support has been increasingly critical throughout the pandemic and recent economic volatility. And to this end, we've adapted our commercial activities in an effort to ensure dosing continuity for our patients and mitigate business disruptions. For instance, for ONPATTRO, we were able to successfully transition a significant number of patients to home infusion.
As of November 2020, 20% of commercially insured U.S. patients and 36% of patients in our CEMEA region were receiving their ONPATTRO infusion at home. We've also adapted our field operations by virtualizing education and disease awareness campaigns, patient engagements, healthcare provider and regulatory interactions, as well as payer negotiations. This action has enabled us to successfully prepare for OXLUMO's launch in a largely virtual environment. We expect these virtual interactions and engagements will become part of our new normal and believe the virtual tools we're leveraging now will ultimately improve the efficiency of our field-facing efforts, and going forward, we see an opportunity to expand the reach of RNAi therapeutics to potentially reimagine the treatment of larger market indications, and as we are all aware, ONPATTRO, GIVLAARI, and OXLUMO are currently for rare disease indications, as well as the focus of preclinical efforts in rare CNS diseases.
We'll be moving into specialty indications such as wild-type ATTR amyloidosis with ONPATTRO and APOLLO-B, as well as with vutrisiran with HELIOS-B. In larger, prevalent indications, we're pursuing markets such as hypercholesterolemia with inclisiran through our partners at Novartis, chronic hepatitis B in partnership with Vir, as well as hypertension with ALN-AGT, and you'll hear about these programs in more detail later today and tomorrow. The profile of our RNAi platform supports expansion into larger market indications. A number of features differentiate our RNAi therapeutics from other classes of drugs, creating an opportunity to reshape treatment paradigms for prevalent diseases with significant unmet need. Key features of this differentiation include infrequent quarterly or biannual dosing, clamped pharmacodynamics with a wide therapeutic index, and convenient subcutaneous administration. When compared to daily orals, weekly monoclonal antibodies, or monthly antisense oligonucleotide therapeutics, the value RNAi brings is clear.
Inclisiran in hypercholesterolemia is an excellent example of RNAi's applicability to larger market indications and the potential ability to address the shortcomings of treatments in these spaces. One can see how inclisiran's biannual dosing, clamped pharmacodynamics, and low cost of goods stack up favorably against biweekly PCSK9 monoclonal antibodies. In fact, this favorable dynamic led to Novartis' acquisition of inclisiran, The Medicines Company, our initial partner in the PCSK9 space earlier this year. The profile of RNAi therapeutics also gives us the opportunity to build on our innovative commercialization and access approaches at a population level. The landmark agreement executed between Novartis and the NHS in the United Kingdom is a great demonstration of this. Through this partnership, access to inclisiran will be managed at a national level.
Furthermore, the NHS is working with Novartis to explore the opportunity for inclisiran in primary prevention, which could dramatically broaden inclisiran's addressable patient population, and we intend to apply broad innovative solutions such as this to our larger market opportunities in the future. Now, I've discussed a lot through this presentation, so I'd like to leave you with three key takeaways. With ONPATTRO's launch, we've built a robust commercial platform with a global reach that has enabled not only strong ONPATTRO growth, but also impressive GIVLAARI uptake. Secondly, we've been able to systematically leverage our commercial platform for successive product launches, as demonstrated by GIVLAARI and OXLUMO, as well as adapting our capabilities to address patient needs in the pandemic.
Importantly, the profile exhibited by our RNAi therapeutics, combined with our mature commercial capabilities, is supportive of our expansion from rare to larger market indications and our aim to reimagine the treatment of prevalent diseases. Let me now turn it over to Akshay, who will discuss our R&D efforts and strategy. Thank you.
Thank you, Yvonne, and good morning, everybody. I'm Akshay Vaishnaw, Alnylam's President of R&D. I've been a part of Alnylam's senior team for over 15 years, and I couldn't be more excited about where Alnylam is today and where we're going in the future. I'm delighted to be here today to talk to you about how we're delivering sustainable innovation with our platform of RNAi therapeutics. Now, John has already shared with you that we work on a unique platform that is based on a Nobel Prize-winning science called RNAi therapeutics.
With this platform, we can silence any gene in the genome and deliver products that have remarkable potency and durability. And we know with our recent approvals that these products are already impacting patients around the world. With the work we've done at Alnylam, we can begin to see RNAi therapeutics emerging as a whole new class of medicines, just like monoclonal antibodies emerged in the late 1980s and 1990s. When I talk about our R&D strategy and how we like to innovate, I like to anchor on this figure from Elbashir et al., who worked in the lab with Tom Tuschl, one of our scientific founders. This was seminal work performed at the turn of the century. Here, for the first time, scientists showed gene silencing with the RNAi mechanism, in this case, in HeLa cells, in the top left showing silencing of the lamin gene.
This was the aha moment that ultimately led to the founding of Alnylam. Indeed, it was the moment where small interfering RNAs, or siRNAs, that were designed against a specific gene were found to silence that gene in human cells for the first time. These data also opened the door to the concept that if you could harness the RNAi pathway, the observations of Elbashir et al. could be translated to novel medicines that would silence disease-causing genes and thereby create a whole new therapeutic modality. With this, we created a focused R&D strategy that has served us well over the last two decades. Our approach is summarized here in the center of this slide.
We selected a target organ, which in the first instance was the liver, then determined, with quite a bit of hard work, I might add, a delivery system to get our RNAi therapeutics to the liver. Then, finally, we focused on genetically validated targets. Over the last few years, we've been able to successfully leverage this simple but powerful strategy to develop multiple products that you've already heard about from my colleague Yvonne Greenstreet, including ONPATTRO, GIVLAARI, and OXLUMO. With that, let me now turn to our progress to date in more detail. With regard to liver-expressed disease targets, Alnylam has built a robust product engine that has delivered four marketed products in just over two years, a remarkable achievement. I already mentioned ONPATTRO, GIVLAARI, and OXLUMO, all transformational medicines for patients.
Now, we can add the approval of a fourth liver-directed RNAi therapeutic, Leqvio, or vutrisiran, for hypercholesterolemia, which was recently approved in the EU, with FDA approval expected by year-end. Beyond this, our liver-focused pipeline is expected to deliver many more products in the coming years. As we look at our late-stage pipeline, we're excited about the many opportunities that we're poised to bring to market in the near term. This includes our label expansion study with vutrisiran in ATTR amyloidosis cardiomyopathy, including wild-type disease, as you'll hear about later today. It also includes our vutrisiran program in hemophilia, which we hope will continue to advance in its Phase III studies. We're particularly excited about vutrisiran, our subcutaneous TTR program that creates an opportunity to extend our leadership in ATTR amyloidosis. Indeed, vutrisiran is currently reaching the finish line in a randomized Phase III study called HELIOS-A.
In this study, patients with hereditary ATTR amyloidosis with polyneuropathy are randomized either to receive vutrisiran administered subcutaneously once every three months or a reference comparator named patisiran. The primary readout is at nine months, where we'll look at the composite neuropathy score, mNIS+7, which will be compared to the placebo arm in the landmark APOLLO study. There are multiple secondary endpoints, including Norfolk Quality of Life, 10-minute walk test, and mBMI. Importantly, we'll also be looking at exploratory cardiac endpoints, including echocardiographic, cardiac imaging, and cardiac biomarker data. We expect top-line nine-month endpoint data from HELIOS-A in early 2021. We expect additional data in late 2021 of the 18-month endpoint. Vutrisiran represents an especially important readout for is to consider as we advance our overall TTR franchise. As you know, both hereditary and wild-type ATTR are mediated by a common pathogenic mechanism of TTR amyloid deposition.
This pathogenesis manifests in a wide spectrum of clinical presentations from polyneuropathy, cardiomyopathy, and often mixtures of both. Our results with ONPATTRO from the landmark APOLLO study have demonstrated definitive results towards halting and even reversing the polyneuropathy manifestations of disease. We've also generated encouraging results with vutrisiran toward cardiac endpoint disease manifestations. The upcoming vutrisiran data and HELIOS-A, we have the opportunity of demonstrating a consistent effect on polyneuropathy. We also have the opportunity of generating yet further data on how a TTR silencing mechanism of action can impact the cardiac manifestations of disease. Additional supportive data on cardiac manifestations will be particularly important since they'll support the potential for TTR silencing with patisiran and vutrisiran in both hereditary and wild-type atypical cardiomyopathy, and of course, this will be further reinforced when the pivotal HELIOS-B readout reads out in the coming years.
With vutrisiran, we also have the opportunity to create a unique and important product profile for ATTR patients. Bottom left, you can see that the Phase I data showed the remarkable durability of vutrisiran after a single injection. Bottom right, modeling data have now shown us that we can achieve the same or better pharmacodynamic effect as the current vutrisiran regimen by dosing at 50 mg q6 monthly, delivering even further convenience to patients and physicians. We intend to incorporate the q6 monthly regimen into the program in the coming months. Vutrisiran is just one product that has clarified the important features of RNAi therapeutics. The schematic here summarizes the key features of our products as we look out at data across the portfolio. Top left, across numerous programs, we've now shown that we can address undruggable targets.
To the right, I note the potency of our drugs with up to 99% knockdown and that the pharmacodynamic effect against the target is tonic and clamped, unlike the seesaw effect with current approaches. Bottom left, we see how the durability of RNAi translates to convenience relative to the once-daily approach of so many current medicines, and finally, our products have ease of administration via the subcutaneous route and are room temperature stable. In upcoming presentations by my colleagues, you'll see how these key features will translate to exciting and impactful product profiles in a range of diseases we're tackling, from hypercholesterolemia to hypertension to NASH and beyond. Finally, the accumulating safety database also allows us to increase the range of diseases we are now studying. We began our journey in rare disease with products such as ONPATTRO, GIVLAARI, and OXLUMO.
But with the features I discussed on the last slide, we've expanded the portfolio from rare via specialty settings such as atypical cardiomyopathy to a wide range of common diseases. No product better illustrates what our product features can do in large prevalent disorders than inclisiran. You will recall that inclisiran targets PCSK9 for hypercholesterolemia and is being developed by our partner, Novartis. Here, we're looking at data from one of the inclisiran Phase III studies, ORION-11. On the left is the consistency of the product's pharmacodynamic action with knockdown in virtually every patient. On the right is the clinical benefit with, again, almost all inclisiran treated patients experiencing LDL reductions and where the vast majority are getting a greater than 50% reduction.
We now know from the Phase III studies published in the New England Journal of Medicine that at steady state, inclisiran can deliver stable and clamped LDL suppression. Here, we see the impressive findings with respect to the extent of LDL changes across the three Phase III studies, with a maximum of 53.8% reduction in ORION-10. Importantly, marked LDL reductions were also seen in the tougher-to-treat heterozygous FH population in ORION-9. More recent data cuts from our partner, Novartis, have shown the consistency of inclisiran's efficacy across subgroups. Here, in the upper panels, you see the similarity in LDL effects across age groups, including younger and older segments. Below, you see consistency across genders. Of course, safety is also very important.
In that regard, it's very encouraging that the Phase III data showed that the adverse event profile showed inclisiran was well tolerated, the safety profile similar to placebo. In fact, overall, the exceptional injection site reactions, the adverse event profile was very similar between inclisiran and placebo across the three Phase III studies in over 3,500 patients. Of note, liver and kidney function and CK were all similar comparing vutrisiran to placebo. In summary, these characteristics of inclisiran, potency, consistency, durability, and safety precisely serve the unmet need in hypercholesterolemia, a common disease where not enough patients achieve target LDL levels and where well in excess of 50% cannot adhere to their daily regimen of statins or other drugs to manage their condition. I now want to turn to how we're evolving the pipeline. Beyond the approved products and late-stage programs, we have a rich early-stage pipeline.
My colleague, Pushkal Garg, is going to discuss the exciting life cycle opportunity we see from the OXLUMO out of the rare indication for which it is approved, PH1, into patients with recurrent kidney stones, a highly prevalent condition. We'll also outline progress with our complement program, cemdisiran in IgA nephropathy, and our hepatitis B program with VIR-2218. Later, in R&D Day, we'll also be doing deep dives into two important future growth areas for us, hypertension and NASH, with ALN-AGT and HSD respectively. This early-stage pipeline continues to be fueled, and we're confident of delivering two to four INDs per year from our organic product engine. These new INDs will come not only from liver targets, but following recent progress with delivery to the CNS, eye, and most recently the lung, also from other tissues.
My colleague, Kevin Fitzgerald, will go over the exciting developments with respect to many of these research programs, which now number well over 20 in total. An important aspect of evolving the pipeline is creating yet safer RNAi therapeutics. We know that seed-mediated off-target activity can on occasion lead to minor LFT changes. The latest generation of our compounds termed ESC+, our scientists have developed a proprietary chemical modification termed GNA, shown here in red. GNA allows maintenance of on-target activity but substantially limits off-target effects. On the right, in a rat model, we can see how GNA translates to preserving liver safety at these histopath sections. But the ultimate question is, how does the ESC+ generation of compounds incorporating GNA perform in the clinic? With HBV01, we saw ALT elevations readily at 3 mg per kg.
However, HBV02, the ESC+ variation of the same sequence as O1, allows dose elevation to 15 mg per kg without the same LFT perturbations. We've seen similar encouraging findings when we have used GNA in our AAT program. Here, first, comparing on-target effects, one can see, looking at left versus right, that AAT knockdown is equivalent between the AAT O1 and O2 molecules. However, with lower panels, one sees that the O2 compound, which is the ESC+ version of the same sequence as O1, could be dosed to 6 mg per kg without the LFT changes observed with O1. These exciting and important data mean that we now routinely use the ESC+ approach in all our compounds to reduce off-target effects and drive to even better safety.
Finally, in terms of pipeline evolution, after all the progress with liver targets, from next year, we're going to see INDs in new tissues such as the central nervous system. The first of these will be ALN-APP, an important target for early onset Alzheimer's and cerebral amyloid angiopathy. But beyond that, we also intend to find many INDs for other neurodegenerative states such as Huntington's disease, Parkinson's disease, and ALS. Again, my colleague, Kevin Fitzgerald, will outline this progress in a future presentation. Let me close by addressing our future plans on how we will sustain innovation into the next decade and beyond. There are two crucial aspects to sustaining innovation: accessing genetically validated targets and maintaining platform advances.
With respect to the first, it is now very clear that genetically validated targets have a much higher likelihood of probability of success, as shown here in this table from a recent publication. In fact, for the industry, the authors show that the probability of success from Phase I to approval is twice as likely for targets with supported genetics. As I noted earlier, this has always been at the core of our R&D strategy. We can access new genetically validated targets from the literature shown here. And in that regard, we have an exciting collaboration with Regeneron after they published their discovery of the role for HSD17B13 loss of function variants in the prevention of NASH, a topic you'll hear much more about later.
However, the way to maintain prioritized access to new genetically validated targets is to study large databases that permit genotype-phenotype analyses for loss of function alleles resulting in disease prevention or attenuation represent potential RNAi targets. As an example of this approach, we entered a collaboration with the UK Biobank two years ago. This collaboration has yielded important insights, as I will shortly share. But to expand on the UK Biobank efforts, we recently joined Regeneron to enter another collaboration, this time with UCLA. This new collaboration significantly diversifies and increases the amount of data we have access to and will likely increase the yield of new targets. A good example of how databases like UK Biobank can help is shown by these findings here. I'm sharing them with you for the first time.
Analyzing data from almost 500,000 individuals in the UK Biobank, my colleagues discovered that a significant number of people had heterozygous deficiency of xanthine dehydrogenase, or XDH. This is an enzyme in a metabolic pathway involved in generating serum urate, with a substantial contribution coming from the liver. Serum urate is the principal driver of gout, the commonest inflammatory arthropathy worldwide. My colleagues therefore interrogated the database for what heterozygous XDH deficiency, about a 50% loss of function in the enzyme, did to the risk of gout. And they found an almost 40% protection. In conclusion, hepatic XDH is now a new target that will enter the pipeline. And where we think we can go well beyond 50% suppression in the liver to substantially lower serum urate, we're trying to help the majority of patients with gout who currently do not appear to reach target levels.
The ultimate effect of our focused R&D strategy on genetically validated targets should be success in the clinic. Here, on the far right, one sees that to date, the cumulative probability of success for our programs from Phase I to the end of Phase III is almost 60%, significantly higher versus the industry averages, which are at 10% or lower. The second aspect of sustaining innovation is continuing to advance our RNAi platform. Here, on the left, you see ESC+, which I've already mentioned. On the right is an area of increasing interest to us, and that is how to multiplex siRNAs against more than one target in complex diseases. But there are other advances that continue to be fine, such as reversing drug effects with Reversir, accessing new tissues, or, bottom right, establishing oral delivery for our platform.
Our scientists have recently shown dramatic data demonstrating hepatic delivery of orally delivered RNAi therapeutics, shown on the left here in the rodent and on the right in the non-human primate. These observations are robust, reproducible, and show every indication of translating in humans, encouraging us to continue our efforts in this area. In summary, I think we can agree that Alnylam has built an industry-leading RNAi therapeutics platform. The liver pipeline has already yielded four important drugs, with many more to come in rare and common diseases. The R&D strategy I've outlined today all works well for us to continue to impact high-value genetically validated targets with unique, potent, and durable pharmacology. Not just the liver, but also many other organs such as the central nervous system, eye, and the lung. With that, I'd like to close, and I think we're now going to take a break.
Thank you for your attention.
Hi. My name is John Vest. I'm Vice President, Clinical Research, and the Global Clinical Lead for the TTR program. I've been working in the TTR space at Alnylam since joining the company six years ago. I'll be talking to you later in the program about our TTR franchise. But first, I have the distinct honor of introducing Dr. Philip Hawkins. Dr. Hawkins is Founder and Professor of Medicine at the National Amyloidosis Centre in London. He has worked in the field of systemic amyloidosis for 30 years, and his research is focused on the pathogenesis, diagnosis, monitoring, and treatment of amyloidosis. He has developed new diagnostic imaging methods, including SAP scintigraphy, DPD scintigraphy, and cardiac MRI. He and his colleagues evaluate over 1,000 new amyloidosis patients each year and have contributed to the development of many new therapies.
Dr. Hawkins will now talk to us about ATTR amyloidosis, now and in the future.
Hello. Today, I'm going to give an overview on ATTR amyloidosis, how things are currently, and my vision of where we will be in five years' time. The term amyloid describes deposits of aggregated protein that accumulate as insoluble fibers in tissues, disrupting the structure and function of vital organs. The resulting diseases, i.e., forms of amyloidosis, are classified according to the protein in question, the transthyretin that is ATTR type, now recognized to be the most common. Diagnosis has traditionally required biopsies, such as this cardiac biopsy shown on the bottom left panel, stained with Congo red dye, which produces the diagnostic green birefringence under polarized light in the center panel. The fibrillary nature of amyloid can be seen on the electron micrograph on the right.
The clinical picture in wild-type ATTR amyloidosis is dominated by massive amyloid deposition in the heart, the left ventricular wall in this case being two to three times the normal thickness, which makes it very stiff and greatly reduces cardiac output. The amyloid protein in wild-type ATTR is normal unmutated transthyretin TTR produced in the liver. It's an increasingly recognized cause of heart failure in older men and is usually fatal within about five years. Most patients give a prior history of carpal tunnel syndrome, typically five to ten years before heart failure develops. Although autopsy studies have shown cardiac ATTR amyloid deposits are present in some 25% of people over age 85, historically, very few patients have been diagnosed during life. The important clues on echocardiography are typically mistaken for commonplace left ventricular hypertrophy.
The bottom left panel describes the first patient we diagnosed in our center in year 2000. In fact, this was the only patient diagnosed during that whole year. He was diagnosed following an invasive and risky cardiac biopsy. There's lately been an explosion in diagnoses in the bottom right panel here in red, wild-type, and black. These are patients with the V122I mutation. This explosion in diagnosis reflects the new non-biopsy imaging methods I'll describe. The repurposing and validation of bone scintigraphy using technetium-labeled PYP or DPD tracers has completely revolutionized the diagnosis of cardiac ATTR. These cheap bone tracers available in most hospitals localize to cardiac ATTR deposits in the heart for reasons we don't really understand. Cardiac uptake greater than bones, i.e., grade two on this scale, occurs in all patients with symptomatic cardiac ATTR amyloidosis.
Further, the remarkable sensitivity of this technique can identify early asymptomatic cardiac involvement. Cardiac MRI is another very important development for ATTR, yielding much more information than echocardiography. The gadolinium contrast agent marks out the presence of amyloid shown in this right upper panel, the white enhancement of the left ventricle. Uniquely, this technique can quantify the amyloid load. Amyloid builds up in the extracellular space, often more than doubling the size of the interstitial compartment, increasing the extracellular volume, which is normally about 30% to typically around 60% in patients with cardiac TTR amyloidosis. This technique uniquely enables serial measurements of amyloid load in the clinic and in clinical trials, which can inform response to treatment.
Severity of cardiac ATTR can be assigned using simple cutoffs of NT-proBNP and eGFR biomarker measurements, in which neither, one, or both of these cardiac and renal biomarkers are out of range. This corresponds to median survivals in the region of six, four, or two years. There is a progressive decline in six-minute walk distance and in renal function. The rate at which patients pass from one stage to the next is also prognostic. Delay in diagnosis has been a major problem. Patients diagnosed in our center have attended hospital a median of 17 times, including three admissions during the prior three years, according to Central NHS Hospital Episode Statistics. Median delay from first cardiac symptom was 39 months, and the diagnosis took more than four years in 42%. Quality of life is severely impaired, with both patients and caregivers reporting substantial burden.
Normal health scores on the KCCQ Cardiomyopathy Questionnaire are 100 and were severely reduced in all domains in this study from our center, and most of these domains worsened over the first 12 months of follow-up. This study shows wild-type in blue. Orange denotes V122I patients, and there was a small group here marked by gray with other mutations causing ATTR cardiomyopathy. The true prevalence of wild-type ATTR amyloidosis is not yet known, but it's certainly much greater than previously thought, with widely proposed figures around two to three hundred thousand cases worldwide. Target populations, which we believe are concealing large numbers of patients, include those patients with heart failure with preserved ejection fraction, patients with aortic stenosis, patients with atrial fibrillation, and quite simply, the elderly population generally. A number of high-quality scintigraphy studies will provide very valuable information on this within the next couple of years or so.
On to treatment. This slide outlines various pharmacologic strategies that might reduce the accumulation of organ-damaging amyloid. Only one of these has unequivocally been validated in any kind of amyloidosis to date. That is treatment which reduces the production of amyloid-forming proteins. This approach has been validated in tens of thousands of patients with AA and AL amyloidosis and has confirmed that substantial knockdown of SAA or light chain protein, respectively, for AA and AL is associated with greatly improved survival on the panels on the left. The panels second from the right, top and bottom, show regression of liver and spleen amyloid in AA amyloidosis in the top panel over a couple of years. In the bottom panel, regression of liver amyloid over the same kind of period in a patient with AL amyloid.
More recently, we've been able to confirm that cardiac AL amyloid also regresses in at least 50% of patients with substantial light chain knockdown over a one- to two-year period. So what about ATTR? Available treatments are shown here in red and those in development in orange. And the treatments comprise, of course, the gene silencers, patisiran and inotersen, the so-called stabilizers, including tafamidis, diflunisal, which is used off-label, and AG10, which is in trial. And there's potential, possibly, for monoclonal antibody therapy to directly target and enhance the clearance of amyloid deposits. So we have three completely different targets for treatment here. Now, this is an important slide. Some 30 years ago, Jeff Kelly proposed the dissociation hypothesis for TTR amyloid formation, which has underpinned development of the so-called stabilizers.
In this model, there is dissociation of the tetramer, ultimately into monomers, which then aggregate to go on to form amyloid. The proposition is that a drug bound to the intact tetramer will prevent this dissociation and this chain of events leading to amyloid deposition. It can certainly do that, at least to some extent, in the test tube. However, more recently, Professor Vittorio Bellotti in our group demonstrated a totally different pathway along the bottom of the image here, in which intact TTR molecules undergo proteolytic cleavage, releasing peptide fragments, shown in red in the middle of the bottom panel, which, enhanced by physical shear forces such as those exerted within the heart, are highly amyloidogenic. Let's consider some potential implications of this. The term stabilizer refers to the pharmacodynamic effect of tafamidis, etc., in a laboratory assay.
At achievable serum concentrations, all of these agents predominantly occupy just one of the two TTR binding pockets, which does not prevent proteolytic cleavage of the TTR tetramer. Crucially, the amount by which ATTR amyloid formation may be inhibited in vivo is neither known nor measurable. By contrast, knockdown is well established in AA and AL amyloid, with knockdown in the order of 80% +, commonly leading to regression of amyloid over the next year or two. I.e., this degree of knockdown reduces the deposition of amyloid to a rate which is less than its slow natural clearance. Regression of amyloid facilitates gradual recovery of organ function so long as this treatment is not introduced too late. Knockdown therapy for ATTR cardiomyopathy is therefore very compelling. And of course, the strategy is strongly supported by the hereditary ATTR neuropathy trials and experience generally.
Delving further into treatment of ATTR cardiomyopathy, this is the Pfizer ATTR-ACT trial that led to the licensing of tafamidis. There was a reduction in mortality and morbidity compared with placebo, but only in patients with NYHA class one or two symptoms. This would exclude 30%-40% of newly diagnosed patients. The NT-proBNP cardiac biomarker, KCCQ score, and six-minute walking distance all worsened despite the treatment. Tafamidis, thus, did not prevent disease progression, and amyloid load was not measured. Inotersen. A subpopulation of patients with amyloid cardiomyopathy was analyzed in the NEURO-TTR neuropathy study, but no cardiac benefits were evident in any of the various echo parameters that were investigated. By contrast, the patisiran APOLLO cardiac subpopulation study demonstrated improvements in NT-proBNP, left ventricular wall thickness, strain on echo, and 10-meter walking times. Further, treatment with patisiran halved the composite rate of hospitalizations and deaths in this post-hoc analysis.
This is a new study from our center describing real-world experience of patisiran treatment in hereditary ATTR cardiomyopathy. Among 16 patients treated for a year, MRI showed regression of cardiac amyloid in six cases and stability in the other 10. In contrast to untreated matched historical controls, the patisiran patients showed reduced extracellular volume on MRI, reduced NT-proBNP biomarker, reduced DPD uptake in the heart, which you can see in the upper panel on the right, and increased six-minute walking distance. This slide summarizes some top-line issues as things stand today here in 2020. The diagnosis needs to be made earlier, but DPD or PYP imaging should now facilitate this and even has the capacity to diagnose early ATTR cardiomyopathy before any symptoms have developed. There's an urgent need for treatment that halts or reverses the disease and not merely slows its progression.
The fully recruited Phase III AG10 trial will provide important further insights into the stabilizer approach in the next year or two. The rationale and clinical benefits of knockdown therapy are firmly proven in other types of amyloidosis, and preliminary evidence I've shown you today strongly supports this in ATTR cardiomyopathy. There are further potential treatments in development, including monoclonal antibody therapy and CRISPR gene editing technology, as well as possibilities for drug combinations and, excitingly, for treating patients before symptoms have developed at all. So finally, this is my vision, my hope, where we will be with ATTR amyloidosis in 2025. There will be substantial awareness of the disease. Biomarkers will have been identified for susceptibility and identifying early disease before symptoms. Amyloid histology will commonly be performed at carpal tunnel surgery and perhaps joint replacement surgery in older people, given that this can identify early deposition.
Technetium DPD or PYP scintigraphy will be used routinely to exclude ATTR cardiomyopathy in at-risk patients, and that is in contrast to how it's being used at the moment, which is to support a possible diagnosis when there is a strong suggestion that it may be present, so I would predict that we will be screening HFpEF populations, aortic stenosis populations, perhaps atrial fibrillation populations with this scintigraphy. There'll be much wider use of multiparametric cardiac MRI, which will also increase the rate of diagnosis and, of course, be incredibly useful for tracking the amyloid burden and response to treatments. Pre-symptomatic diagnosis and hopefully treatment will be possible in many patients, and within five years, I'm confident we will have effective, patient-friendly treatment that reverses this devastating disorder. Thank you very much.
Thank you, Philip.
I am thrilled to have the opportunity to talk to everyone today about our work in ATTR amyloidosis, which is proving to be an incredible and growing opportunity to help patients around the world. ATTR amyloidosis is a progressively debilitating and fatal disease caused by misfolded transthyretin protein that accumulates as amyloid deposits in multiple tissues, including the heart, nerves, and GI tract. There are two forms of the disease. The hereditary form is caused by one of over 120 recognized variants in the TTR gene. The variants are autosomal dominant, and endemic populations are found in certain regions or countries around the world. As with most rare diseases, the true prevalence is difficult to know, but we believe there are approximately 50,000 patients worldwide. In contrast, patients without a TTR variant can also accumulate misfolded transthyretin protein in tissues, leading to wild-type ATTR amyloidosis.
Prevalence estimates for this patient segment are significantly larger. We currently estimate this to be around 200,000-300,000 patients worldwide. However, as we will discuss in coming slides, thanks to increased understanding of the disease and, importantly, improved diagnostic techniques, there is evolving thinking that the wild-type form of ATTR amyloidosis may prove to be far more common than has historically been recognized. The basic pathophysiology of wild-type disease is identical to what we know for hereditary disease. In both forms, transthyretin, which is generated primarily in the liver and normally circulates as a stable tetramer, destabilizes and dissociates to monomers, subject to misfolding and aggregation into amyloid fibrils, which may then be deposited in tissues, resulting in clinical manifestations of the disease. However, unlike hereditary disease, where the pathogenic variant is a clearly identified etiology, it is entirely unclear what is driving the process in wild-type disease.
What we do know is that wild-type typically occurs in older individuals, and thus historically has thought to be in some way related to aging, and it's more commonly seen in men. Wild-type ATTR amyloidosis typically manifests as a cardiomyopathy, with patients presenting with clinical heart failure. However, it is increasingly recognized that, as with hereditary disease, patients with wild-type have extracardiac involvement of amyloid and demonstrate multisystem manifestations, including neuropathy, with a mixed phenotype seen in many patients. Mounting data suggests that wild-type ATTR amyloidosis may account for a substantial proportion of all patients exhibiting heart failure with preserved ejection fraction, or HFpEF. Given how common HFpEF is, if this is indeed the case, wild-type ATTR amyloidosis may be far more common than the estimate cited on the previous slide.
Our understanding of ATTR amyloidosis and the recognition of its prevalence is evolving rapidly during an extremely exciting time for this field. Increasing recognition of the disease and its prevalence has been driven in large part by fundamental advancements in diagnostic techniques. Historically, this has required an endomyocardial biopsy, a common procedure, but one that carries substantial risk, a 1% chance of a serious or life-threatening complication. However, over the last five years, technetium scintigraphy has emerged as a sensitive and specific tool for diagnosing ATTR cardiomyopathy and is now widely accepted as an alternative to invasive biopsy. The test is inexpensive, simple to perform, and simple to read, making it something that theoretically should be widely accessible and is indeed becoming increasingly a standard around the world. This fundamental improvement in technique can vastly simplify diagnosis of the disease.
And in this new era of effective therapies, we hope it will allow a wide range of physicians to more readily identify patients who can benefit from treatment, especially earlier in the course of their disease, ideally even before heart failure symptoms are evident. The combination of simplified diagnostics, enhanced understanding of the disease, and emerging effective therapies has, in turn, driven increased disease awareness and attention among the treating physician community. The common pathophysiology of hereditary and wild-type ATTR amyloidosis across the spectrum of clinical manifestations, including both cardiomyopathy and polyneuropathy, along with the mechanism of action of Alnylam's RNAi therapeutics targeting the fundamental pathogenic protein, both variant and wild-type transthyretin, allows for a single therapeutic hypothesis applicable to all patients with this disease.
Reducing the production of the disease-causing transthyretin protein in the liver will prevent continued amyloid deposition and potentially allow the body to remove existing amyloid deposits, thus ultimately halting or improving the manifestations of the disease. Across our TTR franchise, we are developing two complementary products that we believe will offer choice to patients and physicians such that they can select an RNAi therapeutic option that best fits their individual needs. ONPATTRO, the first RNAi therapeutic ever approved, is administered every three weeks by intravenous infusion and is currently approved in over 30 countries for treatment of polyneuropathy of hereditary ATTR amyloidosis, and it is currently under development for treatment of ATTR cardiomyopathy, including wild-type patients, as we'll discuss in the coming slides. Vutrisiran is an investigational RNAi therapeutic that utilizes the same RNAi mechanism as ONPATTRO.
It is administered as a quarterly subcutaneous injection via a prefilled syringe. Vutrisiran is currently in Phase III studies for the treatment of both the polyneuropathy of hereditary ATTR amyloidosis as well as the cardiomyopathy of ATTR amyloidosis, including both hereditary and wild-type. We are also exploring the potential for an additional dosing regimen that would allow treatment of this disease with only two small-volume subcutaneous injections of vutrisiran per year. We feel extremely well-positioned and able to move forward with confidence in wild-type ATTR cardiomyopathy based first and foremost on our understanding of the pathophysiology of the disease and our ability to target the fundamental pathogenic cause. We have demonstrated this with vutrisiran, where TTR reduction has resulted in robust improvement in polyneuropathy.
As shown on the left-hand panel, with patisiran treatment, we see rapid and sustained TTR reduction, which was observed during the Phase III APOLLO study, shown in blue. This sustained TTR reduction has now been maintained in patients receiving continued dosing for up to seven years in our clinical studies. The right-hand panel highlights recently published data from the Global Open-Label Extension study, where all patients received patisiran starting at month 18. Following the upper red line, you can see that patients who were treated with placebo on the APOLLO study had significant disease progression while they were not on active treatment. But that disease progression halted following initiation of patisiran on the Open-Label Extension. Among patients treated with patisiran on APOLLO, there is a remarkable durability of the clinical treatment effect, with patients continuing to show benefit for up to a total duration of 42 months.
With these data, we feel our therapeutic hypothesis has been confirmed. We are confident, based on our Phase I observations and modeling data, that we can now achieve similar, if not greater transthyretin reduction with vutrisiran through quarterly or potentially less frequent subcutaneous dosing. We are currently exploring paths to enable 50 mg biannually as an alternate dose regimen. As we will discuss in coming slides, there is ample data from the APOLLO study and subsequent data from global investigators' experience with vutrisiran to suggest that TTR reduction has beneficial effects in cardiomyopathy as well. As you may recall, the APOLLO study included a spectrum of exploratory cardiac endpoints that were assessed in study participants with pre-specified evidence of cardiac amyloid involvement.
While by design, the study enrolled patients with polyneuropathy, over half of the enrolled patients met criteria for the cardiac subpopulation, which we now know is reflective of the multisystemic nature and natural history of this disease. What was most compelling about the cardiac data from APOLLO was the consistency across a variety of complementary assessments, which included improvement compared to placebo in assessments of cardiac structure, cardiac function, cardiac biomarkers, and ambulatory function. Importantly, significance of the cardiac assessments was supported by post-hoc analysis of safety data from APOLLO, which demonstrated an approximate 50% reduction in the composite rate of all-cause hospitalization and mortality over the course of the 18-month study. In addition to these data from APOLLO, there have been additional provocative findings from our investigators that further suggest a favorable effect of patisiran treatment on cardiac amyloid involvement.
Initially, compelling data were presented by Julian Gillmore and his colleagues as an uncontrolled case series that included patients who received patisiran through an expanded access program. Serial technetium scintigraphy imaging was shown from a representative patient as seen here. This image is from a 60-year-old man with a V30M variant. He had a mixed phenotype, which included polyneuropathy and cardiomyopathy. He'd been on diflunisal but had continued progression of polyneuropathy, and so patisiran treatment was added. Shown here are the images from baseline and then 12 months later in the same patient. In the baseline image on the left, you can see clear uptake of the technetium tracer in the heart with a signal intensity, the dark pixels in the center of the chest, substantially more intense than what is seen in the bone of the ribs, which qualifies as grade 3 uptake.
In the subsequent image from the same patient obtained 12 months later, shown in the right-hand panel, there's a marked decrease in cardiac uptake. You can see that the uptake in the heart is now equivalent to the uptake in the ribs. Accordingly, this would now be considered a Grade 1 or Grade 2 uptake. Collectively, this suggests the possibility that there's a decrease of amyloid in the patient's myocardium. Importantly, as outlined by Dr. Hawkins during his talk, these initial observations have now been further characterized by Dr. Gillmore. Data were recently published from patisiran-treated patients compared to control subjects who did not receive therapy. Patisiran-treated patients demonstrated compelling evidence of amyloid regression based on cardiac magnetic resonance assessment of extracellular volume fraction and reduction in radiotracer uptake on technetium scintigraphy.
The vutrisiran-treated patients also demonstrated a substantial improvement in change in six-minute walk test compared to the control group at one year. This is a very exciting finding for us, given that this is the primary endpoint of the APOLLO-B study and an important secondary endpoint in HELIOS-B. Collectively, the sound therapeutic hypothesis, pharmacodynamic effect of reducing the underlying cause of the disease, and robust clinical observations provide a solid foundation on which we have designed our cardiomyopathy program with both vutrisiran and patisiran and have driven our enthusiasm as we move towards the substantial opportunity ahead in wild-type disease. Indeed, on this solid foundation, we have now built the largest-ever clinical program in ATTR amyloidosis.
In addition to our HELIOS-A study of vutrisiran in hereditary ATTR amyloidosis patients, which we expect to read out in early 2021, we have ongoing Phase III studies for both patisiran and vutrisiran in ATTR amyloidosis with cardiomyopathy, APOLLO-B and HELIOS-B respectively, and we are thrilled to announce today our intention to initiate the HELIOS-C study of vutrisiran for preventing disease manifestations of ATTR amyloidosis within 12 to 18 months. The APOLLO-B study of patisiran is a randomized placebo-controlled study enrolling patients with ATTR amyloidosis with cardiomyopathy, both hereditary and wild-type, who are either tafamidis naive or on concomitant tafamidis at baseline. APOLLO-B was initiated in September of 2019 and will randomize 300 patients one-to-one to patisiran or placebo. The primary endpoint is six-minute walk test at 12 months.
We will, of course, look at a variety of secondary endpoints, including assessment of death and hospitalization outcomes. The study is now well underway, and we are pleased to announce today that we expect to complete enrollment in early 2021, resulting in top-line data in mid-2022. The HELIOS-B study of vutrisiran is a randomized placebo-controlled study enrolling patients with ATTR amyloidosis with cardiomyopathy, both hereditary and wild-type, who are either tafamidis naive or on concomitant tafamidis at baseline. HELIOS-B will randomize 600 patients one-to-one to vutrisiran or placebo. The primary endpoint is a composite of mortality and cardiovascular events to be read out when the final patient has completed 30 months on study.
There's also a robust package of secondary endpoints, including six-minute walk test and the Kansas City Cardiomyopathy Questionnaire, as well as echocardiographic parameters and biomarkers that will allow us to fully elucidate the treatment effect of this therapy across a broad spectrum of disease manifestations. The study includes an optional interim analysis, which could potentially provide an earlier readout on efficacy. Collectively, the program is taking a broad global approach to accelerate enrollment in both of the cardiac studies. Across APOLLO-B and HELIOS-B, we will be activating over 100 sites in more than 40 countries. We believe this will allow for efficient enrollment and yield a broad spectrum of patients and, importantly, allow for a strong pandemic rebound on top of existing mitigations, which have minimized the impact of COVID-19 on study execution to date.
In summary, there is a singular common pathophysiology in ATTR amyloidosis across hereditary and wild-type forms of the disease that results in disease manifestations, including both cardiomyopathy and polyneuropathy. The production of transthyretin in the liver is the common pathogenic protein. Both of Alnylam's RNAi therapeutics target the production of this fundamental pathogenic protein, including both variant and wild-type transthyretin forms. By dramatically reducing the levels of transthyretin, there is consistent and growing evidence that the Alnylam TTR franchise has strong potential to address the full spectrum of disease manifestations across the broad ATTR amyloidosis patient population. To date, our program has established definitive evidence for the treatment of polyneuropathy in hereditary patients and provided strong corroborative evidence in cardiomyopathy.
Collectively, this solid foundation gives us great confidence as we wait the results of HELIOS-A for the treatment of hereditary patients with polyneuropathy in early 2021, as well as the results of APOLLO-B and HELIOS-B in ATTR amyloidosis with cardiomyopathy in 2022 and beyond. In closing, our comprehensive program across the full spectrum of ATTR amyloidosis, coupled with the marked increase in disease awareness and diagnosis, will allow us to grow the TTR franchise and offer expanding value to patients around the world for years to come. The HELIOS-A study will aim to drive the launch of vutrisiran in the near term, and thereafter, the APOLLO-B and HELIOS-B studies will aim to ensure Alnylam's reach expands to the full ATTR amyloidosis population. Thank you. And I would now like to introduce Lauren Melton from our AGT program.
Thank you, John.
I'm Lauren Melton, Senior Director and Program Leader of the ALN-AGT and Cemdisiran programs. I will be speaking with you later and presenting new data from our ALN-AGT development program. But I first have the distinct pleasure of introducing Dr. Akshay Desai. Dr. Desai is the Director of the Cardiomyopathy and Heart Failure Program at Brigham and Women's Hospital, and he's an Associate Professor of Medicine at Harvard Medical School. Following his undergraduate degree, he began his medical training at Harvard Medical School, where he was awarded the MD degree. He was also awarded a Master's of Public Health from the Harvard School of Public Health. He currently divides his time between clinical care of patients with advanced heart disease and clinical research in cardiovascular clinical trials, emphasizing the pathophysiology, pharmacologic treatment, and ambulatory management of patients with heart failure.
We are happy to welcome Dr. Desai to provide an overview of the hypertension therapeutic area. Dr. Desai?
Thank you, Lauren, for that kind introduction. It's my pleasure to present this broad overview of the current approach to the diagnosis, evaluation, and management of patients with hypertension. There are really three broad objectives for this portion of the presentation. The first is to talk a bit about the basic epidemiology of hypertension and the association between blood pressure and cardiovascular risk. I also want to talk a little bit about how our definitions of hypertension have evolved and how that will have implications for who we classify as being hypertensive and how we treat them.
Focus most of the presentation on therapeutic gaps in the management of hypertension, specifically undertreatment of patients with hypertension in the community, variability in blood pressure both during the day and also visit-to-visit, and its impacts on cardiovascular outcomes. We'll conclude with some review of adherence to antihypertensive therapy and its implications for our clinical practice as it relates to patients with hypertension. All of you who are assembled here have some appreciation for the importance of hypertension as a cardiovascular risk factor. It is the leading risk factor for cardiovascular disease in Western nations and the leading cause of disability-adjusted life years worldwide. Suboptimal blood pressure control is the most common attributable risk factor for cardiovascular disease and for cerebrovascular disease, accounting for more than 50% of the observed variation in the incidence of both of those problems.
And it is a leading cause of chronic kidney disease progression. So this is where the urgency for hypertension management is so plain. This slide depicts the relationship between blood pressure and cardiovascular outcomes and the associated burden of disability-adjusted life years. And you can see that global disability-adjusted life years are attributable to higher blood pressure with a median around 150 mm of mercury. But a large proportion of the disability associated with hypertension is related to blood pressures that we previously considered to be in the normal range between about 115 and 140 mm of mercury.
This really girds the argument that the relationship between blood pressure and risk is really not binary or defined by key cut points like 140 over 90, as we used to think, but rather that there is a continuous and graded association with blood pressure and cardiovascular risk that obtains all the way down to a systolic blood pressure of roughly 120 and a diastolic blood pressure of 80 or even less. At all ages, in both men and women, this continuous graded association with risk of fatal and non-fatal cardiovascular events, including stroke, ischemic heart disease, and heart failure, is present. This relationship is also consistent across racial and ethnic groups. As I said, truly normal blood pressure is probably around 115 over 75 mm of mercury.
Put another way, if we look at the incremental contribution of blood pressure at varying thresholds to the risk of cardiovascular mortality, you can see that for each increment in blood pressure, there is a twofold increment in risk, such that by the time we get to a blood pressure that is severely hypertensive in the range of 175 over 100, patients experience an eightfold increment in risk for cardiovascular mortality compared with normal blood pressure. And it's really this observation that has driven us to be so aggressive with management of blood pressure. And the observation is that, in general, if we look across meta-analyses of clinical trials of antihypertensive therapy for reduction in cardiovascular risk, that the degree of reduction in blood pressure is a tight correlate of the degree of reduction in cardiovascular risk.
For every 10 mm of mercury reduction in blood pressure, we see a 20% reduction in overall cardiovascular events, a 27% reduction in the incidence of stroke, an 18% reduction in the incidence of coronary heart disease, a 30% reduction in heart failure, and a lesser reduction in the incidence of renal failure. Overall, for every 10 mm of mercury, a significant reduction in all-cause mortality that is persistent even after we try to adjust for important comorbidities. The effect is largely consistent across drug classes, so that it doesn't quite matter how we get the blood pressure down, more the amount of blood pressure reduction that is the determinant of risk. How do we approach the therapy of patients with hypertension with this data in mind?
The first strategy for patients with milder variants of hypertension and really all patients with hypertension is to aggressively recommend lifestyle modifications, including reduction in weight, restriction of dietary sodium intake as a major determinant of hypertension, diets that are high in potassium, like the DASH diet, also seem to lower blood pressure. Physical activity is important, not only because of its contributions to weight reduction, but because of the independent effect that there seems to be of aerobic exercise on blood pressure reduction. Moderation of alcohol intake and avoidance of medications that may contribute to hypertensive risk are certainly important as well. Most patients, however, are not controlled with lifestyle modification alone, and it's important to integrate pharmacologic therapy. The vast majority of patients with at least moderate hypertension require more than one drug for management of hypertension.
On average, it's two to three drugs for most patients in large epidemiologic series. The pharmacologic therapy of hypertension really relies on core pharmacologic therapy, including renin-angiotensin system inhibitors, including ACE inhibitors and angiotensin receptor blockers, beta-blockers, calcium channel blockers, and diuretics, either individually or in combination. I think that one of the concerns has always been that there isn't, although there's not a lot of variability in the outcomes according to the type of medication that's used to lower blood pressure. We're moving away in our clinical practice from usage of beta-blockers, partly because they seem to be a little less effective than other classes as first-line therapy for hypertension. They do lower blood pressure, but not as much.
There has been some suggestion of higher rates of stroke with use of beta-blockers to manage hypertension because of the contribution of that class to increased intra-visit variability in blood pressure. There are also higher rates of treatment discontinuation with the class. And so these agents are principally used in those who have a compelling indication for beta-blockade, such as those with low ejection fraction, heart failure, or prior MI. We'll come back to this issue of visit-to-visit variability and its implications for risk in a moment. Many of you may be familiar that our guidelines for blood pressure management have recently evolved in the context of this very important data from the SPRINT trial.
The SPRINT trial is a randomized prospective controlled clinical trial of intensive versus standard blood pressure control with about 10,000 patients over the age of 50 with hypertension and at least one additional cardiovascular risk factor. Patients with those characteristics were randomized in a one-to-one fashion to either intensive therapy targeted at a systolic blood pressure less than 120 mm of mercury or standard therapy based on the guidance at the time of a systolic blood pressure less than 140 mm of mercury and followed to the occurrence of a primary outcome, which was the composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. This trial was terminated early due to overwhelming benefit at median follow-up of three and a half years in favoring the intensive blood pressure control arm.
The mean achieved blood pressure in that arm was 122 mm of mercury systolic versus 135 mm of mercury systolic, and patients in that arm had, on average, 2.8 antihypertensive agents versus 1.8, and you can see the difference in outcomes summarized in the table: an important 25% reduction in the overall primary composite outcome, but also a 27% reduction in mortality and a reduction in acute kidney injury with only a modest increase in the risk of symptomatic hypotension, so these data have importantly evolved our practice because they've highlighted that our previous targets of 140 over 90 were really not adequate to attenuate cardiovascular risk and that more intensive targets, especially for the higher risk patients, may be appropriate.
Now, to get into the SPRINT trial, you had to meet all of the eligibility criteria, which means the SPRINT-eligible patients are really a small subset of the total hypertensive U.S. population, and you can see in the table summarized that the proportion of patients with hypertension in the United States, only about a fifth of them were likely eligible for the SPRINT trial, and this means that as we revise our targets, the implications of the reduction in target blood pressure to 120 over 80 or less than 130 over 80, rather, is to markedly increase the number of patients who are defined as hypertensive requiring therapy, so this is the way the guidelines have evolved from the original JNC 7 guidelines in 2003 to the more updated 2017 ACC/AHA guidelines. The normal blood pressure is defined now at less than 120 over 80.
The treatment threshold for stage one hypertension is now defined at 140 over 90. Even patients with blood pressure between 130 to 140 mm of mercury are now recommended for therapy, where previously those patients were classified as prehypertensive. This means that we've now reclassified a lot of patients. The implications of these new guidelines are that a large proportion of patients in every age category who were previously considered to be controlled are now less controlled. This means that the burden of hypertension in the community has increased simply as an artifact of the change in definitional thresholds. What this does mean is that we have a large proportion of patients not only in the community who are now newly classified as hypertensive, but the proportion of the population that is not controlled according to the newer targets is now obviously a lot larger.
This creates a larger burden to be addressed in our therapeutic practice. The general information is that hypertension is a major determinant of risk. That the higher the blood pressure, the higher the risk, the more effective we are in lowering blood pressure. Whatever strategy we use, the less of the risk. The guidelines have changed with regard to who is actually hypertensive, creating a larger population in need of therapy. I'm going to shift gears for a moment now and talk about factors other than just the numerical blood pressure, which might correlate with risk for cardiovascular events. One of those is blood pressure variability. Now, historically, we've used the mean office blood pressure over several visits to guide our therapy and utilize that as the principal surrogate of cardiovascular risk.
But we understand that there is a lot of day-to-day variability and visit-to-visit variability in blood pressure that is also important. Blood pressure fluctuates over the course of the 24-hour day and from day to day. And in serial visits, if we look at the inherent variability of blood pressure, there's also a lot of change. Generally, in clinical practice, we're looking at average pressures to guide therapy. And so we disregard the extremes of blood pressure, the highs and the lows that show up, either because we think they are aberrations or because we think they are not representative of what's happening to the patient most of the time. However, emerging evidence really suggests that these variations in the diurnal pattern of blood pressure and also the visit-to-visit variability of blood pressure are not just noise, but actually may carry some prognostic importance.
I want to walk you through some of that data now. We'll start with this issue of circadian variation in blood pressure and its implications for cardiovascular risk. When I talk about circadian variation, we're really talking about the way in which blood pressure varies over the 24-hour cycle related to changes in our internal neurohormonal clocks. You can see that, in general, blood pressure is higher earlier in the day. The normal pattern of blood pressure variation is to dip during the night, as marked on the solid line. There is a phenotype, however, of patients who fail to dip during the night. This is a phenotype called non-dipping or even reverse dipping when patients become hypertensive during the nighttime. We know that these phenotypes also add granularity to our prognostication.
And the patients who fail to dip their blood pressure at night or those who actually increase blood pressure at night compared with the daytime have worse outcomes compared to those who have the normal diurnal variation. In general, hypertension at night is a bad thing. And if you look at patients who have any given blood pressure, measuring higher blood pressure in the nighttime hours compared to measuring that same blood pressure during the daytime hours is associated with an increment in risk. In general, when we look across large populations of patients with hypertension, and this is one meta-analysis of nine hypertensive cohorts, that nocturnal blood pressure increase is a more potent predictor of all cardiovascular events, coronary heart disease, and stroke than either the daytime blood pressure or the clinic blood pressure. And it's also the one where there is the most variability and dispersion over time.
And so this diurnal variation is important to pay attention to. And also, 24-hour blood pressure control becomes important for managing long-term cardiovascular risk. Now, more important than this short-term variability is likely the longer-term variability in blood pressure that we see between visits. And this is data aggregated over two large hypertensive cohorts looking at the impact on the risk of stroke according to deciles of standard deviation in the between-visit systolic blood pressure. And you can see that as the standard deviation of the variability between blood pressure measurement between visits increases, the risk of stroke increases quite steeply, such that those with the greatest variability have the highest risk of stroke and coronary heart disease events. This data from the VALUE trial makes that point even more firmly and now adjusts for a number of baseline risk factors.
You can see that even after aggressive multivariable adjustment in this population, there is that same graded association between visit-to-visit variability and overall risk. That risk persists after adjustment for risk factors for key cardiovascular risk factors and is particularly pronounced in patients who are in the younger age groups. Attention to variability of blood pressure, which has traditionally not been a part of our approach to hypertension management, is increasingly recognized as something that is important if we're going to leverage all of our science to improve clinical outcomes for patients with hypertension. I'm going to shift gears for a moment and now talk about this phenomenon of resistant hypertension, which has also emerged from the literature. Resistant hypertension varies depending on the context in which it's being discussed. The generally accepted definition is blood pressure that is uncontrolled despite at least three antihypertensive medications.
As you can see on the slide, there's considerable variability in the prevalence of resistant hypertension depending on the cohort that one has examined. Likely, somewhere between 15% and 20% of patients still have high blood pressure despite application of standard therapies. This is, again, another opportunity for intervention. Why might patients have resistant hypertension? One is just that the hypertension is just that bad, and escalating therapy is inadequate to control it. Another is that there may be factors that are driving hypertension that are structural features like renovascular disease or underlying neurohormonal excess. A big factor associated with the lack of control of blood pressure is also related to social and patient factors or even physician factors that are listed on the slide.
Patients with lack of health insurance or access to care are more likely to be poorly controlled, as are those who don't have access to a usual source of care, such as a primary care physician who can manage their blood pressure. Failure to make the hypertension diagnosis in the first place is a contributor on the physician's side, as is the reluctance to make medication adjustments during our clinic visits because we often have limited time or are reluctant to add medicines to the burden that patients have. Patients sometimes need education and may not have adequate literacy to understand the importance of blood pressure control. And once we prescribe medicines, either because of cost or because of side effects, sometimes patients don't take the medicines as we prescribe them, or they simply forget. Lifestyle modification is often preached but not followed in practice.
This issue of tonic control, which is critical to minimizing the diurnal variation and also the long-term variation in blood pressure, is something else that's likely missing in practice. This issue of adherence deserves special attention. We often don't think about this in practice. But the more medicines that we prescribe to patients, the less likely they are to take them. We know that medicines are only as effective as the ones that patients actually ingest. This issue of adherence to antihypertensive therapy deserves special attention as a factor associated with inadequate blood pressure control. This data from 41,000 Medicare beneficiaries initiating antihypertensive therapy over a five-year period highlights that over time, roughly one in five patients initiating on antihypertensive therapy discontinued that therapy prior to one year. Of those not discontinuing therapy, nearly a third maintained low adherence to therapy based on pharmacy prescription records.
This means that up to half of patients with treated hypertension are either not taking or are suboptimally taking their medications, which may contribute to the observed rates of poor blood pressure control. And this is important because, not surprisingly, if patients don't take their medications, then their blood pressure is not controlled, and the risk should be higher. And that's certainly observed in practice. This is data from 18,000 patients newly diagnosed with hypertension across 400 Italian primary care practices, looking at the risk of cardiovascular events as a function of the adherence to medication defined by pharmacy benefit records. And you can see that higher patient adherence to medication is associated with a 38% lower risk of cardiovascular events than low adherence to medicines.
And while this is not surprising, it girds the rationale for really focusing on the importance of medication adherence in our selection of antihypertensive therapy and in our follow-up of patients with hypertension in clinical practice. Factors associated with non-adherence are important to unpack. And many of these are related to the total burden of medication, since patients who have a lot of pills to take may not consistently take them all. It may be related to convenience factors. So if patients have to take meds multiple times a day, they may not remember to take every dose. Those of you who've taken a three-times-a-day antibiotic understand that missing a dose is not that easy, not that hard to do. There are behavioral factors which may contribute. There are adverse effects of medicines which may make patients more reluctant to take them.
In general, patients who are younger, those with socioeconomic factors that limit their access to care, and those who have comorbid illness, such as depression, are less likely to adhere. It's partly these factors, but also physician factors, that may contribute to the lack of control in the community. We can't ignore our own role as providers in the lack of control of hypertension in the community. This data sort of underscores that if you look at 42 million ambulatory visits with hypertension, only about 7 million of those patients in this large series were actually treated. You can see that that proportion of patients has improved over time, but it is not resolved.
This may be related to a number of factors that we could excuse away, including workflow constraints and time or lack of awareness of the importance of control or concerns about side effects or the desire to wait for additional blood pressure data. But nonetheless, there's a lot of unattended risk in hypertension management in the community, some of which we must own as providers. I'm going to conclude there and underscore in conclusion that there is a continuous and graded association between systolic blood pressure, diastolic blood pressure, and the risk of cardiovascular events. In general, when we control blood pressure, especially to more intensive targets, we are effective at reducing the risk of death, MI, stroke, and other cardiovascular events, including heart failure. Despite this knowledge, a large proportion of patients with hypertension are undertreated.
We see what is apparently resistant hypertension commonly in the community, some of which may be related to factors that are manageable, including patient adherence and physician adherence to guideline-recommended targets and medication prescriptions. Variability in blood pressure is an emerging target for therapy. Short and long-term variation is associated potently with risk and can be modulated with pharmacologic therapy. I think it's important to underscore that improving patient adherence is a major target for improving the control of blood pressure in the community and for reducing the profound disability-adjusted morbidity associated with hypertension in general. Thanks very much for your attention. I hope this has been useful as an overview and will lead you to understand the role of the hypertension development program at Alnylam a little better.
Thank you, Dr. Desai, and welcome to our listeners.
I'm Lauren Melton, the Program Leader of the ALN-AGT and Cemdisiran programs. Today, I will very briefly review the hypertension therapeutic area, our ALN-AGT program, and provide an update on our ongoing Phase I study in patients with mild or moderate hypertension. I will also provide an overview for the clinical development plan and commercial opportunity. As you've heard from others, we're very excited about the potential for ALN-AGT and the opportunity to reimagine the management of hypertension, a highly prevalent disease that has been devoid of new therapeutic intervention for decades. In 2017, the American Heart Association revised guidelines to reduce the threshold for hypertension classification from systolic blood pressure of greater than 140 and diastolic blood pressure greater than 90 to greater than 130 over greater than 80.
With those new thresholds, it is estimated that 108 million people in the U.S. have hypertension, and approximately 38 million are classified as being high risk for adverse cardiovascular events. The disease burden of hypertension is significant. Uncontrolled hypertension is the major risk factor for cardiovascular disease, morbidity, and mortality. Annually, approximately 1.5 million people in the U.S. suffer from myocardial infarction and stroke, with approximately half of these major adverse events attributed to hypertension. We've previously mentioned the recent Novartis announcement that the European Commission has approved Leqvio, or inclisiran, for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. The inclisiran development program was comprehensive, including over 7,000 drug injections and over 2,700 years of patient exposure, with a favorable safety profile and consistent and durable efficacy response with infrequent dosing.
We anticipate following in the footsteps of this important development program with a comprehensive clinical development plan setting a diverse patient population. ALN-AGT is an siRNA therapeutic targeting liver production of angiotensinogen, or AGT. We expect this liver-specific silencing to be differentiated from systemic antihypertensives, as the RAS in extra hepatic tissues is expected to be spared. Additionally, given the MOA of ALN-AGT, there is a durable pharmacologic effect resulting in a sustained and tonic blood pressure lowering over a long dosing period. Given the infrequent dosing, it is expected that ALN-AGT could address poor adherence, which is a notable unmet need in this hypertension therapeutic area. Polymorphisms in the AGT gene are associated with differences in cardiovascular health, and therefore, targeting AGT is genetically validated.
Our preliminary data from the Phase I have confirmed the proof of concept with dose-dependent reductions in AGT and clinically meaningful reductions in blood pressure. We also envision a clear regulatory pathway with a well-established and validated surrogate endpoint of blood pressure lowering, which is associated with improved cardiovascular outcomes. I will now introduce details for our ongoing Phase I study. The study is being conducted in patients with mild to moderate hypertension who are either naive to treatment or have washed out of their antihypertensive therapy. As such, ALN-AGT is being evaluated as a monotherapy in a real-world setting. The study is comprised of a single ascending dose period, a multiple ascending dose period in obese patients, and additional cohorts to assess safety and pharmacology when ALN-AGT is administered within the context of very low salt intake and when administered with standard-of-care antihypertensive medications.
The single ascending dose was comprised of seven cohorts testing a dose range of 10 mg to 800 mg. The dosing of the SAD cohorts has now completed, and we recently presented data at the American Heart Association in November, which included data from five cohorts and dosing up to 200 mg. The results I'm about to present include brand new data from two additional cohorts, including patients receiving single doses of 400 mg and 800 mg. Across seven cohorts that have been dosed to date, baseline characteristics have been generally well-balanced with median age in the mid-50s. Further, we have managed to enroll a diverse population, including both gender and racial diversity in each cohort. As per our design, baseline blood pressures have been within the mild to moderate range.
ALN-AGT has been generally well-tolerated to date, and the safety profile of ALN-AGT is encouraging for advancing into Phase II studies. Most AEs have been mild or moderate in severity and have resolved without intervention. There have been no deaths or AEs leading to study withdrawal and no treatment-related serious AEs. There has been a severe and serious AE of prostate cancer reported in a single patient who received 200 mg ALN-AGT. This was based upon a biopsy that was performed in the screening period and reported as positive after dosing. Importantly, no patient has required intervention for low blood pressure, and there have been no clinically significant elevations in serum ALT, serum creatinine, or serum potassium. The very few injection site reactions that have been reported have all been mild and transient. Single doses of ALN-AGT have resulted in dose-dependent lowering of angiotensinogen.
In the higher dose cohorts, we have observed AGT lowering of greater than 90%. The new data are quite impressive. Indeed, mean percent reduction for the 800 mg group at week four is 97.5%, with a range of 96.2%-98.4%. We're very pleased with the level of angiotensinogen knockdown observed at doses from 200 to 800 mg, and we're not aware of any comparable level of angiotensinogen knockdown reported for other modalities, such as antisense. These data are quite encouraging for the differentiated profile that we hope to achieve with ALN-AGT. The observed AGT lowering is also quite durable. AGT suppression persists through three months following single doses. And as you can see here, the higher dose cohorts continued to display substantial reduction through six months post-dose. These data are encouraging for a potential ALN-AGT dosing regimen of every three months or every six months.
Durability continues to be a distinctive feature of RNAi therapeutics that positions our platform extremely well as compared with small molecules, monoclonal antibodies, and antisense oligos. As previously mentioned, the results presented here include additional cohorts beyond the data that was presented last month at AHA. This also includes data through our highest planned dose of 800 mg that was tested in the SAD period of the study. There are several key takeaways from these new results. First, the dose-dependent serum AGT reductions have resulted in observed dose-dependent reductions of systolic and diastolic blood pressure. In cohorts receiving greater than 100 mg, we have observed clinically meaningful reductions of systolic blood pressure greater than 10 mm of mercury.
Notably, following single doses of 800 mg ALN-AGT as monotherapy, we observed mean 24-hour ambulatory systolic blood pressure reduction of 16.8 mm and mean diastolic blood pressure reduction of 9.1 mm of mercury. Second, these reductions have been observed eight weeks after a single dose administration, indicating that the pharmacologic effect is quite durable and is consistent with the observed durable AGT reductions. Third, these are encouraging results from a development perspective since blood pressure is expected to be the registrational endpoint pending regulatory agency consultations. Indeed, regulatory precedent suggests that systolic blood pressure reduction of greater than 5 mm is an important threshold that would be appropriate for regulatory agency approval if achieved in pivotal studies, and this threshold has been well exceeded here and in small cohorts of patients with generally mild hypertension.
Further blood pressure reductions may even be possible in cohorts of patients with higher baseline blood pressure values. Lastly, the blood pressure reductions noted in the highest dose cohort exceed or are at the higher end of the range of blood pressure reductions reported for monotherapy clinical studies of potent ARBs, which is quite encouraging for the target product profile of ALN-AGT. In clinical pharmacology analyses, we have also generated model data that suggest a clear relationship between AGT reduction and blood pressure lowering, and as you can see here, substantial reductions of AGT greater than 90%-95% are predicted to result in clinically meaningful reductions in systolic blood pressure of approximately 8 to 12 and in diastolic blood pressures of approximately 5 to 7 mm of mercury.
Importantly, these modeling predictions have been validated by our observed clinical data, and these clinical pharmacology results are important as we select doses for our Phase II studies. A long-acting antihypertensive is expected to have significant value across a broad spectrum of patients and disease severity, given the well-established poor adherence in this area. Further, an antihypertensive that achieves tonic control of blood pressure would be expected to improve clinical outcomes such as cardiovascular morbidity and mortality. We are currently considering development and commercialization options across a diverse population, including a population of patients with high CV risk, a broad population of patients with primary hypertension that have difficulty controlling their blood pressure with current standard of care, and we are also beginning to think about the potential to treat patients at high risk for developing hypertension and initiating treatment prior to progressive disease and vascular damage.
Our overall strategy for development of AGT is to enable optionality for future commercialization of ALN-AGT across a spectrum of hypertension patients. As we move into Phase II and beyond to Phase III, we expect to study a more diverse patient population, including patients with comorbidities and more severe hypertension. Gaining experience in patients with some degree of cardiovascular risk during development will be important, given this is the population that we expect to include in our cardiovascular outcome study. Importantly, in Phase II, we will characterize the safety and efficacy of AGT monotherapy across a range of doses and dose regimens. And we also plan to study ALN-AGT when used in combination with an ARB, with the goal of establishing additive efficacy and acceptable safety.
To expand upon our overall development strategy, we expect to initiate Phase II studies in the middle of next year, and I will discuss those studies in greater detail in a moment. We expect to study up to 1,000 patients in our Phase II program across these two studies. We then expect to initiate two Phase III programs that will likely include patients categorized as high cardiovascular risk, and we'll also study patients with primary hypertension across a wide spectrum of disease severity. Importantly, we do not anticipate that a cardiovascular outcome study will be required for regulatory approval. However, we are considering this type of post-approval study to ensure optimal commercial positioning. We are excited to advance our ALN-AGT program into the next stage of development, and today we announce our plans for the Phase II KARDIA studies, which we expect to initiate in the middle of next year.
KARDIA-1 is a planned study to evaluate the safety and efficacy of ALN-AGT monotherapy doses and dose regimens. At this time, we expect to test dose regimen frequencies of three and six months. KARDIA-2 is a study that will evaluate the safety and efficacy of ALN-AGT when used in combination with angiotensin receptor blocker standard of care. We believe these studies will further establish the safety and efficacy profile of ALN-AGT, and if results are positive, we will be well-positioned for advancing into Phase III studies of much larger and diverse populations. Importantly, KARDIA-2 will provide renal safety data for ALN-AGT combination with RAS inhibitors, which is essential for informing further Phase III development. I will now review the global commercial opportunity for ALN-AGT. When considering the future commercial populations for ALN-AGT, we consider the two patient segments that I previously described.
The first patient segment includes patients with uncontrolled blood pressure at high risk for major adverse cardiovascular events. We have estimated the U.S. prevalence of this population to be approximately 38 million people, of which approximately 20 million have uncontrolled blood pressure. The population is defined as patients with a cardiovascular risk or a previous medical history of cardiovascular events. The current treatment landscape in this therapeutic area is dictated by well-established treatment guidelines, with differing classes of medicines being prescribed based on hypertension severity and specific comorbidities the patients may have. As many of these patients are taking medications to address multiple comorbidities, pill burden is significant, and adherence is often suboptimal. Lack of adherence is of utmost concern in patients at high risk for cardiovascular events, where uncontrolled blood pressure can lead to poor clinical outcomes.
An antihypertensive medication with tonic blood pressure control and infrequent dosing could be advantageous in treating this population. The disease burden of hypertension is significant. Uncontrolled hypertension is the major risk factor for cardiovascular disease, morbidity, and mortality, and annually, approximately 1.5 million people in the U.S. suffer from myocardial infarction and stroke, with approximately half of these major adverse events attributed to hypertension. The burden of hypertension and healthcare costs is also quite significant. Annual direct and indirect costs of hypertensive disease and stroke are estimated to be approximately $55 billion and $45 billion. While only approximately half of the stroke costs are attributed to hypertension, additional healthcare costs are incurred due to hypertension within the broad category of heart disease.
Given the unmet medical need for treatments that provide further blood pressure reduction that is durable and less variable in patients at high risk for major adverse cardiovascular events, we estimate ALN-AGT to achieve revenues that are greater than $4 billion at peak. The market for broad hypertension treatment is also significant. 108 million patients in the U.S. have hypertension, and despite the availability of multiple classes of antihypertensive medications, approximately 75% of hypertensive patients do not achieve controlled blood pressure. The general treatment paradigm and disease burden are the same as described for the high CV risk population. However, given the endemic adherence issues that are associated with uncontrolled blood pressure in primary hypertension, ALN-AGT has the potential to be a foundational antihypertensive medication that could be infrequently administered and provide sustained and durable blood pressure lowering in patients that have difficulty in achieving optimal blood pressure.
Given this, we believe that ALN-AGT could be a greater than $4 billion market opportunity at peak. In summary, there is significant unmet medical need for treatment of hypertension in patients with uncontrolled blood pressure. Importantly, sustained blood pressure control with infrequent dosing could benefit patients with difficult-to-treat hypertension or patients at risk for cardiovascular events with uncontrolled blood pressure. Initial data from our ongoing Phase I study in patients with mild to moderate hypertension are encouraging. The safety and tolerability profile continues to be favorable and is supportive for advancing into larger populations in Phase II. A greater than 15 mm mercury reduction in mean 24-hour systolic blood pressure has been observed in the cohort of patients receiving 800 mg. Mean systolic blood pressure reductions of greater than 10 mm mercury have been observed in cohorts receiving greater than or equal to 100 mg of ALN-AGT.
Importantly, these reductions are considered clinically meaningful. The pharmacologic durability is supportive of once-quarterly and potentially biannual dosing. Additional clinical data are expected to be presented at a scientific congress in 2021, including data from patients receiving ALN-AGT in combination with angiotensin receptor blocker. Lastly, the next development milestone includes initiation of two Phase II KARDIA studies in the mid of 2021. In those studies, we will explore the use of ALN-AGT both alone and in combination with standard of care antihypertensives. Thank you for listening, and now I will turn the discussion over to our CEO, John Maraganore, for the Q&A portion of this presentation.
Thank you, Lauren. We are now going to go into our Q&A session. As many of you can cover over the next 45 minutes, the plan here is to end around noon.
The first question is on the hATTR program, and specifically with regard to vutrisiran and the HELIOS-A study. The question is, is the plan to file the NDA on vutrisiran in hATTR polyneuropathy on nine-month HELIOS-A data in 2021 and later submit 18-month data? That's a question I think that should go to John Vest. John.
Yeah, thanks, John. We plan to file an NDA based on the month nine data, and as previously aligned with the EMA, we will file an MAA based on the month 18 data.
Great. Thank you, John. Akshay, anything more to add on that from an overall regulatory strategy standpoint?
No, I think John covered it. We're excited. We're on track to do that, and it'd be great to file next year.
Yeah. The only thing I would add is, obviously, we're very much looking forward to these results.
They'll be happening in the early part of next year. And obviously, one of the important points that Akshay brought up about HELIOS-A is the fact that there will be meaningful cardiac data collected in that study, and we'll have some of that at nine months and then the bulk of it at 18 months later in the year. So we'll look forward to reporting those data in addition to the primary endpoint data, which is focused on polyneuropathy. Okay, so let's go to the next question. This I think will go to Yvonne and maybe Andy Orth, who's joining us on the panel. Why is the home infusion of ONPATTRO so much more widely accepted in the EU versus the U.S., and what barriers are you encountering?
Yvonne, do you want to start, and then maybe we can go to Andy as well?
Yeah, no, that's a great question. We've seen growth in ONPATTRO home infusion in both the U.S. and Europe since launch, and some of that is obviously driven by the pandemic: 20% in the U.S., 36% in Europe. In the U.S., home infusion is driven by the payer and is largely available actually with commercial payers, but isn't covered by Medicare, which is, of course, what covers most ONPATTRO patients. The levels are higher in Europe, but it's not uniform across Europe, and it's higher in some markets than others. France stands out as a market where rates are slightly higher. I mean, we're delighted to see these levels of home infusion, I think, as a testament to the support that we've been able to provide patients, particularly through the pandemic.
Great.
Andy, anything to add? Maybe you could talk a little bit about barriers on this front as well.
Yeah, in the United States specifically, the largest barrier is, in fact, Medicare and the lack of coverage there. On the commercial book of our business, roughly a third of our patients, we've had wonderful success moving patients to home infusion when they have interest in it. So this is something we've been pushing with CMS as well to get this covered, but we're not there yet. So more to come in the future here.
Yeah, absolutely. Good. Thank you, Andy. Okay, next question, which I think will go to Philip Hawkins on this issue and maybe John Vest as well. How cheap are technetium scans for TTR these days? How widespread is the availability, and what is currently being done by Pfizer and Alnylam to promote scanning?
I think I'll leave that last part for Andy Orth. But Philip, do you want to comment on TTR scans?
Sure. I mean, in Europe, we're using DPD tracer. It is just a bone scan imaging agent. Pretty much every hospital has got nuclear medicine gamma camera facilities, so it's widely available. It's cheap. The cost is probably less than $200, I think, per scan. An issue in Europe is that there isn't any reimbursement specifically for DPD scintigraphy, but that has not stopped many, many dozens of centers in the U.K. rolling this out.
And Philip, anything on the U.S. or maybe Andy, you can comment on the U.S. costs for technetium scans and also what's being done to promote?
Yeah. Sure. Sure, John. The cost is certainly not a barrier in the United States. It's a couple few hundred dollars per scan we find.
And certainly, the volume of those scans that we see occurring via claims data and other has continually increased quarter over quarter steadily since as far back as 2017. And it's in the best interest of all companies interested in helping with TTR that we continue to advocate for that. And we're seeing an increase in the number of these scanning techniques and/or devices across the country.
I could just add that actually I think this is an area where it's really helpful to have more than one player in the market driving efforts around diagnosis. I think we've always said this is a market growth rather than a market share story for patients with TTR amyloidosis. And I think it's just wonderful to have seen the growth in use of PYP scans that we've been able to demonstrate over the last period of time.
Yeah, absolutely. That's terrific.
Okay, next question is also on TTR. And this would be good for Philip. Is MRI-based cardiac TTR load being done currently to measure efficacy of tafamidis therapy?
Well, I mean, we're certainly doing that in our routine clinical setting. So every patient who's on tafamidis or indeed any other therapy for TTR amyloidosis is undergoing this quantitative MRI to measure the amyloid load in the heart. And it is being performed as sub-studies in, I think, all of the trials of the various agents being tried for cardiomyopathy.
Yeah. And you said it there, Philip, but maybe John Vest, do you want to confirm that we are doing cardiac MRI in the appropriate studies, the APOLLO-B and the HELIOS-B studies?
Yeah, thanks, John. We are indeed looking at cardiac MRI in APOLLO-B. It is not part of HELIOS-B, but we are looking at it on APOLLO-B.
I think back to the question of tafamidis. We can comment that in addition, of course, to looking at the effect with vutrisiran on that study and the placebo arm for patients who are on concurrent tafamidis during the study, we'll be able to collect data on the tafamidis impact on these measures in that study as well.
Okay, terrific. Okay, next question. John, you may be the right person to ask this here. Will TTR knockdown and safety data be sufficient to support a Q6 monthly profile, a biannual dosing profile for vutrisiran? And have you talked to the FDA on that?
Yeah, thanks, John. We have indeed had interactions with the FDA, and we do believe that TTR knockdown and safety data should be sufficient. And we do not anticipate needing to do an additional trial of clinical efficacy with that alternate dosing regimen.
All right.
I will comment that we announced this morning that we plan on starting that dosing regimen investigation in the early part of next year. So very much on track for doing that. Akshay Vaishnaw, anything else to add on this point from your perspective?
No, I think you guys covered it. We're very confident about the ability to go to Q6 monthly modeling. Clinical pharmacology modeling is so supportive in our work because of the consistency of how our RNAi therapy is performing. So I think we'll be able to achieve that, as John best described.
Yeah. And Andy Orth, do you want to comment a little bit on how we look at a Q6 monthly regimen in the market out there?
Yeah. We're finding that that frequency of visit to the physician is what is happening today.
We think this fits in perfectly with how they're managing the disease once they're diagnosed. It'd be exceptionally convenient.
Terrific. Terrific. Okay, let's go on to the next question. Can you discuss any thoughts around why the ALN-AGT 400 mg dose systolic blood pressure reduction is more similar to 200 mg than 800 mg? Lauren, do you want to answer that?
Sure. Thanks, John. These are relatively small cohorts. The single ascending doses that have been studied, there were an N of 8 in each cohort that received ALN-AGT. So we actually went into this study expecting to see quite a bit of variability, which we have seen variability across the multiple cohorts.
But we're actually quite encouraged that we have been able to see these dose-dependent reductions in both AGT and blood pressure, given that these patients are also being evaluated in an outpatient setting in relatively small cohorts.
Yeah. Akshay, anything else to add to that?
No. I mean, I was very surprised how robust and reliable the findings are as we dose ascend it and gives us a clear direction for further dose regimen exploration in Phase II. And very exciting to have Phase I POC in the approvable endpoint that we will use in Phase III. So I think this is a very exciting development for us.
Yeah. And obviously, we're really thrilled with the latest data that we reported today around an over 15 mm of mercury reduction in systolic blood pressure, which we clearly think shows ALN-AGT to be the best-in-class approach that is out there.
Okay, next question. This might be good for Andy Orth. How do overall U.S. VBA discounts (those are value-based agreements), especially at the max level, compare to the Medicaid discounts?
Yeah, great question. To date, the VBA discounts we've paid out have been relatively small, and that's due to the value-based construct and the excellent experience patients are having on ONPATTRO. So relative to a Medicaid flat discount of the 23.1, etc., we're quite far away from that, and happy to say.
Terrific. Terrific.
John, maybe if I can just add that all our VBA s have a floor that sets at the price for Medicare and Medicaid, so we don't trigger best price, etc.
That's right.
Of course, we're really pleased with nearly 30 or 30 VBA s that we've put in place because it has obviously been a great way to work with the payer community around risk sharing and around having a responsible approach to pricing these types of orphan medicines. Some of the innovation that we've introduced with prevalence-based adjustments and patient need adjustments with GIVLAARI and OXLUMO are being applauded by the payer community. That has been terrific. Okay, next question. How soon should we expect vutrisiran launch if positive mNIS+7? So that would be a good question, John Vest, for you and Andy and Akshay to answer. Will vutrisiran pricing in hATTR -PN be similar to ONPATTRO? And how do you plan to roll out vutrisiran? Yvonne and Andy, you guys should answer that. And will pricing be different for ATTR -CM?
So let's start first with vutrisiran launch if HELIOS-A is positive. Do you want to comment, John Vest?
I actually wonder if Andy might want to comment on that.
That's fine. Yeah, Andy, go ahead.
Yeah. We're prepared to launch vutrisiran in the second quarter of 2022 should we see positive data in the interim at this point in time.
Terrific. And that obviously means filing the NDA in early 2021 based on the results of the HELIOS-A study if they're positive, and then going through a standard review, which is the assumption on timing for that. Next question. This could be.
John, just to add that, of course, Andy's group and others in our commercial organization showed great agility. But if we have a faster review, then I know Andy at the table will be there much earlier, as we did with GIVLAARI, for example, last year.
Absolutely. Indeed.
Indeed. Good question. Will vutrisiran pricing in hATTR-PN be similar to ONPATTRO, and how do you plan to roll out vutrisiran? Let me just start by saying it's obviously too soon to be specific on pricing with regard to vutrisiran. But Yvonne, do you want to start that question? And then the follow-on question on that is, will vutrisiran pricing be different for ATTR-CM? So maybe Yvonne, you and Andy can handle both of those.
Yeah. And I'll start just to kind of add to your comment. Clearly, too soon to talk about pricing. But we have had VBAs, our value-based agreements, as a critical component of how we have thought about access for our medicines. And we will continue to do the same with vutrisiran and think about ensuring that we have a value proposition that is meaningful to both patients and payers.
Andy, is there anything else that you want to comment? It is a little early to be talking about pricing of vutrisiran at this point in time.
Yeah, I think you've said it. Our intent is to be as progressive and innovative as we have been today with the first three launches. And we're in dialogues with large commercial payers today to help partner with them and listen to what their needs might be as we expand this TTR franchise over the next couple of years. It's pretty exciting.
Yeah, absolutely. Good. All right. A couple of questions on AGT, actually a few. So do you think AGT data support Q6 monthly dosing? Do you want to handle that, Lauren?
Sure. In the ongoing Phase I, we're actually seeing quite good AGT reductions, which have to date corresponded to blood pressure reductions.
We're very encouraged that we could at least achieve a Q3 month regimen with potentially a Q6 month regimen. Importantly, in our Phase II, we intend to assess both regimens, Q3 month and Q6 month, with the ultimate goal of aligning on a regimen that will provide flexibility for patients.
Yeahh. Akshay, anything to add to that, perhaps?
No, Lauren covered everything.
Okay. Then the next question is pricing of a drug like ALN-AGT. Andy, do you want to handle that question?
Sure. Again, we're going to leverage the tremendous success we've had in access via our progressive approach on a value-based agenda here on the rare disease products and take that to a more prevalent market. Now, clearly, we understand this is a more prevalent market, and we're going to have to distinguish ourselves a little bit on pricing from what we've done in the past.
But we believe our value-based approach will find success here as well as it has in the rare diseases.
Yeah. Terrific.
If I can just add that, obviously, we'll be closely watching the Leqvio launch and innovative approaches that they may use commercially. We already know that they have this partnership with the U.K., which is an agreement that's at a national level. And these could be innovative approaches that we could look to consider for a drug like ALN-AGT in such a large disease area.
Yeah. And to that point, I think it's a really excellent one on how Novartis is partnering with the NHS. I think those types of access arrangements with single payers like in the U.K., but also with system providers here in the U.S., is something which we are quite keen on exploring.
It certainly is a big part of the future, no doubt about it. So that'll be certainly a factor into our thinking about AGT. All right. Lauren, next question, I think, for you. You commented a little bit about FDA and 5 mm mercury reduction and systolic being the bar for approval. The question is, what are the implications of this? Would you want to pursue multiple dose approvals for ALN-AGT? So maybe you could start. Maybe Akshay, you can comment as well.
Sure. To clarify, we have not yet had specific discussions with FDA about what would be an appropriate package for our own approval. It's really based on regulatory precedent for other agents that have been recently approved in the hypertension space. That being said, going forward in the future, as I mentioned, we will study multiple doses and dose regimen in the Phase II.
And from those data, we will select appropriate doses to take into Phase III, which may, in fact, include multiple dose levels and/or regimens to provide patients flexibility in the future.
Yeah. And Akshay, anything to add to that?
Yeah. And the 5 mm of mercury threshold is a kind of minimal threshold that we know even from the existing data that we can do far better than that. To provide maximum benefit for patients and flexibility for physicians, as Lauren just laid it out, I think we're going to have a pretty comprehensive Phase II that will show the true extent of blood pressure reduction we can achieve. You mentioned more than 15 mm of mercury for the benefit of patients. So I think the 5 mm is the lower bound.
Yeah. And as a reminder to everybody, all the data we've shown so far is with monotherapy.
Obviously, we'll be exploring combination therapy, both as a cohort in the Phase I shortly, and then, of course, in the cardiac studies, the Phase II studies. Question here on Akshay for you. What are the potential applications of Reversir technology? Maybe you can explain what Reversir technology is as well.
Yeah. In short, the Reversir technology is our Alnylam proprietary technology to switch off the RNAi effect once one of our drugs is on board. I won't get into the molecular biology of it, but we've published extensively, and we've reliably done it with a range of targets in animal settings. We know we can deploy it. Now, at the present time, it's not deployed against any particular program, but we always thought it was prudent to have that available.
For example, if we look at the current pharmacological milieu, we know that for antithrombotics, whether you're looking at heparin or warfarin or the new Xa inhibitors, there are ready reversal agents. So in certain therapeutic areas, you do want access to reversal agents that stop the action of your drug efficiently. We have that. We need it. We also know, by the way, from the animal work that we can turn it off, and then once we want to turn it back on again, we can readminister the drug, and we can reattain the drug effect. So it's great to have the tool in the box as yet as no program designated. I mentioned hematology is a general area. Obviously, the hypertension area is another one that we'll have to think about.
But this would be done very much in partnership with clinicians and with regulators as we develop some of these programs should the need arise.
Yeah. Terrific. Okay. So let's move on. This is a question, perhaps, Akshay, you could start maybe talking about it more broadly, but then Professor Hawkins, you can comment as well. I'm curious about how you're thinking about early gene editing data in primates for TTR, and if that were promising, how that might affect your current franchise. So Akshay, do you want to comment to start?
Yeah. Look, the gene editing area is obviously a very, very exciting area in terms of the implications for human health. Nobel Prize this year, terrific recognition of that landmark science. Ultimately, I'm sure drugs will follow from this approach in the appropriate setting. Risk-benefit is always the ultimate yardstick.
Now, as we look at the TTR space and look at what we're developing, once every six months, subQ, convenient, effective, and seeing reversal of disease as we did with ONPATTRO and hATTR-PN. I think we anticipate seeing that in other settings in the ATTR space. That seems pretty user-friendly, safe. With that, with the upcoming studies. Once that's there, I don't know how that leaves the gene editing approach, which is a genome-modifying approach in a disease setting where there are going to be multiple safe and effective therapeutics. And then there are other issues such as how to exactly develop a drug like that. We've had to do active comparator studies, for example, against vutrisiran. And from a safety perspective, it's a new science, and it's a genome-altering science. So again, in this kind of setting, there are questions to answer there, I would have.
And that's not to get into other issues like pricing, etc., which I won't comment on. But I think it's an exciting area of science. Whether it fits in the TTR space or not, for some reason that I've said, I'm not so sure. But it's great that it's progressing, and I'm sure it will impact certain diseases.
Yeah. Philip, do you have some view on this as well? You might want to add?
Yeah. Just one word. Scary. Perhaps a little bit of TTR is good for you. We don't know what the dose and the effect will be with gene editing. And I echo what Akshay has said, especially if we've got a six-monthly subcut injection. I would kind of like to see this being done in somebody else's patients first.
And I say this in addition, John, in the area of science and pharmacology, we're going to want to understand the dose dependency. Does it wear off? I mean, we've heard recently with gene therapy directed to the liver that there's waning of the effect over time. Now, we don't know what will happen with stem cell renewal of the liver, if hepatocytes are created, but they all have the deletion or not. So there's a lot to be worked out if this is going to be a TTR space. And as Philip said, safety is and then into the benefit. I think there'll be a plethora of agents that provide a lot of.
Okay. Very good. Okay. Next question. Maybe this is for you, Lauren.
Can you clarify whether KARDIA-2 will only include combo with an ARB, or will it also include ACEs and other standard of care?
The KARDIA-1 and KARDIA-2 studies are not fully finalized internally yet. We are currently evaluating multiple options for KARDIA-2. We are prioritizing studying ALN-AGT with an ARB, but we are also considering potentially other agents where we would be testing ALN-AGT in combination with those agents. Importantly, we expect to continue dosing these patients in open-label extension periods from the completion of the study all the way through approval, where we will also allow use of additional agents. So we will gain experience with other classes of medications.
Right. Akshay, anything else to add to that?
I think Lauren covered it comprehensively. Thank you.
Great. Okay. Question for you, Akshay here.
You can start, and maybe I'll have a comment at the end. What do you expect an oral dosing regimen would look like in humans based on your NHP data?
Yeah. Currently, both rodent and non-human primate data give a very robust and reliable readout of administration. We get the same potency or similar potency that we've seen with the subcutaneous approach. We see the same durability. And you would expect that, actually, because once the siRNA is in the hepatocyte, it doesn't matter how you got it there, either via the subcutaneous route or oral route, it would have that kind of potency. So I think in the ultimate, in the right indications, it will be a low dose, infrequent, once every three or six months, something like that type of dose and regimen. So I think another very exciting direction for us is going to be.
Again, many of the indications we're in. I don't know that there's a need to develop them orally, frankly, given the unmet need in the current situation. But it's great to have that flexibility, especially as we get to larger market indications.
Yeah. I would just add, it's an interesting question when you've got durability that's two to six monthly for medicines as to whether or not you'd even want to be bothered by oral, which might need to be more frequent. So it'll be an interesting question to find the real killer app for that application given the profile. Obviously, if you have a modality, and this may be the case with ASOs where you have to give it weekly, there might be some benefit with oral.
I think once you deal with a durability profile like you have with RNAi, it's hard to be overly excited by what oral might bring. I don't know, Yvonne, if you have anything to add to that as well.
No, I think you've actually covered it very well.
Good. Okay. Let's go back to the questions then. Regarding TTR, you previously mentioned substantial combination use of ONPATTRO with tafamidis by clinicians. How do you consider the value in terms of establishing global reimbursement and competitive positioning of a formal combination study of vutrisiran, ONPATTRO, or ONPATTRO with a stabilizer to establish the plausibly best-in-class regimen as on label? Maybe, Akshay, you can start with that, and then John Vest can comment as well.
I think there's obviously a lot of experience developing in the field.
I think in the form of the HELIOS-B studies, we're going to get a lot of understanding of the safety of the two agents in combination with a stabilizer and a TTR silencing agent. And within the context of the HELIOS-B studies, if we look at the different groups, there could be informal comparisons of the outcomes of combination approaches. I still think, and as I think Professor Hawkins outlined very elegantly, the most potent approach to systemic amyloidotic disorders is to reduce the level of the pathogenic protein. And as we showed comprehensively with ONPATTRO in the hATTR-PN setting, although there were no head-to-head comparisons, I think most people interpret the data across the different agents as ONPATTRO is the best by far and gives patients the most benefit based on the published results.
Now, I think we expect that we'll have the best approach using TTR silencing to the cardiomyopathy settings. Let's look at the data. But these different avenues of data analysis will be there. And certainly, there'll be a lot of experience with the combination.
Okay. Terrific. Anything to add to that, John Vest?
No, nothing really to add. I just absolutely agree that on the current cardiac studies, as Akshay has pointed out, we're allowing concurrent tafamidis, and I really think there'll be a lot of information that we'll be able to gather from those experiences.
Okay. I mean, John, maybe I can just add that the markets are very different in the U.S. and the rest of the world. And I think the combination use that we're seeing, 15%-30%, is based on ONPATTRO use in the U.S.
Outside the U.S., we're seeing patients come from switching from tafamidis. And I also think it's important to note that in the here and now, we're seeing good physician enthusiasm for the combination approach, and we're seeing no payer headwinds. So I thought it was helpful perhaps to make some points about the current situation as well as what we might consider and explore in future studies.
Okay. Terrific. Next question for Professor Hawkins. Question is, I was very impressed by your recent publication highlighting regression of cardiac amyloid with vutrisiran treatment. I imagine you have some imaging data from clinical practice on how cardiac amyloid levels change in patients on tafamidis. What is your sense of how the regression of cardiac amyloid looks in patients who are on tafamidis and how this compares to your recent results with vutrisiran?
Okay. Thanks, John.
I mean, the actual answer is we don't have that information. And the reason we don't have it is that NICE did not support the reimbursement for tafamidis, either for neuropathy or cardiomyopathy. We do have a cohort of patients who began to take tafamidis in the early access scheme, and we are tracking them with CMR. Over a much longer period, going back more than 10 years, we have been treating patients speculatively with diflunisal, which in our own laboratory experiments appears to be just as good a stabilizer as tafamidis. And we have never been—we've never documented regression of the cardiac amyloid deposits. So I'm not so optimistic.
Thank you. Thank you, Philip. Okay. Next question. For HELIOS-B, what may trigger the optional interim analysis? Do you want to start with that, Akshay, and then maybe John Vest can comment?
Yeah.
There are a number of good options for HELIOS-B in terms of the interim analysis. Certainly, we could look at six-minute walk distance. We could also look at the composite ONPATTRO hospitalization. I think a lot of it rests on the dynamics of involvement and how quickly things go. In our experience in the past, if the involvement is very fast, then the timing between the interim and the final result becomes really tricky, and it's not worthwhile to do the interim, and so if involvement's going well, we certainly think slowing down a little bit during the early COVID period, but it picked up very nicely, so we're going to continue to monitor the dynamics. At the current time, we are making provisions to do an interim because let's see how involvement goes in the finality.
And we will release more information about the interim analysis approach based on the kinds of options I suggested just now in June 2021.
Great. Anything else to add to that, John Vest?
Yeah. I guess the only thing that I'd add is that importantly, we'll have results that are emerging from our other ongoing studies that I think will help to inform the most appropriate strategy here. So information that's coming out of HELIOS-A and then APOLLO-B can help inform our strategy.
Great point. Terrific. Okay. Question here on hypertension. For ALN-AGT, can you offer any thoughts, perhaps based on preclinical studies, on what incremental blood pressure lowering would you expect on top of multiple antihypertensives, oral antihypertensives, I assume? Lauren, do you want to handle that?
Sure. So we actually have explored using ALN-AGT in combination with ARB in non-clinical models.
We've used it in the gold standard model, the spontaneously hypertensive rat, and we've published those results in June of 2019, where we saw very good reductions with siRNA alone and also synergistic blood pressure reductions when used with the ARB. And while those data were really encouraging, both from a pharmacology and a blood pressure perspective, but also based on some of the limited renal assessments that we had done, we do think that this needs to be further evaluated in the clinical setting in humans, and it's very challenging for us to predict what sort of additive benefit we might see.
Yeah, and just as a reminder, we'll be doing a cohort as part of our ongoing Phase I study that'll include combination and then formally evaluating that in the Phase II study. Is that right, Lauren?
That's correct. Yes.
Great. Terrific. Okay. Question here for Philip.
Why is vutrisiran but not inotersen associated with cardiac benefit in the slides you presented earlier?
Sure. Thank you. I mean, I believe this is easily explained by the differing degrees of knockdown with inotersen associated with perhaps 75% knockdown and vutrisiran 80%-85%. There is substantially more of the toxic protein remaining in the inotersen patients. And further, in our real-world clinical use, many of the inotersen patients have had multiple periods of treatment due to thrombocytopenia. So we're certainly in the real world seeing more sustained knockdown with our vutrisiran patients.
Terrific.
John, I would just add to that that in terms of cardiac benefit from vutrisiran, we should recognize that in the European setting, some of those data were incorporated in the label in terms of the biomarkers, the echo, etc.
In the U.S., of course, the regulators were very excited, and we had a productive conversation around those. They're not in the label currently with the indication being hATTR. But I think it's that excitement that led them to encourage us to do the HELIOS-Bs and certainly APOLLO-Bs. And we look forward to providing comprehensive cardiac benefit data so that we can have a U.S. label that reflects that as well.
Yeah. Terrific. Okay. Maybe a question here for John Vest. What are the key disease manifestations of interest in the planned HELIOS-C trial? And what is the potential trial size? John, do you want to comment?
Yeah. Thanks, John. We are really excited about HELIOS-C, and we're excited to announce that today. This is an area of intense interest and ongoing discussion.
I think it's premature to speak about any of the specific details around the study design, but we'll certainly share those as appropriate as we proceed through the year.
Terrific. I mean, Philip, do you want to comment a little bit on how you imagine a study like this in light of your experience, your clinical experience?
I mean, what I would say is that by the time patients are currently being diagnosed with heart failure, i.e., the type of patient who is being studied in HELIOS-B, there are huge amounts of amyloid in the heart. And in the U.K., we can look back at centralized NHS data, and we can see that a year or two before, something like 30% of patients have developed atrial fibrillation.
In fact, 10% of patients have had a stroke in the three years before they have developed heart failure symptoms. So we know this is a progressive disease. We know that currently, patients with heart failure symptoms are at a very advanced stage, and we would plainly like to stop progression and hopefully reverse the disease at a much earlier stage, possibly or probably. We would like to do that before any symptoms have developed.
Terrific. So I think we have time for one more question, and I'm going to ask one to Yvonne. Yvonne, and maybe Andy, you can comment as well. But Yvonne, you should answer first. When you're thinking about the global footprint looking to 2025 with your current direct and distributor markets with now three approved products, how are you thinking about the Asia markets ex-Japan, for example, Australia? Do you want to comment, Yvonne?
Yeah. That's a great question. I mean, look, when we've talked about growth of our business, we've talked about the efforts that we make around patient identification. We've talked about generating new data. We also speak to growing our opportunities through new markets. And so we're open to continuing to expand our global footprint where it makes sense. I think Australia is an interesting market to consider. We're also very thoughtful about the growth of our SG&A. And we plan to grow revenues, of course, ahead of costs. So a lot of thoughts going into this, and we will be planning to potentially introduce additional markets over the next several years.
Yeah. And of course, a very important market for the future is China. And we can speak to China. You just went high level, Yvonne. Yeah.
No, China is a fascinating market, and we're spending quite a lot of time looking at it. I mean, clearly, large numbers of patients that could benefit from our RNAi therapeutics. And clearly, we want to serve patients in that geography as well. It's a very complex market, and there are a number of different market entry models that we continue to review. So China is something that's definitely on our radar. But again, a market where I think you have to be very thoughtful as you look to access that part of the world.
Yeah. But we are very proud to be going into Taiwan directly. And we have a team in Taiwan directly and expect approval in Taiwan imminently as well because that has been filed. So listen, with that, I think we are at the top of the hour.
It's been an exciting morning, and we have more coming tomorrow. So encourage everyone to join us and participate. We'll be doing a deep dive on our NASH program, a deep dive on some of our early and mid-clinical and some preclinical programs in the liver, which I think will be quite interesting to people. And then also the exciting presentation around extra hepatic delivery with our CSO, Kevin Fitzgerald. So we're going to have quite a day tomorrow as well. We'll also have a panel discussion tomorrow in addition to those presentations. Jeff Poulton will also present an update on our progress towards self-sustainability from a financial profile perspective. So it's been a great day. I look forward to tomorrow and want to thank all of our panelists and all of our presenters and all of you for participating.
Talk tomorrow, and have a good rest of the day and good evening. Bye-bye. Bye-bye.