Good morning, everyone. I'm Chris Brickley, Director of Investor Relations at Alnylam, I'm pleased to be kicking off our 10th RNAi Roundtable series this morning. Throughout these events, we aim to highlight a few of the exciting programs in our pipeline that represent some of the next wave of transformative medicines we expect to deliver from our RNAi platform. Today, we'll be covering ALN-6400, which is an investigational therapy targeting plasminogen with the potential to address rare bleeding disorders. Today's event is expected to run approximately 75 minutes.
Pushkal will moderate a question and answer session at the conclusion of the presentations. If you'd like to submit a question, you can do so at any time during the event by typing your question in the Ask a Question field located within the webcast platform. As a reminder, we will be making forward-looking statements during this webinar, we encourage you to read our most recent SEC filings for a more complete discussion of our risk factors. With that, I'd like to turn it over to Pushkal Garg, our Chief Research and Development Officer. Pushkal?
Thanks, Chris, welcome everyone to today's roundtable on ALN-6400, which we believe represents a potentially transformative RNAi therapeutic for patients living with rare bleeding disorders. With me today are two accomplished scientists who embody our world-class R&D capabilities, John Gansner, a hematologist and executive director, and the program lead for the ALN-6400 program, and Martina Slingsby, senior clinical scientist, and ALN-6400 clinical science lead. We're also delighted to have with us today Dr. Hanny Al-Samkari. Dr. Al-Samkari is Associate Professor of Medicine at Harvard Medical School and co-director of the HHT Center of Excellence at Massachusetts General Hospital. He's a globally recognized authority on HHT and other bleeding disorders. As you all know, Alnylam is pioneering an entirely new class of medicines to treat human disease.
This generational technology leverages the mechanism of RNA interference, a natural process of gene regulation that occurs in every cell of our body. RNAi works like a biological scalpel, allowing us to silence any gene in the genome. Moreover, RNAi is a catalytic mechanism that lends itself to highly potent molecules that require low doses to affect biology, the approach is highly specific and entirely reversible, which minimizes safety liabilities.
Additionally, we're able to engineer long half-lives to enable very frequent administration, which allows us to improve patient adherence and convenience. We've harnessed this natural mechanism into a unique and sustainable innovation engine which can enable sustained long-term growth. We continue to invest in the power of human genetics, where we now have access to more than 2 million lives through various biobanks that allow us to uncover new genetically validated targets.
We also continue to advance the delivery of RNAi to major tissues throughout the body. Beyond the liver and CNS, we have our first adipose-targeted program in the clinic, and we believe we're well-positioned to achieve delivery to 10 tissues in the next several years. Of course, we continue to optimize the oligonucleotide backbone of our siRNAs for a wide range of clinical applications. Not only do we continue to evolve our underlying platform capabilities, but we seek to deploy our technology towards creating medicines that have a material impact on the lives of patients with significant unmet medical needs. To do so, we employ a therapeutic area agnostic approach, pursuing diseases with high morbidity and mortality, and ones which we can address with highly genetically validated targets with a strong biologic rationale.
Overall, this integrated approach has enabled us to create drug candidates with high quality and historic clinical probabilities of success far in excess of industry benchmarks. To date, this strategy has yielded what we believe to be one of the most robust pipelines in the biotech industry. With over 25 programs spanning rare, specialty, and prevalent indications across multiple therapeutic areas, these investigational therapeutics underscore the depth of opportunity we have at Alnylam to deliver meaningful growth in the years ahead.
Indeed, you'll be seeing this growth accelerate in the near term as these programs move forward and reach important inflection points. This year in 2026, we have three pivotal studies ongoing, including two cardiovascular outcomes trials for nucresiran and ATTR cardiomyopathy, as well as zilebesiran in hypertensive cardiovascular disease. We also anticipate four key data readouts before the end of this year.
We expect phase I data for both ALN-HTT02, our Huntington's disease program, and ALN-2232 in development for obesity and weight management. As you'll hear today, we also expect results from the ALN-6400 program. We plan to share healthy volunteer data from our phase I study, and we expect initial results from our phase II study in hereditary hemorrhagic telangiectasia. As we look ahead to the next couple of years, the milestones continue to ramp up. In 2027, we anticipate four or more pivotal studies ongoing by the end of the year, growing to five by the end of 2028, and over five key data readouts in each of those years. Additionally, in 2028, we anticipate the launch of nucresiran in hATTR polyneuropathy, assuming positive phase III data and regulatory approval.
Of course, we'll continue to build the pipeline through the filing of three to four new CTAs each year as we scale to meet our Alnylam 2030 goals. A key component of our Alnylam 2030 goals is the growth through sustainable innovation pillar, where we aim to deliver two or more new transformative medicines beyond TTR that have blockbuster potential.
As mentioned earlier, we also aspire to achieve RNAi delivery to at least 10 tissue types and have over 40 programs in the clinic by the end of 2030. Now, when we think of the next wave of growth at Alnylam, there are several programs that we believe can represent the next wave of transformative medicines to be delivered from our pipeline. We'll cover those during our RNAi Roundtable series throughout the rest of 2026, starting with today's session on ALN-6400.
As you'll hear from the speakers, we have a promising and differentiated approach that has the potential to address rare bleeding disorders by targeting plasminogen. In this instance, we're not knocking down a disease-causing protein, but rather reducing expression of a downstream protein that is involved in all forms of bleeding disorders. This strategy has a very strong genetic validation and clinical rationale, and we believe it has the potential to offer durable bleed protection across a variety of bleeding disorders without increasing thrombotic risk.
In upcoming RNAi Roundtables, you'll hear about two other investigational programs that we believe have the potential to change the practice of medicine. Sorbisterit, our program targeting angiotensinogen with the potential to reduce the risk of cardiovascular disease by providing continuous control of blood pressure, and ALN-HTT02, which we're studying to treat Huntington's disease. With that, I'd like to hand it over to my colleague, John Gansner, who'll discuss the compelling opportunity we see for ALN-6400. John?
Thanks, Pushkal. I'm John Gansner, a practicing hematologist and the program lead for ALN-6400 here at Alnylam. I'm delighted to be able to tell you about the opportunity in front of us, which I think has the potential to revolutionize care for patients with bleeding disorders. We believe there's a broad opportunity across a range of bleeding disorders, that the high disease burden patients with bleeding disorders experience underscores the unmet need for therapies that provide durable and safe bleeding protection.
There are approximately 5 million people living with bleeding disorders globally. These disorders have various etiologies, but they all share a common phenotype: bleeding. This bleeding has a significant impact on patients. It is associated with anemia, iron infusions, blood transfusions, various procedures, ER visits, and hospitalizations. Patients living with bleeding disorders experience disruptions to their daily lives and experience social stigma and anxiety.
Furthermore, there are limited or no approved treatments for most of these bleeding disorders. We are developing ALN-6400 to address the significant unmet need in the treatment of bleeding disorders. ALN-6400 targets liver-expressed plasminogen, or PLG, to prophylactically reduce bleeding. On the left side of the slide is a schematic of ALN-6400's mechanism of action. ALN-6400 is delivered by subcutaneous injection and lowers liver production of PLG.
This reduces the amount of a protein in the blood called plasminogen that is converted to plasmin and decreases fibrinolysis or clot breakdown. By stabilizing what I like to refer to as an inner Band-Aid or the natural clot that forms to stop bleeding, we expect ALN-6400 to reduce bleeding in a range of bleeding disorders. We have four strong reasons to believe that our approach will be successful. First, we have a genetically and pre-clinically validated target.
Second, the mechanism is clinically de-risked by an existing class of medications called antifibrinolytics. Third, early data have shown that ALN-6400 is not expected to increase thrombotic risk. That's really quite critical here, and we believe it could be a key differentiator. Fourth, our platform allows for infrequent subcutaneous administration to enable effective prophylaxis. I want to showcase some of the genetic evidence and pre-clinical data that lead us to believe that PLG knockdown will reduce bleeding. Based on a UK Biobank analysis, genetically predicted lower levels of circulating PLG protein are associated with reduced GI bleeding, reduced nose bleeding, and reduced heavy menstrual bleeding. In addition, pre-clinically, we have shown that a PLG siRNA reduces fibrinolysis and mucosal bleeding in non-human primates. We observed a near 70% reduction in menstrual bleeding in this model.
That's pretty impressive given this is not a model of heavy menstrual bleeding and the animals are starting with what we consider to be normal menstrual bleeding. We've been steadily generating evidence that, to this point, show there is not expected to be an increase in thrombotic risk with low PLG and PLG knockdown. Genetic and proteomic data, some of which we'll showcase at the ISTH Congress next month, suggest that low PLG levels are not associated with an increased risk of arterial or venous thrombosis.
Natural history data from 107 patients with plasminogen deficiency showed no history of venous thrombosis. Pre-clinical models of provoked thrombosis have been reassuring. Despite near complete knockdown of PLG, thrombotic response was the same as control. This could be because our mechanism of action does not alter thrombin generation, which we've confirmed pre-clinically as shown in the figure on the far right.
We think the fact that we have not observed an increase in thrombin generation with near complete knockdown of PLG could be a differentiator when it comes to safety. I'm excited to say that we've prioritized not just one, but two indications based on high unmet need and disease burden, specifically hereditary hemorrhagic telangiectasia, or HHT, and von Willebrand disease, or VWD. These are the two most common bleeding disorders worldwide, affecting approximately 1.5 million patients globally in the case of HHT, and 1.5 to 3 million in the case of VWD. It's important to note that despite the high unmet need, there are no approved treatments for HHT and that the current prophylactic treatments for VWD have high burden, which I'll touch on later. HHT is a multi-system bleeding disorder with high clinical burden and no approved treatments.
This is a disease of abnormal blood vessels that are fragile and prone to rupture and bleeding. Here I highlight some quotes from Austin, a patient with HHT who we will hear from at the end of this presentation. 95% of patients with HHT experience nosebleeds, but you really need to hear the patient stories to understand what this means. Picture a faucet of a sink turned all the way on.
That's very distressing and dangerous. More than two-thirds of patients with HHT are anemic or iron deficient due to blood loss. About one-third have gastrointestinal or GI bleeding, and 11% are hospitalized due to HHT at least once a year. It's a terrible disease. We believe that ALN-6400 has the potential to be a first-in-class treatment for HHT. It brings hope with the possibility of durable and safe bleeding control.
We think that its long-acting mechanism could provide sustained bleeding protection with only four injections a year. We also expect that as treatments receive regulatory approval to treat HHT, diagnosis rates will increase, as we have seen in other disease areas after the first treatments are approved. Currently, it is estimated that only about 35% of patients with HHT are diagnosed. This could be much, much better.
I'm going to turn now to VWD, where there are really limited and burdensome treatment options for prophylaxis. Patients with VWD are either deficient in something called von Willebrand factor or make a defective version of it. This disrupts platelet adhesion and affects the stability of factor VIII, leading to increased bleeding. A completely different mechanism from HHT. These patients also suffer from substantial bleeding manifestations, which we believe ALN-6400 has the potential to address.
There is a disproportionate burden for women with VWD, and 90% experience heavy menstrual bleeding. Hysterectomies are unfortunately all too common, as is highlighted by the patient quote. You see the reference to getting stuck over 32 times a day. The injection burden with existing prophylactic treatments is so high that some patients even require ports, which are medical devices that can be used to simplify IV injections, but also have drawbacks. The current state of prophylaxis for VWD is limited to IV factor infusion, which you have to do two to three times a week. This is very burdensome and particularly difficult for children. As you can imagine, it's hard to put an IV in your child two to three times a week.
There are many patients who would benefit from prophylaxis that choose instead to manage their bleeds on demand because of the burden of multiple IV infusions per week. We believe ALN-6400 has the potential to transform prophylaxis for patients with VWD who need effective, durable, and safe bleeding control. Based on ALN-6400's mechanism of action, we believe that patients with VWD would benefit from improved protection from bleeding regardless of VWD type or bleed type.
By offering patients an innovative, less burdensome option to manage their disease, we anticipate that more patients will opt for prophylactic treatment than do today. We believe ALN-6400 has the potential to transform treatment across both HHT and VWD, offering two unique and sizable opportunities. In HHT, there are no approved treatments currently available, it's no surprise that current diagnosis rates are quite low at about 35%.
Based on what we have seen in many other disease areas, we expect that diagnosis rates will increase significantly once a treatment becomes available. We estimate there are approximately 1.5 million patients globally and 70,000 in the U.S. In VWD, while there are treatments currently available, they are burdensome, resulting in low treatment rates as patients often avoid prophylaxis and seek treatment only for severe cases.
The opportunity here is to increase the treatment rate as more patients adopt prophylactic treatment as efficacious and lower-burden options become available. This, too, represents a sizable opportunity given we estimate there are approximately 3 million patients with VWD globally and 140,000 in the U.S. We are really excited about the potential of ALN-6400 as a hemostatic agent with its differentiated approach that has the potential to improve the lives of patients across multiple bleeding disorders by providing long-acting, durable protection from bleeding.
We are highly encouraged by its early safety profile and expect that it could reduce treatment burdens, enabling more patients to benefit from prophylactic treatment. With that, I'd like to turn it over to our guest speaker this morning, Dr. Hanny Al-Samkari. Dr. Al-Samkari is an associate professor of medicine at Harvard Medical School and holds the Peggy S. Blitz Endowed Chair in Hematology/Oncology. He is a classical hematologist and clinical investigator who co-directs the HHT Center of Excellence at Massachusetts General Hospital. Dr. Al-Samkari has published extensively about HHT and cares for several hundred patients at his center. Hanny?
Thank you so much, John. It's my pleasure to chat a bit about HHT and von Willebrand disease and talk about the manifestations of these diseases and a bit about the patient journey and the unmet need from my perspective as a bleeding disorders expert and a provider for these patients. Next slide. Here are my disclosures. Next slide. This is how I think about the spectrum of inherited bleeding disorders, and I encourage you to think about it in a similar way. On one end of the spectrum, we have coagulation factor problems, and the classic disease there is hemophilia, where you have a deficiency of a coagulation factor that leads to bleeding. You have normal angiogenesis and therefore normal blood vessel structure.
On the other end of the spectrum, you have hereditary hemorrhagic telangiectasia, which is, there's no coagulation factor deficiency, but is a disease primarily of angiogenesis and an angiogenic problem. That results in abnormal blood vessels, which we call telangiectasia and arteriovenous malformations that are fragile and they don't properly mature and they bleed, and they cause a huge burden of bleeding in these patients. If you look at the incidences, and John already highlighted this. When we think of inherited bleeding disorders, the first thing that comes to mind is hemophilia. Hemophilia is obviously a very important inherited bleeding disorder and one of the most common inherited bleeding disorders, but it's actually the third most common. I think of these as the three, quote unquote, common inherited bleeding disorders. They're all rare diseases, technically.
When we talk about bleeding disorders, there's the rare and there's the ultra-rare, and these are the rare, which makes them more common, relatively speaking. HHT is about one in 5,000. Von Willebrand disease is in the middle. Von Willebrand disease is a coagulation factor deficiency that actually causes angiogenic disruption. These patients have both impaired hemostasis from bleeding, as well as impaired hemostasis from abnormal blood vessels that form and often form in their intestines. We have over 30 FDA-approved agents for hemophilia. We have addressed really a massive amount of the need there. Thankfully, my colleagues in the hemophilia space, as well as their industry partners, have really transformed this disease in a really incredible way. Whereas for the other two of these diseases, we have a drastic amount of unmet need. We're really in a difficult place.
For HHT, I don't express hyperbole when I say I believe it is the non-malignant hematologic disorder that has the greatest amount of unmet need in 2026. Von Willebrand disease is rather common, and there is a significant gap for patients that have moderate to severe von Willebrand disease that is not currently being addressed by the therapies that are FDA-approved right now.
I have platelet problem over in the corner, and I think it's important to mention that right now we have no approved therapies for the vast majority of the inherited platelet disorders, but that we actually use plasminogen inhibition primarily to treat them. That is a totally separate talk for another time, but is, I think, somewhat relevant to the topic of today's conversation. Next slide. Let's talk about HHT. Next slide. I will give you a few cases.
This is a 41-year-old man with severe nosebleeds. He works in the biomedical field, diagnosed with HHT in his 20s, sent for regular nasal and intestinal cautery procedures that each worked for a couple of months, ultimately, his bleeding came back worse after each procedure, as we know happens in this disease when we use procedures because it is an angiogenic problem, and the more tissue injury you cause, the more you provoke the body to create more telangiectasias and AVMs in these patients.
This patient, unfortunately, ultimately went on disability, and his promising career halted because he just could not work with blood gushing from his face, constantly limiting him at work. I think we all have experienced nosebleeds at some point in our life, and so it is easy to maybe make the, I think, misunderstood thought that nosebleeds are not that big of a deal.
They are not as bad as other kinds of bleeding, when in reality, when they are severe and when they are recurrent, they are perhaps one of the worst kinds of bleeding because they are so obvious and they impact you doing almost anything in your daily life, and that includes working. He had chronic anemia requiring regular intravenous iron, constant ER visits for severe nosebleeds. He was diagnosed with major depressive disorder, not surprisingly from his nose bleeding. About half of patients with HHT ultimately are diagnosed with a DSM-5 diagnosable psychiatric comorbidity because of their nose bleeding. His well-meaning doc started him on an antidepressant, an SSRI, which reduces platelet function, that worsened his bleeding. He said to me, "I am barely 40, I feel like my life is nearly over.
I just want to go back to work and maybe one day be able to have a girlfriend." This is a typical, this is not an unusual case or a kind of a corner case. This is a typical patient I see in my clinic. Next slide. HHT is not, quote unquote, that hereditary nosebleed disease. It is a multisystem inherited bleeding disorder with numerous morbid and potentially fatal manifestations. We have talked a lot about the nose bleeding, and John mentioned 30% of these patients have chronic GI bleeding. Between the nose bleeding and the GI bleeding, there is a huge burden of iron deficiency anemia, and it is very common for these patients to be dependent on intravenous iron infusions. There is a small subset of the most severe patients that are dependent on red cell transfusions.
In addition to that, we have visceral arteriovenous malformations in lung, liver, and brain, which can cause a whole host of complications that are quite morbid. High output heart failure, liver disease, pulmonary hypertension, pulmonary hemorrhage, hemorrhagic stroke, epilepsy, other really serious complications. You might think, well, gosh, those are the real problem with this disease. Actually, no. Patients rank bleeding as by far the most important clinical manifestation because it impacts them on a daily basis and profoundly. AVMs and anemia tie for second behind bleeding, far behind bleeding. As has been mentioned, there's no FDA-approved or European Medicines Agency-approved therapies to date. Next slide. Because this is an autosomal dominant disease, when I see a patient in clinic, half of their family has HHT. Many of them have not yet been diagnosed.
You find one patient, and you find 20 more, and this is why at the HHT Center at Massachusetts General Hospital, I care for several hundred of these patients, several hundred of these families. This is a disease unlike hemophilia, which is a disease primarily of men. As an X-linked disease, this affects all sexes equally and actually is the most clinically significant and morbid inherited bleeding disorder of women.
Women actually tend to have more severe bleeding and visceral disease manifestations than men, although both certainly can have severe manifestations. These patients have reduced overall survival because of their bleeding and non-bleeding manifestations. Next slide. The pathologic lesion of HHT is the arteriovenous malformation or AVM. This is an abnormal lesion, abnormal vascular structure whereby there are these abnormal, fragile, friable connections between artery and vein that bypass the normal capillary network. These lesions appear on mucocutaneous surfaces.
They appear within organs. When they're small, less than a few millimeters, we call them telangiectasias. When they're bigger than a few millimeters, we call them AVMs. The important thing to recognize about them is that they're high-flow lesions. These are connected to arteries, and arteries have the high pressure inside them. When these lesions rupture, they often cause squirting bleeding, gushing bleeding, and that's why we can often see the very profound nosebleeds in these patients. Next slide. These are just some examples of patients that have a lot of telangiectasias. These are very obvious. You don't need 20 or 30 telangiectasias. You only need two or three to make the diagnosis. I've never met a patient yet in my career that has mucocutaneous telangiectasias in typical locations and recurrent epistaxis who didn't ultimately have HHT.
As has been pointed out, this is significantly underdiagnosed because, well, for one thing, there's no approved therapies, and another thing, it's something that has not been adequately, I think, given enough time in medical training and medical school. That's all changing now. Next slide. More examples of telangiectasias. Next slide. These are telangiectasias in the gastrointestinal tract, and when you zoom in very closely, you see the very kind of spidery appearance of them, the very tortuous abnormal vessels.
These chronically ooze in most patients with HHT. Three-quarters of patients with HHT actually have telangiectasias in their gastrointestinal tract, and about half of them have chronic bleeding that is very clinically significant and usually leads to hematologic support dependence through IV iron and/or red cell transfusions. Next slide. These are the telangiectasias in the nose that cause the recurrent epistaxis. Next slide.
Again, because of these manifestations and these telangiectasias, we have 95% of patients. This was from the Comprehensive HHT Outcomes Registry of the United States, a U.S. government-funded registry of HHT Centers of Excellence that enrolled unselected patients with HHT, patients of any age, patients of any severity. This is the initial report that we just published in Blood. 95% with chronic recurrent epistaxis and almost two-thirds of these patients that have moderate to severe epistaxis, as is defined by thresholds based on international consensus report in defining epistaxis severity in HHT. Next slide. 30% with chronic GI bleeding, although only 40% of the patients had even had an upper endoscopy. By the way, many of the lesions are buried deep in the small bowel. They're not easy to find.
For the patients that had GI bleeding, three quarters of them required IV iron, and half of them have required red cell transfusion. Next slide. Heavy menstrual bleeding observed in the setting of essentially chart review was seen in 35% of patients. There's another study, actually, that is soon to be published that shows a rate of heavy menstrual bleeding of three quarters of patients, of women, menstrual age women with HHT.
Certainly something that's been under-recognized and people haven't asked about it. If you don't ask about it, you don't diagnose it. Other bleeding from other areas as well, in 41% of patients. Next slide. The overall burden of mucosal bleeding in patients with HHT that is moderate to severe is three quarters of these patients, which this is the level of bleeding that is very clearly indicated to treat, right?
We want to treat patients with mild bleeding also, right now we're forced to use off-label therapies that have a lot of toxicity, we only treat the moderate to severe bleeders. Next slide. Iron deficiency and iron deficiency anemia is "the norm" in this disease, which is a big problem because in addition to drastic reductions in quality of life, one of the clearest things you can do to increase somebody's quality of life is fix iron deficiency in a patient who's iron deficient. These patients are chronically bleeding it's constantly a game where you're chasing your tail trying to make sure they remain iron replete. About half of patients with HHT, more than half, have anemia in this study that evaluated a snapshot in time, one year of patients with HHT using ICD-10 codes.
About half of those patients received iron infusion or red cell transfusion within that year. Next slide. When we talk about the bleeding complications of HHT, this is a summary from the CHORUS Registry that I mentioned. I didn't mention the pulmonary hemorrhage from ruptured pulmonary AVMs. That happens in one in 50 patients with HHT, which is certainly potentially fatal, and this happens in 1% of all pregnancies in women with HHT. One in 30 patients with HHT developing intracranial hemorrhage. Just to give context, right? That is similar to hemophilia in the 1990s before routine factor prophylaxis. The rate of intracranial hemorrhage in 2026 in patients in the United States treated with non-factor prophylaxis is 0.4% for hemophilia. It's 3% for HHT. Next slide.
The standard of care for bleeding in HHT is highlighted on this slide or described on this slide, and really what we are forced to do is supportive therapy with iron. We do procedures when we have to because, again, we really have moved away from recurrent procedures, certainly at HHT centers, although in the community, because as you can see, the drugs on this slide are cancer drugs that are FDA approved only for patients with terminal or metastatic cancer, which a lot of docs in the community, including hematologists, oncologists, are not comfortable administering drugs like pomalidomide and bevacizumab administered indefinitely to patients with HHT who have decades of life ahead of them. The procedure piece is primarily used in HHT centers to stabilize unstable patients.
Then we treat with drugs, and we treat with oral antifibrinolytics, primarily in those patients that have mild to moderate disease. These are patients getting tranexamic acid or aminocaproic acid, two horse pills every six to eight hours, which is not the easiest thing for patients to take, as you can imagine. The efficacy of this approach is really limited by patient compliance, ability to take the pills, side effects that patients have.
Then we have, on the other end, clinical trials of novel agents because, again, we have no approved therapies or repurposed systemic antiangiogenic drugs, which work, by the way, on average for about three to five years, and then they stop working. The unmet need here is really profound. Next slide. All right. Let's switch gears and talk about von Willebrand disease, the most common inherited bleeding disorder.
Here's another case. A 40-year-old woman with type 2B von Willebrand disease, complicated by chronic GI bleeding. She'd previously managed on three times weekly intravenous von Willebrand factor, plasma-derived, but developed infusion fatigue. She was switched to twice weekly recombinant von Willebrand factor, but this only treated her heavy menstrual bleeding, not the GI bleeding she had from these abnormal vascular lesions in her intestines.
On endoscopy, she has these vascular malformations that intermittently bleed. Put on octreotide with minimal effect. This is a drug that reduces blood flow to the intestines. She's still missing infusions of recombinant von Willebrand factor, which are normally given twice weekly, due to the fact that she's a single mother of three kids, she has a busy job, which she works almost 60 hours a week, and she has infusion fatigue. It's not the easiest thing to continue to do this forever.
Next slide. Von Willebrand factor is an important blood protein that forms clots to stop bleeding. Okay? It protects clotting factor VIII. People who have low von Willebrand factor also have low factor VIII levels, typically in conjunction with the reduced von Willebrand factor. It facilitates the binding of platelets to subendothelial collagen. These glycoproteins, platelet glycoproteins, that bind subendothelial collagen, as well as platelet to platelet interactions.
It serves in many ways as kind of the glue that helps platelets stay together and helps platelets attach to the site of vessel injury. Next slide. Von Willebrand disease is quite common in the bleeding disorder space. I mean, the most common inherited bleeding disorder. It's frequently missed. Like HHT, it's frequently missed. In both of these cases, von Willebrand disease, Type 1 von Willebrand disease, the most common type, is autosomal dominance.
HHT, it's autosomal dominant. What happens is the bleeding gets normalized in families. "Oh, yeah, women in our family, they have heavy periods. People in our family, they get nosebleeds. That's just, quote, unquote, 'our family curse.' We just have a lot of bleeding." It gets normalized, and people don't even know that they have heavy menstrual bleeding. If a doc asks, it's normal because the mother of the woman told them it's normal because their sisters have it. It's just normal to them. It's very frequently missed. It can come to attention because of severe iron deficiency anemia, or in the case of von Willebrand disease, profound or complicated postpartum bleeding or post-procedural bleeding. Next slide. These are the manifestations of von Willebrand disease. Again, not to belabor the point, but heavy menstrual bleeding being a really major one.
This heavy menstrual bleeding in patients that have more mild disease can be managed with tranexamic acid and can be managed with oral contraceptives. In many cases, it's not adequately managed by our current therapies, and there is a gap and a need for a better therapy for these patients. On top of that, these patients not infrequently will have some epistaxis. They can have gingival bleeding.
They can develop gastrointestinal hemorrhages, and they're at increased risk of surgical bleeding and more bleeding after trauma and more bleeding with pregnancy and pregnancy complications with delivery. In patients who have the most severe kind of von Willebrand disease, they can actually look like a severe hemophilia A patient. Next slide. Not to get too into the weeds, but here are the types of von Willebrand disease. Type 1 is a quantitative deficiency.
Most patients have a mild to moderate bleeding propensity. Type 2 is a qualitative deficiency, the typical Type 2 patient has moderate bleeding, these patients can have mild bleeding, and they can have severe bleeding. There's Type 3, which is autosomal recessive, essentially an inheritance of two drastic Type 1 mutations. This is quite rare, but these patients can look for all the world like a severe hemophilia patient. Next slide. Our current treatments for von Willebrand disease really leave a conspicuous gap. Patients with mild Type 1 and Type 2 disease are generally managed all right with desmopressin before most procedures, von Willebrand factor-containing concentrate before major procedures, and they take antifibrinolytics, which certainly do work to help with bleeding after dental procedures, certain surgeries. Sometimes these can be used as an abortive for a particularly bad nosebleed.
Patients will take two tranexamic acid pills. Patients that have moderate, severe Type 1 and Type 2 disease and the patients with Type 3 disease, however, there is a clear unmet need in this group of patients. The Type 3 patients and the severe Type 2 patients, as was given in the example case that I gave. They are often dependent on intravenous infusions of von Willebrand factor, plasma-derived or recombinant. These infusions can reduce bleeding, they do reduce bleeding, but they're a really significant burden on the patient. It's really challenging if you're in this kind of middle group where you have multiple nosebleeds a week, you have heavy menstrual bleeding that's not managed by typical therapies. You don't technically have Type 3 disease. You don't technically have severe Type 1 or Type 2 disease, but it's moderate.
Most of these patients don't want to go on regular infusions. It's just too much of a burden. There is a clear gap there for those patients. It's not enough to give these patients oral antifibrinolytics, because they're not adequate in managing the bleeding. Next slide. What do we need in von Willebrand disease and HHT? We need safe and effective medications for moderate, severe mucocutaneous mucosal bleeding. We ideally want a drug that's convenient.
It should have a minimal or nil thromboembolic risk in patients with HHT that have increased thromboembolic risk over the general population. In any bleeding disorder, you don't want to give patients a higher thromboembolic risk if you can avoid it because of, obviously, the challenges with antithrombotic therapy in these patients. The ideal drug is prophylactic as opposed to something on demand and should be ideally administered infrequently.
It's got to reduce epistaxis in HHT, and it's got to reduce overall mucocutaneous bleeding in HHT and von Willebrand disease. In a perfect world, would reduce the burden of anemia and the requirements for hematologic support, IV iron, red cell transfusion, particularly in HHT, and of course, would improve patient-related health-related quality life. With that, I'm happy to hand it off to Dr. Martina Slingsby.
Thank you, Dr. Al-Samkari, for the excellent and comprehensive overview of the clinical burden of HHT and von Willebrand disease. Your examples really bring to light the devastating impact of these diseases on patients' lives. My name is Martina Slingsby, and I'm a PhD scientist, and I've been the research lead and now the clinical science lead for the ALN-6400 program at Alnylam.
I will now take you through our clinical plans and progress. I've had the privilege of working on this exciting program right from the idea stage around four years ago, where the Alnylam model of genetic and preclinical validation and a streamlined approach allowed us to quickly identify a lead candidate and start a phase I study at the end of 2024. Only about a month later, under three years from the idea, we were able to demonstrate clinical proof of mechanism in humans.
In September last year, we initiated a phase II study in patients with HHT, and last month, we initiated another phase II study in patients with von Willebrand disease. Here is an overview of our phase I study in healthy adult volunteers. This was a double-blind, placebo-controlled study testing four ascending single-dose levels of ALN-6400. An innovative aspect of this phase I study was the oral tranexamic acid, or TXA, benchmark run-in and washout period. As we heard from Dr. Al-Samkari, the antifibrinolytic drug TXA is commonly used in both HHT and von Willebrand disease but is not an approved therapy for these conditions. Due to its short half-life, it needs to be given frequently at high doses, typically at two tablets, three times a day, for a total of three to four grams a day.
It is common for patients with HHT to take this dose of oral TXA continuously every day for years, whereas patients with von Willebrand disease typically take TXA more on demand. In the phase I study, we performed this TXA benchmark run-in, where all participants received standard-of-care doses of TXA prior to their subcutaneous injection of ALN-6400 or placebo.
This allowed for mechanistic comparison of the intra-individual antifibrinolytic effect and how durable this response was with TXA relative to ALN-6400 using a mechanistic assay called tPA-ROTEM, performed at various time points in the study, which I will show on the next slide. We designed a study like this to learn what level of plasminogen lowering is needed in order to have a similar antifibrinolytic effect as oral TXA and what level of plasminogen lowering could lead to a more durable antifibrinolytic effect in the blood.
This study has now been completed we remain on track to share data in the second half of this year. In the phase I study, we demonstrated clinical proof of mechanism that ALN-6400 is able to inhibit fibrinolysis in humans. For this, we used tPA-ROTEM, which is an ex vivo assay which shows whole blood clot formation, clot stabilization, followed by clot breakdown or fibrinolysis. A larger area of blue trace means that the clot is more stable and lasting for longer, signifying an antifibrinolytic effect. The top panels show representative ROTEM traces from a healthy volunteer dosed with oral TXA, as you can see, at the TXA peak effect, the blue trace was extended, meaning clot breakdown of fibrinolysis was reduced.
This effect only lasted for a few hours, since at TXA trough, eight hours after TXA dosing, the antifibrinolytic effect had, to a large extent, worn off. The lower panels show the ROTEM responses from the same healthy volunteer after they were dosed with ALN-6400, showing a deep antifibrinolytic effect that was sustained for three months. Based on the phase I results, we have now selected two dose levels of ALN-6400 that demonstrated mechanistically greater and more durable antifibrinolytic effects in the blood compared to oral TXA, which we hypothesize will translate to a greater reduction in bleeding.
The bleeding protection effect of TXA lasts hours per dose. We now plan to investigate whether a single dose of ALN-6400 can offer bleeding protection for several months in our phase II studies, where we hope to demonstrate clinical proof of concept of ALN-6400 for the reduction of bleeding. Here is an overview of our multinational HHT phase II study called InsigHHT, where patients with HHT are randomized to receive multiple doses of ALN-6400, dose level one, two, or placebo.
In this study, we are focusing on patients with HHT who suffer from moderate to severe nosebleeds, like Dr. Al-Samkari referred to in his talk, make up the majority of the HHT patients that he sees. The goals of the study are to evaluate safety and tolerability, to determine the phase III dose and regimen, and assess efficacy by a reduction in nosebleeds. We expect initial results in the second half of this year. We aim to begin a phase III study in HHT, as well as to present full phase II data at a scientific congress in 2027.
We have just started a multinational von Willebrand phase II study called HM BEACON, where adult and adolescent patients with all types of von Willebrand disease and heavy menstrual bleeding are randomized to receive multiple doses of ALN-6400, dose level one or two. As you heard from Dr. Al-Samkari, heavy menstrual bleeding, despite the current treatment options, remains a huge unmet need in von Willebrand disease. A paper was just published that emphasized that menstrual outcomes are frequently overlooked in von Willebrand disease trials. I am very proud to be part of this Alnylam effort to change that and to be the first company to do a study focusing on women with heavy menstrual bleeding.
The goal with this study is to evaluate safety and tolerability, determine the phase III dose and regimen, achieve a quick path to proof of concept by focusing reduction in menstrual bleeding, since that is a reliable bleed type that happens every month. We will also be collecting information on other types of bleeds, since we're planning to conduct a phase III trial in both male and female patients with von Willebrand disease of all types, where the primary endpoint is anticipated to be annualized bleeding rate.
In summary, we believe ALN-6400 offers a differentiated approach with broad impact potential across bleeding disorders. We are encouraged by our data so far and believe that ALN-6400 has the potential to safely provide durable bleed protection and reduce treatment burden, which could meaningfully address the unmet needs of patients living with rare bleeding disorders. We will listen to a patient story from Austin and his family about what it is like to live with HHT.
In the last year, I've been to the hospital 25 times, emergency room visits to have emergency blood transfusions. I've had around 30 iron infusions as well to try to keep me from being severely anemic and low on blood. My name is Austin. I live in the Lakes Region in the state of Maine. I'm 44 years old, professional chef at a restaurant in Freeport, Maine.
I have a family of three sons and a lovely wife. As a family, we just really like to try to spend time together when we have it, go out, take the kids to the park, really just try to make the best of the time that we have when I'm not working. I run a team of roughly 24 other chefs, working long hours every day to try to provide a great experience. If you've seen the show "The Bear," it's pretty much the exact same thing.
All day, every day, fast-paced, nonstop work. In my mid-30s, when really the HHT started to manifest, I was having nosebleeds that were lasting upwards of 30 minutes at a time. If you could picture a faucet of a sink and you turn it on full, that would be generally the worst of what could be happening as far as a flow. It's also not just out the front of your nose, it's also down the back of your throat. It could be potentially filling up so much that it's coming out of your eye. It is the most intense type of nosebleed you could imagine. What started my path to discovering that I had HHT was I all of a sudden became very lethargic, was having a real hard time working.
I was having a lot of swelling in my ankles, and then that progressed around my knees, and then I decided that I needed to go to the hospital. They quickly found out that I only had 3.6 units of blood in my body, so they emergency rushed me to another hospital to get me blood that I needed to make sure that I could stay alive. My father had HHT, and it was passed down to him from his father. Two of my sons, Xander and Parker, they're both diagnosed with HHT. I was diagnosed due to a genetic test that I was finally able to have. Knowing what you have can at least let you give people the knowledge as to why things might be a little off with you.
Otherwise, before I was diagnosed, there's a lot of questions, "Well, what's wrong with you when you're bleeding everywhere?" The most inconvenient or troublesome thing with being a chef and having HHT is that at any random moment, you could start to bleed, and you have to leave what you're doing and go deal with that, and then return to work and be wondering what's happening.
My wife is ultra-supportive in everything I do, but especially with anything that has to do with my health and dealing with HHT because we really have figured it all out together. As far as the future for treatment of HHT, I really hope that we find something that helps people manage it. I hope for my children, for other people's children, and other people's lives, that there's something that really helps people manage it or cures it altogether so that people can have a normal life.
Giving us such a powerful window into the realities of living with HHT. Their experience really brings to life what Dr. Al-Samkari was highlighting in his presentation about the profound
Unmet need this disease places on patients, their families, and why we're working with such urgency to advance ALN-6400 for patients with HHT and von Willebrand disease. We're going to move now into the Q&A session. As a reminder, please submit your questions through the dialogue box located within the webcast platform, and we'll answer as many as we can within the time remaining. Joining me today for our Q&A are our three presenters, John Gansner, Martina Slingsby, and Dr. Hanny Al-Samkari. In addition, Christi Kelsey, Senior Vice President of Value and Pipeline Commercialization at Alnylam, will be joining us for the Q&A session.
I'll just give a moment for the questions to come in. All right. Maybe, here we go. One is maybe for you, John. Dr. Al-Samkari talked a little bit about the variety of bleeding disorders that are out there and across the spectrum of factor, structural defects, platelet defects. What gives us the confidence, or you the confidence, that plasminogen lowering would work across these various etiologies?
That's a very important question, Pushkal, I'll start by just saying that ALN-6400 targets liver-expressed plasminogen, or PLG, which is really a central mediator of fibrinolysis. That, again, is the process that breaks down blood clots. Our goal with ALN-6400 is to stabilize the fibrin mesh that holds together naturally occurring blood clots, thereby reducing and preventing recurrent bleeding. You can really think of the therapeutic hypothesis as ALN-6400 is a drug that aims to stabilize an inner Band-Aid. We believe our approach could be effective across multiple bleeding disorders because plasminogen is a central mediator of fibrinolysis across bleeding disorders and bleed types. This is really substantiated by the fact that antifibrinolytics are used to reduce bleeding across multiple bleeding disorders.
That's super helpful. Maybe then a related question that came in is, I guess this assumes if you describe this as a Band-Aid approach, that these patients clot sufficiently for this mechanism to work. Maybe Dr. Al-Samkari, can you just talk about across this variety of bleeding disorders, do they have enough clotting that's happening for this kind of an approach to work? Then, what would we expect? Would we expect this to reduce the intensity of bleeds that have already started, or to prevent bleeds, or both?
Yeah, great question. Yes, these patients do have adequate clotting, adequate thrombin generation for this approach to work. They do produce clots. The issue here, and with HHT, the amount of thrombin generation is totally normal. In other bleeding disorders, the amount of thrombin generation is reduced, but still adequate to produce clot. Just one thing I think that's really important to recognize is that when we talk about the hemostatic system, we have the coagulation system and the fibrinolytic system. They are two separate systems under the hemostatic system, and they both are important. The fibrinolytic system, it functions kind of constitutively and normally independent of what's going on with the coagulation part of the system.
This helps us to address, sort of rebalance the amount of fibrinolysis with the amount of coagulation that's going on in patients that have coagulation defects, and it sort of rebalances the amount of fibrinolysis that's occurring in patients that have vascular structural defects. It's also worth noting that in HHT, patients do have increased fibrinolysis within lesions. That's something that we didn't actually mention. It is also relevant to reduce that as well. Would I expect it to reduce bleeding incidents, bleeding intensity, bleeding duration, all of those things? We know that currently, right, are sort of not very adequate from a PK/PD standpoint, antifibrinolytics that we use. They certainly work.
When you give somebody two horse pills every six to eight hours, and the effect is only really therapeutic for about two to three hours after the patient takes the medication, takes the pill. We know that these drugs work when we give intravenous infusions, right? In the hospital, they work quite a bit better because the person's getting a high dose and good inhibition of plasminogen. It reduces frequency of bleeds, it reduces intensity of bleeds, and it reduces duration of bleeds. All of those things I expect this approach to work for.
Super helpful. Martina, maybe a question for you. There are a variety of indications. These are two diverse indications that we're pursuing. Why did we pick these two to sort of deliver proof of concept and to pursue first?
As you mentioned in your presentation, Pushkal, it's really the philosophy at Alnylam when we select indications. It's really based on around three main criteria. That is the first being the overall scientific rationale, it's got to make sense. Second, the degree of unmet need, and thirdly, and probably most importantly, where do we have the potential to show the greatest impact on patients' lives? Looking at these three criteria, HHT and von Willebrand disease really fulfilled them and really rose to the top here as a good starting point. Where, as we've heard, the mechanism of lowering fibrinolysis to reduce bleeding, it's likely to have a transformative impact on the management of these bleeding disorders. Then based on their high unmet need, but they have high unmet need for different reasons.
As we heard mentioned in Dr. Al-Samkari's talk, in HHT, there are no approved treatment options. There is really a medical need for a therapy that can offer prophylactic bleeding control, reduce nose bleeding, and overall blood loss from other sources of bleeds, alleviate the profound anemia burden, and the need for frequent hematologic support, such as iron infusions. Whereas in von Willebrand disease, there are prophylactic treatments, but they are burdensome, requiring IV infusions two to three times a week, leading many patients to opt out of prophylaxis, which results in under-treatment. We believe that ALN-6400 can potentially offer durable bleed protection across all von Willebrand types with a lower treatment burden of infrequent quarterly subcutaneous dosing. This is why we selected HHT and von Willebrand disease.
That's great. Maybe, Dr. Al-Samkari, I think questions for you around, given your kind of perch across all that's happening in this space, can you just kind of calibrate your level of, I guess, enthusiasm based on all the biology that was covered here today and what you know in terms of potential of this therapy? What's your sort of general level of enthusiasm about this approach to treat these bleeding disorders?
I'm very enthusiastic. Right now, when I write about antifibrinolytics and when we talk about them and use them in clinical practice, we refer to them as nonspecific universal hemostatic agents. The challenge is they just are not good at an outpatient perspective, use an outpatient perspective, and use chronically because of their pharmacokinetic and pharmacodynamic limitations. We know we have lots of evidence that they're safe in patients with bleeding disorders. We have lots of evidence, even in HHT, as an inherited bleeding disorder with an elevated thromboembolic risk, that they're safe. We have longitudinal data. We have multiple randomized controlled trials that they're safe. It's just that we need a better mousetrap.
We need a way to affect plasminogen to a greater degree and much more consistently, which is why I'm very enthusiastic about the prospect for plasminogen knockdown in HHT and across other bleeding disorders. Right now, when we have any inherited bleeding disorder that has no FDA-approved therapies, and even for those with FDA-approved therapies, one of the most common drugs, if not the most common drug we use is tranexamic acid. Right. If you could have a much, much better version of this, that is easier to use, that has a longer effect, that is much better at actually reducing fibrinolysis, we anticipate the safety profile will be similar, and the safety profile of tranexamic acid is very, very good. That's one of the main reasons why I am as enthusiastic as I am. It's good to have something that works across different pathophysiologies.
These diseases are genetically heterogeneous. Von Willebrand disease and HHT both are very genetically heterogeneous, and bleeding is the major problem to both of them. Having something that works independently of what's going on from a genetic standpoint is also very reassuring that I can have a therapy that most likely will work for any of my patients with the disease.
Fantastic. Then you started to touch on this, but can you just elaborate in terms of what safety concerns? I mean, thrombosis is one. Martina reviewed some of the data. What's your take on the data that supports or around the thrombosis risk? These patients have a baseline thrombosis risk. What is that? How do you monitor for thrombosis in the clinic?
Excellent question. The baseline increased thromboembolic risk in patients with HHT is about two to fourfold that of the general population. It is driven by multiple different mechanisms, but one of the major ones is chronic iron deficiency, which causes increased factor VIII levels and which leads to a higher risk for thrombosis. Obviously, if you can reduce the bleeding, you can reduce the iron deficiency.
It's a virtuous cycle in that way. How we monitor these patients clinically, when we treat these patients, we don't monitor things like D-dimer or prothrombin fragment in HHT because these are patients that are chronically bleeding. They're chronically going to be producing D-dimers and prothrombin fragments, and it's not helpful to monitor those over time because very frequently, they're elevated at baseline. We monitor these patients clinically. We do proper physical exams. We ask them proper questions.
We educate them in advance of the symptoms and signs to look for and give them a low threshold to talk to us and reach out if they develop those symptoms or signs. We also have a low threshold to do proper imaging to evaluate if somebody is potentially having an event. The other part of your question, sorry, Pushkal, you mentioned the data.
Yeah.
The data. Why do I feel comfortable? I feel comfortable because we have a real substantial body of evidence, and Dr. Slingsby pointed out a lot of it. We have great data in patients with HHT showing no increased thromboembolic risk, multiple RCTs, multiple real-world evidence cohorts with over 100 patients followed for years, receiving four grams a day of tranexamic acid or aminocaproic acid that show no increased propensity for thrombosis. We have studies in non-human primates. We have studies in a mouse model with drastic knockdown of plasminogen showing no increased thrombin generation, no increased incidence of thrombosis. We have real-world experimentation in patients with congenital plasminogen deficiency.
People who have 5% or 1% of normal plasminogen levels living their entire lives with these levels, followed for decades in a study called HISTORY, which is the major natural history study, just published a large report in "Blood" last year. No increased propensity for thromboembolism in these patients, despite having very low levels for decades. We have UK Biobank data, which looked at over 50,000 patients, which was queried by two independent groups that came to the same conclusion. You could have reduction in plasminogen levels of 85%, 90% from normal and no increased thromboembolic risk. It doesn't get a whole lot better than that when it comes to the level of evidence that we're not really worried about thromboembolism. Let me tell you, it's not easy to anticoagulate these patients. It's not easy.
It's very important to me that what I'm using to treat my patients does not have a substantial thromboembolic risk. It's important to note that right now, in HHT, the drugs that I do use for patients that don't qualify for clinical trials are things like bevacizumab and pomalidomide that have known thromboembolic risks, right? The bleeding is so significant that we're forced to use those drugs. It's very reassuring to me the safety of plasminogen lowering as we've seen it, and plasminogen inhibition as we've seen it thus far.
That is super clear. Thank you for really reviewing all of that. I think that's super important, and we got a number of questions wanting to clarify that. Maybe we should then shift. We were excited about this approach. Martina, maybe this is to you, what data can we expect to see in the clinical readouts later this year? What does good look like in HHT and von Willebrand? Then maybe, John, you can speak to will the HHT data read through to the von Willebrand disease, given we're going to see the HHT data first? Is that predictive of what we might see, and why do we start that first, and then will that be somewhat predictive of what we see in von Willebrand? Martina, I'll start with you there.
Well, we are now excited to have complete data from our phase I trial, and we will communicate these results later this year about our learnings of safety and pharmacology of ALN-6400 in healthy volunteers. In terms of the HHT phase II study, just to recap, that includes 48 patients with moderate to severe HHT treated with ALN-6400 or placebo over a 24-week double-blind period. Recruitment has gone very well, attesting to the high unmet need in patients with HHT and also to the excitement of our investigators for enrolling patients in this study.
This study is really designed to tell us about safety and tolerability and show us how ALN-6400 can reduce nose bleeding and improve on other hematologic parameters. We expect initial phase II results this year, and we plan to share the full data at a medical conference next year, so in 2027. In terms of what wins would look like in these two parallel phase II studies, a successful outcome for both studies is to demonstrate that ALN-6400 is safe and well-tolerated across these two indications.
In HHT phase II, we'll be focusing on a reduction in bleeding, particularly in nose bleeding, but also the overall blood loss and the impact that has. In our phase II study in von Willebrand disease, we are focusing on this reduction in menstrual bleeding, and we are also looking at reductions in other bleed types that these patients may experience, also to inform our phase III studies. I'll hand it over to John to comment.
I just want to go back to what I emphasized earlier, which is ALN-6400 targets liver-expressed plasminogen, which again, is that central mediator for fibrinolysis, and therefore, we really think that it has the potential, as Dr. Al-Samkari said, to work across bleeding disorders and also bleeding types. We do think that, Pushkal, to answer your question, what we see in HHT will be predictive of what we see in von Willebrand disease.
We're very hopeful that we will have positive results in both studies. We'll have to run them to see, but there's actually a lot of overlap between the bleeding types, even within those two diseases themselves. You see epistaxis or nosebleeds in patients with von Willebrand disease just like you do in HHT, and you see other bleed types, heavy menstrual bleeding, as Dr. Al-Samkari also emphasized. We do think the one will be predictive of the other.
Fantastic. Maybe Dr. Al-Samkari, as a clinician, what's a clinically meaningful reduction or impact in these two diseases?
Yeah. It's a really good question. We've defined this in HHT, an international consensus report that was published last year. In an individual patient, an improvement in epistaxis intensity, frequency, or duration, and we say or, but usually effective therapies affect all three of these domains of epistaxis. An improvement of 30% relative to baseline is a clearly meaningful improvement. That's what we call an epistaxis response.
Between clinical arms of a study, we define the minimal clinically important difference of an improvement of at least 15% relative to baseline in one of these epistaxis parameters, which equates to about 50% of patients achieving that epistaxis response threshold. Okay. This is a difficult disease to treat. It is not easy. It's very clear that patients have significant improvements in their quality of life and in their overall blood loss when we achieve at least a 30% improvement. In von Willebrand disease, an improvement in the annualized bleeding rate of approximately 50% is what I would say would be a clearly meaningful improvement over disease.
Very helpful. Let's shift. We're getting a number of questions around sort of just the market opportunity here and the value. Maybe Christi, I'll bring you into the conversation. How are we thinking about the market opportunity in these two diseases? We've got some epidemiology in our presentation, but can you just speak to what's the addressable proportion of those patients? Where do we see the value? How much is in these indications versus we've talked about a variety of other bleeding disorders. Where does the value come from?
Yeah, no, great questions. Maybe just to pull through a couple of key themes. On value, we expect significant value creation from these opportunities with combined blockbuster potential, and we expect these two first indications to really be the lion's share of value for the asset. I think a theme I've heard today is just the profound unmet need. If we think of HHT, just to go through the numbers, obviously 70,000 patients in the U.S., over a million globally, no approved therapies. The reason why that's important in value, and I think it's been mentioned today, when there's no approved therapies, that often results in not a strong urgency to diagnose. Naturally, from a value perspective, we see this as a market build opportunity. As treatments become available, there's increase in awareness, diagnosis, and ultimately utilization.
To dig a bit deeper on who would this be appropriate for, we anticipate ALN-6400, when thinking about HHT, to be most appropriate for those patients that have moderate to severe disease with high clinical burden. We heard today of the profound clinical burden of this disease, and that's about 30%-40% that meet this criteria. Now it's important to note the current criteria of severity is based on the epistaxis severity score, and that's based on, obviously, nosebleeds alone.
Given the multi-system bleeding disorder that this is, we expect that these measures will evolve over time, taking into account the full clinical burden and hence increasing the opportunity. For von Willebrand's, I'll be quite quick. This is an underserved market. From the numbers, we know 140,000 patients in the U.S., 3 million globally. I think as Dr. Al-Samkari communicated, there is a gap.
There's about 25% of patients treated in hemophilia treatment centers, but our internal estimates say upwards of 80% of those patients are eligible for prophylactic treatment, and they're not getting it. The current treatments are very invasive. They're very time-consuming. They're very burdensome. I love the example of the patient with a job and obviously children. It's very difficult to take IV infusions two to three times a week. We know from other prophylactic markets like HAE and hemophilia that dosing frequency is a very strong commercial differentiator and basically shifts markets in unlocking significant value. I think bottom line is significant value creation, combined blockbuster potential, and both of these disease areas are just waiting for this next wave of innovation that we've seen in some of the other areas that we've mentioned.
That's fantastic. I guess a related question came in which is people were noting that Incyte recently did a transaction in this space of treating von Willebrand disease. Does that change our assessment of the opportunity here and for more innovation?
Not at all. If anything, it's another kind of external proof point or validation of the opportunity that we see. We really look forward to bringing forward this innovation at pace, and we do believe very strongly that our quarterly dosing profile, especially in von Willebrand disease, is quite differentiated and again, unlocking significant value. It's great to see others that recognize the opportunity that we're talking about today.
Great. I think we just have time for one or two more questions. Maybe, Dr. Al-Samkari, for you, Christi, feel free to add if you do, why are the diagnosis rates so low for these HHT patients? Why are the treatment rates so low for the von Willebrand patients? What's the diagnostic journey for these patients? Is there genetic testing? If you could just kind of spend a couple moments to tell people why they are so low and where-
Absolutely. In HHT, the CHORUS registry recently, the recent publication, it taught us that in the U.S., the average patient with HHT has clear signs and symptoms of HHT by age 16, but is only diagnosed on average at age 37. All right. Over a two-decade diagnostic delay, which is really unacceptable. The reality here is that it's a manifestation of the fact this is an inherited bleeding disorder that's progressive. It gets worse as people get older and really adult docs, and I'm an adult doc myself, so I will speak for us, right? We don't do the best job in the world at diagnosing inherited disorders. Really truly, many people assume that the pediatricians have done that or are supposed to do that, and many children don't have that severe manifestations of disease.
The most severe manifestations in HHT are really between ages 30 and 70. That's when things come up, and these patients are adults. I teach everyone now, a recurrent epistaxis in an adult is HHT until proven otherwise, because it's the most morbid potential cause of that, and quite frankly, usually ends up being the diagnosis. Why is it under-diagnosed? A lot of sort of fragmentation of care, number one. There are about 28 HHT centers of excellence in the U.S., a number that is increasing. Not all of those centers are even funded by the government yet. That's changing. There are 145 hemophilia treatment centers for half the number of patients. Most states don't even have an HHT center of excellence yet. Now, starting in 2022, HHT has federal funding.
That funding is going up and has already gone up, and more and more HHT centers are being opened. Certainly, when we have approved therapies, that's an if-you-build-it-they-will-come kind of situation. It's an educational gap, and that educational gap is something that the federal funding is explicitly addressing with funding for CME for docs and for centers to teach their surrounding community. The under-diagnosis rate is getting better. There's actually studies that have shown these huge increases in prevalence in the U.S. of HHT in the last 10-15 years, and that's not because more patients have suddenly come down with HHT, it's because of increased diagnosis.
This is really going into hyper-speed right now, and I suspect that within the next 5-10 years, our under-diagnosis rate will be down to 20%-30% from the current 60% or so that it is today. Why are so many patients with von Willebrand disease not adequately treated? It's because you either have a toy hammer or a sledgehammer. There's nothing in between, right? The toy hammer is the desmopressin, the sledgehammer is the prophylactic infusions. A lot of these patients are just kind of left in the middle and even a lot of docs feel like, "Well, your disease isn't bad enough for three infusions of Wilate every week. It's too much for tranexamic acid and desmopressin." These patients are sort of left in the middle. I really think that obviously, advances here will help to address that issue.
Very helpful. Thank you for clearing up. Clearly a lot of room for improvement here, and hopefully we can make a difference in that as we develop medicines. I think the last question that came in, we did get a number around what our phase III plans are. Maybe I'll start the first part, what do we know about regulatory endpoints? John, I'll say to you should speak a bit to what we understand about endpoints. I can just speak about the phase III plans. I think we've highlighted in our presentation, obviously we're waiting for phase II data first, that's a clear milestone we need to get through, we're anticipating phase II initial results, as Martina said, at the end of this year for HHT, we'll plan to share those in early 2027 at a scientific meeting.
Von Willebrand's, that study is ongoing, we'll wait to see. Pending positive results in HHT, we may start a phase III next year in 2027, von Willebrand's to follow. We'll give you more updates on that. Again, these are programs that we think, given that the short timeline, we may be able to conduct fairly rapidly, again, assuming compelling efficacy and safety data along the way. Maybe, John, you can just speak to what the thinking is around what registrational endpoints might look like in these diseases.
Sure. Of course, Pushkal, I'll give a concise answer since I know we're short on time. For von Willebrand disease, I think it's pretty clear, as Martina said in the slide, the primary endpoint is expected to be ABR. There's a clear precedent in von Willebrand disease trials that have resulted in marketed approvals for ABR to be used, I think that's very clear, that's what we'll use. For HHT, there are no approved treatments, therefore there is less certainty. However, we are pretty convinced that because epistaxis is so important from a disease burden perspective to patients and to physicians, that will be one component that we need to take into account. Again, we think we will have an impact on that in our phase II study. We have to show it.
Obviously we also think that other things like red cell transfusions, IV iron infusions, healthcare resource utilization, and anemia are also important things that we need to take into account when we're thinking about phase III endpoints.
Fantastic. All right. Well, look, I think that brings us to an end. I want to thank everyone for your questions who participated in the webinar. Particular thanks, John, Martina, Christi, to each of you, and especially Dr. Al-Samkari for sharing your insights as a treating physician to today's discussion. This concludes today's RNAi Roundtable, you can access the replay of the webinar and download the slides in the Capella section of Alnylam's website. The 10th season of the Roundtable series continues on September 17th with a session on zilebesiran, which has the potential to reduce the incidence of cardiovascular events by providing continuous control of blood pressure, followed by a spotlight on ALN-HTT02, which aims to reduce the progression of Huntington's disease on October 26th. Thank you all for joining, and have a great day.
Ladies and gentlemen, that concludes today's meeting. Thank you all for joining. You may now disconnect.