Good day, and thank you for standing by. Welcome to the Prime Medicine Wilson disease KOL event conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Greg Dearborn , Head of Investor Relations. Please go ahead.
Good morning, everyone, and welcome to Prime Medicine's virtual event to discuss our liver disease franchise and strategy focused on Wilson disease. Our goal this morning is to provide additional detail on our strategy in Wilson disease and to explain how we are leveraging the modularity of our platform to develop prime editors that have the potential to offer durable cures for patients. You'll hear perspectives from a key opinion leader and from our management team as we discuss the opportunity ahead of us. Before we begin, I remind you that today's remarks will include forward-looking statements. Such statements are subject to the risks and uncertainties that could cause actual results to differ materially from those described. These risks are detailed in our SEC filings, including our most recent annual and quarterly reports.
This call will be recorded, and the recording can be found under the event section of our investor relations website. The slides we'll be referencing today are available within the webcast and on our website. We are joined today by three speakers. First, you will hear from Allan Reine, our Chief Financial Officer, who will provide a brief introduction to Prime Medicine, contextualize Wilson disease as a cornerstone of our strategy, and describe the global opportunity. Then, Dr. Michael Schilsky, a hepatologist and one of the world's foremost experts in Wilson disease, will share a clinician's perspective on the disease, its presentation, diagnosis, and current disease management. Finally, Dr. Mohammed Asmal, our Chief Medical Officer, will outline Prime Medicine's approach to Wilson disease, review our existing and new preclinical data presented at AASLD this past weekend, and walk through our clinical development plans.
With that, it's my pleasure to turn the call over to Allan.
Thank you, Greg, and good morning, everyone. It's a pleasure to be on with you today to speak about Prime Medicine and our efforts in Wilson disease. To quickly orient you to today's event, we've designed the agenda to provide insight into our corporate and clinical development strategy. Now, we stand at a real inflection point for Prime Medicine and prime editing technology. Prime editing has the potential to fundamentally transform the care and treatment of genetic diseases and beyond. Over the past five years, we've generated clinical and preclinical data that demonstrate the unequivocal power of prime editing to change patients' lives, offering potentially curative benefits in a matter of weeks. Now, our strategy is initially focused on programs targeting diseases with high unmet need, well-understood biology, clearly defined clinical and regulatory pathways, and the potential for meaningful commercial impact.
To that end, we're focusing initially on Wilson disease and alpha-1 antitrypsin deficiency, cystic fibrosis, and ex vivo CAR- T therapy through our BMS collaboration. And today, we are delighted to share additional details on our program for Wilson disease. Now, turning to slide four. Now, first, our Wilson disease is an area of high unmet need. There are no curative therapies available, and the current standards of care, they're highly burdensome, they can be costly, they're limited by tolerability, and compliance tends to be very low. Second, prime editing has the potential to provide a durable cure by precisely and permanently fixing the mutation at its source and restoring normal enzyme function, and subsequently normalizing copper metabolism and halting and hopefully reversing disease.
Now, as part of today's discussion, we will review new preclinical data shared for the first time at the American Association for the Study of Liver Diseases Conference this past weekend, which further confirmed that prime editing has the potential to revert a diseased patient completely back to a normal phenotype. We believe this represents one of the most complete demonstrations to date of molecular correction translating into phenotypic normalization in a Wilson disease model and provides further evidence of the transformative power of our approach. Finally, we at Prime Medicine have a deep and nuanced understanding of the opportunity in Wilson's disease and are leveraging the modularity of our platform to quickly and efficiently develop prime editors for the most prevalent mutations globally.
While our initial efforts are focused on a mutation called H1069Q, which is the most prevalent mutation in the Caucasian population, and R778L, which is the most prevalent mutation in the Asian population, our ambitions are much larger, and we plan to expand rapidly into additional mutations that would allow us to address this multi-billion-dollar global market in Wilson's disease and develop fast followers and other liver-directed indications. Now, turning to slide five and taking a bit of a step back, allow me to begin with a brief introduction to Prime Medicine. Now, Prime Medicine was founded in David Liu's lab to harness the full potential of prime editing, a next-generation gene editing technology that allows us to precisely rewrite DNA. This technology is highly differentiated from other gene editing approaches. Prime Editing is the most versatile, and it's the safest way to edit the genome.
Other gene editing approaches have many liabilities that prime editing does not have. There's the potential to create neoepitopes from different indels or the body to view something as foreign. There's the risk of chromosomal rearrangements and translocations, risk of off-target editing, and in the case of base editing, the potential for bystander edits. Now, prime editing, again, our programs do not result in any of these. It is the very highly differentiated technology, and I believe will be the primary way genes are edited in the future to target many different diseases and helping many patients across the globe. Now, why is prime editing different? Well, we use what's called a modified Cas9 nickase, meaning we make single-stranded breaks in DNA versus double-stranded breaks. This is very important as we think about off-target edits, chromosomal rearrangements, and translocations that I mentioned before.
Now, this Cas9 nickase enzyme is fused to a reverse transcriptase enzyme along with a specialized guide RNA so we can rewrite or dictate what base pairs get written into the DNA, and this is really the only technology that can do this, and we can do this with a very high degree of precision. We can insert, we can delete, or we could correct stretches of DNA, as you see in slide six, and we can even put in multi-kilobase of DNA as well using our PASSIGE technology, so that means we can fix a wide range of disease-causing mutations, including the missense transversion mutations and frameshift mutations that underlie Wilson's disease. On slide seven, we're just highlighting our current pipeline. This is where we are today.
I just want to emphasize again the potential to slot in additional liver programs once we demonstrate initial success in Wilson disease and alpha-1 antitrypsin deficiency. The modular platform that we have will allow us to incur lower cost and move with higher speed as we think about additional programs. There's a great degree of synergy as we go from liver program to liver program. There's also a lot of opportunity beyond the tissue types listed here. We believe there's a tremendous amount of potential as we think about using prime editing in other cell-based therapies, both ex vivo and in vivo, in addition to diseases of the eye, diseases of the ear, and diseases of the brain, just to name a few. Now, turning to slide eight, from a timeline perspective, our IND-enabling studies are currently ongoing for both Wilson disease and alpha-1 antitrypsin deficiency.
We expect to file an IND and/or CTA for Wilson disease in the first half of 2026, and for alpha-1 antitrypsin deficiency, because of the modularity of our platform, that's only a few months behind Wilson disease, and we expect to file an IND and/or CTA in the middle of 2026, with data for both programs expected in 2027. Now, on slide nine, this slide really makes a crucial point. All of our liver programs share a common foundation, our proprietary universal lipid nanoparticle delivery. Now, the drug product is composed of eight components, including lipids, cholesterol, a targeting ligand in this instance, and RNA, six of which are consistent across programs. Now, this commonality enables us to leverage shared learnings and infrastructure, such as toxicology studies, manufacturing processes, and regulatory experience, again, helping us accelerate development, reduce risk, and lower costs for subsequent efforts.
This approach applies both as we transition from Wilson disease to alpha-1 antitrypsin deficiency and, as we call it, our March of the Chromosome strategy, where we use our initial work in H1069Q mutation in Wilson disease and R778L to inform the development of fast follow-on programs for other prevalent disease-driving mutations in Wilson disease. Now, turning to slide 10 and Wilson disease and the commercial opportunity, I want to give you a brief overview of how we think about this market and why we at Prime are so excited about this program. Although Wilson is a rare disease, it's a significant market opportunity in the US and globally. There are potentially 25,000 prime editing addressable patients in the three main geographies alone: US, Europe, and Japan. In the US and Europe, there are about 11,000 Wilson disease patients in each geography.
We think with a handful of prime editors, we can target 60% plus of this population. Turning to Asia and the Japan market, there is a higher prevalence rate there. Based on the mutational backdrop, we believe we can potentially get up to even 70% plus of these patients, again, with a handful of prime editors. On the very low end, we think this represents a $20 billion plus commercial opportunity. We think this could easily be a $40 billion plus opportunity globally. I also think it's important to note that the incidence rate here of a few hundred patients per year. So as we think about the long-term value of Prime, stacking up incidence rates across a number of indications really creates a business model beyond treating just prevalent populations. Now, turning to slide 11, I want to talk specifically about Wilson's disease.
As I've explained before, it's caused by a well-characterized mutation in the ATP7B gene. There are clear biomarkers of copper metabolism, and this represents a significant unmet need that Dr. Schilsky will delve into in greater detail. Now, prime editing offers the potential for a one-time curative treatment for patients suffering from Wilson disease. Our strategy begins with PM577, which targets the H1069Q mutation. We call this our anchor mutation. We've established preclinical proof of concept, which Mohammed will expand upon later. And we anticipate enrolling H1069Q patients following our regulatory filing in the first half of next year. Now, we're developing R778L as a fast follow-on. And then we have a list of a handful of other prevalent mutations that we will go after in the relevant geographies.
Now, because our Wilson disease programs use the same backbone, swapping out only the guide sequence, we can expand rapidly from our initial work with PM577 to develop additional prime editors to address other disease-causing mutations in Wilson disease. And as I mentioned a moment ago, we've already identified our initial expansion opportunities. With that, I'd like to hand it over to Dr. Michael Schilsky, who will provide the physician's perspective on Wilson disease.
Thank you, Allan. For those that are on the slide deck in the next few minutes, I'm going to refer to only four of the slides, starting with that of the cartoon of the liver cells. A little background for you. Wilson disease is a disorder of copper transport in humans inherited in an autosomal recessive fashion.
And the underlying pathology is the gene product for ATP7B that Allan has been referring to for the correction that is critical for maintenance of copper homeostasis. And the liver is where this is highly expressed. And in the liver cell, ATP7B is responsible for biliary and for the bioincorporation of copper into ceruloplasmin. Now, on that little cartoon, which is a simplified schema of copper handling, shown on the left is the normal function, and on the right is the consequence of ATP7B dysfunction, with those little dots representing copper accumulation in the liver cells due to the reduced biliary copper excretion that is in part dependent on ATP7B. And because of the high expression and main expression of ATP7B in liver cells, the liver is really critical for copper homeostasis in the body.
It's the target when ATP7B functions impaired and copper accumulates pathologically in the liver and then later in other organs as the capacity of the liver is sort of overloaded, and the main site that we concern ourselves with, although many organs through the central nervous system can be affected. The proof that the targeting of the liver for the correction of the genetic defect underlying Wilson disease is essential for restoration of normal copper homeostasis is provided by outcomes of liver transplantation for Wilson disease, where normal copper for the medical therapy for treating patients for copper overload is needed. I refer next to the slide showing the relationship of time for the diagnosis of Wilson disease and patient disease expression. The diagnosis of Wilson disease is established by a matrix of clinical complemented by testing for pathogenic ATP7B mutations.
Most asymptomatic patients, or those with just liver-related signs or symptoms, typically present in the second decade of life or in the late first decade. There are some and those with neurologic disease about a decade later. Patients with neurologic or psychiatric disease typically have delays in diagnosis of one to two years as their symptoms are really thought to be other disorders initially, and those are sort of mistaken and then later on, when considered, then they become potentially partially treatable, or unfortunately, because of delays, some are left with disability for life. In practice, the current diagnosis of Wilson disease is made most often in the second and third decades of life when clinical signs and symptoms become evident. There is a lead time bias as to what the clinical phenotype of the disease is, asymptomatic and then hepatic presentations that occur in younger patients.
Typically, older patients may begin developing manifestations of the central nervous system, copper accumulation, such as neurologic or psychiatric symptoms. This is shown in the graph that shows the natural history of disease over time without treatment. Now, the next figure I want to refer to is that one from one of our guidances from the AASLD. This shows the natural history of the disease without treatment and highlights what the goals of treatment would be in different phases of disease with our current pharmacotherapy. In young patients, there are first laboratory abnormalities before symptoms begin. Then with time, there's progressive liver damage. As you enter the second decade, there's a risk of developing signs and symptoms of neurologic or psychiatric disease. Untreated patients go on to have consequences of advanced liver failure, and death is inevitable.
A small percentage of acute liver failure develops typically in the second or third decade of life. Before the development of more disease and keep patients asymptomatic, once signs and symptoms develop, the goal is to help reverse any injury, then prevent progression. However, when severe disease is present, then rescue therapies, including liver transplant, are needed. The treatment slide. The first treatments were developed in Wilson disease in the 1950s and the first oral therapies in the 1960s with D-penicillamin e and then trientine. These were chelators, initially grabbers of copper in the circulation for excretion. The second drug, trientine, that I mentioned was developed due to the development of both hypersensitivity reactions that occurred with early use and later toxicities, including nephritis, nephrotic syndrome, lupus-like reactions, and other late dermatologic effects with the long-term use of D-penicillamine.
Due to the ability to titrate the dose to increase urine copper excretion, this was typically the way we did follow patients. Now, there is an additional concern in early treatment of patients with neurological involvement with chelation therapy could be accompanied by worsening of disease and the risk of permanent disability in many of these individuals. Later on, zinc salts were introduced by Dutch investigators and then studied later on by Brewer and his colleagues at the University of Michigan, and this drug, or salt, well, I should say elemental treatment, is approved for maintenance therapy of Wilson disease. There are really no perfect medications that are good for 100% of patients with failure rates between 10% to 20% for standard therapies and up to a 30% rate of side effects noted for chronic therapy.
Most importantly, there are very significant rates of non-adherence to therapy, which begs the question of whether we can achieve a curative treatment that will benefit patients with Wilson disease. While liver transplant can be curative, it comes with both surgical risks as well as the need for lifelong immune suppression. Reserve liver transplant for rescue therapy for the 5% of patients presenting with acute liver failure and others with advanced end-stage liver disease, which are beyond the capability of rescue by pharmacotherapy. Transplant for neurologic Wilson disease is commonly used to prognosticate patients for this. However, there are some successes reported, and particularly by our colleagues from France. Aside from symptomatic treatment for Wilson disease, for example, for tremors or anxiety, depression, there is therapeutic intervention for our patients, which is dietary restriction of copper, which is another burden upon patients' quality of life.
And for some, this is an extreme hardship. For example, our vegetarian patients who then have to limit their amounts of soy, legumes, or other nuts, and some shellfish and mushrooms. And another issue with diet is the inability of the current to take these medications at the same time patients are eating. And therefore, most patients have to construct a daily schedule to avoid taking their medication, or indeed, half the time they forget, and then they become less effective when taken with food. Now, there are no current treatments that have undergone human trials yet that are capable of enhancing biliary copper excretion outside of the early stage of AAV -mediated. And even with that, as yet, no one's really demonstrated enhanced biliary copper excretion following gene transfer. Studies on tetrathiomolybdate had some hopes of enhancing biliary copper excretion based on some preclinical studies.
However, the PET imaging studies with radiocopper showed more that it was blocking copper absorption. And yet, we still need to see more data as to whether it really is changing biliary excretion. And if it is merely blocking copper, then it is really comparable to what zinc is doing as well. Therefore, if gene is successful and without off-target effect, this really offers the best opportunity for effectively achieving a cure for Wilson disease. Now, I'll turn the discussion back over to Dr. Mohammed Asmal.
Thank you, Dr. Schilsky. Your insights from clinical practice are greatly appreciated. Turning to slide 18. In short, we believe prime editing can fundamentally change how Wilson disease is treated. Today, the standard of care is built around chronic chelation therapy and strict dietary restrictions. Patients take large pill burdens, often multiple times per day under fasting conditions, for the rest of their lives.
Even when adherence is excellent, these regimens are only partially effective, and many patients eventually progress to liver failure, where transplantation becomes the only curative option. Our vision with prime editing is very different. A one-time therapy that precisely and permanently repairs the ATP7B gene, restoring physiologic copper transport. By returning hepatocytes to wild-type function, we aim to normalize copper metabolism, halt disease progression, and potentially provide a lifelong cure. In short, we're moving from managing copper overload to truly correcting the disease at its genetic source, a transformation in both patient experience and long-term outcome. The preclinical package supporting PM577 continues to exceed expectations and provides a very strong foundation to our IND submission. Beginning with delivery, as we've shared before, we've engineered an optimized lipid nanoparticle specifically tuned for hepatocyte uptake. This LNP achieves high intracellular delivery efficiency with minimal innate immune activation.
Regarding safety, both mouse and non-human primate studies have shown an encouraging safety profile. No evidence of off-target editing, no meaningful cytokine activation, and only transient reversible changes in liver function tests at clinically relevant doses. From an efficacy standpoint, we see efficient correction of both H1069Q and R778L mutations in fully humanized mouse models. And today, we are excited to review new data in a partially humanized mouse model believed to better recapitulate the human pattern of hepatic copper trafficking and biliary excretion than the fully humanized system. These data, which we shared at AASLD this weekend, demonstrate clear phenotypic rescue, complete restoration of hepatic copper concentration in vivo, and normalization of copper excretion. In addition, using radio-labeled copper PET imaging, we can now visualize copper being rerouted through the correct biliary pathway, providing a direct, non-invasive functional readout of ATP7B activity.
Together, these results build a compelling case that PM577 can safely achieve durable functional correction in vivo, exactly what we want to replicate in the clinic. We start with editing efficiency on slide 20. The data on this slide are from previously published studies demonstrating efficient correction of the two most prevalent pathogenic variants in ATP7B, H1069Q and R778L, using prime editors delivered with our universal liver-targeted lipid nanoparticle. In these fully humanized homozygous mouse models, we achieved hepatocyte editing efficiencies approaching 90% following a single administration at clinically relevant doses. These data were originally presented earlier this year and have now been reproduced across multiple independent experiments. Just as importantly, using an extensive suite of off-target assays, we have detected no off-target editing. After in silico identification of an exhaustive list of potential off-target sites, we evaluated hundreds of these sites in vitro in a patient-derived cell line.
We detected no quantifiable off-target editing at any of these nominated sites. The key takeaway here is that prime editing can reproducibly achieve efficient and precise on-target correction across multiple ATP7B genotypes using a single LNP backbone, highlighting both the robustness and modularity of our platform. Turning to the next slide, these data were newly presented at the 2025 AASLD meeting and represent our most advanced preclinical evaluation of PM577, our lead prime editor targeting the H1069Q mutation. Following a single systemic dose of our optimized prime editor, we observed greater than 80% hepatocyte editing. Most importantly, this level of correction was accompanied by a complete restoration of hepatic copper concentrations to wild-type levels, as shown in the middle panel. By eight weeks post-dose, hepatic copper content in the treated animals was indistinguishable from wild-type controls. We also performed a functional copper excretion assay using radio-labeled copper chloride.
At four weeks post-treatment, treated animals demonstrated normalized biliary excretion of copper consistent with restoration of functional ATP7B protein. Taken together, these data confirm that prime editing not only corrected the disease-causing mutation at the DNA level but also restored copper handling at the physiologic level. We believe this represents one of the most complete demonstrations to date of molecular correction translating into phenotypic normalization in an in vivo Wilson model. Finally, on slide 22, to complement the biochemical and molecular endpoints, we incorporated copper PET imaging as a non-invasive translational readout of ATP7B function. This slide summarizes findings from a PET imaging study that we also presented at AASLD 2024 using radio-labeled copper chloride to visualize copper distribution and clearance in vivo.
On the left, you see wild-type mice, where copper is rapidly taken up by the liver and efficiently cleared through the biliary system into the gut within 24 hours, producing a high signal in the intestines and minimal hepatic retention. In contrast, the middle panel shows the partially humanized ATP7B mutant animals, which, when left untreated, display persistent hepatic copper retention and reduced biliary clearance, a pattern consistent with the pathophysiology of Wilson disease. The image on the right shows prime-edited H1069Q mutant mice four weeks after treatment. These animals exhibit copper kinetics nearly indistinguishable from wild-type controls, with loss of the hepatic signal and restoration of normal intestinal and fecal distribution within 24 hours. This imaging modality is important because it provides a quantitative, longitudinal, and translatable biomarker for assessing treatment responses in humans. Liver quantification via biopsy is not always feasible for all patients in clinical trials.
However, copper PET imaging offers a non-invasive way to monitor copper metabolism dynamically. Collectively, the copper PET and excretion data, together with the high editing efficiency and normalization of hepatic copper levels, demonstrate full restoration of ATP7B function following prime editing. These results form a critical bridge between our preclinical studies and the translational strategy we'll carry forward into the clinic. Now that we've established robust preclinical proof of concept for PM577, let me briefly outline our clinical development strategy. We are advancing PM577 towards an IND and/or CTA filing in the first half of 2026, which will mark the first in-human evaluation of prime editing in an in vivo setting. Our planned phase I/II study will initially enroll adult patients with Wilson disease who are maintained on standard chelation and/or zinc therapy. The primary endpoints will focus on safety and tolerability.
We will also measure key efficacy biomarkers, including ceruloplasmin, serum copper, and urinary copper, and importantly, incorporate copper PET imaging as a non-invasive translational tool to assess restoration of ATP7B-mediated copper transport in some patients. Over time, the study is designed to evaluate whether patients can safely reduce and eventually discontinue chelation therapy while maintaining normal copper balance. Long-term follow-up will help confirm the durability of editing and the stability of copper metabolism. We expect to initiate dosing shortly after regulatory clearance and to generate initial proof of concept data in 2027. Those results will represent a critical milestone for Prime Medicine, demonstrating clinical validation of in vivo prime editing in a systemic genetic disease and potentially enabling us to expand into additional Wilson disease populations with global impact. With that, let me turn it back to Allan to close. Thank you, Mohammed.
As you've heard today, we believe prime editing offers the opportunity to deliver a durable, one-time therapy that corrects the genetic defect in Wilson disease and can transform patient lives. As we transition from preclinical proof of concept to the clinic for our first in vivo program in Wilson disease, I want to close by framing what the next 18 to 24 months look like for Prime Medicine. Now, first, 2025 has been a pivotal year for the company. We had clinical proof of concept that we've already established in our first clinical program in chronic granulomatous disease. And now, two liver programs that are advancing in parallel into the clinic were really entering a new era of prime editing, one defined by clinical execution and our platform modularity. Looking ahead to 2026, our focus will be on translating these results into human studies.
For PM577 in Wilson disease, we are preparing to file an IND and/or CTA in the first half of 2026, initiating our phase I/II trials shortly thereafter. That will provide the first human data for prime editing in an in vivo setting with proof of concept efficacy data expected in 2027. In parallel, our a
lpha-1 antitrypsin deficiency program called PM647 is on track for a mid-2026 IND or CTA regulatory filing, positioning both liver programs to generate initial human proof of concept data in 2027. For cystic fibrosis, supported by our collaboration with the CF Foundation, we plan to share additional in vivo proof of concept data next year as we march towards IND-enabling studies for that program. Now, this coordinated execution reflects the strength of our modular platform.
Each program within a given tissue builds on the same underlying prime editor architecture and delivery system, potentially enabling us to leverage shared toxicology manufacturing and regulatory experience. As a result, every success compounds the next, accelerating development while reducing cost and risk. On the business side, we continue to pursue strategic partnerships to extend our reach and reinforce our balance sheet. Our existing collaborations with Bristol Myers Squibb and ex vivo CAR-T cell therapies, and with the Cystic Fibrosis Foundation exemplify this approach. We expect to enhance additional partnerships that can both accelerate pipeline progression and expand the application of prime editing into new therapeutic areas. Taken together, these milestones mark the beginning of a period of sustained data generation across multiple indications.
By 2027, again, we expect to have human clinical readouts for our first two in vivo liver programs, firmly establishing Prime Medicine as a clinical stage leader in gene editing. In short, we are moving from discovery to delivery, from demonstrating what prime editing can do in preclinical models to showing what it can do for patients. I strongly believe today more than ever that prime editing is the gene editing modality of the future, and this technology will transform the lives of many people suffering from disease across the globe. I want to thank Dr. Schilsky for sharing his clinical insights, for Dr. Mohammed Asmal for detailing our clinical approach, and I want to thank you all for joining us today. With that, we are delighted to take your questions. As time permits, Operator, please open the queue.
As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from Maury Raycroft with Jefferies. Your line is open.
Hi, good morning. Congrats on the progress, and thanks for taking my questions and hosting this event. Maybe to start off, if you could just talk about what the bar is for functional cure in Wilson's and just the importance of demonstrating reduction or elimination in chelator or zinc use, or is it more about normalization of copper? And yeah, maybe talk more about that.
Thanks, Maury. I think for that question, why don't we start with Dr. Schilsky, and then we can also pass it off to Mohammed to fill in as well.
Sure. That's a great question. And for sure, the two actually follow together. So if you can normalize the copper metabolism and reduce copper in the liver where it's pathologic, you'll also reduce it from spilling into other sites and achieve the goal of actually eliminating the need for standard of care therapy. So I think the two go together. Got it. And maybe talk about just the best way to assess improvement in liver pathology in these patients. Would you be relying on FibroScan in a clinical study, or how would you be assessing just the improvement in these patients? So to the first part, I mean, to know that you've achieved the reduction in copper, patients don't like to have multiple biopsies, but Mohammed Asmal referred correctly to the potential use of PET imaging, which can be non-invasively employed.
Those are things that are being used even in our standard clinical practice to look at how urine copper excretion is. And there's also some new development in terms of biomarkers of bioavailable copper, things like the non-ceruloplasmin copper by speciation that could be employed to look at the changes in the circulation that should parallel what's going on in the liver. So I think we have a much better opportunity to have a handle of using both these non-invasive surrogate markers. You also point out the use of elastography, which is incredible. We have both the use of the physical elastography, whether it's by sonographic means or MR means, but there's also use of the non-invasive testing. And some of our other registry studies have been working on sort of establishing the boundaries of what the cutoffs are for disease-specific states, such as Wilson disease, using that.
So those can all be looked at in tandem and provide us with a more global view on how the patient is doing. Got it. And maybe last quick question, just would you use this gene editing technology in patients with compensated cirrhosis, and what proportion of patients could have reversible liver pathology? So the answer to that is you point out correctly in the beginning, using decompensated cirrhosis would be inadvisable for many reasons. One, for safety, and second is in terms of whether we can deliver product as well once you have the microcirculation of the liver disrupted. But I believe we will see, and again, this is probability based on our knowledge of what happens with current treatment as well as in animal models, that you'll see a regression of inflammation.
Over time, we do see reduction in liver stiffness, and in the smaller numbers of patients that have had multiple biopsies over time, standard of care treatment can cause regression in fibrosis. So the surrogate marker of decreased liver stiffness, the parallel improvement in function, surrogate marker of platelets, which also indicates the recompensation and improvement in the microcirculation, they all go together. And so I think we have an opportunity to treat a large spectrum of patients. And in the future, with other tricks one can do, you can actually potentially reach even the more advanced patients. But I think you have to walk before you run. Yeah. And maybe, Mohammed, do you want to comment as well on sort of the clinical plans as we think about decompensated liver disease at the outset and in the future?
Yeah, certainly. I think, as Dr. Schilsky pointed out, it would be ill-advised to go after individuals with decompensated cirrhosis right off the bat as they pose a higher safety risk. So our plan would be to initially go to individuals who do not have decompensated disease. Now, most individuals with Wilson's disease do have some underlying degree of liver damage, so we will need to address those individuals upfront. I think once we have established a comprehensive safety and efficacy package in individuals with moderate liver disease, I think then we may begin to investigate individuals with more advanced disease. We are optimistic that with a safe and effective therapeutic, we may be able to establish and demonstrate some reversal even in the most advanced settings, as has previously been demonstrated for individuals with viral hepatitis receiving antiviral therapy.
Got it. A hopeful perspective. Thanks for taking my questions. Thank you.
Our next question comes from Samantha Semenkow with Citi. Your line is open.
Hi, good morning, and thanks very much for taking the questions. I have a few for you, Dr., patient's journey with Wilson's, do you think it does make sense for treating them? I guess I'm asking how early can you treat them? How severe do they need to be for a prime editing therapy? And then just building on that as well, I guess how many of your patients do you think today, if you had the therapy, would be eligible for treatment?
Okay. Well, take the last part first. So in the population in the United States, a third of our patients have the H1069Q mutation. So as heterozygous and about 10% are likely of that.
Only we have less in the Asian population, so here in the United States, so probably only a few %. Again, you have to look at this worldwide and in terms of which populations around the world. Also the fact that over time, you're going to develop technology, again, editors for other mutations in the disease, whether it's going to be all single point or hotspots in the gene, that can then be expanded. Certainly, I think there is great potential to help a lot of patients here, especially Spike. Now, as to when to treat, in the beginning, obviously, because you have an underlying liver disease, you probably will start with treated patients so that way you have the best safety profile and then can withdraw standard of care therapy.
Once we know safety and efficiency, where we could potentially turn around and even go into untreated individuals that are not having any consequence of their disease, but you also have to be mindful, as I stated, that you have a background liver disease. Even in asymptomatic patients, there's accumulation of copper, and there can be some background inflammation, and so you do want to have, we can take advantage of what we have currently and hopefully even other new therapies to get the patient in the best condition to treat, so I can really see short of those with decompensated disease early on and eventually, perhaps all patients.
Okay. That's super helpful. Thank you for that, and just one for Allan, I guess, as well, just on strategy.
If you look into the future and you're thinking about expanding the pipeline beyond this first edit for Wilson's and AATD, how do you think about balancing expanding into additional mutations for Wilson's disease, let's say, versus adding new programs to your pipeline?
Yeah. I mean, look, I think the ability is going to be there to do both. I mean, as we think about Wilson's, the cost of going our belief is the cost of going into additional mutations is going to be very low and very fast. There may be a world where we can even do this with in vitro data in the future if the translation's there without even getting in vivo data.
I think the incremental cost and the benefit of even just getting to some of the patients that are even 1% or low single-digit % will be a very positive sort of net present value to make that small investment, especially as we believe that can get slotted into the same IND or other regulatory filings, and hopefully that'll play out in the commercial setting as well. At the same time, once we, as we believe, we'll establish good safety and efficacy with Wilson disease and Alpha-1, the ability to really pivot to other liver indications, especially where prime editing is, we believe, the better approach. We've got a number of diseases that we're evaluating today. Some are orphan rare diseases, and some are actually much larger diseases where we're not looking at thousands of patients, but hundreds of thousands or millions of patients.
So there's a lot of potential opportunity here, and I think it'll be a great cost-effective way to explore both.
Super helpful. Thanks very much for taking the questions.
Thank you. As a reminder to ask a question, please press star 11 on your telephone. Wait for your name to be announced. In the interest of time, we ask that you please limit yourself to one question. Our next question comes from Troy Langford with TD Cowen. Your line is open.
Hi. Thanks for taking our question and congrats on all the progress. Maybe just one for Dr. Schilsky.
Maybe just to follow up to some of the other questions asked, I guess what percent of your H1069Q mutant patients would you say are currently not well-managed or not adherent to current standard of care chelating agents or dietary therapy and might make better candidates for a prime editing therapy for Wilson disease?
You can look at it two ways. One, which people are having a lot of trouble. Again, about 30% to 50% of patients become non-adherent over the course of their time. The second, you can look at it as enhancing quality of life of patients. If you ask patients why they want to look at curative therapies, they tell you they don't want to have to worry about timing their medicines to food. They want to eat what they want, and they want to be normal.
So it's not just a question of failing therapy, and we're good for most of our patients. But again, if you take the very long-term view, we're going to have trouble for patients. And then also the question becomes, as we start to understand the natural history of the disease over time, there's significant associations of depression, major depressive disorder, anxiety disorders. And these can still occur while on current standard of care. And so whether an early treatment or curative treatment can even give you better quality of life overall to eliminate the development of these other associated problems that we see in high frequency in patients.
I tthink there's the potential there. And I think patients really would welcome that.
Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Hi. This is Srinath for Salveen. Thank you for taking our question. You've spoken a great deal about the LNP, which is the basis of your platform. What are your thoughts on AAV-based therapies like the one that Ultragenyx is developing on Wilson's and how do you see it being differentiated from your approach?
Yeah. Thank you for the question. I can take that, and others are free to add. We think this is a very differentiated approach to a gene therapy. Obviously, with prime editing, we're making a permanent change in the DNA, and that means essentially that all daughter cells will have that change as well. With the AAV approach, they're using a truncated version of the gene. So it's actually not the full gene. It does have, obviously, the catalytic complex.
But as you think about different forms of the gene and tertiary structures, what that total function is, it's still a little bit in question. I think the other thing that's important is with AAV, it can wane over time as you think about years. If you think about hepatocytes, they turn over less frequently than many other cells, but we don't think they turn over every, call it, six months, year, two years. So that effect could be diluted out over time. And there's other drawbacks, obviously, with AAV. You can only be dosed once, as one example. So we think this is, frankly, a real cure for this disease, a one-time cure. And we think there are a lot of advantages versus other types of therapy, AAV approaches included. I don't know if anyone else wants to mention anything on that.
Yeah. The other thing with AAV, once it gets in cells, first of all, you end up premedicating patients and keeping them on immunosuppression for a period of time. And even when you stop that, you have to watch and wait and see if they develop any more inflammatory changes, which are usually then responsive to immune suppression just to maintain those cells. But that's another risk to a patient.
Thank you. Our next question comes from David Nierengarten with Wedbush Securities. Your line is open.
Hey, thanks for taking the question. I just had one on kind of thinking about the outcomes in the upcoming human study. What is the right benchmark when you think about copper reduction or copper stabilization, given that the patients are likely to have some copper release early if it's working, right? The chelated copper that's in the tissues and such should be eliminated over time.
So they might have an increase in copper, paradoxically, right, initially at least. So just how are you thinking about the right time points to measure the biomarkers and other outcomes over time when you start treating patients? Thanks.
Yeah. Maybe I'll quickly comment that if you look at our preclinical studies, we're seeing a pretty significant effect even at two weeks. But definitely, as we look at the four weeks, we're really almost getting to maximal copper reduction, almost to normalization. So we do see that pretty rapidly. But maybe for your question, I'll pass it over to Dr. Schilsky to answer that.
Thank you. Yeah. So I think the important distinction is that when you're mobilizing copper, you're not mobilizing it back in the circulation. You're pulling it out into bile, which is a one-way.
That's shown beautifully in those PET studies that Mohammed Asmal told you about and shared. But I think that's a real big difference. So I don't think you're going to see any of those paradoxical changes or injuries occurring because of the pathway that the copper will be traveling.
Thank you. Our next question comes from Arthur He with H.C. Wainwright, and your line is open.
Hey, good morning, Allan and Dr. Schilsky. Thanks for hosting this event. So maybe for Dr. Schilsky, I'm just curious. When you look at these different trials or drugs under development for Wilson disease, what do you think about the endpoint for an accelerated approval potentially for the agent? Is the only one we're looking at the copper reduction or copper-centered endpoint good enough for the approval, or do we need to include some neurological improvement measurement there?
So the endpoints have to consider biochemical endpoints and how the patient is doing. So I agree with you. You certainly don't want to cure the liver and have your patients continue to become neurologically worsened. So that would have to be the reason to follow patients very globally in this disease that has a wider field. But again, it also depends on the stage of disease that you start to treat people. So if you're able in the future to capture very early patients, whether eventually screening for the disease is universal, and you find patients at very early stages, then you're only working in the preventive mode.
But I think the biochemical endpoints, ultimately, you have to show that you're restoring the natural pathway, that by doing so, the parameters that we look at in terms of copper in the liver, as well as copper in the circulation or excreted into urine, which is in parallel with that in circulation, have improved. So it's a matrix of things that will be more convincing than just one single parameter alone. But if you look to a past example, the primary endpoint for the study for trientine tetrahydrochloride was with plasma and copper. And the reason was in that in standard pharmacotherapy, now you want to maintain kind of the patient where they are. And you certainly want endpoints that will point to how safe it's going to be over time because there is a lag from the changes biochemically to the time you have clinical manifestations.
So you want to have things that are early and then have follow-up that allows you to say that you can maintain the patient and not have those phenotypic changes, as you point out so correctly.
Thank you. Our next question comes from Terence Flynn with Morgan Stanley. Your line is open.
Good morning. This is Chris Ahn for Terence, and thank you for doing this informative KOL call. So a question for Dr. Schilsky. Just want to understand what is the current guideline for screening for Wilson's disease in fetus or infants and the efforts in making that more mandatory? Thank you.
Okay. So good question. The answer is there is none at this time for mandatory screening. There are exploratory programs, one beginning in the state of Washington using the peptide studies that were developed by Dr. Si Houn Hahn on blood spots from infants.
That is in the testing mode in the state of Washington and may expand elsewhere. Around the world, there are other pilot programs looking at genomic screening. Those that are there, depending upon the ethics involved and societal acceptance for that. In Europe, it's right now a very difficult sell. In the US, there are some startup programs already beginning pilots for genetic screening. The big question separately, how do you follow those you find, and what degree of phenotypic characterization do you have, and when do you begin safe therapy? Because if you take an infant and overtreat them, it's very different than the risk in an older patient because the young ones have growth and development to consider, especially brain development, which is copper-dependent. If you look at Menkes disease, it's a great example where copper transport problems lead to neurologically significant degenerative disease.
So you don't want to recreate that. So we hope in the future that we will have screening. We're seeing a 70% to 95%. There's still a big gap for various different reasons. Even in genetics, you may find changes in what's acceptable as a pathogenic mutation versus a variant of uncertain significance. And those change over time as we have better tools to characterize patients. So nothing is going to be perfect, but we believe it's certainly going to find patients earlier on, which will be better for all.
Thank you. Our next question comes from Silvan Tuerkcan with Citizens. Your line is open.
Hey, good morning. And also, thank you for me for this informative webcast. I just have a question on the current standard of care. First of all, you mentioned that there's about 30 to 50 patients that become non-adherent to their chelator or zinc.
I mean, what do these patients do once they come off? Do they just cycle up to other therapies, or can they just live without treatment? And then on the liver transplant numbers, are they, this is to the doctor or maybe the company, are the numbers of liver transplants due to Wilson's disease known? And how much of the Wilson's disease patients get a transplant? Thank you.
So I'll answer the second one first. The numbers of patients with transplants are 5% of the patients with Wilson's disease. And those are usually two main indications: acute liver failure and those who present with very advanced liver disease or who stop therapy or who fail therapy and have progressive disease. And these are patients usually with very advanced decompensation that don't do well otherwise.
It's only a small percent of patients, and it accounts only for a small percent of patients in the larger community of patients that are transplanted. With respect to non-adherence or complications from therapies, this is consequential, for example, with zinc, there's a non-tolerance, gastric non-tolerance, in about 30% upfront. And what happens with these, especially when you get patients who are left to their own, is people who don't feel well, and they get stomach upset after taking them, obviously stop taking the medicine. Now, hopefully, patients communicate well with their providers. We try to provide them with alternatives. But sometimes those are challenging, and often they come back much later, either after suffering for a long period of time or not. We'll take those to care and be conscious of this.
Similarly, with the other therapies, there are those developmental delays that we find in patients who do not perform well. We do well most of the time. But how you define well, I caution you, because when you start to look very, very carefully and follow mental health, follow neurologic function, follow liver function, there are stutterings in some of the patient course, whereas you would prefer to see, obviously, a straight line to improvement than maintenance. You see a lot of up and down and other issues. Not to mention the cost of therapy and monitoring that becomes challenging. If you have patients who advance to cirrhosis, then you have to do the standards for patients with cirrhosis, for hepatocellular carcinoma, for varices, and you have to treat them as you would any other patient with advanced liver disease. There are consequences.
And including those who stop therapy and end up with liver failure and end up transplanted, fortunately, not that many, but it happens.
Thank you. Our next question comes from Soumit Roy with Jones. Your line is open.
Good morning, everyone. And thank you for taking the question. Maybe a question for Dr. Schilsky. Initial phase one patients, I guess they would be on a copper-restricted diet and on the chelators. What does a functional cure eventually look like? Six months off chelators? And the second one is probably for Allan. Trying to get a—so the IND would be just for 1069Q, or would you also do for R778Ls? Because the East Asian populations probably have more of that. And any overlap in those populations where some are double mutants?
So success can be measured in different ways in a phase one.
Obviously, the functional cure where six months isn't the benchmark that we would provide at much longer term. But to be honest, if we learn in the dosing that we have a partial cure, then we've learned something in the very early phase. And we still may reduce the amount of medicine needed or restriction for some of those patients or help improve their hepatic histology. So there may be benefits even if we don't get to the final endpoint. But this is why we do studies, because we don't have the answer instantly. We can only give our best estimate based on those three studies that we hope to get to the best endpoint. I'll turn that back now to Allan or Mohammed.
Yeah. I mean, the initial study will be first our what we call our anchor mutation in H1069Q.
So that will be the first regulatory filing with 778 to follow. We'll study, obviously, 778 and 1069Q likely in the US, and then 778 also in the US and Europe, and then 778 also as we think about the Asian population. But we do have a list of a handful of other editors that will be fast followers as well. But again, we expect to be able to slot these right into the same IND. So it should be very, again, as we talked about our modularity and efficiency approach, a lot more cost-effective and faster as we kind of slot in additional indications.
Thank you. I'm showing no further questions at this time. Oh, now I'd like to turn it back to Keith Gottesdiener for closing remarks.
Thank you very much for attending our Wilson disease event this morning. And we look forward to executing on our Wilson disease strategy in the months and years to come. You may now disconnect. Good day.
This concludes today's conference call. Thank you for participating. You may now disconnect.