Good morning and welcome to the ProQR Therapeutics Virtual Investor and Analyst event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the ProQR website following the conclusion of the event. I'd now like to turn the call over to Sarah Kiely, Vice President of Investor Relations and Corporate Affairs. Please go ahead, Sarah.
Thank you, and good day, everyone. We appreciate you taking the time to join us today. I'm Sarah Kiely, Vice President of Investor Relations and Corporate Affairs at ProQR. Before we begin, I'd like to briefly walk through today's agenda and introduce our speakers. We will start with opening remarks from our CEO, Daniel de Boer, who will provide an overview of our pipeline and recent advances. Following that, our Chief Medical Officer, Dr. Cristina López-López, will discuss AX-810, including a reminder of our ongoing phase I healthy volunteer trial, expectations for the upcoming target engagement readout, as well as an overview of our initial indication selection. Next, our Chief Scientific Officer, Gerard Platenburg, will present updates on our platform and discovery efforts, including the introduction of new pipeline programs and recent preclinical data across our pipeline. Cristina will cover the corresponding development plans and clinical strategy for these programs.
We'll conclude with remarks from our Chief Financial Officer, Dennis Ho, followed by Q&A with covering analysts and our management team. We're looking forward to sharing these updates with you today. Today's event is being recorded and a replay, along with the presentation slides, will be available on our website following the event. Before we get into the program, please note the forward-looking statements on slide three. During today's presentations, we will make forward-looking statements and actual results may differ materially from those described. Please refer to our SEC filings for a discussion of these risks. I will now turn the program over to Daniel. Daniel?
Good morning, everyone. Thank you all for joining our investor and analyst event. Today, we will share a number of important and exciting updates across our pipeline and development strategy, including two new programs and multiple clinical data readouts within our current runway. To start with our lead program, AX-0810 for cholestatic diseases, the trial execution is going according to plan, and we remain on track to report target engagement data from healthy volunteers later this quarter. This is a key milestone for ProQR, where we expect to demonstrate target engagement on bile acid transport, which is the key driver in cholestatic diseases. Cristina will briefly review this trial and also announce that we have selected biliary atresia as the initial indication for phase II development. We will also share how we are advancing the platform with our AI-enabled discovery engine.
Over the last 18 months, we have built an AI model that enables us to accelerate discovery and generate improved RNA editing medicines. To further scale this capability, we have announced a strategic partnership with Ginkgo Bioworks, which enables roboticized high-throughput data generation to feed our AI-enabled drug discovery. In addition, we have established an AI advisory board with leading experts in the space to maximize the use of AI and machine learning to deliver medicines for patients. Together, the AI-guided model, the high-throughput screening, now enabled with robotics, and the external expertise enable us to generate and optimize lead candidates more efficiently and improve editing performance across our programs in a very meaningful way. One example is AX-811, a next-generation Axiomer editing oligonucleotide that is targeting NTCP.
As Gerard will present today, our AI-enabled discovery engine produced an optimized EON for NTCP with multifold higher editing performance in vivo at lower dose levels. As we are committed to bringing continued innovation forward to patients, we are advancing this program in parallel with AX-0810 in the clinic. For AX-0811, we expect to file a CTA in mid-2026, and initial clinical data is expected by the end of this year. With the involvement of John Maraganore and Martin Maier at ProQR, we're modeling this strategy to the example of Alnylam, who advanced multiple generations of siRNAs targeting TTR in parallel as their platform evolves. A successful business strategy that led to multiple approved drugs for patients. This program reflects our continued platform innovation and is designed to extend our NTCP franchise over time, building durable therapeutic area leadership.
We are also introducing a new pipeline program for Hurler syndrome or MPS I, named AX-0422. This program addresses the high unmet need in liver and CNS in patients with the most common mutation in the IDUA gene. This program originated from our internal discovery efforts and was advanced as part of the partnership with Eli Lilly. As a result of a portfolio review, ProQR will regain full rights to AX-0422, allowing us to advance it as a wholly owned asset. The Lilly partnership continues to progress very well, with multiple programs advancing in the collaboration. AX-0422 for Hurler syndrome is currently in CTA-enabling activities with the CTA filing expected early 2027, and initial clinical data in patients expected in the first half of 2027. The emergence of the Hurler program offers a unique opportunity to bridge from liver into CNS, given its dual tissue biology.
This allows us to build on our existing validation in liver and extend Axiomer into CNS in a de-risked way. Using the same underlying molecule to unlock CNS, which we see as a key area of opportunity for the Axiomer platform. As a result, we're ordering our CNS programs in a stepwise manner. Therefore, we will continue to work on the Rett program and advance it from a stronger and more validated foundation after successful clinical translation of Hurler in CNS. Today, we will also shine more light on AX-2911, targeting PNPLA3 for MASH. Gerard will walk us through the preclinical proof of concept in a relevant animal model, and Cristina will outline the clinical development strategy.
Taken together, this reflects progress across our portfolio with AX-0810 as our lead program, our commitment to cholestatic disease, with a focus on biliary atresia, and our continued innovation across our platform and pipeline. Within our current runway, we now expect to generate multiple clinical data readouts across the pipeline. We're excited for the upcoming AX-0810 clinical data and the broader pipeline progress. I will now hand it over to our Chief Medical Officer, Cristina, to discuss our programs after a brief refresher on AX-0810. Cristina.
Thank you, Daniel. I will start with AX-0810, our lead program, and first clinical proof point for Axiomer. AX-0810 is ProQR's lead investigational RNA editing oligonucleotide targeting NTCP, the key transporter responsible for bile acid uptake from the bloodstream into the liver. By modulating NTCP, AX-0810 is designed to reduce bile acid transport into the hepatocytes, and thereby limit the toxic bile acid accumulation that drives cholestatic diseases. Bile acids are produced in the liver and then leaves the liver through the bile ducts to the intestine. Subsequently, they come back into the systemic circulation and are taken back up into the liver by NTCP. Approximately 95% of the bile acids in the liver get there through NTCP re-uptake. In a liver with cholestatic disease, and in particular with biliary atresia, there is an obstruction or an absence of bile ducts preventing bile acids from leaving the liver.
This leads to accumulation of bile acids in the hepatocytes, which causes inflammation and ultimately fibrosis. In an attempt to protect itself, the liver activates alternative channels like MSR3, MSR4, and OST alpha beta to pump bile acids out of the hepatocytes into the bloodstream. This only has a marginal effect as the NTCP channel is continuously taking up bile acids from blood, which maintains the high concentration of bile acids in the liver. AX-0810 converts wild type NTCP into the protective Q68R variant. This NTCP variant limits bile acid re-uptake. By limiting bile acid uptake into the cells, the liver has the opportunity to normalize the concentration of bile acids by pumping out bile acids through MSR3, MSR4, and OST alpha/ beta, which removes the driver of the liver disease.
This therapeutic strategy has been demonstrated in multiple cholestatic disease animal models by our collab orator, Professor de Graaf, at the Amsterdam University Medical Center. NTCP was blocked in these cholestatic disease animal models, which led to a two- to three-fold increase in bile acids in serum, as observed on the left, and resulted in a normalization of liver weight and fibrotic markers, as observed on the right. A robust validation of the therapeutic strategy. With this mechanism, we believe AX-0810 has the potential to be a disease-modifying therapy, alleviating symptoms and slowing or preventing disease progression. Our ongoing first-in-human study in healthy volunteers is designed to assess safety and tolerability, pharmacokinetics, and importantly, biomarker-based target engagement. Earlier this year, we announced that initial data from our first cohort demonstrate a favorable safety and tolerability profile. With pharmacokinetics consistent with our non-clinical observations.
A key objective of this study is to demonstrate target engagement through biomarkers. We are using three complementary readouts. First, total bile acids in serum, where we expect to see an increase as less bile acids are taking up into the liver. We are targeting a two-fold increase as considered a meaningful indicator of NTCP modulation. Second, bile acid profile, which allow us to assess the specificity of the effect, particularly the shift to conjugated bile acids. And third, TUDCA challenge, which provides a functional readout of NTCP-mediated transport by administering a synthetic form of TUDCA and measuring clearance. Together, these biomarkers allow us to directly measure target engagement, confirm mechanism, and inform dose selection. We look forward to reporting target engagement data from the phase I this quarter.
Following the healthy volunteer assessments, we plan to open a cohort in the trial for PSC patients with data at the end of this year. As part of our development strategy, we are pleased to share today that we have selected biliary atresia as the initial indication for phase II development. Biliary atresia is a severe pediatric cholestatic disease affecting approximately 20,000 patients worldwide. There are currently no approved pharmacological therapies that modify disease progression. Despite early surgical intervention, most patients still progress. In fact, biliary atresia accounts for approximately 45% of all pediatric liver transplants, and even with Kasai portoenterostomy, 60%-80% of patients ultimately require liver transplantation before adulthood. Even with a successful Kasai procedure and liver transplant, patients have a significantly shortened life expectancy. This underscores both the severity of the disease and the lack of effective treatment options to alter its course.
Based on this, we have selected biliary atresia as our initial indication for phase II. There are several key factors that support this decision. First, as already mentioned, the severity and high unmet medical need. Next, a strong biological rationale. Importantly, this is where Axiomer is uniquely suited. AX-0810 is designed to precisely modulate NTCP function at the RNA level, selectively reducing bile acid uptake into the liver without affecting other functions of the protein. By doing so, we aim to lower bile acid accumulation in the hepatocytes, which is a central driver of liver disease. Also, clinical study execution. Patients are diagnosed early and managed in specialized centers, allowing for efficient study execution and clear assessment of disease progression. Patients with biliary atresia represent a well-defined and relatively homogeneous population, supporting more interpretable clinical outcomes.
Finally, a clear development pathway supported by established pediatric regulatory guidance, leveraging liver biomarkers such as direct bilirubin, GGT, liver stiffness, and the PVEL score to support development and potential accelerated approval alongside clinical outcomes such as transplant-free survival and bilirubin normalization. Taken together, biliary atresia offers a strong combination of biological rationale, unmet need, and development feasibility, including strategic launching considerations. At the same time, we continue to see significant potential in PSC, which represents a larger patient population and remains an important follow-on opportunity where the same mechanism applies. Overall, this gives us confidence in both the clinical path for AX-0810 and the broader potential of NTCP modulation across cholestatic diseases. In parallel with the progress AX-0810 is making in the clinic, we are continuing to evolve the platform and expand the pipeline, including next-generation approaches targeting NTCP.
We are now using AI-driven high-throughput screening models trained on 12 years of Axiomer data to develop our next generation of Axiomer, as Daniel noted. This enables us to predict key parameters, such as editing efficiency and stability before we even make them. That means we can move faster, reducing time from the discovery process. Plus, the AI keeps learning from every round, getting smarter each time. Here are clear examples of how our AI-enabled discovery process translates into measurable improvements. What used to take us up to three years using manual discovery can now be completed in roughly six months, reflecting a significant reduction in discovery timelines, making the process about 90% faster. In addition to speed, we also see improvements in candidate quality, including EONs with up to sixfold increases in editing efficiency compared to the earlier designs.
The next generation of EON for our NTCP program, AX-0811, reflects the impact of our AI-driven discovery and HTS capabilities. In humanized mouse models, we see editing efficiencies of around 60% with AX-0811, representing a threefold increase compared to the previous generation, and this is also combined with improved stability. Together, these data demonstrate how our ongoing platform optimization translates into improved performance at the molecular level.
Building on this data, let me walk you through the clinical development plan for AX-0811. The AX-0811 clinical trial design closely mirrors that of AX-0810, featuring ascending doses across multiple cohorts of healthy volunteers. The study will evaluate safety, pharmacokinetics, and target engagement. We are advancing this program rapidly with CTA submission expected mid-year and initial clinical data by year-end. This study will also allow us to better understand the relationship between editing performance and biological effect. AX-0810 represents our first clinical validation of NTCP editing. AX-0811 builds on this with our next generation of Axiomer, reflecting continued innovation in editing oligonucleotide design and performance. Together, these programs allow us to build an NTCP franchise over time. Similar to, for example, how other RNA-based platforms have evolved across multiple generations of products.
Now let me introduce AX-0422, our RNA editing therapy targeting IDUA for Hurler syndrome, the most severe form of mucopolysaccharidosis type 1, or MPS1. Hurler syndrome is a lysosomal storage disorder affecting multiple organs early in patients' life, leading to significant morbidity and reduced life expectancy. It is caused by mutations in the IDUA gene, resulting in deficiency of the alpha-L iduronidase enzyme. This results in the toxic accumulation of glycosaminoglycans, or GAGs, driving the disease pathology. The most common mutation is a nonsense variant, the Trp402X variant, which is present in up to 60% of patients with a severe phenotype. AX-0422 uses our Axiomer RNA editing platform to directly correct this mutation to wild type at the RNA level, restoring production of functional IDUA enzyme. By doing so, we aim to decrease toxic GAG levels in lysosomes.
Current treatment options like enzyme replacement therapy and hematopoietic stem cell transplantation do not fully address all disease manifestations and present some limitations. As mentioned, Hurler syndrome represents the most severe form of the MPS I spectrum. Patients present with a range of debilitating symptoms like hepato and splenomegaly, as well as neurological impairment. From a biochemical perspective, even a small increase in IDUA enzymatic activity can have a meaningful clinical impact. The attenuated forms, Hurler-Scheie and Scheie, have higher enzymatic activity and are associated with a better prognosis. Looking at current treatment options, there are important limitations. Enzyme replacement therapy can improve some of the systemic symptoms but does not cross the blood-brain barrier, so it has little to no impact on CNS manifestations. In addition, its efficacy may be reduced over time due to antibody formation against the recombinant IDUA enzyme.
Stem cell transplantation can provide some benefit, including effects on neurological outcomes, but it comes with significant risk, requiring specialized centers and suitable donors. Even after transplant, patients often continue to experience significant disease burden. As such, there remains a clear unmet medical need, especially for therapies that can address both systemic and neurological aspects of the disease. This is where AX-0422 is designed to play a role. In our preclinical data, AX-0422 drives both enzymatic recovery and biomarker normalization. Following subcutaneous delivery, there's a robust restoration of IDUA enzymatic activity in the liver, reaching approximately 20% of wild type levels at eight weeks. Importantly, this level of restoration translates into meaningful biomarker impact, and substantial and dose-dependent reductions in GAG levels. On the order of 50% in the liver to almost 90% in the urine compared to control, demonstrating effective toxic substrate clearance.
Taken together, these data show that AX-0422 can achieve levels of enzyme restoration that are within the range expected to drive clinical benefit, along with clear reductions in disease-relevant biomarkers. When comparing RNA editing to standard of care, our data show improved effects in biomarker normalization and functional outcomes. On the biomarker side, we see a great reduction in urinary GAGs, over 90% with RNA editing compared to around 60% with ERT. This translates into functional benefit, where RNA editing shows improvement in the motor skill test compared to the standard of care. Beyond systemic effects, we evaluated the potential of AX-0422 following delivery to the brain, and the preclinical studies demonstrated meaningful restoration of enzymatic activity across multiple brain regions. Our experience shows that the Axiomer EON enables robust and sustained editing in the CNS.
These findings support the potential of AX-0422 to address the neurological manifestations of Hurler syndrome. In summary, AX-0422 is designed to address both the systemic and neurological aspect of Hurler syndrome with a single targeted approach. From a patient perspective, this means potential for additional clinical benefit over the current standard of care. We are developing AX-0422 with a two-step approach. First, focused on the liver with our lead compound now being in ID-enabling stage, followed by addressing neurological symptoms through intrathecal administration. Cristina will now give you more details about the development plan.
Our initial clinical approach focuses on liver-directed editing, where we have already established non-clinical delivery and pharmacology. This provides a clear and efficient path to generate early clinical data and demonstrate proof of concept in patients. From there, we plan to expand into the central nervous system through intrathecal administration, building on the translational insights generated in the liver and extending our understanding of editing performance across tissues and routes of administration. Hurler syndrome is a severe multisystem disease affecting both the liver and the brain. This creates a unique opportunity to bridge liver correction to addressing the neurological symptoms that drive long-term patient outcomes. Our staged approach is designed to de-risk development early while building toward a therapy that can address the full burden of disease over time.
It also directly supports our broader CNS strategy, including programs such as Rett syndrome.
Overall, this program not only addresses a high unmet need in Hurler syndrome, but also serves as a critical step in expanding Axiomer into CNS indications. Our Hurler program is advancing towards the clinic with CTA-enabling activities ongoing for AX-422, a CTA filing expected in early 2027, and initial clinical data anticipated in the first half of 2027.
Let's now focus on our Axiomer program, AX-2911, targeting PNPLA3 to address MASH. MASH is a highly prevalent disorder and increasing worldwide. Individuals with the disease have a high unmet medical need due to progression into cirrhosis, hepatocellular carcinoma, and liver-related mortality, with limited therapeutic options available. PNPLA3, or patatin-like phospholipase domain- containing 3 I148M variant, is the strongest known genetic risk factor for liver disease progression with approximately half the MASH patients carrying the variant. PNPLA3 represents a genetic driver of disease that is independent of metabolic factors. That means that even when metabolic pathways are addressed, patients carrying this mutation may continue to progress, highlighting an important unmet need in current treatment approaches. Indeed, patients with this variant may be less responsive to existing therapies such as GLP-1 agonists.
From an epidemiology perspective, homozygous carriers of this variant represent approximately 8 million individuals in the U.S. and EU. By editing the methionine to a valine in this variant, AX-2911 is designed to restore wild-type protein function and address the root cause of MASH. To evaluate AX-2911, we use a humanized PNPLA3 148 methionine model. Unlike standard preclinical models, which rely on diet or chemical injury, this model incorporates primary human hepatocytes carrying the homozygous variant. As such, this model closely reflects human disease progression compared to standard models, and together with an established Western diet, it provides a highly translatable and efficient system to assess therapeutic impact. We use this model to compare two different approaches, PNPLA3 knockdown using an ASO previously evaluated in clinical studies, and correction of the mutation with AX-2911. Approximately 90% of PNPLA3 messenger RNA knockdown with ASO led to 36% reduction in lipid droplets.
In contrast, 23% RNA editing of PNPLA3 with AX-2911 led to approximately 80% reduction in lipid droplets. Lipid droplets accumulation reflects excess liver fat, a key driver of disease progression in MASH. Taken together, these results show that correcting the underlying genetic variant can drive a stronger functional outcome than simply reducing PNPLA3 148 methionine expression. This supports the potential of AX-2911 in addressing the unmet medical need in MASH.
As Gerard highlighted, this program is supported by a strong human genetic and preclinical evidence linking PNPLA3 to MASH disease biology, providing a highly validated target. From a development perspective, we declared a development candidate earlier this year and are planning to advance this program through an investigator-initiated trial in China. This approach allow us to efficiently generate early clinical data, leveraging local clinical expertise, access to well-characterized patient populations, and a streamlined development environment. The study is designed to assess safety, pharmacokinetics, and exploratory biomarkers related to liver fat and disease activity. This approach enable us to generate a clear early read on clinical potential while maintaining capital discipline and flexibility on next steps.
Thanks, Cristina. I'll close by briefly summarizing our expanded pipeline of Axiomer-based RNA editing programs and the key milestones ahead. As you've heard today, our lead program, AX-0810, targeting NTCP for cholestatic diseases, is on track to read out target engagement data in healthy volunteers later this quarter, followed by initiation of a patient cohort later this year. At the same time, we are advancing additional clinical catalysts within our cash runway. For AX-0811, our next generation NTCP program, we expect to file the CTA this year with initial clinical data in healthy volunteers before year-end. For AX-0422, targeting IDUA for Hurler syndrome, CTA-enabling activities are ongoing. We expect to file the CTA in early 2027 and read out initial clinical data in the first half of 2027. For AX-2911, targeting PNPLA3 for MASH, we are actively planning an investigator-initiated trial in China.
In addition to our programs, we will continue to advance our Axiomer platform, including AI-driven discovery and high-throughput screening capabilities, as Gerard highlighted. Taken together, this reflects a pipeline that is progressing across both liver and CNS indications, supported by the breadth of our Axiomer platform. In addition, through our partnership with the Rett Syndrome Research Trust, we are working on AX-2402, our RNA editing approach for MECP2, aligned with our broader CNS strategy. We continue to progress our collaboration with Eli Lilly, which is focused on advancing multiple RNA editing targets enabled by the Axiomer platform, and supports the scalability of our approach. Financially, we continue to be funded into mid-2027, consistent with prior guidance, while delivering existing, and new clinical data catalysts across the pipeline in this period. With that, we'll open the call for questions with our covering analysts.
Speakers, please hold for a brief moment while we poll for questions. Our first question comes from Steve Seedhouse at Cantor Fitzgerald. Please go ahead, Steve.
Great. Thanks so much. I have a couple questions, actually, if that's okay. First, just wanted to ask about the strategy of focusing 0810 in biliary atresia as opposed to PSC, given that's where obviously the initial patient data will be generated, and if that means that 811 maybe is your bet for PSC, or are you thinking about development away from PSC altogether?
Hey, Steve. Thank you for the question. I'm going to ask Cristina to address this for you.
Cristina, you may be on mute. Please press star six.
Okay. With that in mind, I will address the question for you, Steve. We've gone through a rigorous indication selection process to select our primary indication. We are not moving away from PSC, but we are prioritizing biliary atresia as we see that is the strongest combination of the unmet medical needs, biological clarity, and development feasibility. As you know, BA is a very severe pediatric disease with no approved therapies, and the mechanism is very clean. Bile acid toxicity is the key driver in that disease, and patients are diagnosed early. They're treated in specialized centers, and the disease course is well-characterized. That supports efficient and rapid trial development. At the same time, PSC, we are also very excited about, but we decide to stage that subsequently to biliary atresia.
Okay. Thanks, Daniel. Second question, and then I just have one quick one after. On Rett, it's interesting. I think you mentioned that you wanted to get some clinical translational data in CNS first and leverage that for the Rett program, but that program is also largely funded, I think, by the external grant with RSRT. Just curious about the decision to sort of step back from Rett and slow that program down, and is it just a function of the Hurler program being closer to the clinic or something else?
Yeah, that's a great question, Steve. Yeah, so of course, the Rett program is really important to us. We're pursuing that in a partnership with the Rett Syndrome Research Trust, who are co-funding the work here with 50% in the program.
The RET program would directly go into CNS. I think the IDUA program that is novel to our pipeline and now recently added gives us the opportunity to really bridge in a staged way. We can leverage the dual tissue biology that allows us to take one molecule into the liver first, and subsequently bridge into CNS, which is a very elegant way to, in a stepwise and de-risked way, go into CNS. That will be very informative as we translate RET. We think on the base of that, we could take the RET program in a much more validated and de-risked way into trials.
Great. Thank you. Just lastly, with the return of that program, the Hurler program from Lilly, just curious if you could comment on the current status of that collaboration, if they're working on one or multiple other programs preclinically that they've retained following this pipeline review, that ultimately sent the Hurler program back to ProQR?
Yeah, absolutely. Obviously, in the Lilly collaboration, we have many different targets that we're pursuing. This program is a program that, as a result of their prioritization review, was decided to come back to ProQR, and we're actually very pleased with it. I think it's a program that fits very well with our pipeline. It's a program that we know well and it's one that is mid ID-enabling stage, so allows us to rapidly progress into clinical trials. This also on the Lilly side, frees up a lot of resource to really allocate to other programs that are more strategically aligned with their portfolio. The Lilly collaboration is going forward without any change in priority, and we're really excited about the progress that's being made there.
Thanks so much.
Terrific.
Thanks for the question, Steve. Our next question comes from Joe Thomas at Oppenheimer. Please go ahead, Joe.
Everybody, thank you for taking the question. This is Joe on for Costas. Maybe just a quick clarification about the bar for success in the upcoming readout with bile acid increase. Is the two x referring to versus baseline or versus placebo? Just looking for some clarification because in the NHP data we saw an increase in placebo as well. I was wondering if you're expecting to see the same in the human data. Thank you.
Hey, Joe. Thank you for that question and thank you for dialing into our call today. The bar for success is multifold. We're going to look at three different measures. We're going to look at the total bile acids, which is a holistic view of the bile acid accumulation in the periphery and in the serum. We will look at bile acid profile, which looks specifically at the conjugated bile acids versus the unconjugated bile acids. We are specifically interested in the conjugated bile acids as those are the ones that are regulated through NTCP. As a third endpoint, we're going to look at TUDCA challenge. TUDCA is a chemical form of bile acids that is orally administered and that is regulated through NTCP. We can completely isolate TUDCA from the other bile acids as it's separate.
To answer your question, the twofold threshold we have set for the total bile acids, and we're going to look at it both compared to baseline as well as compared to placebo. For the other measures, we're going to look at the qualitative change towards an increase in conjugated bile acids.
Okay. Thank you. Maybe just a quick follow-up, if I may, just thinking about.
Sure.
The choice to proceed with the biliary atresia and PSC data coming at the end of the year, what would the read-through be, do you think, in PSC patients, the potential efficacy in BA?
Yeah, that's a great question. The patient cohorts will indeed be conducted in PSC patients, because this is an adult population. While biliary atresia is the key indication, we plan to pursue AX-0810 for both PSC and biliary atresia. The PSC cohorts will allow us to understand the translation from healthy volunteers to the disease context. We think that will be very valuable information to help us bridge towards the biliary atresia phase II, which is going to be a pediatric study. We think the totality of the data will help us inform dose frequency, and expected effect size.
Great, thank you. Congrats on all the progress.
Great. Thanks for the questions, Joe. Our next question comes from Gavin Clark-Gartner at Evercore. Please go ahead, Gavin.
Hey, guys. Great to see all the updates. Just one quick clarification on AX-0810 first. All three of those cohorts, they all unblind at the same time, right? You haven't actually seen any of the unblinded data internally. That's right?
Yeah. Correct. Thank you for the question. The study is a double-blind, placebo-controlled study, and the study remains blinded.
Perfect. All right. For AX-0810 in biliary atresia, when are you planning to start dosing patients relative to their Kasai procedure? Are you planning to do more of a focus on long-term outcomes like Ipsen is doing with Bylvay, or could there be some type of accelerated path here by looking at bilirubin maybe earlier on?
Yeah. Obviously this is to be discussed with the regulators, but the plan is that we indeed pursue an accelerated development path where we look at liver biomarkers and liver health, liver stiffness, and those will help us towards an accelerated approval with then long-term follow-up as a post-market commitment. We expect to treat different stages of the disease post Kasai procedure. It's still to be designed, what exactly we will do in the phase II. You will have to stay tuned for that.
Sounds great. Just one last quick question on the Hurler commercial opportunity. I guess, how big of an issue are ADAs or discontinuations for any reason for Aldurazyme today, and how much efficacy do they leave on the table, especially on the CNS side? Really just trying to understand how much AX-0422 could expand this market further. Thank you.
Yeah, thanks for the question. The CNS part of Hurler syndrome is largely untreated. The Aldurazyme enzyme replacement therapy does not cross the blood-brain barrier, so it does not treat the CNS element of the disease. We think AX-0422 has the opportunity to treat both the liver and the CNS. Currently, patients take a weekly IV administration of the enzyme replacement therapy, which is obviously fairly burdensome and takes quite a bit of time. In addition to that, our preclinical data, the animal model data suggests, that there is additional efficacy to be gained with AX-0422 when we compare this head-to-head in the disease model. We think that the therapeutic proposition for patients with Hurler syndrome is very significant, both for CNS as well as for the liver.
Perfect. Thank you.
Thanks for the questions, Gavin. Our next question comes from Catherine Novack at Jones Trading. Please go ahead, Catherine .
Hi. Thanks for taking my question. Just curious about for the Hurler syndrome program, how frequently would AX-0422 be delivered intrathecally? What's the expected half-life for sub-Q versus IT delivery?
Hey, Catherine . Thank you for the question. Our molecules delivered IT for CNS are generally very stable, and AX-0422 is no exception to that. If anything, it is a bit more durable than other molecules that we work with. We anticipate that it is probably once every nine to 12 months administration IT for the CNS element.
Got it. The sub-Q element for, what's the anticipated dosing regimen in that?
The liver residence time of any oligonucleotide, and this molecule is no outlier there, is shorter than for IT. We expect to dose once every three to six months subcutaneously for the liver treatment. That compares to the current standards of care that is weekly dose through intraventricular administration.
Got it. Are you thinking about you're enrolling PSC patients into the phase I-B, is there anything you would see in patients that might impact your decision to prioritize biliary atresia?
Could you repeat the question? I didn't completely get it, Catherine .
You still plan to enroll PSC patients into the phase I-B. Is that correct? Is there anything that you would see-
Yeah
... in patients that would impact your decision to prioritize biliary atresia as the target for AX-0810?
Yeah, I think that's a good question. I don't think there's anything that would change our plan for the phase II. We think the plan for the phase II is set to have the lead indication in BA, but I do want to stress that we're not moving away from PSC. PSC remains a very important indication for us to target. It's just a matter of staging.
Got it. Thank you.
Thank you.
Yes, thanks for the questions, Catherine . Our next question comes from Suzanne van Voorthuizen at Kempen. Please go ahead, Suzanne.
Hi, team. Thanks for taking my questions. On BA, I appreciate the trial design is yet to be determined, but could you elaborate on how AX-0810 could be positioned in the current care and management of patients? I also have a clarification on AX-0810 and AX-0811. How do you foresee the development of these programs beyond the phase I's? Should we expect that you choose the next gen over first, or is there a reason to believe these programs can coexist in different indications or settings?
Yeah. Thank you, Suzanne, for the questions. I'll take the second question first. We think that AX-0810 and AX-0811 can each stand on their own legs. AX-0810 is our lead program and represents the fastest path to clinical proof of concept and potentially fastest path to market. Where AX-0811 reflects our continued platform optimization and is part of our broader NTCP strategy. Importantly, for both of them, we are in parallel generating clinical data, and that will accelerate our learning and maximize the opportunity around the targets, and we are committed to bringing the best medicine to patients.
We think that through this approach, we will learn a lot, and, ultimately, with this, we are following a quite successful business strategy that was pursued by companies like Alnylam, who pursued multiple programs for TTR in the clinic and actually to approval, and what Vertex did in cystic fibrosis. You can compare it to what they've done. For your first question, I'm going to see if Cristina is back online. Cristina?
Yeah. I'm here. Absolutely. Can you hear me all well? Apologies for the
Yes. We can hear you well, Cristina.
Okay, fantastic. Basically, what we're trying to achieve here is a staggered approach.
First, we really want to validate the platform, meaning that we can target NTCP. Second, to move from healthy volunteers to patients, and to patients when we're thinking about the [inaudible] in adults, PSC, as this is a driver mechanism for all cholestatic diseases. PSC, it was the right indication to try in the phase I-B cohort. After, based on very established regulatory requirements, we can extrapolate for different populations. This is why we have decided to go to phase II because of the unmet medical need, biological rationale, and the clear developability. Saying that, as Daniel nicely said, PSC is still in the bank, and this will be part, actually, of the lifecycle management. In terms of the AX-0810 and AX-0811, I think that Daniel put it very nicely.
We will really optimize the best molecule to the patient population, trying to establish an NTCP franchise that could serve all the population need.
Got it. Thanks. Maybe one additional question on AX-2911 on MASH. Can you remind us how the hypothesis you test with correcting PNPLA3, how that differs from the previously tested ASO? You highlighted the stronger effect on liver droplets, but is it a matter of potency or is there more to it? Maybe if you can also give some color on the rationale to go for an IIT in China, that would also be helpful. Thank you.
Yeah, thanks for the question, Suzanne. Gerard will address your first question on the mechanism.
Thanks for the question. The rationale behind the technologies is such as follows. Where we see the knockdown approach giving rise to a limited, let's say, a decrease in steatosis, we see that by limited editing, by creating a functional protein, we see a massive decrease in steatosis, up to 80%. We feel that by correcting the protein to a wild-type-like protein is the major differentiator there. You need a little bit of a function of the protein for it to be most active.
Cristina will address your second question on the IIT.
Actually, this is a beautiful question, so thank you for asking. There are different pathways to actually do the risk programs. One pathway is definitely to go to the standard IND or CTA submission. Another pathway is to go to investigator-initiated trial. Investigator-initiated trial, there are a possibility to have exploratory hypothesis with a much more focused IND, or CTA profile while keeping flexibility in terms of capital, the risking and learning for IND-enabling activities. This is why we have decided to go with AX-2911 for an IIT in China. You have seen that this potential mechanism cannot address a MASH in general, but actually can optimize lean MASH and non-lean MASH for those therapies that are not so responsive to treatment.
Using the local regulations in China, we are really hoping that we are really going to deliver a clinically meaningful outcome to the Rett program and optimize our clinical development plan, meaning we will optimize pharmacology, PK, PD, biomarkers that will translate, and the population to follow to maximize the effect and to get as soon as possible to the patients that deserve this treatment.
Thanks, Cristina.
Great. Thank you for the question, Suzanne. Our next question comes from Ryan Deschner at Raymond James. Please go ahead, Ryan.
Thanks for the question. You've already mentioned this, and I missed it, but has AX-0811 shown higher preclinical editing levels versus AX-0810? Have a follow-up question on 422.
Hey, Ryan. Yeah, thanks for the question. AX-0811 showed about a threefold higher editing in the animal model that we use. It showed about 60% editing in the humanized mice.
Got it. For 422, the two different delivery administrations, what differences are there between the actual drug format going into the liver versus what's going into the intrathecal version, and what PD metrics we'd be targeting for each administration route? Thanks.
Yeah. Thanks for the question, Ryan. I'm going to have Gerard address this question for you.
Yeah. Thanks. That's a great question. I think the interesting idea is we see a staged path towards the clinic where we are starting with liver, and then to expand into intrathecal dosing into CNS. We are actually testing a GalNAc molecule taking forward into the liver, as we would do typically. We are now testing also different molecules to go into the CNS. We are testing both the GalNAc molecule as the naked oligo to be tested in the CNS as well. What we do see is that we see restoration of the IDUA enzyme activity across relevant brain regions. We also see reductions or activation of the enzyme activity across the brain. That reflects the target engagement in a disease model as well.
If I may add, to continue with the clinical development plan, this is what is so fantastic about this program. That, as Daniel mentioned, we have a single molecule that could not only address the peripheral symptoms, but also the CNS symptoms. For those that are following the pathway, recently, not in Hurler, but in Hunter, FDA was willing to have a conditional approval using a biomarker. Actually, this particular biomarker we are using is in terms of intrathecal administration. At the end of the day, we will have a single clinical development path where we're going to be targeting peripheral and CNS, looking at the gaps in the peripheral compartment, in the central compartment, supported by clinical data in the periphery, most likely for a vital capacity and six-minute walk test.
In the CNS, we have already optimized, depending on the age of the patient, which neurocognitive assessments we will be looking at. Because we are talking about a progressive neurodegenerative disease with early neurodevelopmental symptoms. It's a complicated disease, but with Axiomer, we can target both peripheral and CNS, and this is why we are so excited about that.
Thank you very much. Thank you, Ryan.
Yes. Thank you for the questions, Ryan. Our next question comes from Katherine Okukani at Citizens JMP. Please go ahead, Katherine.
Hi, this is Katherine on for John. I just had kind of a quick question about biliary atresia. I know you mentioned that potentially even partial improvements in bile flow could have an impact. Can you just expand on that? If you have a clinical target in biliary atresia that you would want to see in patients that would be clinically meaningful and what might be upside potential. Is there any precedent for what might be meaningful as far as reductions go? Thank you.
Hey, Katherine. Thank you for that question. I'm going to have Cristina address this for you.
Yeah, this is a very smart question, so thank you for asking. In biliary atresia, what we like about the disease is that we have a single cause, a single etiology. Basically, you have an obstruction in terms of the release of bile acids, the bile acids accumulate in the liver, and therefore it cause the disease. After surgery, and after the Kasai procedure, you start to relieve the liver. When these bile acids accumulate, the basolateral of the hepatocytes try to get rid of the bile acids, but it's not sufficient. Why? Because the NTCP is still working, meaning that we're pumping bile acids from the periphery into the hepatocyte. By blocking the NTCP, what we're doing is we're really helping the liver to release the toxic bile acids in the hepatocytes.
One could ask, are we going really to get rid of entire cholestatic disease markers, for example, bilirubin normalization, et cetera? We don't know yet, but we are going to measure those. What is most important is that the toxic driver of the disease, we're going to be cutting by decreasing the uptake from the NTCP and helping the basolateral receptors get pumped out of the toxic bile acids. We are going to try different ages in the disease, and we are going to see how we can optimize and maximize the benefit for the entire disease aspect.
Thanks, Cristina. Thank you for that question, Katherine.
Thank you.
Our next question comes from Keay Nakae at Chardan. Please go ahead. You might be on mute.
Sorry about that. Yeah, thank you. Question for Gerard. The three x improvement in AX-0811, can you talk about a little more detail how you're able to achieve that? Is it substitutions in the sequence? Is it the length of the sequence?
Yeah, thanks for the question. I think this translation of the knowledge that we've gained over 12 years gets together now in the AI. We are looking at indeed variations of lengths, chemical modifications, and the stability of the molecule. We won't disclose any specifics on the improvements. However, the optimizations, you can look into that area. We now start to understand way better how to optimize these molecules through our HTS AI.
That optimization you're getting with AX-0811 in the liver, are they applicable to engaging ADAR in other tissue types?
Yeah. We are expanding that to different liver programs as well as in the CNS, and we're seeing very impressive improvements across the board. The system is learning, and we are feeding the data back into the AI, and across the board, we see very nice improvements. Yes.
Very great.
Thanks, guys.
Great. Thank you for the questions. Our final question comes from Ananda Ghosh at H.C. Wainwright. Please go ahead.
Hey. Hi, guys. Thanks for the question. I have one structural-related question with respect to the biliary atresia program. If you look at the definition of biliary atresia, the issue is actually the absence of bile drainage or the entire drainage system. I was wondering, how does blocking the NTCP channel kind of fit into the mechanistic aspect of disease modification? And then I have one follow-up question on this and one for the Hurler syndrome.
Hey, Ananda. Thank you for that question. Yeah, you're completely correct. The physiological defect in patients with biliary atresia is blockage of the bile duct or absence thereof. The cells have a mechanism to get rid of excess bile acids through alternative channels like MRP3, MRP4, and others, who can pump bile acids into the blood through the basolateral side of the cell. What happens, though, is that through NTCP, those same cells are taking those bile acids back up into the cell, so it's a circular pump, and what we do is we break that cycle by reducing the uptake through NTCP, and therefore a normal balance can evolve inside the liver cells.
Got it. Thanks. I had two questions on the upcoming data readout. If you can remind me, how are you defining measuring NTCP editing efficiency in the HV setting and if you have thought about the NTCP turnover kinetics as you were thinking about designing the trial?
Yes. Thank you for the question. Gerard, would you like to address this question?
Yeah. Sorry. We don't measure editing in the trial. In the trial, we cannot measure editing because the editing takes place inside the liver, and in healthy volunteers, we cannot take biopsies, so therefore, we will not be able to measure editing directly. What we can measure, though, is the biomarkers that will allow us to correlate it back to the preclinical data, which will allow us to establish an approximate editing efficiency. Would you remind me of your second question?
Yeah. Regarding the..
Yeah. Regarding the second?
turnover NTCP.
Yes. Correct. For the NTCP, we are really looking at the natural history in terms of the disease, cholestatic diseases, to see NTCP expression. The good news is that in biliary atresia, NTCP is upregulated and actually can correlate with bile acids and long-term outcomes. We are confident that we have sufficient expression of the target, and we can maximize the efficacy, meaning because this target is contributing to the disease by inhibiting NTCP, that is upregulated in biliary atresia, we can actually block this uptake of the toxic bile acids that drive inflammation, fibrosis, and ultimately to transplantation. I don't know if you remember, but it's up to 80% of children that despite the Kasai procedure, need to go to liver transplantation. Definitely, we believe that this can be a transformative mechanism.
All right. Maybe a last question on the Hurler syndrome program. How much of wild-type restoration do you think can be disease-modifying, and what kind of editing efficiency can that equate to? Thank you.
Yeah. Thanks, Ananda, for the question. Gerard, do you want to address Hurler editing efficiency?
Yeah. That's a great question. I think the idea is that the editing levels that we are seeing in the Hurler models are sufficient to overcome nonsense-mediated decay, restoring a more stable IDUA messenger RNA and enabling enzyme production. Because IDUA functions through a catalytic turnover, even modest increases of enzyme levels drive a disproportionate large reduction in the substrate GAGs. We believe the level of restoration is really meaningful, because the literature shows that restoration of approximately 1%-15% of normal IDUA enzymatic function can already improve disease phenotype. What we see is that restoration of 21% drives to close to normalization of urinary GAG levels. Yes, we do see a field that is really very meaningful.
Great. Thanks, guys.
In addition to support Gerard's comments, when you think about the different phenotypes and percentage of IDUA enzymatic activity, when you think about the three spectra, the ones that have close to 1%, they don't have a phenotype. As soon as you go to 8.5 or 8.1, then it's like Brethren disease. If this data that we're showing translates into humans, we are really thinking about a revolutionary transformation, not only in the periphery but also in the CNS. Actually, beyond preclinical data that Gerard just mentioned, when you look at the clinical data and the deficiency in the enzyme, this tell us that we are well above the threshold to show clinical meaningful results.
Got it. Thanks very much.
Thank you for the question, Ananda.
Yes. Thank you for the questions. This concludes today's Q&A session and the overall event. We thank everyone for joining tonight. You may now