Good day and thank you for standing by. Welcome to Denali Analysts' Call 2026 WORLD Symposium. 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. I will now turn the call over to Mr. Ryan Watts, Chief Executive Officer. Please go ahead, sir.
Great. Thank you. We're looking forward to previewing our Enzyme Transport Vehicle highlights from the WORLD Symposium, which we're here attending in San Diego. Slide 2 is our forward-looking statements. Onto Slide 4, just a reminder that Denali was founded to deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases. On Slide 5, an introduction into the Transport Vehicle. I know many who are attending this call today are familiar with our technology. We've engineered the binding of transferrin receptor into an Fc, giving us the ability to cross the blood-brain barrier and also access the whole body. On Slide 6, excuse me, on Slide 6, you can see our three different franchises: the Enzyme Transport Vehicle, the Oligo Transport Vehicle, and the Antibody Transport Vehicle.
Today, we'll focus on our enzyme transport vehicle programs and the new data that's been presented here at the WORLD Symposium. On Slide 7, you can see the totality of our enzyme transport vehicle franchise, including our preclinical and clinical molecules. Again, the focus today will be on tividenofusp alfa, ETV-SGSH, as well as ETV-GAA. On Slide 8 is a summary of the presentations that have been given here at WORLD. There are seven presentations, two of which were oral presentations just recently delivered, including new data for TIVI as well as DNL126. We'll also highlight the clinical trial design for ETV-GAA and new preclinical data. Our key messages are as follows: the continued analysis of the phase 1/2 study in Hunter syndrome reinforces the potential for TIVI to address the full spectrum of disease.
We've established launch readiness in anticipation of the April 5th PDUFA date, and are looking forward to launching this medicine. For DNL126, preliminary data from the phase 1/2 study was presented, showing an 80% mean reduction in CSF heparan sulfate and substantial reduction in other biomarkers, as will be highlighted today. The safety profile is generally consistent with established ERTs, and I think, importantly, we're expecting to file our BLA and receive accelerated approval in 2027 using these interim data as the foundation for this program. For ETV-GAA, we will describe the design of an ongoing DNL952 phase 1 clinical study and also present preclinical data. We expect biomarker proof-of-concept data in 2027. I'll now hand it to Peter, where we'll begin on Slide 11.
Thank you, Ryan. Hello, I'm Peter Chin, Acting Chief Medical Officer and Head of Development. I'm pleased to join you from WORLD Symposium today. First, I'll briefly summarize the presentation by Dr. Joseph Muenzer on the tividenofusp alfa phase 1/2 study results with additional follow-up. On Slide 12, tividenofusp alfa is designed to address both the neurologic and systemic manifestations of Hunter syndrome by leveraging TfR-mediated transport to deliver IDS to the brain and the body. On Slide 13, you'll see the E2 study design. This is the phase 1/2 tividenofusp alfa study that was recently published in the New England Journal of Medicine. It's an open-label, first-in-human study with initial dose-finding cohorts, followed by long-term treatment in all cohorts with weekly IV tividenofusp alfa at a dose of 15 milligrams per kilogram.
The data in this particular presentation with extended follow-up have a clinical cutoff date of March 28, 2025. This represents when the last patient enrolled completed the week 49 visit. On Slide 14, we see the disposition. I'll note that there's no change in disposition since the primary data cut published in the New England Journal. In this updated analysis, the cumulative treatment exposure includes a median of 134 weeks and a maximum of 243 weeks. On Slide 15, the biomarker results, as previously presented, both CSF and urine heparan sulfate showed substantial reductions in normalization following treatment with tividenofusp alfa. These reductions were maintained long-term through 201 weeks. On Slide 16, serum NfL showed substantial reduction with normalization in the majority of participants after week 104. Moving to Slide 17, here are the updated data on hearing threshold.
Improvements in hearing threshold, as assessed by pure tone average, are maintained with the additional follow-up through week 201. This was reflected across all frequencies tested. On Slide 18, you see the updated data for liver volume. Normal liver volumes were maintained through the MRI assessment at week 153. On Slide 19, these next two Slides I'll show data in a way that we haven't presented before. And so note that these two Slides have an animated build. The plot in green shows the overall mean change in Vineland Adaptive Behavior Scales composite, which demonstrated continued skill gains through 213 weeks. If you advance the animation, it shows subgroups by age at the time of treatment initiation. The younger age groups depicted in teal and the medium blue plots show continuous skill gains up to the extent of follow-up at the time of the data cutoff.
The participants who were over the age of four at the time of treatment initiation, depicted in dark blue, remained stable in their abilities through 213 weeks. This is a meaningful outcome relative to the decline that one would expect to see over time. On Slide 20, once again, the green plot depicts the overall change in Bayley Scales cognitive raw score through week 201. Advancing the animation, similar to the Bayley results on the previous slide, Bayley Scales cognitive ROSCORs demonstrated improvement with continued cognitive skill gains in younger age groups up to the data cutoff. The older patients above the age of four maintained stable cognitive scores over the course of nearly four years.
Just a note on this: while the youngest patients appeared to gain the most in terms of the rate of skill acquisition while treated with tividenofusp alfa, these data show the potential for treated patients to improve or stabilize meaningfully across the broad study population, as highlighted in videos from Dr. Muenzer, who showed cases of neuronopathic siblings who were participating in our study at our R&D Day recently. The next Slide shows the safety overview, Slide 21. With additional exposure since the primary analysis, tividenofusp alfa continued to exhibit a stable and manageable safety profile in the study participants with MPS II. On Slide 22, we once again show updated data on the infusion-related reactions. These IRRs are known risk of ERTs. They were the most common adverse event in the study. And as you can see, they decrease in incidence and severity over time.
On Slide 23, you see the conclusions. In this updated analysis of tividenofusp alfa in the phase 1/2 study with additional follow-up, we continue to see substantial reductions in normalization in the majority of participants on CNS and peripheral biomarkers, which were maintained over time. And we continue to show improvement across multiple domains, including cognition, behavior, and hearing. The safety with the additional follow-up time remained consistent with the primary analysis. And as noted earlier, TIVI was designed to treat brain and body in Hunter syndrome. And in this phase 1/2 study, we continue to see positive outcomes across a broad age range and in both neuronopathic and non-neuronopathic phenotypes. If we move forward to Slide 25, I'll briefly summarize a poster that's being presented by Dr. Irene Chang of UCSF describing the outcomes of two non-neuronopathic siblings enrolled in the phase 1/2 tividenofusp study.
The full details of the cases will be presented in the poster itself. On Slide 26, here we present the data on the cases. And so there's a male sibling pair enrolled in the ongoing phase 1/2 study. The data in this presentation, of note, also includes standard-of-care observations from the clinical site beyond the study protocol. Both siblings enrolled in cohort D of the study, which included treatment-naive individuals with preexisting hepatomegaly, both initiated tividenofusp treatment in September of 2022. The younger sibling notably missed his week 24 assessments due to illness not related to the study drug. On the right-hand side, table 1 summarizes the baseline demographics and clinical characteristics of the siblings. They were aged six years and eight months and four years and three months at the time of treatment initiation. Both had evidence of reduced IDS activity, and neither had received any prior MPS II therapy.
The composite cognitive DQs, as noted, show a normal age-typical range in both siblings, but both had clinical signs of somatic involvement on clinical exam. If we move to Slide 27, you see the biomarker results, which basically showed baseline levels of CSF HS and DS, as well as urine HS and DS, being elevated above the upper limit of normal, as noted in figure 2. All levels normalized by week 49, and the substantial reductions were maintained through week 104. If we move to Slide 28, we'll look at the somatic manifestations. And there were several. So both siblings had diagnoses of carpal tunnel syndrome, which resolved over time while treated with tividenofusp alfa. And this was true both clinically as well as by EMG/nerve conduction study.
Anecdotally, in the study week 24 interview, parents noted that both of the boys wanted to play video games, whereas in the past, they had previously avoided this due to pain in the wrist. Joint mobility also improved, particularly in the older sibling who had bilateral impaired shoulder abduction at baseline, which normalized at week 104. Both siblings achieved 6-minute walk test distances within the typical range for boys their age. Of note, both siblings followed typical height and weight trajectories expected for their ages, with the older sibling in the 50th percentile for height and the younger sibling in the 90th percentile for height in recent measurements. We also, as part of the poster presentation, have videos, which are accessible through the poster itself and the QR code. These demonstrate the range of motion and activity levels of the siblings following treatment.
If we move to Slide 29, the cognition results in these two siblings are also quite interesting. So the processing and cognitive abilities in both siblings improved from screening to week 29, reaching above average to what we might consider upper extreme ranges for age. The standard score gains indicated cognitive development exceeding age-matched Kaufman score norms. And so these improvements were consistent with parent-reported academic and functional gains, supporting meaningful cognitive change while on treatment. So on Slide 30, as a brief summary, while treated with tividenofusp alfa in the phase 1/2 study, these two non-neuronopathic siblings with MPS II exhibited normalized disease biomarkers, improved their somatic manifestations and mobility, demonstrated age-typical growth and stature, and cognitive function in an above-average range. And while anecdotal, these collective outcomes appear to suggest that tividenofusp alfa is enabling these siblings to reach their physical and cognitive potential.
If we move forward, next, I'll change gears and summarize the preliminary data from the DNL126 Phase 1/2 study, which was presented by Dr. Elizabeth Jalazo a short while ago. On Slide 32, a brief note about MPS IIIA. It's an autosomal recessive lysosomal storage disorder resulting in the loss of SGSH, leading to an accumulation of heparan sulfate in the brain. This drives lysosomal dysfunction, neurodegeneration, early developmental delays in childhood, followed by severe neurological decline. And sadly, death in adolescence is typical. There are also somatic symptoms associated with the disease. There are no approved therapies for MPS IIIA, thus it represents an area of high unmet medical need. On Slide 33, DNL126 is designed to leverage TfR-mediated transport to deliver SGSH to the brain and address the relentless neurological manifestations of the disease while also delivering ERT to the body.
On Slide 34, we'll look at the study design. DNL126 is being evaluated in the phase 1/2 open-label study in children with MPS IIIA. Enrollment is complete with 20 participants. This update in this presentation includes preliminary data from 14 participants with a data cutoff of June 4, 2025. Safety data in the presentation are shown for all 14 participants. The preliminary biomarker efficacy data are shown for the eight patients in the dose-finding cohorts who had available data through week 49. The dose-finding cohorts involved weekly and every other week infusions with intra-participant dose escalation at three dose levels, which informed the optimized dose regimen for the efficacy cohorts that you see in the bottom portion of the figure. The eight cohorts recruited participants across a broad pediatric range, including severe and allowance for slower progressing phenotypes. Cohort B1 recruited participants less than 28 months of age at enrollment.
Cohort B2 was proposed for siblings of participants in cohort B1, but no siblings were enrolled in B2. The primary endpoint is percent change from baseline in CSF heparan sulfate at week 49. If we go to Slide 35, data from 13 out of 14 participants were available through week 25, and from eight participants in the dose-finding cohorts, data were available through week 49. The median age at enrollment was approximately four years, with the youngest participants aged 27 months at the time of treatment. The eight participants in the two dose-finding cohorts had an age range of 36-78 months. Six were female, and two were heterozygous for a slower progressing variant. If we go to Slide 36, preliminary biomarker results in the dose-finding cohorts were robust, with substantial reductions in CNS biomarkers after 49 weeks of treatment with DNL126.
On the left-hand side, CSF heparan sulfate reductions were observed by week 13, and they showed a mean reduction of 80% at week 49, with some participants achieving normalization. On the right, you see CSF GM3, a marker of secondary lysosomal storage pathology, was reduced by approximately 60%, with most participants in the normal range, suggesting improved lysosomal function following treatment. On Slide 37, we showed the peripheral effects of DNL126. Treatment resulted in a rapid reduction in urine HS by week 3 and showed a mean reduction of 83% at week 49. Variability beyond week 3 is consistent with intra-participant differences in dose escalation and dosing frequency, as described on the study design Slide. The liver volume normalized in all participants by week 49. These findings support systemic activity of DNL126 in addition to enzyme replacement in the CNS. Slide 38.
The preliminary safety profile of DNL126 is generally consistent with established enzyme replacement therapies. Adverse events were primarily mild or moderate in severity, and there were no treatment-related serious AEs. There were no study discontinuations or treatment discontinuations due to adverse events. The infusion-related reactions were the most common AE, as expected, for ERTs. On Slide 39, you'll see additional information on infusion-related reactions. These were mild or moderate in severity, and the frequency and severity of IRRs decreased over time, as noted by the figure, which depicts IRRs by cohort. Reactions were manageable with premedication and infusion rate adjustments and dose escalation. Notably, treatment with the optimized dosing in the later cohorts appeared to show improved tolerability with the use of gradual dose escalation, as noted earlier. On Slide 40, you see the conclusions and takeaways.
In this preliminary analysis, DNL126 treatment resulted in CSF reductions of 80% with normalization in three out of seven participants. This appears to be the largest magnitude of CSF HS reduction reported in this very difficult-to-treat disease. Treatment also led to substantial reductions in other disease-relevant biomarkers, including GM3, CSF, and heparan sulfate in urine, as well as normalization of liver volume. The preliminary safety was consistent with enzyme replacement therapy, with IRRs being the most common AE. These decreased in frequency and severity over time and were clinically manageable. These preliminary data support continued evaluation of DNL126 in the ongoing efficacy cohorts. And Denali remains on track for a potential accelerated approval in 2027, based on CSF heparan sulfate as a surrogate marker reasonably likely to predict clinical benefit. And now I'll turn it over to Joe Lewcock, our Chief Scientific Officer.
Thank you, Peter. I'm Joe Lewcock, Chief Scientific Officer at Denali Therapeutics, and I will be sharing highlights from two posters presented at WORLD evaluating DNL952, a novel investigational therapy for treating patients with Pompe disease. Just a reminder, Pompe disease is caused by a deficiency in the lysosomal enzyme, GAA, leading to glycogen accumulation in muscle cells and progressive muscle weakness despite existing enzyme replacement therapies. In addition, glycogen buildup in the nervous system can cause severe neurological defects in infantile-onset Pompe disease, IOPD, and may also contribute to weakness in late-onset Pompe disease, or LOPD. Therefore, there's a need for therapies that enhance enzyme delivery to both muscle and the nervous system.
So if you go to Slide 43, I'll start with the first poster that was presented, which is entitled "Enhanced Correction of Skeletal Muscle and Brain Pathology in a Pompe Mouse Model Using Transferrin-Mediated Delivery of GAA." Moving on to Slide 44, it outlines the architecture of DNL952 on the left-hand side of the Slide, where recombinant GAA, shown in blue, is fused to Denali's transport vehicle in gray, which, as you will likely recall, is an engineered Fc fragment that contains a transferrin receptor binding site illustrated in gold. On the right-hand side of the Slide, it illustrates the delivery of DNL952 to the key tissues impacted in Pompe disease, where transferrin receptor-mediated delivery enables efficient delivery to muscle cells as well as neurons via transport across the blood-brain barrier.
In addition to trafficking to the relevant tissue types, TfR also enables the cellular uptake and intercellular trafficking through the endolysosomal pathway. Therefore, through engaging transferrin receptor, DNL952 is designed to biodistribute properly and enhance delivery and lysosomal targeting in affected tissues. If we move on to Slide 45, you can see some of the preclinical data with this molecule. This is looking first at pharmacodynamic effects of DNL952 in a mouse model of Pompe disease, in which the GAA gene has been knocked out. These mice also express a chimeric human-mouse transferrin receptor to enable binding to the TV.
What you could see on this Slide in GAA null mice, which are shown in dark blue, on the left-hand side of the Slide, as well as on the right-hand side, you see in muscle on the left and in nervous system on the right, significant accumulation of glycogen in both of these tissues. Again, that's shown in blue compared to wild-type animals in gray. What you could see across a dose range is really a substantial reduction of that glycogen accumulation after 5 every other week doses of DNL952, which at all dose levels is superior to the level of glycogen reduction using the same dosing regimen with 20 mg per kg of the standard of care. Very encouraging pharmacodynamic activity with this molecule.
If we move on to Slide 46, now we can look at the pathologic hallmarks of Pompe disease in muscle downstream of glycogen accumulation. What you're looking at here is LAMP2 and P62, which are two markers of autophagic morphology in these tissues, which is abnormal in the mice that lack GAA enzyme activity. That can be seen in the pictures on the top panels of the Slide. If you then look down at the bottom panels of the Slide for quantification of both LAMP2 on the left-hand side and P62 on the right-hand side, you could see that increased staining in muscles of mice that lack GAA enzyme activity and a dose-dependent reduction of these pathologies after treatment with DNL952 in the same dosing regimen shown on the previous Slide.
By contrast, 20 mg per kg of the standard of care is unable to effectively impact these disease pathologies, showing clear differentiation of a TfR-enabled DNL952 molecule. If we then move on to Slide 47, here provides a QR code where, if you're interested, you can go and take a look at all of the details of this data, the preclinical package, with the conclusions of this work being that the biomarker evidence we've established from these animals provides proof of concept for DNL952 and supports advancement into clinical studies. We then move on to Slide 48. I'll go over the second poster presented here at WORLD, a phase I multi-center open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL952 in adult participants with late-onset Pompe disease, pardon me. So we'll go over the study design on Slide 49.
This study, DNLI-J0001, is the first-in-human phase I study of DNL952. It is an open-label study in adult participants with late-onset Pompe disease. The primary and secondary objectives of this study are to characterize the safety, tolerability, pharmacokinetics, and immunogenicity of DNL952. Exploratory pharmacodynamic markers, including urine Glc4, serum creatine kinase, and other markers, will be measured as part of this study. This study will also include exploratory clinical measures of motor and respiratory function. As shown on the graphic on the right-hand side of the Slide, enrolled participants will receive DNL952 during a 24-week core period and a 24-week extension period. Initial dose exploration will be conducted in two planned cohorts enrolling ERT experienced participants with optional additional cohorts to evaluate alternative doses or dose frequencies.
Following initial dose exploration, selected dose regimens may also be evaluated in optional ERT naive cohorts shown on the bottom right-hand side of the Slide. So if we move on to Slide 50, it's just the conclusions of this poster as well, which was meant to outline the design of the DNLI-J0001 study and the goals of this study. For more information, you can visit ClinicalTrials.gov or scan the QR code on the right-hand side of the Slide for additional information. So now I'll turn it over to our CEO, Ryan Watts, to provide conclusions for the presentation.
Thank you, Joe, and thank you, Peter. This ends the formal presentation portion of today's call. We'll now turn to the Q&A.
Thank you. Ladies and gentlemen, as a reminder to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 11 again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Andrew Tsai with Jefferies. The line is now open.
Hey, good afternoon. Thanks for taking my question, and thanks for sharing the nice set of datasets. So for Sanfilippo, as we think about the next steps, is it fair to assume that the full 20-patient worth of data could look even better than what you're seeing right now since these next batch of patients are being dosed at the "key efficacy" cohorts? And then secondly, with this nice dataset you're seeing so far, especially on heparan sulfate, does it make sense to file for a breakthrough designation? Thank you.
Great questions. Thank you, Andrew. I'm going to hand it to Peter, and maybe we'll add a little bit as well. Peter.
Yeah, thank you. It's a great question about what we could expect to see with the efficacy cohorts. As you pointed out, the A1 and A2 dose-finding cohorts had various doses and every other week dosing for a substantial period of time, as we noted on the study design. It's a Slide with a study design. The efficacy cohorts will have an optimized slow dose escalation and weekly dosing, getting to the high-dose weekly dosing at a faster rate. We hypothesize that it should be at least as good as what we've seen in the dose-finding cohorts, but we have to actually gather the data and show that in the future.
I think I'll add to that, that we're very enthusiastic about the 80% reduction, the ability to normalize. I think one thing we've learned in Sanfilippo is this is a very difficult-to-treat disease, and this is, I think, clearly the best-in-class that's been shown to date on the ability to impact heparan sulfate. Now, obviously, we've had a lot of experience with the transport vehicle, but of note, you'll see even when we look at urine heparan sulfate and then ultimately at CSF, those first two cohorts were really important in optimizing. And so we think that this is, I think, fantastic data to really set us up for accelerated approval. And Andrew, I think you may have had a separate second question. I don't know if we answered both questions in answering that.
Thank you. To the extent you can share whether it makes sense to file for a breakthrough designation.
Oh, yeah. I mean, my guess is we'd be moving in that direction as we did with TV. Yeah, thank you.
Okay. Thanks. Congrats.
Thank you. Our next question coming from the line of Salveen Richter with Goldman Sachs. The line is now open.
Good afternoon. Thanks for taking my question, and congrats here on the data. I was wondering if you could just speak in the context of TV here showing about 62% of patients being previously on standard of care, how you think about outcomes or what you're seeing with regard to outcomes amongst previously treated patients versus treatment-naive patients? Thank you.
That's a good question. I'll hand it to Peter, and again, may add a bit as well.
Yeah, it's a great question. The first thing I'd say is there's heterogeneity across the population. The second thing I would say is that as an overall group, as you've seen, there's improvement, particularly in the younger population. And so I think those are the individuals that stand the greatest opportunity for benefit. The earlier we treat, the more likely they are to be treatment-naive. But I think the other thing we want to say is the stabilization is highly important. And whether it's a very young patient or an older pediatric patient, as we had in the study, I think the data are really important in maintaining skills over the course of up to four years in the latest data cut.
I'll just add, and maybe, Salveen, what you're trying to get at is the switching dynamics, the fact that a large number of these patients were previously on standard of care and then switched to TV. Do we see any differences in clinical outcome with treatment-naive versus switching? Notably, our COMPASS trial is designed so that patients initially start on standard of care and then switch. So most of our data, including, by the way, looking at urine heparan sulfate, obviously, CSF heparan sulfate, patients are on standard of care. So we're seeing a robust effect even on patients that are switching from idursulfase to TV. I hope that answers your question.
Yes, thank you.
Thank you. Our next question coming from the line of Paul Matteis with Stifel. The line is now open.
Hi, this is Matthew on for Paul. Thank you so much for taking our questions, and thanks for presenting all the data. I guess some of the questions on the urine heparan sulfate for Sanfilippo, you mentioned there was some variability in response due to the dosing titration schedule. Can we infer from that that there is dose dependence all the way up to the high dose? And perhaps, why are we only seeing it in the urine heparan sulfate and not the other CSF markers?
Thank you. Yeah, thank you for that question. I'll answer it first, and then, Peter, you feel free to add to it. What's been interesting for us is the sensitivity of urine seems to be greater than CSF. In other words, it returns to baseline more rapidly than CSF. The duration of response seems to be longer in cerebrospinal fluid. So I think that allows us to, let's say, a more acute measure of activity. And I think what's interesting is if you line up the dose-finding portion of A1 and A2 with that urine, you can see when we essentially switched everyone to weekly dosing at the high dose. So I think that's probably the best way to look at it. Yeah, I'll end there. Do you want to add anything else, Peter?
Yeah, I think you've summarized it well. The only other thing I'd add is the A2 cohort was treated with every other week low dose for approximately 20 weeks. And so that, as Ryan said, urine tends to be more sensitive, and that may explain some of that variability. But as the patients in the dose-finding cohorts escalated to the higher dose, you see that we achieved an 83% reduction at week 49, which we consider quite robust.
I'll add one other point, which is worth noting. I think when you think of Sanfilippo, you think of the severe and rapid neurological decline, which is certainly the case. But it's actually interesting in this dataset to see elevated urine heparan sulfate and increased liver volume, which we can normalize. So this is clearly a whole-body disease as well. And I don't think others have really shown data around that, at least to this extent. But just an important point to highlight.
Thank you so much.
Thank you. Our next question to you coming from the line of Mayank Mamtani with B. Riley Securities. The line is now open.
Yes, good afternoon. Thanks for taking our questions, and appreciate the comprehensive presentation. So on DNL126, Ryan, if you are able to contextualize the depth and durability of CSF heparan sulfate that we are seeing here, say, relative to a gene therapy approach, and also if you've looked at any clinical measures yet, and is your expectation to have younger age groups do better like you have in TV? And in terms of next steps, are you looking to assess any differences on the clinical measures relative to, say, a natural history comparison that we've seen some of that being done? Obviously, unlike TV and Hunter's, there's nothing out there here to compare against. And then I have a follow-up.
Okay. So the first question is the depth of response for CSF heparan sulfate. Let's start with that one. So maybe, Peter, you can comment on that.
Yeah, I think, again, in these dose-finding cohorts, we've shown an 80% mean reduction. To our knowledge, that's the most robust effect that has been seen. I'll also reiterate that it occurred pretty rapidly with effects shown by week 13 and an 80% reduction at week 25 as well as at week 49. We find these data to be highly compelling, even if they're preliminary.
Yeah. And then the second question, or at least part of that, is what is our plan to show cognitive benefit? And then the third question is, are we planning to enroll younger patients? So let's talk about the cognitive benefit as we go forward on this program.
Yeah. As you know, these cognitive assessments are more interpretable over time. And so this is a very preliminary analysis with limited follow-up. Of course, we are measuring those data over time, and there's an open label that follows the week 49 period. And so we will be assessing those. In terms of natural history, we don't have a direct natural history comparator, but that will serve as an important reference in the future as we accumulate longer-term data.
Yeah. And I think there are some—I mean, in our experience, there's some challenge in who you select to compare in natural history. I think you asked one other, and I'll just add one other point around the depth of the heparan sulfate. I think, once again, people choose to measure heparan sulfate in different ways. It's either absolute number, percentage, AUC. In our case, we see this as really the best-in-class example and similar to what we've shown previously in other diseases, so.
Great. Thank you. And my follow-up on TV was, have you broken down and sorry if I missed this, the biomarker and our clinical data by severe and attenuated phenotypes? Have you broken that down, and what does that look like? Thanks for taking the question.
Yeah, sorry. May I? Can you restate? Did you get that? Can you restate broken down the biomarkers? Say that again.
For TV, have you broken down your biomarker and/or clinical data by severe and attenuated phenotypes? Have you shown that?
Yeah. Peter.
Yeah. So the A2 study, the phase 1/2 study that we just presented on, 44 out of the 47 participants were neuronopathic. And so we don't typically do, because it's such a small non-neuronopathic cohort, formal analysis by subgroup. As we showed in the two siblings, both CSF and urine, HS and DS, were elevated, even in the so-called attenuated patients. And we showed an ability to normalize all of those markers rapidly. So the short, long way of saying, the biomarker effects that we've seen with tividenofusp cover both the neuronopathic and the non-neuronopathic patients in the ability to normalize. I think from a clinical outcome standpoint, as we presented in the case studies, these are individuals who were already performing at an average level cognitively at baseline, and they actually continue to gain skills at quite a rapid rate.
The standard scores in the poster suggest that they're actually performing at an above-average level currently. Then finally, the somatic manifestations, I think this poster illustrates very nicely, the improvement on both preexisting somatic manifestations such as the joint mobility as well as the resolution of carpal tunnel syndrome and some of the other highlights that are noted in the poster. As noted, TV was designed to treat brain and body. I think in both neuronopathic and non-neuronopathic patients that are available in the study, we've been able to demonstrate that fairly convincingly.
Very helpful. I'll hop back in the queue. Thank you, guys.
Thank you. Our next question coming from the line of Sean Laaman with Morgan Stanley. The line is now open.
Hi, Ryan and team. Thank you for the great presentation, and thank you for taking my questions. My question's around sort of potential clinical differentiation to elsewhere. But think about 126 and the HS reduction in the CSF of about 80%. How can you correlate that, or how clinically meaningfully different might that be to something that sort of reduced HS by 65% or 50%? Or do we not know that yet is the sort of first part of the question? And the second part's still on clinical differentiation, the 61% reduction in CSF GM3. Is that meaningful in trying to demonstrate clinical differentiation to elsewhere? Thank you, Ryan.
Yeah, it's a great question. And I think this is a question for all of the MPSs. What level of reduction leads to benefit? And clearly, we see substantially greater reduction than others have reported. I think ultimately, what's going to play out is the subsequent biomarkers like GM3. I'm glad you pointed that out, where 6 of 7 participants had normalized. So remember that % reduction is relative to the amount of increase for that particular biomarker. So when you achieve that level of reduction for GM3, we're actually normalizing the function of GM3 and, frankly, what we believe is normalizing lysosomal function. But there's probably a cutoff at some point where you're not reducing it enough, and we don't know what that is. Our goal is to maximize CSF heparan sulfate reduction.
Wonderful. Thank you. That's the only questions I had. Appreciate it, Ryan.
Yep.
Thank you. Our next question coming from the line of Tazeen Ahmad with Bank of America. The line is now open.
Hi, guys. Thanks for taking my question. For 126, I just wanted to clarify, what are you expecting the go-forward dosing regimens to look like? And then secondly, what are you thinking about the trial design for phase 3 for Sanfilippo? When could that start, and how many patients do you think, roughly, you'd need in order to enroll? And then lastly, can I ask a quick question on your interactions with FDA on TV's review? Do you think it could get approved ahead of your PDUFA? Thanks.
Yeah, great. So we'll answer those three questions. We'll start first with dosing.
Yeah, so great question. What I refer you back to is the study design in the efficacy cohorts, where we have this is Slide 34, where we show the dose escalation scheme starting with a low dose for approximately 6 weeks, going to a mid-dose, and then going to high dose with q-weekly infusions. So this is based on the preliminary data, what we believe to be the optimized dosing regimen.
Yeah. I'll just add very briefly. I know we have many questions to answer here. I mean, as you can see in the study design, we compared every other week versus weekly dosing. This has been something that has been explored often. The enzyme replacement build for us, the great thing about heparan sulfate is its responsiveness and our ability to change the dose. But we now have the optimized dose that will be the same dose we're selecting for the phase 3. To answer your phase 3 question, we will be sharing more. That's been a big topic with the FDA, is the design and finalization of that phase 3, which we're very near to that now. It will not be a placebo control, thank goodness, but it will actually be a comparator to baseline, which will be fantastic.
We'll share more on the number of patients. It's not going to be a very large study. Our goal with 126 is to spend about half as much as we did on 310 and move about as twice as fast. So that's the ultimate plan. Your last question was on TV and where do we stand with the FDA. So right now, it's all about defining the post-marketing commitments and the ongoing label discussions. I can't comment. If we imagine an early approval, that would be fantastic. Right now, the base case is April 5th as a PDUFA date.
Thanks, guys.
Thank you. And our next question comes from the line of Michael Yee with UBS. The line is now open.
Hey, guys. Thanks for the question. On the Pivotal Hunter study that is ongoing, a couple of questions. One is, have you guided to exactly when you would complete cohort B? What is the general purpose of the cohort B? Because I understand that, obviously, that's non-neuronopathic. And so what's your confidence that that would actually hit on a six-minute walk or other endpoint? And is that for safety, or do you actually think that population would be in the label? Thank you so much.
Yeah, great question, Mike. In fact, I think there might have been a misstatement in the presentation by Dr. Muenzer. Maybe I misheard it. But cohort B is not the rate-limiting step in completing the COMPASS trial. It's a 1-year endpoint as opposed to the 2-year endpoint for cohort A. So cohort A is fully enrolled. I think Dr. Muenzer may have mentioned we're in search of several more patients for cohort B. It's not rate-limiting. And the purpose of that is to show comparability, really, to Elaprase. So 6-minute walk, but also maintaining reduction in liver and spleen and heparan sulfate. So at least that's the way that that was designed as we've engaged with the FDA now several years ago to show that we basically are comparable to Elaprase. The ultimate goal for us, obviously, is to have a broad label as possible.
Thank you.
Thank you.
Our next question coming from the line of Myles Minter with William Blair. The line is now open.
Hi. Thanks for the questions and congrats on all the data and the presentations here at WORLD. My question's actually about Dr. Jalazo said that one patient, I think, required a second bag infusion because of infusion-related sort of reactions. Do you know what dose that was at in the Sanfilippo program, and if it was at the high dose? What's your confidence that this will remain a single bag infusion as opposed to a two-bag infusion, which seems quite a lengthy process? Thanks.
I'll hand the computer for that. Yeah.
Yeah. I would have to get back to you on the exact dose. I think what I would say is there are occasional idiosyncratic reactions that patients receiving ERT have. And this is an individual who had IRRs that, as we noted in the presentation, can be managed with reduction in bag concentration and slowing the rate and then slowly re-escalating at some point. And so this is an individual who continues to dose in the study, and we don't think that that has broader implications on the tolerability of the drug.
Okay. Cool. And then just a really quick one. Thanks for breaking down all the Vineland III scores in the Hunter program as well. Based on age, seems like younger than two years is where you get the most benefit, but I agree there's clear benefit in stabilization for those older patients. What are you going to do with the younger age group here? What's your plans there? Because I don't believe that they are included in COMPASS. I don't think any patients below two years of age are included in that trial. So what is your plans there for that population? Thank you so very much.
Good, Peter. Yeah.
Yeah. So it's a great question. The way we think about the development program being a rare disease was to have complementary data coming from the E2 study, which did study patients as young as three months of age and all the way to adults in the COMPASS phase 2/3 study that we've been discussing. And so we view the totality of the data as being important for both confirmation of accelerated approval in the U.S. as well as global approval. So the data that we have in E2 are going to be very important in showing longer-term outcomes for the youngest patients.
Thanks. Thanks for the questions. Congrats.
Thank you.
Thank you. Our next question coming from the line of Ananda Ghosh with H.C. Wainwright. The line is now open.
Hi. Thank you and congrats for the data. I have two questions. The first one with respect to the Hunter syndrome, where you show very nice adaptive and cognitive behavioral. I was wondering, how does it compare with Elaprase-only patient if you have? Is there any data on that? That's the first question. I have a follow-up question also.
Yeah. I'll hand it to Peter. I think the question is natural history, but in reality, natural history is on standard of care. So what would you expect on standard of care with these patients?
Yeah. Thanks for the question. I mean, our expectation is that these patients would decline over time knowing that Elaprase does not cross the blood-brain barrier and does not address the neurological manifestations. There's limited long-term data that's interrogated, interrogatable, if that's a word, for doing an actual comparison. But based on the data that are available and with additional follow-up, we anticipate that these patients will continue to stabilize on tividenofusp or improve and deviate from the natural history.
All right. Thanks. And my next question, if you look across the programs like Sanfilippo and the GM3 biomarker and then the preclinical data from the Gaucher mice, what does it tell? I mean, what does it obviously, you are reaching intracellular organelles. You are targeting the lysosomes. Does that open up other how-to-treat lysosomal diseases like Tay-Sachs or Niemann-Pick? Or how are you interpreting those data with respect to the future pipeline development?
Yeah. The short answer is absolutely. I think what this data, the data in Hunter and in Sanfilippo, including liver volume, urine heparan sulfate, but also all the central nervous system, has very much opened our minds to other targets that we can go after in muscle and bone, including the central nervous system. But in your case, what you're bringing up is really going after the lysosome. So the short answer is absolutely. I think we have six minutes left. We're going to go into rapid fire for the next six minutes. So apologies if there are shorter answers, but we'll do our best. We'd really love to answer everyone's questions.
Thank you. Our next question coming from the line of Laura Chico with Wedbush. The line is now open.
Hey. Good afternoon, everyone. This is Thomas Yip asking a couple of questions for Laura. Thank you so much for taking our questions. So first, I wonder if you can help us understand the primary data points in the TV data package that you believe will be most useful to encouraging switching treatments, and what do you believe will resonate most with doctors?
I'll hand it to Peter for a brief answer.
Yeah. I think first and foremost, the urinary GAG data showing normalization, including in those patients in the E2 study who were already treated with Elaprase with no washout. I think those are highly compelling data. And then the other peripheral data that we have includes the normalization of liver volume and maintenance of normal liver volume in those who were at baseline. We're continuing to gather clinical outcomes over time, but I think the biomarker evidence strongly suggests that there is an advantage to switching.
Thank you.
Great.
Our next question coming from the line of Joseph Thome with TD Cowen. The line is now open.
Hi there. Good afternoon. Thank you for taking my question. Maybe on Sanfilippo, just based on your conversations at WORLD, if we assume that a gene therapy approach and 126 are commercially available, based on the doctor conversations, is there a subset of patients that they think might be more applicable for one versus the other? And could you combine these approaches, assuming they'd be able to get reimbursed? Thank you.
Yeah. I mean, I think the last point you made is probably the most relevant point, which is combination. Certainly the case in Hunter, where gene therapy is delivered directly to the brain. I haven't seen the peripheral data in detail on the systemically delivered gene therapy, but we imagine that there will be room for both and likely in each patient as gene therapy may wane.
Our next question coming from the line of Marc Goodman with Leerink Partners. The line is now open.
Hi. This is Basma on for Mark. Thank you for taking our question. We just would like to clarify why would there be need to have a titration for the DNL126 in the Sanfilippo program? Because when we compare with the Hunter program, we noticed that you were able to get to the therapeutic dose in the efficacy cohorts without titration. And would that may need to mitigate the side effect profile, or there was other reason for it? Thank you.
Yeah. So the brief answer is to mitigate IRRs. And I think we've really nailed it. As you can see, with the IRRs over time, with the different dosing regimens in the different cohorts, you see actually substantially less IRRs. So that dose escalation allows you to do that. That would be common across most enzyme replacement therapies.
Thank you. Our next question coming from the line of Jay Olson with Oppenheimer. The line is now open.
Oh, hey. Congrats on these results, and thanks for hosting this event. We had a question about the DNL126 biomarker data. What do you think is more important for driving clinical benefits, GM3 normalization or HS normalization? And then separately, can you provide any color on antidrug antibodies or neutralizing antibodies that you observe with DNL126 and whether or not the presence of ADAs or neutralizing antibodies have any impact on the efficacy of 126? Thank you.
Yeah. So I'll start, and Peter can add, although we're running out of time. So I think what the GM3 data shows is that the amount of heparan sulfate reduction we achieved was sufficient to basically normalize lysosomal function as it relates to GM3, which is a separate marker. So that gets back to, I think, one of the previous questions around the percent reduction you need to achieve. Ultimately, there's going to be downstream biomarkers that will also be very informative that may move later in disease, for example, like neurofilament. I think that answers the first question. Remind me again on the second question.
ADAs or neutralizing antibodies?
Yeah. So ADAs are common in all ERTs, and they're present, obviously, in our other programs. We most certainly see anti-drug antibodies with 126. I think your question is, does it seem to affect efficacy? That actually remains to be seen. I think part of these dose escalation protocols and optimizing dose is really to optimize dosing over ADAs. That's what we learned with TIVI, is that we push the dose. There's often a question about the dose level, but our goal there was to try to treat all Hunter patients, including those that have high anti-drug antibodies to enzyme, which is commonly observed. We don't have enough data yet to really define that for 126, but I think likely optimizing the dose is related to ADAs.
Our next question coming from the line of Michael DiFiore with Evercore ISI. The line is open.
Hi, guys. Thanks so much for taking my questions. Two quick ones for me. Just want to revisit perhaps the first question that was asked around what we could expect in the efficacy cohort since these patients are dosed at the full dose or at the target dose. Could we possibly see a 90% reduction in CSF/HS here? Is there a reason not to expect a greater dose response? And then separately, regarding NFL biomarker data, I know it's way too early to tell now, but could we expect 126 to exhibit similar kinetics on NFL reduction to what was seen in Hunter, where most of the reduction happened after one year's therapy? Thank you.
Yeah. So I'll answer that question. Peter gave a great answer the first go-round. We can read the transcript, but I'll add to that. So we believe 80% reduction is very robust, and we believe will be sufficient not only for the accelerated approval but to drive clinical efficacy. I think the questions around ADAs and heterogeneity, that will play out over time now that we've optimized the dose. I don't necessarily think you have to achieve any specific percent reduction as long as you get the downstream biomarkers corrected like GM3 and ultimately NFL. So I think your question is a fantastic question thinking about, "Okay, what is needed then to drive the halting of neurodegeneration?" But we see this as a robust data set as we've now optimized the dose and are moving forward.
Thank you. Our next question coming from the line of David Hoang with Deutsche Bank. The line is now open.
Hi. Thanks so much for fitting me in. So maybe just quickly, in terms of commercialization of tividenofusp alfa, what's your level of confidence to get broad coverage and effect switches from Elaprase with an accelerated approval? Is it possible that any insurers may be looking for the COMPASS data and a full approval? And then on Pompe, are you thinking accelerated approval path there, or would that may be a more full traditional path? Thanks so much.
Yeah. Both good questions. And obviously, that's a huge focus of us to imagine how to get coverage on TIVI, and that will play out over time. I don't think we have anything new beyond the data that we presented today. And then related to Pompe, I think our base case is actually head-to-head LOPD. We want to capture the broader market. We are thinking of other creative ways, but I would just say for that, stay tuned. And for now, we're looking at sort of a best-in-class against the competitors that are out there.
Thank you. Our next question coming from the line of Charles Moore with Baird. The line is now open.
Hey, guys. Thanks for fitting me in. So just quickly, wanted to know if there's any correlation between baseline cognition and improvement that you've seen with tividenofusp alfa, as well as checking in on how the post-gene therapy or stem cell transplant patients are performing. And then I was just also quickly curious if you anticipate exploring infant-onset Pompe as well with your asset after establishing proof of concept. Thanks.
Yeah. I think with respect to the correlations, there's a lot of heterogeneity in the clinical trial. I think we did present some correlations at Congress last year at ICIEM. So there are some baseline correlations, but it's difficult to have strong correlations that predict all the varied outcomes that we showed earlier across the different groups. With respect to IOPD, I think that remains to be determined. Definitely, IOPD has involvement of the brain, and that's something that we'll have to consider.
Thank you. Our last question will come from the line of Tom Shrader with BTIG. The line is now open.
Thanks. All IRR questions. The 310 patients that still have IRRs at 200 weeks, do they get normal benefit? Are the IRRs worse for 126, and do they explain any of the variability? And any read on Pompe? I think that's an extremely immunogenic payload. Thanks.
Yeah. I like the questions, Tom. I think each of these diseases have a different immunogenic profile. I think what we've learned from TIVI is that if you're seeing IRRs a lot after they've been on dose for a long time, it's usually because they've missed multiple doses. It's very often the case. Not always, but often the case that these patients have missed multiple doses, and then they go on vacation or whatever, and there's a higher rate of IRRs. I don't think we have enough data with 126 to say if there's more or less risk around IRRs or where Sanfilippo falls relative to Pompe versus Hunter. But there are certainly different immunogenicity profiles with these diseases.
Thank you. There are no further questions. I will now turn the call back over to Ryan Watts for any closing remarks.
Yeah. Thank you. Appreciate everyone calling in, and we move on. Thank you.
This concludes today's conference call. Thank you for your participation, and you may now disconnect.