I'm Laura Hansen, Vice President of Investor Relations. I'd like to thank you for joining us today. Please note that the press release we issued earlier today and the slide deck for this webinar are available in the Investor section of our website, denalitherapeutics.com. Before we get started, I'd like to note that the presentations given today and the responses to questions will contain forward-looking statements regarding Denali's future plans, business strategy, product candidates, planned preclinical studies, and clinical trials, among other things. Such statements are subject to numerous important risks, uncertainties, and assumptions. Should any of these risks or uncertainties materialize, should our assumptions prove to be incorrect, our actual results could differ materially from these forward-looking statements.
These risks, uncertainties, and assumptions are more fully described in our filings with the SEC, including our latest quarterly report on Form 10-Q and our latest annual report on Form 10-K. Any forward-looking statements are based on information available to us as of today, and we disclaim any obligations to update any forward-looking statements except as required by law. On the webcast today, I am joined by members of Denali's management team: Ryan Watts, Chief Executive Officer; Carole Ho, Chief Medical Officer; and Alexander Schuth, Chief Operating and Financial Officer. I'd like to take a moment to review the agenda and Q&A logistics for today. We have scheduled 30 minutes for the webinar, including presentations and a Q&A session at the end. If you would like to ask a question, you may do so by typing it into the Q&A box.
We'll do our best to answer as many questions as possible during the Q&A session. Now I'd like to turn the program over to our Chief Executive Officer, Ryan Watts.
Thank you, Laura. We're very much looking forward to sharing data today and discussing our DNL310 program for Hunter syndrome. Just a reminder that Denali has a broad portfolio of therapeutic candidates. Our focus today will be on our rare neurodegenerative diseases, in particular, our enzyme TransportVehicles or ETV-enabled programs, specifically in Hunter syndrome. If you look at our portfolio, the portfolio is split into two. One part of our portfolio is enabled by our TransportVehicle technology, which I'll introduce briefly. The second is our small molecule programs. As you see here, the program that will be the focus of today's webinar will be our iduronate-2-sulfatase or ETV:IDS program. This program is numbered DNL310. What is the technology that we use to get large molecules across the blood-brain barrier?
The technology we use is called the TransportVehicle technology, and it's basically the engineering of the FC portion of an IgG to bind to the transferrin receptor, which is an iron transporter at the blood-brain barrier. Using this technology, we've shown that we can get antibodies, enzymes, antisense oligos across the blood-brain barrier. Today, again, we'll focus on our flagship program, DNL310 or ETV:IDS. When this molecule binds to the transferrin receptor, it binds in a non-blocking way and is transported across the blood-brain barrier. I think importantly, we've shown robust reduction of substrate and subsequent correction of neuronal and cellular dysfunction. This highlights the other technologies that are enabled by the TransportVehicle platform. Our focus will be on the ETV today. However, we've shown that we can get antibodies as well as proteins and antisense oligos across the blood-brain barrier.
Now let's focus on what we are joined, why we're here on this webinar. Today, we're going to show interim results demonstrating a robust reduction in serum NfL as well as CSF NfL. The FDA has recommended assessment of NfL as an exploratory biomarker of neuronal axonal damage in MPS II. We plan to share additional interim data of the DNL310 program at SSIEM in August. With that, I'm now going to hand it over to Carole to get into the data.
Good morning, and thank you, Ryan. Let's go to the next slide. DNL310 is an IV therapy that is dosed once weekly, and as Ryan noted, utilizes Denali's TransportVehicle technology to deliver the IDS enzyme, missing or defective in MPS II, to the brain and body. DNL310 is currently being evaluated in an ongoing open-label phase I/II study and a randomized, double-blind phase I/II pivotal trial, the COMPASS study. For patients receiving DNL310, DNL310 is administered once weekly IV, which is the same dosing frequency as standard of care ELAPRASE. DNL310 is in clinical development to replace the current standard of care by delivering treatment to the brain, a current unmet medical need, while also treating the body. We have taken a methodical approach to systematically mapping the downstream impact of glycosaminoglycan accumulation in MPS II on pathway biomarkers of disease.
We have characterized these biomarkers in natural history patient samples and in the ongoing open-label phase I/II study. We previously hypothesized that successful treatment of MPS II would require biochemical correction of the elevated GAGs in the brain and CSF, cellular correction of lysosomal function in all cells of the brain, including astrocytes, microglia, and neurons, and subsequent neuronal correction that may translate to patient impact. In our phase I/II, we have evaluated the ability of ETV:IDS to directionally normalize these biomarkers. We previously demonstrated a sustained ability to normalize elevated CSF GAG and the ability to reduce and normalize gangliosides and lysosomal lipids. Today, we will present data on the effect of DNL310 treatment on neurofilament in MPS II. In the ongoing phase I/II study, we also continue to evaluate clinical endpoints with positive trends observed across a number of clinical endpoints.
Together, these data support the current DNL310 development strategy. Today's presentation will review data previously presented at World 2023 for context and share the new data for the patient population highlighted below in the demographics for the neurofilament analysis. The new data set consists of 23 patients that have reached one year of dosing. This is four more than previously presented at World, and 13 patients that have reached two years of dosing, or 104 weeks. This is approximately nine since World. The clinical cutoff date was early March of 2023, and notably, the DMC reviewed safety data from this data cut on May 31st of this year. The DNL310 phase I/II study is an open-label, six-month study, followed by an open-label extension plan for approximately 45 MPS II patients, aged two through 18.
There are five cohorts, A through E, in the study, designed to enable dose selection for the ongoing phase II/III COMPASS study and also evaluate the safety profile of DNL310 in a broad range of MPS patients in age, neuronopathic status, as well as previous treatment. Importantly, all patients that are on standard of care are switched to DNL310 at the start of the study without a defined washout period. The key primary, secondary, and exploratory endpoints have previously been presented and are summarized on the right side of the slide. The key primary endpoints are safety, adverse events, infusion-related reactions, and total urine glycosaminoglycans. The key secondary and exploratory endpoints include CSF and urine heparan sulfate and biomarkers of lysosomal function, biomarkers of neuronal function, including NfL and clinical outcomes.
Cohort A is a within-patient dose escalation cohort and includes neuronopathic patients aged five through 10. Cohort B is a dose-finding cohort to enable dose selection for the phase II/III. Cohorts C, D, and E evaluate additional younger patients, siblings, treatment-naive patients, and patients who have completed our biomarker natural history study. The next slide shows the importance of heparan sulfate as a glycosaminoglycan that accumulates in this disease. MPS diseases are all characterized by the accumulation of different species of glycosaminoglycans. Depending on the deficient enzyme, certain GAG species accumulate in key organs, causing clinical disease. Across the MPS diseases, it's notable that the CSF HS glycosaminoglycan appears to be necessary and sufficient for brain dysfunction and impairment. In the family of MPS disorders, all of those that have CNS manifestations have increases in CSF HS.
Higher levels of CSF heparan sulfate in MPS II are also associated with the neuronopathic phenotype, carry a poor prognosis, and are effectively normalized with DNL310 therapy, as we can see on the next slide. After switching from IDS or ELAPRASE to DNL310, a rapid and sustained reduction and normalization of CSF HS is achieved. The DNL310 safety profile enables achievement of these normal levels of CSF HS, sustained over time, including those in orange that have high levels of pre-existing ADAs, which are seen in this disease, given that for patients with deficient enzyme, the enzyme replacement is a foreign protein. These data demonstrate that rapid normalization of CSF HS is observed across all of the dose ranges tested in the phase I/II study in the cohorts that I outlined in the study schema.
These data suggest robust and efficient crossing of the blood-brain barrier with reduction of CSF HS to normal levels. We also looked at lysosomal biomarkers on the next slide. Reduction of GAG is hypothesized to improve lysosomal function and is shown here across biomarkers of lysosomal function that are associated with other CNS diseases and accumulate indirectly due to the deficiency in iduronate-2-sulfatase. We see here that after switching from IDS to DNL310, near or complete normalization of lysosomal biomarkers are observed in most participants and is sustained. Denali is the first to characterize these lysosomal biomarkers and the effect of treatment on MPS. The biomarkers shown here are important, as each of these accumulates in rare genetic diseases that are missing or defective in an enzyme that prevents appropriate processing. For example, GM1 gangliosidosis cause severe neurologic disorders.
GM2 accumulation is associated with Tay-Sachs and Sandhoff, and glucosylsphingosine accumulates in Gaucher disease and is associated with neurocognitive dysfunction. In addition to these lysosomal biomarkers, to our knowledge, Denali is the first to characterize neurofilament in MPS II. I'll now present the new interim data from the phase I/II study for serum neurofilament. With longer-term treatment and data from 23 patients that have reached approximately one year of dosing and 13 that have reached approximately two years of dosing, or 104 weeks, a robust reduction of 64% in serum neurofilament is observed at 104 weeks. Notably, the statistical significance is observed starting at 61 weeks. The serum neurofilament is run using a fully validated Quanterix method.
Reduction of serum neurofilament in the 13 patients evaluated was similar and well correlated to the reduction of CSF neurofilament in the 11 patients evaluated, where a 53.5% reduction was observed. The correlation coefficient of 0.76 for the change from baseline at week 104 was observed between serum neurofilament and CSF neurofilament, where 11 samples were available for CSF. These data demonstrate that DNL310 can correct biomarkers of biochemical function, cellular function, and neuronal injury. Neurofilament has emerged as an important biomarker of neuroaxonal damage across multiple neurodegenerative and lysosomal storage disorders. Neurofilament has the demonstrated ability in its utility as a biomarker of therapeutic response in other neurodegenerative diseases, including CLN2, MS, spinal muscular atrophy, and ALS....
In all of these diseases summarized, an elevation of neurofilament in disease versus control individuals is responsive to therapies where reduction in neurofilament has been associated with clinical impact and consequent FDA approval. For the first time, the FDA recently granted accelerated approval of a rare form of ALS based on plasma neurofilament as a biomarker predicted of clinical efficacy. This is for SOD1 ALS, which was treated with a SOD1 ASO. In 2020, we were the first to characterize a roughly five-fold increase in serum neurofilament in MPS II. With this level of increase, a reduction of 64% is impactful in patients moving in the direction of neurofilament normalization, and we continue to evaluate clinical data in our ongoing phase I /II to further understand the relationship of this neuroaxonal biomarker to clinical endpoints.
As presented at World, open label data suggests improvement or stabilization of clinical symptoms, including behavior on the VABS, across all domains evaluated, improvement in cognitive BSID or Bayley scores, stabilization or improvement in global impressions, and improvement in auditory brainstem evoked responses, a test of hearing function. This open label data continues to support the design and objective of the phase II/III COMPASS study, a randomized, double-blind study comparing the effects of DNL310 after switching from standard of care to ELAPRASE. The phase II/III COMPASS study has been actively recruiting since summer of 2022, and along with the phase I/II study, is designed to support approval for DNL310. I will now turn it back over to Ryan to summarize and conclude this webinar.
Thank you, Carole. In summary, what we've shown today in, and in the past is biochemical correction, cellular correction, and today, neuronal correction with robust reduction in neurofilament. In addition to this, we see positive changes across multiple measures of exploratory clinical outcomes, including adaptive behavior, cognition, and auditory brainstem response. We also observed improved peripheral activity and importantly, the safety and tolerability profile up to two years of treatment is consistent with current standard of care. We are now enrolling a global phase II/III study known as the COMPASS study. What does this all mean? I think importantly for us, it's further validation of the TV platform and specifically the enzyme TransportVehicle technology. This shows, for the first time, the potential utility of NfL in MPS II, and in particular, our regulatory strategy.
Importantly, we're now building out the broader ETV franchise, including bringing another ETV into the clinic for Sanfilippo. With that, I just want to thank everyone, especially all of our families and patients and everyone at Denali who's been working on this data. This interim data is very important, and I think highlights the impact of the TransportVehicle and specifically in Hunter syndrome. With that, we'll enter the Q&A session. If I could bring Carole and Alex on. Let's dive right in here. The FDA input suggests NfL could be a biomarker for clinical benefit. Could this enable accelerated BLA for review? Carole?
We have been in ongoing discussions with the FDA, as noted, as part of these ongoing discussions, they have asked us to evaluate neurofilament as a potential exploratory biomarker. We certainly are looking forward to these discussions together with our understanding now of multiple biomarkers, including CSF HS, which is an important biomarker directly linked to the disease and neurofilament, we certainly will proceed if the path opens up for accelerated approval for this disease.
A number of questions around both the FDA, also around neurofilament as a biomarker. Can you speak to the consistency and meaningfulness of NfL results? There has been prior commentary about NfL not being a biomarker of interest in the FDA for MPS II. How do you now think about the potential to use NfL as a registrational endpoint?
Yeah. You know, I think neurofilament, while we have seen its utility across a number of other therapeutic areas in the lysosomal storage diseases, pediatric space, this is not a biomarker that is very familiar to many that have been studying this disease. As noted, we are the first to characterize neurofilament in MPS II, but we are not the first to start to explore neurofilament in lysosomal storage diseases. For example, for CLN2, many have seen the publication of a reduction in neurofilament over three years with treatment of CLN2 with Brineura. That data is also data that suggests that this biomarker may be important in these lysosomal storage diseases that have CNS impact.
Yeah. I think I'll just answer, I think, specifically this question, where there's been prior commentary about NfL not being a biomarker of interest to the FDA. The interesting thing is there's been no conversation actually with the FDA about neurofilament until recently. The FDA proactively suggested neurofilament as a potential biomarker. I think part of that is just as you highlighted, Carole, how the field is, you know, very much focused, especially with the recent tofersen data on neurofilament as a marker of neuronal axonal damage. We see obviously, that the FDA is now quite keen on this. Now, another one, you know, related to the FDA. Is there alignment with the FDA on accelerated approval filing using NfL as a surrogate biomarker?
I think as we've discussed before, the CDER and CBER divisions have had a different approach, at least in what they've publicly shared around accelerated approval. While Peter Marks with CBER has indicated potential interest in accelerated approval using biomarkers, CDER has been very clear in this division of medical genetics and rare disease that a clinical endpoint would be necessary for approval. That being said, you know, I think the understanding of biomarkers is rapidly expanding. I think as Ryan noted, the recent approval for the tofersen, a drug for accelerated approval for ALS in a rare population of ALS, suggests the importance that now the agency is seeing for these rare diseases of accelerating approval using biomarkers.
We think it's very encouraging that the FDA is now asking us to look at these biomarkers and, so potentially, in the future, these could be applied to an accelerated approval strategy.
Now a couple of questions on the COMPASS study on the phase II, III. Can we provide an update on the study enrollment? Then more broadly, I think, you know, how is that study going, Carole?
I think the study is going quite well. I think there's a lot of tremendous interest globally, in that study, given the data that we've shared to date from the phase I , II study. We haven't provided specifics on enrollment, but it is rolling globally across a number of sites and countries.
Great. Well, again, many questions around the FDA. I think we've answered most of them. Maybe just the next steps on the interactions with the FDA.
We have not discussed this data yet with the FDA, but plan to in an upcoming meeting and as part of our continuing dialogue with the FDA, both on our phase I/II study as well as our pivotal COMPASS study.
I guess, would you feel comfortable speculating on the different scenarios here? For example, could you do an interim of the phase III? What do you imagine are the scenarios?
I think it may be challenging to speculate for the FDA what the scenarios are. I think we're very focused on advancing the field in terms of the understanding of these biomarkers. I think as we've seen in the past across other disease areas, the interest in the FDA for accelerated approval generally requires a community understanding, both the academic as well as the industry community, and understanding of these biomarkers. I'll just say that we're very encouraged with this neurofilament data also because there is a standardized, validated assay using Quanterix that is used for this field in measuring neurofilament. I think this addresses some of the challenges, perhaps, in some of the other biomarkers, like CSF HS, where companies have proprietary assays, and there isn't a standardized assay.
You know, I think as we think about our interactions with the FDA and our understanding of this disease across multiple treatment paradigms, we are very hopeful that others will begin to measure this as well, so we can gather additional natural history data for neurofilament and better understand treatment response. I think if anyone tuned in to the Tofersen Advisory Committee, the wealth of data in the ALS community that was generated around natural history data for neurofilament was very helpful in support for the accelerated approval.
Have we had any discussions with the EMA? Is there any inclination on where they might or might not stand as it relates to an accelerated path to market?
We've absolutely had multiple interactions with the EMA and global regulators, given our phase II/III study is enrolling across a number of countries. You can see it on ClinicalTrials.gov, all of the active sites. In general, the EMA has taken a very similar approach to the FDA, the CDER division, in terms of requesting clinical data to support approval and the design of our randomized phase II/III study. I think as noted, the field is really evolving and advancing in terms of understanding of surrogate biomarkers and biomarkers that may be correlated with clinical response. You know, I think particularly in the neuro division, for years, there were no accelerated approval biomarkers that we've seen just in the past two to three years. Openness to, for example, amyloid and then now neurofilament to support approval.
I think we feel this is a very dynamic time, and we feel it's important to continue these discussions and hope that we can start to shift the approach to thinking about approval for these therapies.
The two questions related, and I'll bucket them into one. Is there any correlation between neurofilament reduction and clinical benefit?
Yeah, we have shared top-line data for our neurofilament today. We do plan to do multiple additional analyses, and we'll present these at a scientific conference at a future date.
How long is the lag time between heparan sulfate normalization and neurofilament reduction? Maybe I'll take this one, Carole, to give you a break. What's really interesting is that we start to see by six months, sort of at that point, a decrease in neurofilament over one year and then two years. The advantage of, you know, measuring serum neurofilament is that we can measure more frequent time points. If you look at sort of the steps in correction of biochemical deficits, cellular deficits, and then neuronal axonal deficits, they're. Each one has a bit of a lag time. We see a very rapid normalization of heparan sulfate, and then some delay for correction of lysosomal biomarkers such as GM2 and GM3.
By six months, we now start the beginning of the reduction out to one year and two years with neurofilament. We, of course, are very excited to see this data and especially the robustness of the data, including, as Carole highlighted, the, you know, nearing normalization with neurofilament. I think it's a sort of expected biological sequence of events from starting with correcting the enzyme to ultimately, you know, halting or slowing neurodegeneration. Now some questions around the ETV franchise. I think I'll start here, and then, Carole, you can add related to this. Given the observation of heparan sulfate being necessary and sufficient for neuropathic disease across MPS cohorts, could there be a strategy beyond Hunter? I'll answer this, and Carole, you'll add to that.
I think importantly for us is that heparan sulfate, you know, is at that top of the cascade and is now predicting a benefit across multiple, you know, cellular and then clinical endpoints. This is exactly our hope. Our hope is that with this Hunter program, we can establish basically heparan sulfate as the primary biomarker. Therefore, when we go in Sanfilippo and other MPSs, we can essentially draw that line between heparan sulfate and ultimately clinical benefit, and really having a robust biomarker package, I think illustrates that. Carole, do you want to comment? Because I know we've had a lot of discussions about heparan sulfate as really the primary biomarker.
No, I think you covered it. You know, certainly, we believe that, you know, looking at the primary substrate, if we can reduce that and demonstrate that we can replace enzyme, we believe that over time, this should have an impact on this monogenetic disease. That's very clear. We do really believe, though, that these additional biomarkers, particularly the lysosomal biomarkers that are elevated in other diseases and are known to cause neurocognitive function issues, are very important. There we're showing not only are we reducing that primary substrate that can cause CNS symptoms, but we're also reducing the accumulation of these others, which on their own can cause neurocognitive symptoms. We think it's very important to demonstrate that. I think all of that data, again, really supports the importance of CSF HS as a biomarker in this disease.
Continuing on the ETV franchise, does the latest NfL data from Hunter change your thinking or design of other MPS programs you're running, such as the Sanfilippo program? What do you think, Carole?
Well, I think this really comes down to, you know, how regulators will look at this data to potentially accelerate development plans. You know, I think just in terms of measuring serum neurofilament, we will certainly measure it. It's actually easy to measure, given that we don't have to collect CSF for this. You know, the serum neurofilament enables more data points so that, you know, I think over time, we can get better understanding of the trajectory over time as we showed today with multiple time points. I think absolutely this will impact our future development programs as well as, I believe, for the field.
Alex, this is a question for you. Again, related to ETV franchise, but more around portfolio strategy. We've started to expand, obviously, in Sanfilippo. Could we speak to a higher level on the overall strategies towards targeting MPS diseases? Would there be an interest in further building out this area as a focal point?
Yes. Thanks, Ryan. The ETV platform does drive a broad franchise opportunity in lysosomal storage diseases. About two-thirds of all lysosomal storage diseases have CNS involvement, which is currently not addressed by standard enzyme replacement therapy. Based on encouraging early data with DNL310, we did start to build out a broad portfolio. As we mentioned, in addition to the DNL310 program, the ETV:SGSH, or DNL126 program, is on track to start clinical trials in the second half of the year. We've built a broad portfolio of five preclinical-stage enzyme replacement therapies, which are all enabled by the ETV platform. In addition, we're currently working to accelerate launch readiness to be ready and to launch these programs in key markets when possible.
Actually, along those lines, Alex, you and I can answer this: Would we be ready to launch 310 in 18-24 months if an upside opportunity to file soon did emerge? What would we do? What would we need to do on the CMC and commercial build-out side? Maybe I'll begin that, Alex, you can add to that. In fact, we're actually very aggressive preparing for launch because of sort of this unique circumstances with CDER and CBER. You know, we have actually started to build out, I mean, for a long time, the CMC side, so they're, I think, very strong, but also on the commercial side, preparing for launch specifically globally. Alex, do you want to add anything to that?
Short answer is yes, we will be ready.
Okay, great. Now a more technical question. Any differences in measuring NfL in the CSF versus the serum? Maybe I'll hand this to Carole.
Yeah. As we noted, our serum assay is a fully validated assay, and also our serum assay allows us to collect more data points over time. However, what we have observed is that we see a very similar reduction in neurofilament in the CSF and serum. As noted, we had a 53% reduction in the CSF, and this was highly correlated at week 104.
Okay, I actually am not familiar with this. As JCR has shown encouraging recent data at a higher dose, how do you think about differentiating versus that program now? Maybe I'll answer it, and then, Carole, you can add to that. We actually compared the JCR architecture, and head-to-head in a publication, and happy to share that publication where we did dose ranging. Interestingly, at least in our experience, JCR is sort of dose limited at 2 mg per kg, doesn't hit that 4 mg per kg, and there they see sort of a plateau effect on CSF heparan sulfate. Do you want to add anything to that, Carole?
I think the only thing that I would add is, as a field, there has been recognition that there has been consistent underdosing of therapy in these patients. Standard of care ELAPRASE, which is given peripherally and addresses the peripheral manifestations of the disease, that is likely underdosed. Physicians feel like that there is certainly room to improve on that. We've noted with our urine HS and DS, that we can reduce levels even further after switching from standard of care therapy. Our approach to this was really to not underdose and evaluate DNL310 and its safety profile fully so that we could dose to a level that would treat all patients, including those that have these high levels of anti-drug antibodies.
We think dose is very important, but as you noted in the data that we presented on CSF HS, even those individuals that were in Cohort B that had a lower dose regimen, they were able to normalize their CSF HS as well.
I think with that, we've hit the majority of questions. We thank everyone for showing up early this morning and, you know, fantastic turnout and great questions. You know, we're very excited about the data today and look forward to further advancing our TV platform and specifically our enzyme TransportVehicle franchise. With that, we thank everyone. Take care.
Bye-bye.