Thank you for standing by, and welcome to the AVLAYAH FDA approval call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. If your question has been answered and you'd like to remove yourself from the queue, simply press star one one again. As a reminder, today's program is being recorded. Now I'd like to introduce your host for today's program, Laura Hansen, Vice President of Investor Relations. Please go ahead.
Thank you, Jonathan, and good day, everyone. Thank you for joining us today for our AVLAYAH FDA approval conference call. I'm Laura Hansen, Vice President of Investor Relations at Denali Therapeutics. Joining me on the call today are Ryan Watts, Chief Executive Officer; Alexander Schuth, Chief Financial and Operating Officer; Peter Chin, Chief Medical Officer; and Katie Peng, Chief Commercial Officer. Earlier today, we issued a press release announcing the FDA approval of AVLAYAH. The press release and the slide presentation to accompany today's call are available in the investor relations section of our website at denalitherapeutics.com. Before we begin, I'd like to remind you that today's call will contain forward-looking statements within the meaning of the federal securities laws, including statements related to the approval, commercial launch, and potential therapeutic impact of AVLAYAH, tividenofusp alfa-eknm.
Our expectations regarding patient access and update the potential addressable patient population and our plans and objectives for commercialization and future operations. These statements are based on information available to us as of today and are subject to risks and uncertainties that could cause actual results to differ materially. We undertake no obligation to update these statements except as required by law. For a discussion of factors that could affect our results, please refer to our recent SEC filings, including our annual report on Form 10-K and its risk factor discussion. On today's call, we will discuss the U.S. Food and Drug Administration's approval of AVLAYAH, the first enzyme replacement therapy designed to cross the blood-brain barrier using our Transport Vehicle platform for the treatment of Hunter syndrome, and we will outline plans for commercial launch. Following our prepared remarks, we will open the call to your questions.
With that, I will turn the call over to Ryan.
Thank you, Laura, and thank you all for joining us on short notice. Many of you have followed our progress over the years and this is a significant moment for Denali. We're excited to share what this approval represents. To begin, I wanna recognize the Hunter syndrome or MPS II community that made this milestone possible. As shown on slide four, each of these photos represents just a few of the individuals and families who have been so instrumental in reaching this moment. We are deeply grateful to this community for their partnership, their courage, and for continually challenging all of us to move faster and do better. At the same time, this approval reflects the collective efforts of many, including clinicians, researchers, advocacy partners, and especially the entire Denali team, all working with a shared sense of urgency to address a devastating rare disease.
We also want to recognize the FDA for a rigorous, thoughtful, and highly constructive review process. This approval under the accelerated approval pathway based on a surrogate biomarker represents an important scientific and regulatory advancement. It underscores both the strength of the data and a shared commitment to bringing meaningful therapies to patients as efficiently as possible while continuing to build the evidence base. Hunter syndrome is a progressive, life-limiting condition that affects children from a very young age. While some aspects of the disease have been managed historically, the neurological manifestations have remained largely out of reach. What has always stood out to us is the clarity of what this community has been asking for, therapies that reach the brain. That input has shaped how we think, how we design our studies, and how we move with urgency and purpose.
We view this moment as a shared achievement and also as a responsibility to continue delivering for this community. Importantly, we believe this regulatory path may help open the door for future programs targeting similar diseases. With that foundation, let me highlight why this approval represents such an important inflection point, both for the MPS II community and for Denali on slide five. First, this is a historic FDA approval. AVLAYAH is the first and only therapy for Hunter syndrome designed to address the whole body, including the brain, directly targeting one of the most critical unmet needs in this disease. Second, this marks the first meaningful therapeutic advance for MPS II community in nearly two decades.
Importantly, AVLAYAH demonstrated significant reduction and normalization of cerebrospinal fluid heparan sulfate, a key disease biomarker, supporting activity in the central nervous system and forming the basis for this accelerated approval. Third, this approval validates our Transport Vehicle platform. This is the first FDA-approved biologic and a new class of medicines engineered to cross the blood-brain barrier, one of the most persistent challenges in medicine. Fourth, this milestone has broader implications beyond MPS II. It provides a regulatory and scientific framework that may inform the development of other programs, including DNL126 for Sanfilippo syndrome and additional lysosomal storage disorders. Finally, this establishes the foundation for Denali's lysosomal storage disease franchise. We're entering commercialization prepared, and we see this as the beginning of a broader opportunity to address diseases across the MPS spectrum.
Stepping back, as we noted in our announcement, this milestone validates our platform and its potential to overcome the long-standing challenge of delivering biologic medicines across the blood-brain barrier with the aim of transforming treatment for a wide range of serious diseases. Taken together, this is not just a single product approval. It represents a meaningful step forward for patients, an important advancement in how therapies can be developed and approved, and a defining moment for Denali. Building on what I just outlined, both the significance of this approval for MPS II community and what it represents for Denali, let me walk you through how we will spend our time today on slide six. I've just framed the key messages coming out of this approval and what we believe matters most from a clinical, scientific, and strategic perspective.
Next, Peter Chin will take you deeper into Hunter syndrome, the disease burden, the long-standing unmet need, and why reaching the brain has been such a critical challenge for this community. Peter will also review the clinical data and the FDA label for AVLAYAH, including the biomarker evidence supporting approval and how we're continuing to build the data set through our ongoing COMPASS study. Katie Peng will then present our launch readiness and commercialization strategy, including how we're working closely with the community to enable access. I'll come back at the end to connect this approval to the broader Denali story, particularly how it advances our Transport Vehicle platform and expands the opportunity across our pipeline. We'll open it up for questions. I will now turn the call over to Peter.
Thank you, Ryan. Turning to slide eight. Mucopolysaccharidosis type II, or Hunter syndrome, is a rare inherited lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase, or IDS enzyme. IDS deficiency leads to accumulation of glycosaminoglycans, or GAGs, throughout the body. The disease course can vary across patients, but progression begins early in childhood, and life expectancy in severe forms often extends only into the teenage years. Cardiac and respiratory failure are the leading cause of premature mortality. On slide nine, MPS II is a multi-system disorder with manifestations that can affect nearly every organ system, as depicted on the figure on the left. The most prominent neurologic manifestations are progressive cognitive decline and behavioral changes, but can also include motor impairment and hearing loss. At the same time, patients develop significant peripheral disease burden, including cardiac, respiratory, skeletal, and gastrointestinal complications.
Because of this, it is important to address both the peripheral manifestations and the disease in the brain with a whole-body treatment approach. Turning to slide 10. The current standard of care for MPS II is intravenous enzyme replacement therapy, which does not cross the blood-brain barrier. There remains a significant unmet need for therapies that can address the neurologic manifestations and better address whole body disease. As a result, neurologic manifestations, including cognitive decline, behavioral symptoms, and hearing loss, remain inadequately addressed. Moreover, patients may continue to experience peripheral symptoms and show abnormal urine GAG levels even after treatment with IV ERT. Cardiac, skeletal, and other manifestations may persist or progress despite treatment. Thus, new therapies in MPS II should aim to address both the neurologic and peripheral manifestations of disease. This is exactly the challenge AVLAYAH was designed to address.
With today's approval, we now have a therapy engineered to reach both the periphery and the brain, enabled by our transport vehicle platform. Let's go to slide 12 to discuss further how that works. AVLAYAH uses Denali's transport vehicle technology, which is designed to optimize delivery of biotherapeutics across the blood-brain barrier. The approach leverages the transferrin receptor, which is naturally expressed on cells of the blood-brain barrier and throughout other tissues. AVLAYAH is designed to deliver IDS to both the brain and the body. On slide 13, the clinical data supporting AVLAYAH were recently published in the New England Journal of Medicine, describing results from the phase I/II study of tividenofusp alfa in pediatric patients with Hunter syndrome. Treatment with tividenofusp alfa produced large and sustained reductions in biomarkers of disease activity in both the CNS and the periphery.
CSF heparan sulfate, a biomarker of primary substrate accumulation in the CNS and the basis of this accelerated approval, was substantially reduced to levels seen in unaffected children. Neurofilament light, an established marker of neuronal injury, was also reduced to normal levels. Urine heparan sulfate normalized to levels in unaffected children, reflecting clearance of peripheral substrate in both previously treated and ERT-naive participants. On slide 14, overall mean change in Vineland Adaptive Behavior Raw Score functional composite demonstrated continued skill gains over time. Bayley Scales cognitive raw scores similarly demonstrated improvement with continued cognitive skill gains. Improvements in hearing threshold, as assessed by pure tone average, were maintained throughout the period of follow-up. These data show the potential for treated patients to improve or stabilize meaningfully.
On slide 15, with respect to safety, infusion-related reactions, a known risk of ERT, were the most common adverse event, decreasing in incidence and severity over time. Hemoglobin levels remained generally stable during treatment following an initial decrease. Overall, the safety results were consistent with ERTs and manageable for chronic therapy. Taken together, these data represent the culmination of years of work to address the full spectrum of peripheral and neurologic manifestations of Hunter syndrome, applying our understanding of the disease and leveraging the Transport Vehicle platform to deliver therapy to the whole body, including the brain. Importantly, this body of evidence is now translated into regulatory recognition in the United States, marking a meaningful step forward for patients. With that context, I'll turn to slide 16 to highlight key elements of the AVLAYAH U.S. prescribing information. Here are select highlights of the U.S. label.
AVLAYAH is now approved under U.S. accelerated approval for the treatment of MPS II based on CSF heparan sulfate as a surrogate biomarker reasonably likely to predict clinical benefit. AVLAYAH is indicated for the treatment of neurologic manifestations in patients with Hunter syndrome when initiated in pre-symptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. AVLAYAH is not recommended for use in combination with other enzyme replacement therapies. The recommended AVLAYAH maintenance dosage is 15 mg/kg , administered once weekly as an intravenous infusion over approximately four hours. Treatment should be initiated with a dose escalation regimen. The prescribing information reflects the robust effects on the primary substrate of IDS in both CNS and periphery.
With respect to CSF heparan sulfate, treatment with AVLAYAH resulted in a significant 91% mean reduction of CSF HS from baseline, with 93% of patients having CSF HS levels below the upper limit of normal at week 24. For urine GAG, at baseline, 4% of patients had total urine GAG levels below the upper limit of normal. After treatment with AVLAYAH, 68% of patients had total urine GAG levels below the upper limit of normal at week 24. With respect to safety, the prescribing information includes the following. A box warning regarding hypersensitivity, including anaphylaxis, consistent with other approved ERTs. Guidance on management of infusion-associated reactions. Anemia typically occurring early, with guidance to assess hemoglobin prior to treatment initiation three months after initiation and as clinically indicated thereafter. Membranous nephropathy related to immune complex deposition in one reported case.
General guidance is to monitor serum creatinine and urine protein to creatinine ratio at a frequency to be determined by the prescriber. On slide 17, AVLAYAH's clinical development continues with a clear path from U.S. accelerated approval to full approval. The phase I/II study with 47 participants supported U.S. accelerated approval and will continue to support select country approvals. The COMPASS phase II/III confirmatory study in approximately 63 participants is ongoing. The design is a head-to-head randomized controlled trial versus standard of care ERT across disease phenotypes and a broad age range. This study is designed to evaluate both neurologic and somatic clinical outcomes. COMPASS includes adults living with Hunter syndrome and represents an important evidence package to potentially broaden future access in the United States and internationally. Now I'll turn it over to Katie Peng.
Thank you, Peter. Good afternoon, and thank you for joining us on this milestone day for Denali and the MPS II community. Today, I'll briefly cover what this approval means and how we are positioned to execute on a successful launch. On slide 19, as Peter outlined, MPS II is a progressive and multi-system condition. What is most compelling to physicians about the AVLAYAH data is that patients achieve normalization of CSF HS in nine of 10 patients as early as six months, with sustained normalization at 12 months. None of the patients in the study had normal CSF HS at baseline. AVLAYAH also achieved normalization of urine GAG, a key biomarker of disease progression, in nine of 10 patients by 12 months. Only two patients had normal urine GAG at baseline.
Importantly, majority of patients in this study were previously receiving standard of care enzyme replacement therapy, reflecting a real-world transition, as more than 90% of patients today are on treatment. No other therapies to date have demonstrated this level of normalization across key disease biomarkers. This is setting a new bar. For the first time, we are seeing data that support addressing both systemic and neurologic disease burdens in a single therapy. Slide 20. Now let's step back and take a look at the broader landscape. In the United States, approximately 30 new patients are diagnosed each year. There are roughly 500 patients living with MPS II in the U.S. and 2,000 worldwide. With this approval, the opportunity is to capture approximately 75% of the treated U.S. prevalent population. With a positive COMPASS study, we should be able to address the entire MPS II population.
Today's prevalent population reflects the reality that individuals born with severe disease often experience shortened lifespan. With AVLAYAH, we believe there is the potential to alter that trajectory over time. Early treatment may improve neurologic outcomes longer, and longer survival could gradually expand the prevalent population. While this evolution will occur over time, it represents the potential for meaningful long-term impact for families and a durable opportunity for Denali to continue advancing therapies in rare disease. Slide 21. Our commercial confidence is grounded in stakeholder insights gathered pre-launch. 90% of physicians view AVLAYAH's data as highly motivating to prescribe. 80% are aware of new treatments in development and are excited to try AVLAYAH. We have also engaged with payers that cover approximately 90% of commercial lives. The feedback has been constructive. Payers recognize the unmet need and have indicated that they will likely manage to the FDA-approved label.
We have seen similar excitement from the patient and advocacy community and have been engaging with them frequently as they were critical in helping to shape our launch. This is not a market where awareness needs to be created from scratch. It is a community that is informed, organized, and ready for change. On slide 22. The structure of the MPS market is an advantage for our launch. Of the 500 U.S. patients currently treated with enzyme replacement therapy, the majority are managed by clinical geneticists in about 100 centers of excellence. The concentration enables a small and focused field team. We have already established relationships with all major MPS II centers. Our sales team have profiled and segmented all accounts with MPS patients to optimize execution from day one. Slide 23. I could not be more excited or confident in the team we have in place.
Our leadership team brings experience across product strategy, U.S. and global marketing, market access, analytics, and medical affairs. We have marketed oral products, injectables, and IV infused products. Collectively, the team has launched 19 products or indications, including global blockbusters and rare disease therapies. Across our field organization in the U.S., 96% of our team has lysosomal storage or rare disease experience. The depth of that experience is on average 12 years. Slide 24. As the first TfR-enabled enzyme replacement therapy designed to cross the blood-brain barrier, AVLAYAH addresses progressive neurologic decline in MPS II, a critical unmet need not targeted by existing therapies. The innovation meaningfully differentiates AVLAYAH within the current MPS II treatment paradigm. The degree of biomarker normalization and CNS engagement is unprecedented and reflects the differentiated value of the therapy.
AVLAYAH's pricing balances our four core principles, access, affordability, sustained R&D investment, and the therapeutic innovation of our medicines. Our wholesale acquisition price is $5,200 per 150 mg single-use vial. AVLAYAH is dosed weekly at 15 mg/kg. Most pediatric patients will require two-three vials per week, depending on weight. The annual cost of maintenance dosing for a 10 kg infant is about $270,000. The annual cost of maintenance dosing a 30 kg child is about $811,000. We are deeply committed to broad and equitable access for eligible patients. Our teams have engaged with payers pre-launch and will continue those discussions to support coverage for eligible patients at launch and beyond. Importantly, this launch establishes a sustainable revenue stream that supports expansion of our TfR-enabled platform across additional neurodegenerative diseases.
We believe AVLAYAH is well-positioned for long-term success, driven by the significant unmet need it addresses and the strength of our commercial execution. We are confident this pricing supports a successful launch while balancing innovation, access, and sustainable value creation. Slide 25. Market access execution is critical in rare disease, so we invested heavily here. Through our Denali Care Program, we will provide personalized support throughout the treatment journey. Our comprehensive patient support services include benefit investigation, prior authorization, and assistance navigating insurance coverage. In addition, the team will support treatment coordination, provide information and educational resources, and financial assistance support where appropriate. Our objective is simple. Reduce the time from prescription to first infusion and minimize friction for families. Slide 26. Looking ahead, our roadmap is structured across stakeholders. For physicians, we are supporting in-service education, infusion training, and robust scientific exchange to instill confidence in clinical use.
For payers, we are securing commercial coverage policies, advancing Medicaid access, and operationalizing prior authorizations and exceptions processes. For patients and caregivers, we are activating with the advocacy community, driving awareness and consideration, and focusing on reducing the time to therapy initiation. AVLAYAH is expected to be available in the United States two weeks from tomorrow. We are prepared operationally for that timeline. Rare disease launches follow a predictable uptake curve. In 2026, the focus is activation and access. In 2027 we expect adoption acceleration when we will see coverage policies in place and revenue inflection as workflows stabilize and confidence in AVLAYAH matures. Slide 27. Let me briefly walk you through how we think about global access following our U.S. approval. The U.S. decision really serves as the anchor for our ex-U.S. regulatory strategy.
In many markets, we can leverage that approval through a mechanism like the Certificate of Pharmaceutical Product, or CPP, and other conditional approval pathways to begin the registration process. Of course, registration is just the first step. After approval in each country, we will still need to go through local reimbursement processes to ensure patients can access the therapy. We expect global access to occur in phases. Roughly a third of the markets could become available in the near term, with additional markets opening in the mid and longer term as both regulatory and reimbursement processes are completed. To support that expansion, we have already established distributor partnerships across select markets in LATAM and MENA regions. Slide 28. Let me leave you with a few key takeaways. AVLAYAH represents the first meaningful advancement in MPS II treatment in 20 years.
Second, we have built a fully staffed and experienced rare disease commercial organization. Third, the competitive landscape is favorable and no direct CNS penetrant therapies are currently approved. Fourth, the community is ready and waiting. Our priorities are super clear. Drive patient starts, ensure smooth reimbursement, deliver a consistent high-quality patient experience, and build a durable franchise starting with MPS II. We look forward to updating you as we move through the first phases of launch. Now I'll turn it back to Ryan.
Thank you, Katie. Slide 30. Established by today's approval of AVLAYAH, I'd like to discuss the broader strategic context, which is the ETV franchise we're building in lysosomal storage disorders. What this slide shows is that we are not pursuing a single indication, but a platform-driven opportunity across multiple diseases with meaningful patient populations, including MPS II, MPS III A, Pompe, Gaucher, and others. Collectively, this represents a substantial addressable market. What differentiates our approach is that the ETV platform is designed to address both systemic and neurologic disease. Historically, enzyme replacement therapies have been limited to peripheral tissues, leaving the brain untreated. We believe AVLAYAH demonstrates that this paradigm can change. From a commercial standpoint, this is also a highly leverageable model. We can build on existing infrastructure, apply a consistent development and launch approach across indications, and drive efficiencies as we scale,
Importantly, we are entering a large, well-established ERT market with significant precedent for adoption, reimbursement, and long-term value creation. When we talk about AVLAYAH, we see it not just as a product, but as the foundation of a durable multi-program franchise in lysosomal storage disorders. Slide 31. Let me close by putting this moment into perspective. With AVLAYAH, we believe we have reached an important first summit, one that reflects years of scientific invention, disciplined execution, and deep partnership with patient community. First, this is proof. AVLAYAH is the first FDA-approved biologic designed to cross the blood-brain barrier, demonstrating that we can deliver medicines to the brain in a meaningful way. Second, this validates our platform. The transport vehicle is now proven in humans, opening the door to an entirely new class of biologic medicines. Third, this fuels our pipeline.
What we've established here creates a clear path to expand into additional lysosomal storage disorders, including DNL126 for Sanfilippo syndrome, which we plan to advance towards launch next year as well as into broader neurodegenerative diseases such as Alzheimer's disease, where we expect to have two programs in clinical development this year. Most importantly, this is about our patients. While we are starting in rare diseases, our ambition is much larger to transform treatment for millions of people affected by serious diseases. While today marks a major milestone, we see it as the beginning of what this platform can deliver. We remain steadfast in our purpose to transform life for patients. We look forward to continuing this journey with all of you, and now we will take your questions. Operator, could you please open the lines for questions?
Certainly. As a reminder, ladies and gentlemen, if you do have a question at this time, please press star one one on your telephone. Our first question for today comes from the line of Andrew Tsai from Jefferies. Your question, please.
Hey, guys. Good afternoon. Congratulations on approval. It's exciting. Thanks for taking my questions. I know you guys have mentioned to think about an S-type trajectory, you know, acceleration later in 2027. Is there a low-hanging fruit, though, right now, maybe within naive or switch patients? Maybe asked another way, what exactly would it take for this S-curve to look more linear or parabolic instead? Thank you.
Thank you, Andrew. I'll hand that to Katie to answer that question.
Thanks for the question. Yes, I mean, certainly the patient population is very excited. We've already gotten a lot of outreach since the announcement from the community, excited to start. I think as we've spoken before, a lot of it has to do with the mechanics of getting reimbursement. It will take time, you know, for, of course, the product to get into the channel, which will take about two weeks, then for the reimbursement process to start. That's why we're guiding to an S-curve more because of the mechanics of launch and not for the lack of excitement from the community.
Makes sense. You know, as you guys mentioned, you clearly have data showing clear benefits on functional outcomes, Vineland and Bayley. The label technically doesn't have that right now. Can your sales reps technically go out and message the functional data you're seeing? You know, it was published in the NEJM paper. Or what do we have to technically wait for COMPASS data in order for you to promote that? Thank you.
That's a great question. Our sales team will focus on promoting what is within the label and consistent with label. In terms of the clinical data that's available through the NEJM article, our medical affairs team will be able to speak to that in engaging on scientific exchange with the physician. It's a dual approach, essentially, with our field team very much focused on the biomarkers and the safety data that's in the label. Medical affairs will certainly be able to talk to the data set that is in The New England Journal of Medicine.
Makes sense. Congratulations again.
Thank you.
Thank you. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your question please.
Hi, this is Lydia on for Salveen. Congrats on the approval. I guess just given the language in the label, do you anticipate any payer pushback for the non-neuropathic or attenuated patients? If you could just talk about your plans to monetize the PRV. Thank you so much.
Great. Thank you, Lydia. Great to hear from you. Katie will answer your first question around payers and the details and label, and then Alex will answer your second question on the PRV.
Yes. That's a great question. No, we don't expect there would be any limitations from the payers because the label indicates that it's for pre and presymptomatic and symptomatic patients. Attenuated, less severe patients also have neurologic manifestations. Our expectation is that the payers would cover to the label indication.
Yeah. Lydia, we are, of course, pleased that the FDA has granted the Rare Pediatric Disease Priority Review Voucher, the PRV, for the approval of AVLAYAH. As we know, this PRV can be transferred or sold, and we intend to do so, in support of our operating expense, in support of our long-term goals. Stay tuned on that.
Thank you. Our next question comes from the line of Michael Yee from UBS. Your question please.
Hey, guys. Congrats on the approval. Two questions. I guess just thinking about the ramp, how do you technically determine if someone is neuropathic or has neurological disease? Is there a specific criteria or requirement to determine the eligibility for that? And then, secondly, how does this approval and your regulatory discussions you just went through read through to Sanfilippo and the process there and how that's going? Thank you.
Thanks. Thanks, Mike. I'll have maybe both Katie and Peter comment on neurologic manifestations. As you sort of find that, maybe we'll start with Katie.
Yeah.
The read-through on this for Sanfilippo, we'll have Peter comment on that.
Thanks, Mike, for that question. In terms of how you think about the treatment landscape, the disease is really a spectrum disease. In practice, we don't really think about neuronopathic versus non-neuronopathic. If you look at the label today, it's really covering all of the pediatric patients. They should be able to gain access. It's specifically addressed in thinking about neurologic manifestations, which is different than neuronopathic. If you look at the literature as well as our claims data, about 90%+ of patients actually have neurologic manifestations. That is not necessarily only relegated to neuronopathic patients. That's why we're thinking in terms of the opportunity, it is really the pediatric population in the prevalent population in the U.S. Hopefully that addresses your question.
Maybe I can add to what Katie has just shared. I do think it's important to note the distinction in the labeling language between neurologic manifestations versus neuropathic. There's no mention of neuropathic or non-neuropathic or attenuated phenotypes. Really the focus is on neurologic manifestations, recognizing that CSFHS is the basis of approval as a surrogate marker. On the question of Sanfilippo, I think what this precedent sets is that CSFHS is an approvable surrogate marker for as a reasonably likely to predict clinical benefit. In our discussions with the agency, through the START program, we have frequent interactions and anticipate and have already had discussions that CSFHS could lead to an approvable path. Each disease is different. I think that's an important thing to consider as well.
I'll also note that at this time, Sanfilippo has no standard of care, and so we'll have specific discussions in that disease state.
Thank you. Congrats again.
Thank you. Our next question comes from the line of Sean Motton from Morgan Stanley. Your question please.
Hi, this is Mike Riad on for Sean. Thank you for taking our questions, and congratulations on the AVLAYAH approval. Could you just maybe comment more generally on, like, neurological manifestations? Is this, like, restrictive or advantageous in terms of the positioning versus Elaprase? Like, how does that, like, influence early age uptake and commercial positioning over the long run?
I'll hand that to Katie to comment.
Yeah. In terms of commercial positioning, it really doesn't change. The only, you know, difference compared to the current standards of care has to do with the separation between pediatric and adult. We feel with the current label, it is holistically being able to treat all different manifestations of the disease, whether it's symptomatic or pre-symptomatic. If a physician deems that a patient, even pre-symptomatic, has the likelihood to show neurologic manifestations, they are able to treat. I feel like this label is very holistic and able to help us address the pediatric population with MPS II.
Perfect. Thank you. Just a quick follow-up. You noted that, like, with the expansion of a prevalent patient population with disease burden reduction over time, that would grow the patient population. Is this more of a result of just early intervention or, like, post COMPASS, would there be additional label expansions to help grow the addressable population?
Yeah. I think it's threefold. Newborn screening is now increasing in the United States, so we'll be able to identify patients earlier on. Certainly with this disease, earlier treatment will result in better benefits. As you know, with the severe population today, lifespan is shortened, right? It's late teens. We believe with early treatment, newborn screening, we will be able to address the disease more holistically. Over time, we expect with the COMPASS data set, we would then be able to unlock adult patients as well. Given these three things over time, we believe the prevalent population should grow with MPS II.
Maybe just two comments. One is I want our resident neurologist, our lead neurologist, Peter, to make a comment on neurologic manifestations and just to restate what we stated before about the breadth. The second is that this is. I think it's important to understand this. On initiation of treatment, it's in the pediatric time period, but patients will stay on drug throughout life, so they will continue as adults on AVLAYAH. Maybe a comment on neurologic manifestations.
Yeah. Thanks, Ryan. I think echoing what Katie has said, neurologic manifestations are prevalent across the spectrum of MPS II. Importantly, the indication includes pre-symptomatic and symptomatic stages of the disease prior to advanced neurologic impairment. I think that's important from a clinical perspective because it allows the patients and the families to make the assessment of the most appropriate treatment. Even in the pre-symptomatic stage, one can anticipate that patients will develop or may develop neurologic symptoms.
Thank you so much for all the color there. It's really helpful. Congratulations on the BLA approval.
Thank you. Our next question comes from the line of Tazeen Ahmad from Bank of America. Your question please.
Hey, guys. This is Daniel on for Tazeen. Congratulations on the approval, and thanks for taking our questions. Just two on our side. We're just wondering what kind of metrics you plan to provide to help us track the launch, once you get this product on the market. In terms of coverage, do you expect there to be differences between patients switching versus newly diagnosed patients? Do you expect any sort of step therapy requirements before patients can start on AVLAYAH? Thank you.
I'll hand that to Katie.
Okay. I'll answer your second question first, which is no, we do not expect there would be any differences in how payer would handle naive patients versus switch patients, given the strong label that we have. In terms of updates on the progression of the launch, I think for the first year, we're not going to be providing a lot of details other than to give qualitative updates on the mechanics of working through launch. As the data and our launch evolves, we will then share additional information.
Okay, great. Thank you.
Thank you. Our next question comes from the line of Paul Matteis from Stifel. Your question, please.
Hey, thanks so much for taking our questions, and let us offer our congratulations. This is Julian on for Paul. I guess I think a lot of people are wondering whether you guys think there's a bolus of patients that may be lined up waiting to switch from Elaprase. Is anything that you could say about that? I guess just thinking about what types of patients you think may be interested, again, that are in line with the label. One other follow-up question is FDA mentioned in its press release that you're 95% enrolled for the confirmatory phase III.
Just wanted to get your thoughts on, you know, how far along you think you need to be enrolled for the Sanfilippo study in order to file a BLA there? If any specific considerations for that indication we should think about with respect to regulatory. Thank you.
I'll hand it to Katie on the first one and then myself, and Peter will comment on the Sanfilippo enrollment.
Great. In terms of bullish, I would not think of it as bullish. Usually you think about that when there's no treatment available in a current disease area. What I will say is the bottleneck will be access and reimbursement, right? We won't have coverage from payers from day one, and there will be a medical exceptions process in order to get reimbursement for patients. As you know, with rare disease being expensive, the patients will not have access until reimbursement can be assessed for each of the patients. In addition, there is, you know, logistics of getting back into the clinic for infusion. Those are the sort of mechanistic bottlenecks.
In terms of patients that are excited and waiting, certainly, the newly diagnosed patients, the younger patients, that have been identified as having more severe disease. We have already heard a lot of excitement from the community on getting these patients on treatment as soon as possible. We always think about, you know, time is time is neurons, so we need to get these patients on. It's more about logistical hurdles that we'll have to work through in launch and not about excitement. There's not a lack of that in the community.
Yeah. I'll add a couple points now to the second question around Sanfilippo, the implications, and maybe just make a general comment on the progress we've made with the FDA. We're quite satisfied, very grateful about the rigorous and constructive review that we've had with the FDA, you know, and have got actual documentation for. I think also for our filing at the FDA, the real-world trial data we have that guides us in both the neuroimaging and in the real-world trial data. The comment on the confirmatory trial, I think, was handled accurately. I think for me the lesson is absolutely, you know, we're as far as we're ever gonna be able to go. You know, we've been utilizing that program to help us design the phase III to get it off the ground for Sanfilippo.
I think Peter already mentioned that you need the best data for Sanfilippo. There is no standard of care. It's different than the hydrocephalus example where there is a standard of care. Obviously getting the phase III off the ground is a priority as we will file for accelerated approval next year. Any other thoughts on that, Peter?
Just one additional thought. I think that it's important to note that the COMPASS study started years ago with the intent for a robust phase II/III design to enable global approval, not just confirmation for the accelerated approval today. While the FDA noted the 95% enrollment, I don't think that is the regulatory expectation per se. It's that the confirmatory study is underway.
Okay.
Thank you. Our next question comes from the line of Mayank Mamtani from B. Riley Securities. Your question please.
Yes, thanks for taking our questions and huge congrats on getting the brain shuttle field its first FDA-approved product. Sorry if I missed this. You know, as you mentioned, the initial focus is on the early symptom pediatric subjects. There's some dose escalation monitoring period up to, I think, eight weeks for a variety of things, infusion reactions, anemia, et cetera. Could you sharpen the split between the ERT naive newly diagnosed versus the switch patients that, you know, you intend to get on drug inside of the next two, three quarters? Also, I wonder in your physician research how important, you know, some of the attributes that you have in your data, like hearing improvement and even, you know, NfL improvement.
How does that kind of weigh in versus, you know, some of the other things that may come later, like the six-minute walk test or other neurological endpoints which, you know, are obviously not in the label. If you could maybe give some more color there, that would be great.
Okay. I'll hand it to Katie, and Peter will sort of tag team on this question. Thanks.
I'll start with that. In terms of the dose escalation, two things. The patients, the switch patients, as well as the new patients, naive patients, will need to come into the centers of excellence to get their infusion. The dose escalation schedule is three, seven, and 15th. There are some logistics around, you know, getting patients set up for infusion. This is why we have guided to the S-shaped uptake curve because of the getting the patients back into the clinic. That is very common for a new ERT that's approved with a new safety profile. Physician will need to gain experience infusing the product in the clinic before patients can be sent home.
We do very much expect all patients to be able to go home for home infusion for those that would like to get their infusions at home.
Maybe just to add, the dose escalation was scheduled to support positive patient experience by reducing infusion-related reactions early on. Remember that the data suggests that the incidence was highest early upon initiating treatment. The dose escalation really is designed to support positive patient experience. We want patients to get to the maintenance dose as rapidly and as predictably as possible. I think the second part of the question had to do with NfL and other outcomes. The label, I wanna emphasize the label is based on the phase I/II study design, and that design had a primary study period of 24 weeks. The labeled outcomes are based on that primary study period.
Now that said, as we've talked about before, we're highly encouraged by the NfL results and the large proportion of participants who normalized on NfL, and we think that also is highly meaningful. COMPASS is our confirmatory trial, and we will be analyzing a large number of outcomes, both peripheral and CNS, across a very broad population from age six to 26. That is intended to provide a very definitive and comprehensive efficacy.
You know, just to add one other point, which I think you asked about hearing and some of these other endpoints. I think very much meaningful within the community. I think the great thing we have here is we have a rigorous FDA that based a label on the 24-week endpoint from the phase I/II, and then we have the New England Journal of Medicine publication that shows really longer-term data and what this medicine can actually do. I think it's a great combination. And then of course, what Peter already mentioned, which is the COMPASS study as follow up. But definitely viewed as meaningful obviously behavior, cognition, and I think we hear a lot about hearing in particular.
Thank you, team. Congrats again.
Thank you. Our next question comes from the line of Ananda Ghosh from H.C. Wainwright & Co. Your question please.
Hi, congrats on the data and of course on this very fulfilling journey since inception. I have two questions. The first one, you know, given the concentrated prescriber base, what does your survey work kind of tell about the percentage of docs willing to prescribe now versus those, you know, willing to see or wishing to see results from the head-to-head RCT study of the study in the RCT?
Go ahead, Katie. Yeah.
So our market research suggests that once they see and understand our biomarker data, they do see it as unprecedented, given that no one has shown normalization in this treatment paradigm. Of course, with all, you know, all launches, there will be a segment of physicians who have the wait and see approach, but there are much fewer of those because as I stated earlier, 100 centers of excellence are managing these patients, and they have the level of depth and understanding of what is not being addressed with the current standard of care. Given that this is a progressive disease, we do see the level of excitement and willingness to prescribe.
I would say there may be a segment of physicians that's not as familiar with our data today that of course we're gonna need to get to as part of the launch.
Got it. Thanks. Maybe, yes, sorry.
I just said. You have a second question, Ananda. Go ahead.
You know, the second question is, I think the extension of what others have already asked, and that is, you know, based on some of the regulatory interactions you had over past several months now, what are some of the ramifications, you know, what is the regulatory ramification with respect to some of the other assets in the platform beyond Sanfilippo? You know, what have you learned from this process, and how do you see a path forward for other programs?
Yeah. I'll comment on that. Just to restate what we've stated before. I think it's obviously a positive read-through, especially for Sanfilippo, which is a very aggressive neurologic disease where, you know, there's no standard care. Patients advance very rapidly. I think importantly, it's precedent setting that heparan sulfate is used as a surrogate biomarker reasonably likely to predict clinical benefit. Now we think about the broader pipeline. That's I think clear for Sanfilippo. Our broader pipeline, each one of our medicines and each one of our, you know, desired therapeutic areas will have its own nuances. Pompe, for example, you know, Gaucher, Alzheimer's. I think most importantly these data and this approval, you know, validates that the transport vehicle works. We can get biologics into the brain, but we'll approach each of those separately.
We of course are looking for indications where biomarkers can allow for an accelerated approval. That's obviously advantageous.
Great. Thanks. Congrats again.
Thank you. Our next question comes from the line of Laura Chico from Wedbush. Your question please.
Hey, good afternoon and congrats. Thanks for taking the question. A couple of follow-ups on my side here. Great color from Katie on the launch setup. Just wondering if you could expand a little bit more on the expectations around the payer mix within the U.S. This is more of a logistical clarification. Will there be patients converting from the trial to paid status? I know you're not looking for a bolus of switches or anything like that coming through, but just trying to understand if there's a conversion that has to happen here for.
Of AVLAYAH patients already on drug. Thanks very much.
I'll hand that to Katie for those questions.
Thanks, Laura, for your question. In terms of the payer mix, our expectation is that 50% will be roughly 50% are commercial payers who have MPS II today, and then the other 50% is likely Medicaid with very little Medicare. Maybe I'll address part of your question, and Peter can add in terms of the study. Now, of course, with the U.S. approval, patients could drop out of study to get onto commercial therapy. But we haven't made any decisions or announcements in terms of our E2 program. There will be more to come on that.
Yeah. I'll just add that the study remains ongoing at this time.
Thanks very much.
Thank you. Our next question comes from the line of Peyton Bohnsack from TD Cowen. Your question, please.
Hi, guys. This is Peyton on for Joe . Thanks for taking our questions. I guess the first one is, when you look at the label and you can finish the confirmatory trial, do you think that you could broaden it and get rid of the neuro manifestations part of the label? The second thing is, if you have any dose interruptions, do you imagine that you will have to go through a reauthorization step? Thank you.
Okay. We'll have Peter talk about broadening the label, and then Katie will talk about if there needs to be reauthorization. Go ahead, Peter.
Thank you for the question. The question about the neurologic manifestations, you know, that is a reflection of the accelerated approval based on the CSF surrogate. I think with the confirmatory study and the way that we have designed this with cohort A with neurologic manifestations and cohort B, which is an attenuated population, and the totality of endpoints that we anticipate showing efficacy on, we should be able to remove the neurologic manifestations. Because the study, the confirmatory study, is designed to assess comprehensive efficacy across a broad population.
In terms of reauthorization, what we understand from the standard of care today is that the reauthorizations and payers are usually at six months or at one year, and that's our assumptions to date.
I'm just gonna add one other point around neurologic manifestations that Peter made earlier in the call. You know, I, again, linking it to CSF heparan sulfate is key, and that was, I think, a key for the FDA. Importantly, the majority, the vast majority of patients experience neurologic manifestations, both neuropathic and attenuated. I think what we think more about is, you know, would we initiate treatment in adults, which of course is a smaller fraction of the overall patient body as we think about the expansion of the label. We're very happy with the label. We think it does reflect the phase I/II data and, you know, it's a great place for us to start.
Great. Thank you, guys.
Thank you. Our next question comes from the line of Myles Minter from William Blair. Your question please.
Hi, this is John on for Myles. Congrats on the approval, and thanks for taking our question. Maybe just one final one on the neurological manifestations. Maybe can you just provide us some clarity on what percentage of the attenuated population would not have those manifestations and therefore would not be eligible, as indicated?
Yeah. Okay. We'll start with Peter on defining neurologic manifestations, and then we'll hand it to Katie around the percentages.
Yes. Thank you. Thank you for the question. I think the first thing to reiterate from my perspective is the indication is for neurologic manifestations in the pre-symptomatic and symptomatic stages. Remember that approximately 2/3 - 70% of MPS II patients have a more severe phenotype with neurological involvement. As Katie noted earlier, a large proportion of patients who are attenuated or classified as attenuated will also develop neurologic manifestations. It's hard to put a specific number to it, but the majority of patients are expected to have neurologic manifestations. The other thing I would say is important in the indication statement, there is a note that AVLAYAH is not recommended for use in combination with other therapies. That is an implicit acknowledgement that AVLAYAH does address peripheral manifestations as well.
You know, the urinary GAG normalization is also labeled in the pharmacodynamic results.
Maybe I'll just add a little bit of color because what the data that we have, you know, there is a paper published that shows that actually before the age of 10, attenuated patients will develop neurologic manifestations. Based on our claims dataset, when we looked at the list of what is considered neurologic manifestations, about 94% of patients have codes that code to neurologic manifestations. That's why we believe it is the majority of the population, of the pediatric population.
Thank you. Very helpful.
I think we have time for at least one more question. I know we're at time, but we wanna be able to get more questions. I think as we start repeating some questions, we realize we've kinda hit that limit. Let's take another question.
Certainly. Our next question comes from the line. Jay Olson from Oppenheimer. Your question please.
Hey, congratulations on this landmark approval. We have a few questions. Can you talk about any educational support that you'll provide for patients to transition from Elaprase to AVLAYAH in clinical practice? Second, can you share any color on the potential launch timing and strategy for countries outside the U.S. that also might provide approval based on your phase I/II study results? Finally, can you talk about whether there could be a platform technology designation granted by the FDA along with this AVLAYAH approval? And if so, how important would that be for future programs? Thank you.
Hand it to Katie.
Great. Thanks, Jay, for your question. Our Denali Care Program or the care team, they will absolutely be supporting every patient and family with educational resources on how to transition from the current standard of care to AVLAYAH. Our team is ready and waiting to be able to do that. In terms of the global expansion, Peter mentioned this as well, we will be seeking regulatory approval. With the U.S. approval now in hand, we can leverage the CPP or CMA process to be able to access other markets. As you know, other markets will also require reimbursement, unlike the U.S. market where we can go on day one. We'll have to be able to obtain reimbursement in those countries.
It will be local country by country, you know, as we go forward with registration in these various countries.
Yeah, I'll end and we'll end the call after this comment. Great question around the platform designation. It's something that we have contemplated multiple times. As you know, we have three different platform franchises, the Enzyme Transport Vehicle, the Oligonucleotide Transport Vehicle, and the Antibody Transport Vehicle. In our assessment of the three, the one probably most likely to qualify for platform designation may actually be the oligo transport vehicle because the core can be similar across medicines. With the enzyme, you know, each enzyme actually behaves pretty differently. For example, SGSH and IDS behave differently. That being said, it's something that we would, you know, pursue that path if we believe it would be the fastest way to get more medicines to patients. I think with that, we'll close questions.
Those that we didn't get to, we apologize. We'll be following up with you directly.
Thank you. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.