Denali Therapeutics (NASDAQ:DNLI) used an analyst call from the 2026 WORLD Symposium in San Diego to highlight new and updated data from its enzyme transport vehicle (ETV) franchise, including clinical follow-up for tividenofusp alfa (TIVI) in Hunter syndrome (MPS II), preliminary Phase 1/2 biomarker results for DNL126 in Sanfilippo syndrome type A (MPS IIIA), and preclinical and clinical study-design updates for DNL952 in Pompe disease.
ETV platform and symposium focus
Chief Executive Officer Ryan Watts reiterated Denali’s goal of delivering “the power of biotherapeutics to the whole body, including the brain,” describing the company’s approach as engineering transferrin receptor binding into an Fc fragment to enable transport across the blood-brain barrier and broader biodistribution. Watts said the WORLD Symposium program included seven Denali presentations, including oral presentations with new data for TIVI and DNL126, along with updates on DNL952.
TIVI: longer-term Phase 1/2 follow-up in Hunter syndrome
Acting Chief Medical Officer Peter Chin reviewed updated follow-up from the open-label Phase 1/2 E2 study of tividenofusp alfa in MPS II, which he noted was recently published in The New England Journal of Medicine. After initial dose finding, participants received weekly IV tividenofusp alfa at 15 mg/kg. The updated analysis used a clinical cutoff date of March 28, 2025, corresponding to when the last enrolled patient completed the week 49 visit.
Chin reported cumulative treatment exposure with a median of 134 weeks and a maximum of 243 weeks. He said CSF and urine heparan sulfate showed “substantial reductions” with normalization following treatment, maintained long-term through 201 weeks. Serum neurofilament light chain (NFL) showed substantial reduction, with normalization in the majority of participants after week 104.
On clinical measures, Chin said improvements in hearing threshold were maintained through week 201 and normal liver volumes were maintained through MRI at week 153. Denali also presented Vineland Adaptive Behavior Scales composite and Bayley Scales cognitive results stratified by age at treatment initiation, with Chin describing continued skill gains in younger age groups and stability in patients treated after age four through roughly four years of follow-up—an outcome he characterized as meaningful relative to expected decline.
Chin said the safety profile remained stable and manageable with longer follow-up. Infusion-related reactions (IRRs) were the most common adverse event, consistent with enzyme replacement therapy (ERT), and decreased in incidence and severity over time.
Case poster: two non-neuronopathic siblings on TIVI
Denali also summarized a poster from UCSF describing two non-neuronopathic male siblings treated in the Phase 1/2 study. The siblings were treatment-naïve, began therapy in September 2022, and had somatic involvement despite baseline cognitive scores in a typical range. Denali reported that CSF and urine biomarkers (heparan sulfate and dermatan sulfate) were elevated at baseline and normalized by week 49, with reductions maintained through week 104.
Chin said both siblings’ carpal tunnel syndrome resolved clinically and by EMG/nerve conduction study, joint mobility improved (including normalization of impaired shoulder abduction in the older sibling by week 104), and both achieved six-minute walk distances within typical ranges for age. Denali also described cognitive testing showing improvements into above-average or “upper extreme” ranges, alongside parent-reported academic and functional gains.
DNL126: preliminary Phase 1/2 biomarker results in MPS IIIA
Chin described DNL126 as an ETV designed to deliver SGSH to the brain and body in MPS IIIA, a disorder with no approved therapies. DNL126 is being evaluated in an open-label Phase 1/2 study with 20 pediatric participants enrolled. The WORLD update included preliminary data from 14 participants with a June 4, 2025 cutoff; biomarker efficacy data through week 49 were available for eight participants in dose-finding cohorts.
Denali reported that CSF heparan sulfate decreased by week 13 and showed an 80% mean reduction at week 49, with some participants reaching normalization. CSF GM3, described as a marker of secondary lysosomal storage pathology, was reduced by approximately 60%, with most participants in the normal range. Peripherally, Denali reported a rapid reduction in urine heparan sulfate by week 3 and a mean 83% reduction at week 49, along with normalization of liver volume in all participants by week 49.
The company said the preliminary safety profile was generally consistent with established ERTs, with adverse events primarily mild or moderate and no treatment-related serious adverse events. IRRs were the most common adverse event and decreased over time; Denali said reactions were manageable with premedication, infusion-rate adjustments, and dose escalation, and suggested optimized dosing in later cohorts improved tolerability.
During Q&A, management said the efficacy cohorts use an optimized slow dose escalation with weekly dosing and hypothesized results “should be at least as good” as dose-finding data, while noting additional data are needed. Watts also said the company would likely pursue a breakthrough designation for DNL126, similar to its approach with TIVI. On clinical outcomes, Denali said cognitive assessments require longer follow-up and that natural history would be an important reference, even without a direct comparator.
DNL952: Pompe preclinical poster and Phase 1 study design
Chief Scientific Officer Joe Lewcock presented highlights from two posters on DNL952, an investigational therapy for Pompe disease that fuses recombinant GAA to Denali’s transferrin receptor-binding transport vehicle. Lewcock said the goal is enhanced delivery to muscle and the nervous system, including neurons via blood-brain barrier transport, to address glycogen accumulation and downstream pathology.
In a Pompe mouse model, Denali reported that after five every-other-week doses, DNL952 produced substantial reductions in glycogen accumulation across a dose range in muscle and nervous system, and that results were superior to the same regimen using 20 mg/kg of standard-of-care therapy. Denali also reported dose-dependent improvements in muscle pathology markers LAMP2 and P62, while stating standard of care was unable to effectively impact those pathologies in the model.
Lewcock also outlined the design of a first-in-human Phase 1, multi-center, open-label study (DNLI-J0001) in adults with late-onset Pompe disease. The 24-week core period includes a 24-week extension, with initial dose exploration in two planned cohorts of ERT-experienced participants and optional cohorts that may evaluate alternative doses, dose frequencies, and potentially ERT-naïve participants. Objectives include safety, tolerability, pharmacokinetics, immunogenicity, and exploratory pharmacodynamic and clinical measures.
About Denali Therapeutics (NASDAQ:DNLI)
Denali Therapeutics is a clinical‐stage biopharmaceutical company focused on developing therapies for neurodegenerative diseases. The company’s research leverages a proprietary Blood–Brain Barrier Transport Vehicle (TV) platform designed to enable large molecules, including antibodies and enzymes, to penetrate the central nervous system. Denali’s approach includes small molecules, monoclonal antibodies and gene therapy candidates aimed at key drivers of disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
Among Denali’s lead programs is an orally delivered leucine‐rich repeat kinase 2 (LRRK2) inhibitor for Parkinson’s disease, and an anti‐TREM2 antibody designed to modulate microglial activity in Alzheimer’s patients.
