Denali’s DNL310 Eyes Accelerated FDA Approval With Encouraging Phase 1/2 Data in Hunter Syndrome

Carole Ho

According to a new announcement, the FDA’s Center for Drug Evaluation and Research (CDER) division and Denali Therapeutics have completed a successful meeting outlining a path towards potential accelerated approval for the company’s investigational agent DNL310 in patients with mucopolysarcharidosis type II (MPS) syndrome, also known as Hunter syndrome. The company plans to submit a biologics license application (BLA) in early 2025 under the accelerated approval pathway.¹

Ultimately, the parties agreed that cerebrospinal fluid heparan sulfate (CSF HS) is likely to predict clinical benefit and can serve as a surrogate endpoint for accelerated approval. DNL310, also known as tividenofusp alfa, has been supported by data from an ongoing, open-label, single-arm phase 1/2 study. It is also being studied in phase 2/3 COMPASS study (NCT05371613), a larger-scale trial pinning the agent against idursulfase for up to a 96-week treatment period. That study, which is currently enrolling, is expected to complete in 2025, according to clinicaltrials.gov.

At this year’s Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM 2024), taking place September 3-6, in Porto, Portugal, the company is presenting new interim data from the phase 1/2 study highlighting the treatment’s effects in MPS II. The presentations comprise of data on more study participants (n = 37) and longer treatment duration (up to week 129) with DNL310, as well as new biomarker findings and clinical outcomes.

"We thank CDER for a positive and collaborative discussion and their guidance on CSF HS as a surrogate biomarker, which we see as a significant step towards accelerating development of medicines for individuals and families living with MPS II,” Carole Ho, chief medical officer at Denali, said in a statement.¹ "This milestone reflects a collective effort across the patient community, academia and industry to communicate the science and advocate for faster paths to effective treatments addressing these devastating rare diseases."

An overview of the new phase 1/2 data showed that treatment with the investigational agent resulted in a 90% mean reduction in CSF HS after 24 weeks, with all participants showing normal or near normal levels at that time. Notably, this reduction was sustained through week 104 of treatment. Above all, the therapy was safe and generally well tolerated, with a safety profile that Denali noted supports its development as a treatment for MPS II.

Additional data from the conference presentations showed that treated patients either improved or stabilized in outcomes of adaptive behavior and cognition, hearing, liver volume, and growth. From baseline to week 24, the number of treated patients with normal total urine glycosaminoglycans (GAGs) increased from 5% to 77%, with effects sustained through week 129. Of note, most of these patients were previously on standard of care therapies, meaning the improvements suggested an additive treatment benefit.

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Ho added, "We are excited by the potential to deliver a new MPS treatment sooner using the accelerated approval pathway. We also look forward to plans for conversion to full approval following completion of the global Phase 2/3 COMPASS study, and we are grateful for the continued participation and commitment of patients, clinicians, and study teams involved in the tividenofusp alfa clinical studies."¹

Study investigators also observed significant and sustained reductions in neurofilament light (NfL), a marker of neuroaxonal damage, for up to week 129 in treated participants. This was similar to results presented at the 2023 meeting, where researchers saw a 61% reduction in serum NfL after 2 years of treatment with DNL310.²

DNL310, a brain-penetrant enzyme replacement therapy, is composed of iduronate-2-sulfatase (IDS) fused to Denali’s proprietary enzyme transport vehicle, which is engineered to cross the blood-brain barrier via receptor mediated transcytosis in the brain. DNL310 delivers IDS to lysosomes, where it is needed to break down GAGs commonly found in Hunter syndrome.

"The Phase 1/2 data show that treatment with tividenofusp alfa produces robust and durable effects, with normalization of key disease biomarkers and improvement or stabilization in associated CNS and somatic clinical endpoints," Barbara Burton, MD, a professor of pediatrics, genetics, genomics, and metabolism at the Feinberg School of Medicine in Chicago, Illinois, said in a statement.¹ "The totality of data support Denali's plans to file for accelerated approval of tividenofusp alfa with the potential to address a critical unmet need for CNS-penetrant therapies in MPS II."

COMPASS, a multicenter, double-blind, randomized study, is expected to enroll 54 participants with MPS II who will be randomly assigned to either DNL310 or idursulfase. The study is comprised of 2 cohorts: cohort A (participants aged ≥2 to <6 years) and cohort B (≥6 to <26 years). The study uses percent change in CSF HS over a 24-week period as the primary outcome, with additional changes in the Vineland Adaptive Behavior Scale, Third Edition over 96 weeks as an additional key outcome.

REFERENCES
1. Denali Therapeutics Announces Successful Meeting with the FDA and Plans to File for Accelerated Approval of Tividenofusp Alfa (DNL310) for the Treatment of MPS II (Hunter Syndrome). News release. Denali Therapeutics. September 3, 2024. Accessed September 3, 2024. https://finance.yahoo.com/news/denali-therapeutics-announces-successful-meeting-120000316.html
2. Denali Therapeutics Announces New Interim Data from Phase 1/2 Study of DNL310 (ETV:IDS) in MPS II (Hunter Syndrome) at SSIEM 2023. News Release. Published August 30, 2023. Accessed September 3, 2024. https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-new-interim-data-phase-12-study-0