Denali Plans to Submit BLA for Tividenofusp Alfa in Hunter Syndrome Following Positive Phase 1/2 Data

Joseph Muenzer, MD, PhD

New promising data from a phase 1/2 study showed that treatment with investigational tividenofusp alfa (Denali Therapeutics) resulted in substantial and significant reductions to critical biomarkers among patients with Hunter syndrome, otherwise known as MPS II. Based on the totality of the evidence, the company plans to submit a biologics license application (BLA) in early 2025 under the accelerated approval pathway for the agent as a potential new treatment of Hunter syndrome.¹

Otherwise known as DNL310, the therapy is a brain-penetrant enzyme replacement treatment 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.

In the newly announced primary analysis, featuring 47 participants with MPS II, treatment with the investigational agent led to reductions to normal and near-normal levels in central nervous system and peripheral biomarkers of the disease at 24 weeks. These included changes in cerebrospinal fluid and urine heparan sulfate and neurofilament light (NfL), a common marker of neuroaxonal damage. Notably, clinical outcomes demonstrated normal liver volume at 24 weeks, improvements in hearing thresholds across all tested frequencies, and skill gains in adaptive behavior and cognitive measures for most participants.

"Longer-term clinical data add to confidence that normalization of key biomarkers endures over time and that treatment with tividenofusp alfa is associated with continued improvement in hearing, cognition and behavior, which is meaningful to affected individuals and their families,” investigator Joseph Muenzer, MD, PhD, director of the Muenzer MPS Center and professor in pediatric genetics at the University of North Carolina at Chapel Hill School of Medicine, said in a statement.¹ "I look forward to new treatment options urgently needed by the Hunter syndrome community that effectively address the full spectrum of the disease."

Overall, tividenofusp alfa was considered safe and well tolerated by those in the study, with most treatment-related adverse events (TEAEs) considered mild or moderate in nature. The most common TEAEs observed included infusion-related reasons, anemia, vomiting, pyrexia, respiratory infections, and rash. Serious TEAEs occurred in three participants (6.4%) but were manageable, with resolution or stabilization during continued treatment, although one participant discontinued due to a moderate IRR and other non-treatment-related adverse events.

Carole Ho, MD

"Our primary analysis in 47 participants with MPS II and the additional long-term data in up to more than four years, support the potential of tividenofusp alfa to address neurocognitive, behavioral, and physical effects for all individuals living with MPS II. We are working as fast as possible to enable tividenofusp alfa as a treatment option for individuals living with MPS II and enable access for them and their families," Carole Ho, MD, chief medical officer at Denali, said in a statement.¹ "We expect the progress achieved in our Hunter syndrome program to inform and accelerate additional therapeutics programs in our lysosomal storage disease portfolio, including Sanfilippo syndrome Type A (MPS IIIA)."

Tividenofusp alfa is also being studied in the ongoing phase 2/3 COMPASS trial (NCT05371613), a large-scale investigation pinning the agent against idursulfase for up to a 96-week treatment period. The trial, comprised of 54 individuals with MPS II, includes 2 cohorts based on patients’ age: cohort A (ages ≥2 to <6 years) and cohort B (≥6 to <26 years). The study uses change in cerebrospinal fluid heparan sulfate (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.²

In September 2024, Denali announced it completed a successful meeting with the FDA’s Center for Drug Evaluation and Research (CBER) division outlining a path towards potential accelerated approval for tividenofusp alfa in MPS II. In the meeting, both parties agreed that cerebrospinal fluid HS is likely to predict clinical benefit and can serve as a surrogate end point for its accelerated approval.

REFERENCES
1. Denali Therapeutics Announces Primary Analysis and Long-Term Follow-Up of Phase 1/2 Study in Hunter Syndrome (MPS II) with Tividenofusp Alfa. News release. Denali Therapeutics. February 6, 2025. Accessed February 7, 2025. https://www.globenewswire.com/news-release/2025/02/06/3022238/0/en/Denali-Therapeutics-Announces-Primary-Analysis-and-Long-Term-Follow-Up-of-Phase-1-2-Study-in-Hunter-Syndrome-MPS-II-with-Tividenofusp-Alfa.html
2. 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 February 7, 2025. https://finance.yahoo.com/news/denali-therapeutics-announces-successful-meeting-120000316.html