Denali Announces Rolling Regulatory Submission of Tividenofusp Alfa for Hunter Syndrome

Carole Ho, MD

According to a recent announcement, Denali Therapeutics has begun initiating its biologics license application (BLA) submission of tividenofusp alfa, an investigational agent, as a potential treatment for Hunter syndrome, otherwise known as MPS II. The submission, expected to be complete by May 2025, will be through the accelerated approval pathway, using change in cerebrospinal fluid heparan sulfate (CSF HS) as a surrogate end point to support approval.¹

Hunter syndrome, a rare genetic disorder impacting more than 2000 people globally, has traditionally been managed with symptomatic treatments such as enzyme replacement therapy (ERT). Tividenofusp alfa (DNL310) is a novel therapeutic that combines the iduronate 2-sulfatase (IDS) enzyme with Denali’s proprietary Enzyme Transport technology to deliver IDS throughout the brain and body, aiming to address the behavioral, cognitive, and physical manifestations of the disease. To date, the agent has received fast track and breakthrough therapy designations by the FDA, recognizing it as a promising therapeutic.

The Center for Drug Evaluation and Research (CDER) of the FDA, which will review the BLA, has been in contact with Denali, with both parties in agreement that CSF HS may be used as a surrogate end point for accelerated approval. In its announcement, the company noted a potential commercial launch in late 2025 or early 2026, with ongoing conversations on a path for traditional, full approval as well.

"We are grateful to the FDA for their ongoing support of our BLA filing and continued dedication to advance new medicines," Carole Ho, MD, chief medical officer at Denali, said in a statement.¹ "This regulatory milestone brings us closer to our goal of delivering a new treatment option to the Hunter syndrome community as we continue to listen, learn, and seek their advice in bringing tividenofusp alfa to patients. Our progress has broader positive implications supporting the expansion of our Enzyme TransportVehicle franchise of next-generation enzyme replacement therapies to treat the brain and body."

She added, "In this context, we appreciate the ongoing and productive collaboration with CDER through the START program as we align on an accelerated development and approval path for DNL126 for the potential treatment of Sanfilippo syndrome."

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The BLA submission for tividenofusp alfa was based on data from a promising phase 1/2 study in which treatment with the agent resulted in substantial and significant reductions to critical biomarkers among patients with Hunter syndrome. In the latest trial update, featuring 47 participants, treatment with the agent led to reductions to normal and near-normal levels in central nervous system (CNS) and peripheral biomarkers of the disease after 24 weeks. These included changes in CSF HS and neurofilament light, a notable biomarker of neuroaxonal damage.²

Discussions between Denali and CBER on a potential path for tividenofusp alfa have been in the works for months now. A successful meeting between the parties, announced in September 2024, outlined that CSF HS may be used as a surrogate biomarker based on its ability to predict clinical benefit. For context, Hunter syndrome is caused by a deficiency of the enzyme IDS, which is essential for the breakdown of glycosaminogylcans (CAGs) such as HS and dermatan sulfate. In the absence of functional IDS, HS accumulates in tissues and body fluids–including the CNS.

Tividenofusp alfa continues to be evaluated in the ongoing phase 2/3 COMPASS trial (NCT05371613), a large-scale study comparing the therapy to idursulfase over a treatment period of up to 96 weeks. The trial includes 54 participants with MPS II, divided into two age-based cohorts: cohort A (ages ≥2 to <6 years) and cohort B (ages ≥6 to <26 years). The primary endpoint is the change in CSF HS levels over 24 weeks, with key secondary outcomes including changes in adaptive behavior as measured by the Vineland Adaptive Behavior Scale, Third Edition, over 96 weeks.

In the phase 1/2 study, the therapy was viewed as safe and well tolerated, with most treatment-related adverse events (TEAEs) mild or moderate in nature. Throughout the 24-week period, infusion-related reactions (IRR), anemia, vomiting, pyrexia, respiratory infections, and rash, were among the most common TEAEs observed. Serious TEAEs, observed in only 3 participants (6.4%), were manageable, with resolution or stabilization during continued treatment. Of note, 1 patient did discontinue because of a moderate IRR and other non-treatment-related AEs.²

REFERENCES
1. Denali Therapeutics Announces Initiation of BLA Filing for Accelerated Approval of Tividenofusp Alfa for the Treatment of Hunter Syndrome (MPS II) and Positive Ongoing Interactions with FDA on DNL126 Through START Program. News release. Denali Therapeutics. April 2, 2025. Accessed April 7, 2025. https://www.globenewswire.com/news-release/2025/04/02/3054211/0/en/Denali-Therapeutics-Announces-Initiation-of-BLA-Filing-for-Accelerated-Approval-of-Tividenofusp-Alfa-for-the-Treatment-of-Hunter-Syndrome-MPS-II-and-Positive-Ongoing-Interactions-w.html
2. 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 April 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