FDA Grants Breakthrough Therapy Designation to Denali’s Tividenofusp Alfa for Hunter Syndrome

Carole Ho, MD

(Credit: Denali Therapeutics)

According to a new announcement, the FDA has granted breakthrough therapy designation to Denali Therapeutics’ investigational therapy tividenofusp alfa (DNL310), also known as DNL310, for the treatment of patients with Hunter syndrome. The company noted that it anticipates submitting a biologics license application for the agent in early 2025 for regulatory review under the accelerated approval pathway.¹

“My reaction was elation for what this could mean for the Hunter syndrome community and gratitude for the FDA's recognition of the potential of tividenofusp alfa as a meaningful treatment option for individuals with Hunter syndrome.” Carole Ho, MD, chief medical officer at Denali Therapeutics, told NeurologyLive^®.“Tividenofusp alfa is uniquely designed to optimize enzyme delivery to both brain and body. It is the only candidate therapy to normalize key biomarkers, CSF HS, urine HS, and neurofilament light (NfL), in a lysosomal storage disease.”

In September 2024, the company announced that it completed a successful meeting with the FDA’s Center for Drug Evaluation and Research (CDER) division outlining a path towards potential accelerated approval for the tividenofusp alfa in Hunter syndrome, also known as mucopolysarcharidosis type II (MPS) syndrome. In the meeting, both parties agreed that cerebrospinal fluid heparan sulfate (CSF HS) is likely to predict clinical benefit and can serve as a surrogate end point for its accelerated approval.²

Tividenofusp alfa has been supported by data from an ongoing, open-label, single-arm phase 1/2 study and 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. At the 2023 Symposium of the Society for the Study of Inborn Errors of Metabolism, held September 3-6, in Porto, Portugal, the company presented new interim data from the phase 1/2 study highlighting the treatment’s effects in MPS II. The presentations comprised of data on more study participants (n = 37) and longer treatment duration (up to week 129) with the agent, as well as new biomarker findings and clinical outcomes.

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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.

“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 suggesting the potential to address the full spectrum of Hunter syndrome,” Ho said.

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.

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 U.S. FDA Breakthrough Therapy Designation Granted to Tividenofusp Alfa for the Treatment of Hunter Syndrome. News Release. Denali Therapeutics. Published January 8, 2024. Accessed January 8, 2024. https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-us-fda-breakthrough-therapy
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 January 8, 2024. https://finance.yahoo.com/news/denali-therapeutics-announces-successful-meeting-120000316.html
3. 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 January 8, 2024. https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-new-interim-data-phase-12-study-0