FDA Grants Breakthrough Therapy Designation to Tividenofusp Alfa for Treatment of Hunter Syndrome

The FDA granted breakthrough therapy designation (BTD) for tividenofusp alfa (DNL310; Denali Therapeutics) for the treatment of patients with Hunter syndrome (MPS II), a rare genetic disease that can lead to physical, cognitive, and behavioral complications, according to a news release from Denali Therapeutics.¹

FDA breakthrough therapy designation allows for drugs that can treat rare diseases and have positive clinical data to receive more attention towards development. | Image Credit: © JHVEPhoto | stock.adobe.com

Previously, tividenofusp alfa received FDA fast track, orphan drug, and rare pediatric disease designations. A biologics license application is expected to be submitted for tividenofusp alfa in early 2025 under the FDA’s accelerated approval pathway. The FDA’s BTD will allow for expedited review and development for tividenofusp alfa, as preliminary clinical evidence suggests that the therapy will be a substantial improvement over currently available treatments for Hunter syndrome.¹

“Data from the open-label phase 1/2 study have shown promising results, with positive effects on evidence-based surrogate endpoints and early signs of improved clinical outcomes in participants with Hunter syndrome,” Carole Ho, MD, chief medical officer of Denali Therapeutics, said in the news release. “We are grateful to the FDA for recognizing the potential of tividenofusp alfa as a meaningful treatment option for individuals with Hunter syndrome.”¹

The positive data from a phase 1/2 trial were revealed in August 2023 during an oral presentation at the Society for the Study of Inborn Errors of Metabolism Annual Symposium. According to additional biomarker data from up to 2 years of treatment, tividenofusp alfa continued to demonstrate sustained and rapid normalization of cerebrospinal fluid (CSF) heparan sulfate to healthy levels, while showing improvement in lysosomal function biomarkers.²

Critically, normalization of CSF was observed in patients with high pre-existing anti-drug antibodies. Additionally, improvements in CSF lysosomal lipids were observed in most participants, consistent with improved lysosomal function. There was also a robust reduction in serum neurofilament light (NfL), a marker of neuronal damage; the outcome reached statistical significance after 61 weeks and a 64% reduction following 2 years of treatment with tividenofusp alfa.²

Furthermore, safety data from 2 years of treatment indicate that tividenofusp alfa was generally well tolerated among enrollees. It is noted that previously reported data showed statistically meaningful reduction of NfL, in addition to positive changes in clinical outcomes of cognition, adaptive behavior, and auditory function.²

Hunter syndrome primarily affects males and is caused by mutations in the iduronate-2-sulfatase (IDS) gene, leading to deficiency of the IDS enzyme. Often, symptoms begin to emerge around the age of 2 feature physical complications, such as joint stiffness, organ dysfunction, hearing loss, and neurocognitive symptoms with impaired development. During the disease course, there is a buildup of glycosaminoglycans in lysosomes.^1,2

Current standard of care for patients with this condition include enzyme replacement therapy that partially treats physical symptoms associated with Hunter syndrome, but do not cross the blood-brain barrier. Due to this, many patients with Hunter syndrome that experience behavioral and cognitive symptoms do not have proper relief for their condition.²

A new phase 2/3 trial, called COMPASS, is now enrolling participants globally with Hunter syndrome, both with and without neuronopathic disease. The trial is expected to enroll 54 participants, with patients randomized 2:1 to receive either tividenofusp alfa or idursulfase, respectively. The results of this study will garner further support for the development of tividenofusp alfa and provide a deeper look into the efficacy and safety of this new treatment.^1,2

REFERENCES

1. Denali Therapeutics. Denali Therapeutics announces US FDA breakthrough therapy designation granted to tividenofusp alfa for the treatment of Hunter syndrome (MPS II). GlobeNewswire. News Release. Released January 8, 2025. Accessed January 8, 2025. https://www.globenewswire.com/news-release/2025/01/08/3006194/0/en/Denali-Therapeutics-Announces-U-S-FDA-Breakthrough-Therapy-Designation-Granted-to-Tividenofusp-Alfa-for-the-Treatment-of-Hunter-Syndrome-MPS-II.html

2. Denali Therapeutics. Denali Therapeutics announces new interim data from phase 1/2 study of DNL310 in MPS II (Hunter syndrome) at SSIEM 2023. BioSpace. News Release. Released August 30, 2023. Accessed January 8, 2025. https://www.biospace.com/denali-therapeutics-announces-new-interim-data-from-phase-1-2-study-of-dnl310-etv-ids-in-mps-ii-hunter-syndrome-at-ssiem-2023