Significantly Amelioration of Neurofilament Light Observed in Phase 1/2 Study of DNL310 in Hunter Syndrome


Biomarker data at 49 weeks continued to demonstrate that DNL310 enabled rapid and sustained normalization of CSF heparan sulfate to normal healthy levels and improvement in lysosomal function biomarkers.

Joseph Muenzer, MD, PhD, Bryson Distinguished Professor in Pediatric Genetics, University of North Carolina at Chapel Hill

Joseph Muenzer, MD, PhD

Interim findings from a phase 1/2 trial assessing DNL310 (Denali Therapeutics), an investigational fusion protein agent, showed robust reductions in neurofilament light (NfL) among treated individuals with Hunter syndrome after a 2-year period. The global phase 2/3 COMPASS study (NCT05371613), which includes a larger population of participants, is still ongoing.1

After 2 years of dosing, investigators observed a mean reduction of 64% in NfL, a biomarker of neuroaxonal damage, in 13 DNL310-treated individuals (P <.001). The findings come after the FDA recently recommended to Denali the assessment of NfL as an exploratory end point to assess its potential as a possible biomarker of diagnostic, prognostic, or therapeutic response in individuals with neuronopathic Hunter syndrome. There are currently no approved therapies that address the behavioral, cognitive, and physical manifestations of the disease.

"The serum NfL reduction in MPS II patients receiving longer term dosing with DNL310 is very promising, particularly in the context of DNL310’s ability to normalize CSF heparan sulfate, which is the primary substrate that is associated with neurodegeneration in MPS disorders," Joseph Muenzer, MD, PhD, Bryson Distinguished Professor in Pediatric Genetics, University of North Carolina at Chapel Hill, said in a statement. "I look forward to seeing how CSF heparan sulfate and serum NfL could support approval to expedite treatment options for the MPS II community."

Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare genetic disease that affects over 2000 individuals, primarily males, and leads to behavioral, cognitive, and physical symptoms. DNL310, a brain-penetrant enzyme replacement therapy, is composed of iduronate-2-sulfatase (IDS) fused to Denali’s proprietary enzyme transport vehicle (ETV), 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 glycosaminoglycans commonly found in Hunter syndrome.

Previous data from the phase 1/2 trial showed that treatment with the agent resulted in an 89% reduction in cerebrospinal fluid heparan sulfate levels after 49 weeks, including in 2 children with preexisting high levels of anti-IDS antibodies. In addition, at week 24, investigators observed a mean decline of 64%, 54%, and 57%, respectively, in lysosomal lipid biomarkers of gangliosides GM2, GM3, and glucosylsphingosine lipids. These levels were sustained at week 49 (63%, 49%, and 48%, respectively).2

Additional data from the trial presented at the 19th Annual WORLDSymposium, held February 22-26, 2023, demonstrated positive changes across measures of exploratory clinical outcomes including Vineland Adaptive Behvior Scales (VABS)-II and Bayley Scales of Infant and Toddler Development (BSID)-II assessments. These raw score results, which assessed adaptive behavior and cognitive capabilities, respectively, were consistent with previously reported 1-year findings from the Clinician Global Impression Scales of Change and Caregiver Global Impression Scales of Change, which demonstrated improvement or stabilization across all domains at week 49.

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Hearing, as assessed by auditory brainstem response (ABR) testing, numerically improved over time after initiation of DNL310 across all frequencies. At week 49, ABR thresholds showed statistically significant improvements across 3 of the 4 frequencies, with a trend toward greater improvement at higher frequencies. The safety profile of DNL310 remains consistent with standard of care, with infusion-related reactions as the most frequent treatment-emergent adverse events, which decreased in frequency and severity with continued dosing.

"The robust reduction and normalization of CSF heparan sulfate, and now the downstream reduction in NfL after treatment, are consistent with positive changes in clinical outcomes measures we have observed from interim analyses of the ongoing Phase 1/2 study,” Carole Ho, MD, chief medical officer, Denali, said in a statement. “As we advance DNL310 as a potential treatment option for individuals living with MPS II, we look forward to ongoing engagement with the FDA and the MPS community."

The phase 2/3 COMPASS study, which is still in recruitment, will randomly assign patients 2:1 to either DNL310 or idursulfase, assess changes in CSF heparan sulfate concentration as the primary outcome. Cohort A will include children ages 2 to 6 with neuronopathic disease, while cohort B will include children ages 6 to 17 without neuronopathic disease. The results of that study are intended to support registration of DNL310 for the treatment of Hunter syndrome.

1. Denali Therapeutics announces robust reduction in neurofilament light (NfL) with DNL310 treatment in MPS II (Hunter syndrome). News release. Denali Therapeutics. June 20, 2023. Accessed June 20, 2023.
2. Denali Therapeutics announces new interim data from DNL310 phase 1/2 study for MPS II and DNL126 preclinical data for MPS IIIa at WORLDSymposium. News release. February 22, 2023. June 20, 2023.
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