Additional biomarker findings from up to 2 years of DNL310 treatment suggest positive changes in adaptive behavior and cognition as well as improvement in auditory function among pediatric patients with Hunter syndrome.
Recently presented at the 2023 Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, held August 29 to September 1, in Jerusalem, Israel, new interim data from the ongoing open-label, single-arm phase 1/2 COMPASS study (NCT05371613) of DNL310 (Denali Therapeutics) continued to show robust reductions in neurofilament light (NfL) after a 2-year period. These findings suggest continue to support the development of DNL310, an investigational enzyme replacement therapy for pediatric patients with Hunter syndrome.1
In the additional analysis, investigators observed a robust reduction in serum NfL, which reached statistical significance after 61 weeks, and a 64% reduction following 2 years of treatment with DNL310. Notably, researchers observed improvements in mean cognitive Bayley Scales of Infant and Toddler Development III and Vineland Adaptive Behavior Scales II raw scores, and auditory brainstem response thresholds at week 49 of DNL310 treatment.
“It is encouraging to see normalization of hepara+9n sulfate in CSF as well as reductions in lysosomal lipid biomarkers and NfL over 2 years, even in patients with high pre-existing antidrug antibodies," lead investigator Barbara Burton, MD, an attending physician in Genetics, Genomics, and Metabolism at the Ann & Robert H. Lurie Children’s Hospital of Chicago, said in a statement.1 "The treatment effect seen on these biomarkers of neurocognitive decline, along with 1-year data demonstrating positive changes in adaptive behavior, cognition, and auditory function, continue to support the potential of DNL310 to offer meaningful benefit for patients living with Hunter syndrome. I look forward to learning more as recruitment continues in the global phase 2/3 COMPASS study."
The new interim data included biomarker and safety data from additional participants receiving the treatment up to 2 years of with DNL310. The COMPASS trial is an open-label, 24-week study followed by an open-label extension study with approximately 45 pediatric participants with Hunter Syndrome being enrolled into 5 cohorts. COMPASS, which is still in recruitment, will randomly assign 54 patients 2:1 to either DNL310 or idursulfase, assessing changes in cerebrospinal fluid (CSF) heparan sulfate concentration as the primary outcome. The primary end points in this analysis were adverse events, infusion-related reactions, and other indicators of safety and tolerability. The key secondary end points included CSF and urine HS, antidrug antibodies, and adaptive behavior. The key exploratory end points were CSF and serum biomarkers including NfL, cognition, and clinical outcomes of physical manifestations.
"We are excited to share sustained effects on key disease biomarkers in Hunter syndrome with DNL310 treatment, now out to two years," Carole Ho, MD, chief medical officer at Denali, said in a statment.1 "Importantly, the robust reduction in serum levels of NfL suggests improvement in neuronal health, which is not addressed by current enzyme replacement therapies. We are encouraged to see positive changes across multiple clinical outcomes measures in the ongoing phase 1/2 study. We look forward to continued partnership with the MPS community as we enroll the global phase 2/3 COMPASS study in Hunter syndrome and plan for expanding the enzyme transport vehicle, including initiating clinical studies in other lysosomal storage diseases."
In the new analysis, rapid achievement of normal or near normal levels of CSF heparan sulfate sustained over at weeks 49 and 104 in all participants including those with high preexisting antidrug antibodies. In addition, sustained normal levels of CSF lysosomal lipids in most of the participants were consistent with improved lysosomal function. The safety profile is based on 33 participants with Hunter syndrome, with a median treatment duration of 91 weeks. All participants reported mild or moderate treatment-emergent adverse events (TEAEs), with no reported dose-related safety findings. Infusion-related reactions (IRRs) were the most frequent TEAEs, which frequency and severity declined over time with continued dosing.
Adverse events of special interest (AESIs) included 20 patients who reported moderate IRRs, and 1 participant had severe IRRs. There were 4 participants who had moderate anemia with 3 of them resolved. Authors observed 1 discontinuation related to TEAEs in a participant with complex underlying disease and 3 others discontinued treatment because of social reasons. Severe adverse events occurred in 10 patients of which 2 had IRRs, and 8 had SAEs that are largely known comorbidities of Hunter syndrome and are unrelated to the study.
Hunter syndrome, known as mucopolysaccharidosis type II, is a rare genetic disease affecting over 2000 individuals, primarily in men, 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, 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.