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After switching from idursulfase to Denali’s DNL310, patients demonstrated mean declines of more than 80% for both heparan sulfate and dermatan sulfate biomarkers at week 49 of treatment.
Joseph Muenzer, MD, PhD
Newly announced interim data from a phase 1/2 trial evaluating DNL310 (Denali Therapeutics), an agent in development for Hunter syndrome, showed a rapid and sustained reduction of relevant central nervous system (CNS) and peripheral biomarkers to normal levels, along with a safe profile that was observed for up to 85 weeks of dosing.1
The agent will continue to be evaluated in a phase 2/3 study, called COMPASS (NCT05371613), that includes a larger population of participants with Hunter syndrome with and without neuronopathic disease. These findings, which included available data until cut-off of March 22, 2022, were presented at the 2022 Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium.
Patients treated with weekly intravenous doses of DNL310 showed rapid normalization of cerebrospinal fluid (CSF) heparan sulfate levels after 4 to 6 weeks, which continued to approach normal levels by week 24. By week 49, patients demonstrated an 89% reduction from baseline in these levels, including in 2 children with preexisting high levels of anti-iduronate-2-sulfatase (IDS) antibodies.
Presenting author Joseph Muenzer, MD, PhD, Bryson Distinguished Professor in Pediatric Genetics, University of North Carolina, said in a statement, "We have not previously seen reductions in CSF heparan sulfate to normal levels with any therapy, suggesting that we may see long-term cognitive stabilization with DNL310 in a population destined to have CNS decline. Furthermore, normal levels of CSF heparan sulfate were observed even in participants who entered the study with high levels of anti-drug antibodies against idursulfase. I am excited for the phase 2/3 COMPASS study to continue to explore the potential of DNL310 as a treatment for the entire MPS II patient population."1
Following positive phase 3 findings, a second study featuring more than 300 patients will aim to confirm PXT3003’s effect in patients with Charcot-Marie-Tooth disease type 1a.
DNL310, a brain-penetrant enzyme replacement therapy, is composed of 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.
All but 1 of the 27 included participants had neuronopathic Hunter syndrome. Following treatment, investigators observed normalization of lysosomal lipid biomarkers in CSF, which was consistent with improved lysosomal function. At week 24, the mean decline in levels of gangliosides GM2 and GM3 were 63% and 52%, respectively, which was sustained at week 49. Additionally, patients who switched from idursulfase to DNL310 demonstrated a mean decline of 84% and 88% for heparan sulfate and dermatan sulfate biomarkers in the urine, respectively, at week 49.
"The achievement of healthy normal levels of heparan sulfate in all participants in the phase 1/2 study, including those with high preexisting anti-iduronate-2 sulfatase antibodies, was also accompanied in most participants by improvement or stabilization in clinical symptoms and function as reported by both clinicians and caregivers," Carole Ho, MD, chief medical officer, Denali Therapeutics, said in a statement.1 "These latest interim data continue to differentiate DNL310 and demonstrate sustained effects on key MPS II disease biomarkers as well as a safety profile similar to standard of care. We are actively engaged in enrolling our phase 2/3 COMPASS study in which we aim to demonstrate a meaningful impact for children with Hunter syndrome and their families."
Similar to previously reported findings from the study, DNL310 continued to show a safe profile that was equivalent to standard of care. After 85 weeks of treatment, the most frequent treatment-emergent adverse events (TEAE) were infusion related reactions (IRR), with no treatment withdrawals or study discontinuations from TEAEs. Notably, IRR frequency and severity decreased with continued dosing, demonstrating tolerance to dosing with DNL310. For the first time, 1-year exploratory data of the study was presented. At week 49, most participants that had available data on Clinician Global Impression Scales of Change and Caregiver Global Impression Scales of Change demonstrated improvement or stabilization across all domains since entering the study.
The phase 2/3 COMPASS study, which is still in recruitment, will randomly assign patients 2:1 to either DNL310 or idursulfase, and 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.
