Results and safety data from the phase 1/2 study of the therapy for Hunter syndrome/MPS II were presented at MPS 2021, the 18th International Symposium on MPS and Released Diseases, on July 25.
Denali Therapeutics announced positive interim data from the study of a brain-penetrant enzyme composed of enzyme iduronate-2-sulfatase (IDS) and Denali’s proprietary enzyme transport vehicle (ETV) at MPS 2021 on July 25. The ETV:IDS therapy, known as DNL310, will potentially be used to treat both central nervous system (CNS) and peripheral manifestations of Hunter syndrome (also known as mucopolysaccharidosis II [MPS II]).
As a result of the safety data and clinical improvement in symptoms, efforts to initiative a phase 2/3 study in 2022 have been accelerated. Results showed that heparan sulfate in cerebrospinal fluid (CSF) was normalized in all patients (n = 15) in both study cohorts (A and B), and rapid reduction was seen in most patients (n = 12) by week 7, following the switch from standard of care (SOC) idursulfase enzyme replacement therapy to DNL310. This was consistent with DNL310’s crossing of the blood-brain barrier (BBB), with rapid normalization of herapan sulfate further indicating the ETV’s efficiency. In addition to normalization, participants also experienced a reduction in urine and herapan sulfate and associated enhanced peripheral activity.
Safety data were presented from both cohorts at weeks 25 and 43, as well as 6-month biomarker data from Cohort A and 3-month biomarker data from Cohort B. Interim analyses included data on 5 patients from Cohort A and 12 patients from Cohort B, with a median participant age of 6 years. All participants had neuronopathic MPS II disease, except for 1 participant in Cohort B, who had non-neuronopathic MPS II; all received intravenous doses of DNL310 on the first day of the trial.
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“The longer-term safety data and 6-month biomarker data on DNL310 from Cohort A continue to demonstrate durability of effect with CNS impact, improved peripheral activity after switching from SOC, and a safety profile consistent with standard of care enzyme replacement therapy,” Carole Ho, MD, chief medical officer, Denali, said in a statement. “We are also encouraged by initial indications of improved clinical symptoms and function reported by investigators and parents in all 5 patients enrolled in Cohort A. In addition, this is the first time we are sharing data from Cohort B, which is designed to inform dose selection, and exploratory biomarker data demonstrate activity of DNL310 across all dose regimens. Based on these data, we are accelerating our efforts…to begin enrolling Cohort C in the phase 1/2 study to further investigate clinical end points.”
According to investigators, biomarker data found that 5 patients in Cohort A experienced an improvement in symptoms, as well as behavior and cognitive and physical abilities. Data was analyzed via the Global Impression of Change Scales (Clinician Global Impression of Change and Parent Global Impression of Change).
The exploratory biomarker data showed high variability in neurofilament levels (NfL) both before and after treatment, necessitating further research into Nf-L as a treatment response biomarker in MPS II. Additionally, patients in both cohorts saw reductions in CSF lysosomal lipid biomarkers, indicating improved lysosomal function.
The most frequently observed adverse events (AEs) were infusion-related reactions (IRRs), occurring in 12 out of 17 patients (71%), but DNL310 was generally well tolerated, and the safety profile was similar to SOC enzyme replacement therapy. A total of 3 serious adverse events (SAEs) were reported, 1 patient with a mild IRR and another patient with 2 severe IRRs; both patients continued in the study following resolution of SAEs.
“DNL310 is our lead program enabled by our blood-brain barrier Transport Vehicle platform, and these data continue to validate the platform’s potential as we advance additional TV-enabled programs toward the clinic,” Ryan Watts, PhD, chief executive officer, Denali, said in a statement. “Our DNL310 program exemplifies application of Denali’s core scientific principles to increase likelihood of success by targeting degenogenes, engineering therapeutics to cross the BBB, and using biomarkers to inform development. We are encouraged by these interim data and we look forward to continued collaboration with the community to advance MPS II research and DNL310 as a potential treatment for affected individuals and their families.”