Denali's TV platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration.
Hunter syndrome is a rare neurodegenerative lysosomal storage disorder caused by a mutation in the gene that encodes for the enzyme iduronate 2-sulfatase (IDS). The resultant reduction or loss of IDS enzyme activity leads to accumulation of glycosaminoglycans (GAGs), which causes lysosomal dysfunction and neurodegeneration as well as progressive damage to multiple organs including bone, cartilage, heart and lung. Current standard of care enzyme replacement treatment (ERT) does not address neuronopathic manifestations of the disease as it does not sufficiently cross the BBB.
'The robust reduction in cerebrospinal fluid (CSF) GAG levels observed after only four weeks of treatment with DNL310 in the Phase 1/2 study exceeded our initial goal in both magnitude and timing of heparan sulfate reduction after treatment,' said
'A long-standing challenge in developing biotherapeutics to treat neurodegenerative diseases is the ability to transport large molecules across the blood-brain barrier safely and at therapeutic levels,' said
The Phase 1/2 Study 4-Week Safety and Biomarker Results
The Phase 1/2 study of DNL310 is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics, and pharmacodynamics of increasing dose levels of DNL310 administered once weekly by intravenous infusion. The study has two staggered cohorts: the first (Cohort A) enrolled a total of five patients with neuronopathic MPS II aged five to ten years; the second (Cohort B) will enroll either neuronopathic or non-neuronopathic MPS II patients aged two to 18 years.
All five patients were previously on idursulfase ERT and were switched to DNL310 on Day 1 of the study. DNL310 is administered once weekly by intravenous infusion starting with a dose level of 3 mg/kg. In Cohort A, after two doses at 3 mg/kg, based on safety and tolerability, intrapatient dose escalation proceeded per the study protocol.
Key findings in five patients enrolled in Cohort A who received four weekly intravenous doses of DNL310 are summarized below
An independent data monitoring committee (DMC) reviewed the safety data from Cohort A and made a recommendation to continue the study and open Cohort B without protocol modifications, enabling progression to Cohort B, including enrollment of younger patients, and continuation of dose escalation in Cohort A.
Total urine GAG levels were maintained within the same range observed in patients prior to switching from idursulfase ERT to DNL310.
A mean reduction from baseline of 76% (p-value
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