This week at the 14th
Annual WORLDSymposium in San Diego, ArmaGen reported full 52-week results from a Phase 2 proof-of-concept study with AGT-181 in mucopolysaccharidosis type I (MPS I; Hurler Syndrome).
Initial results from the ongoing Phase 2 were presented at last year’s WORLDSymposium, and led to the U.S. Food and Drug Administration (FDA) granting Fast Track designation to the investigational enzyme replacement therapy in November, allowing for expedited review of the potential treatment option.
Hurler syndrome is primarily caused by a mutation in the iduronidase (IDUA) enzyme, which is vital to the breaking down of complex sugars. Without a properly functioning IDUA enzyme, large sugar molecules called glycosaminoglycans (GAGs) build up within the lysosomes, leading to the enlargement of different organs and tissues within the body.
AGT-181 targets the insulin receptor and benefits from the body’s natural ability to transport proteins and other large molecules non-invasively across the blood-brain barrier (BBB), in this case, by binding the same receptor that transports insulin across the BBB into the brain. This process is intended to alleviate the neurological complications associated with Hurler syndrome.
The data were presented by Dr Roberto Giugliani, M.D., Ph.D., of Hospital de Clinicas in Porto Alegre, Brazil, in an oral presentation entitled “Safety and clinical efficacy of AGT-181, a brain penetrating human insulin receptor antibody-iduronidase fusion protein, in a 52-week study with pediatric patients with mucopolysaccharidosis type I” and validate previous findings that demonstrated the ability of the company’s proprietary drug technology (“Trojan Horse”) to transport biopharmaceuticals across the BBB. The results that the drug can prove provide therapeutic benefit to patients and suggest that AGT-181 stabilized the neurocognitive development quotient (DQ) in patients with severe cases of the lysosomal storage disorder.
“The full results from this Phase 2 study validate our preliminary findings that AGT-181 crosses the blood-brain barrier and benefits neurocognitive function in children with severe MPS I,” said Dr. Giugliani. “Whereas the existing enzyme replacement therapy improves many of the somatic manifestations of MPS I, its inability to cross the blood-brain barrier prevents it from addressing the severe and progressive neurological symptoms of the most severe form of the disorder. Now that we have demonstrated proof of concept, a controlled phase 3 clinical trial is warranted to examine long term impact in cognition in MPS I patients with CNS involvement.”
None of the patients enrolled in the study had undergone successful hematopoietic stem cell transplantation, and out of more than 570 infusions, there were only 10 infusion-related reactions (IRRs) (1.7%). Overall, AGT-181 was well-tolerated, and 60% of IRRs were observed in a single patient not previously on enzyme replacement therapy (ERT). The most common adverse event (AE) reported was transient hypoglycemia (resolved within 15 minutes of taking high-dose (6 mg/kg) AGT-181 therapy). The incidence of hyperglycemic events in patients being administered an infusion dose of 1-3 mg/kg was only 2.8%.
“By confirming our initial findings of neurocognitive stabilization/improvement in children with MPS I, the full results from the Phase 2 proof-of-concept trial – coupled with our recent receipt of a Fast Track designation from the FDA – sustain the momentum of finding a new treatment option for patients with MPS I,” said Mathias Schmidt, Ph.D., Chief Executive Officer of ArmaGen. “The latest results add to the growing body of evidence that our proprietary ‘Trojan Horse’ technology can deliver the missing enzyme into the CNS of patients and benefit neurocognitive function.”
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