The US Food and Drug Administration (FDA) has granted accelerated approval to Avlayah (tividenofusp alfa) for the treatment of neurologic manifestations of Hunter syndrome (MPS II). This is the first FDA-approved transferrin receptor (TfR)-enabled therapeutic specifically designed to cross the blood-brain barrier.
MPS II is an inherited disorder of carbohydrate metabolism that occurs almost exclusively in males. It is characterized by distinctive facial features, a large head, hydrocephalus, hepatosplenomegaly, umbilical or inguinal hernia, and hearing loss. Individuals with the more severe form of the disease also show progressive cognitive decline and behavioral issues. MPS II is caused by genetic changes in the IDS gene.
Tividenofusp alfa is an intravenous enzyme replacement therapy (ERT) composed of duronate 2-sulfatase (IDS) enzyme fused to Denali’s proprietary TransportVehicle (TV) platform. The Fc component binds to the apical domain of the transferrin receptor (TfR) and delivers IDS to peripheral tissues and the central nervous system through receptor-mediated transcytosis across the blood-brain barrier.
The accelerated approval of tividenofusp alfa is based on a Phase 1/2 international, multi-center, open-label trial in 47 ERT-naïve (n=15) and previously treated (n=32) patients with MPS II. The primary objective of the study was to evaluate the safety and tolerability of tividenofusp alfa. Secondary objectives evaluated central nervous system and peripheral effects by measuring the glycosaminoglycan (GAG) heparan sulfate (HS) in cerebrospinal fluid (CSF) and urine, adaptive behavior and liver volume.
Tividenofusp alfa demonstrated a 91% reduction in CSF HS levels from baseline by week 24 of treatment. At week 24, 93% of tividenofusp alfa-treated patients had CSF HS levels within the range of individuals without MPS II. The most common adverse reaction in the study was infusion-related reactions. The study was recently published in the New England Journal of Medicine that additionally showed that reductions in HS were maintained after 153 weeks of therapy and adaptive behavour in these boys either stabilized or improved.
Continued approval for AVLAYAH may be contingent upon verification of clinical benefit in the Phase 2/3 COMPASS confirmatory trial, in which participants are randomized 2:1 to receive either AVLAYAH or idursulfase, respectively. Cohort A of the COMPASS study has completed enrollment, and Cohort B is currently enrolling. More information about the COMPASS study can be found here.
Alognside the approval, the FDA granted Denali Therapeutics a Rare Pediatric Disease Priority Review Voucher (PRV). This voucher may be used to obtain priority review for a future marketing application or transferred to another sponsor. The PRV program is intended to incentivize the development of therapies for serious and life-threatening rare pediatric diseases by providing a mechanism to potentially accelerate regulatory review timelines for subsequent applications.
For more information, visit Denali Therapeutics.
To learn more about MPS II and other rare metabolic disorders, visit https://checkrare.com/diseases/metabolic-disorders/
