The intrathecal injection requirement for GTX-102 should ensure...

The intrathecal injection requirement for GTX-102 should ensure that 2591 will be the preferred drug;

Angelman syndrome gene therapy aiming to reactivate paternal UBE3A gene

Ultragenyx, which is developing GTX-102 after acquiring GeneTx, plans to share data covering at least six months of treatment in 20 or more expansion phase patients early next year. Findings are expected to provide a “meaningful comparison” between children treated with GTX-102 and progression in untreated patients (the disease’s natural history).

Angelman syndrome is caused by a mutation in the UBE3A gene. UBE3A provides instructions to make UBE3A, an enzyme that sends unwanted or faulty proteins off for recycling within cells to keep them healthy.

Each person receives one copy of UBE3A from each biological parent, but only the mother’s copy is active in certain brain cells. Because the father’s copy is silent, a mutation in the mother’s copy means no UBE3A is made, resulting in disease symptoms.

An antisense oligonucleotide, GTX-102 is designed to reactivate the father’s UBE3Agene copy. An antisense oligonucleotide is a short snippet of genetic material that can control how much of a protein is made by cells.

GTX-102 pairs with another antisense oligonucleotide occurring naturally within brain cells, called UBE3A-AS, that normally silences the father’s copy of UBE3A. This is expected to restore UBE3A levels, easing symptoms.

Early evidence supports therapy’s potential to ease Angelman symptoms

Interim data from 11 patients followed for six months, announced last year, showed early evidence of improvement with GTX-102 in areas that include communication, behavior, sleep, and gross and fine motor skills.

The study was paused in late 2020 after five patients, given high doses of GTX-102, experienced serious yet reversible leg weakness. It was cleared to resume about one year later after changes to the study’s protocol that narrowed the dose range and altered the mode of administration (intrathecal, or into the spinal canal, injection).

The U.S. Food and Drug Administration agreed to allow higher trial dosing in May, following similar decisions in the U.K., Canada, and Australia. The decision means trial sites will be testing a similar dose range.

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