- The Food and Drug Administration has removed its hold on testing of an experimental treatment for Angelman syndrome developed by GeneTx Biotherapeutics and California-based Ultragenyx Pharmaceutical, the companies announced Monday.
- The suspension, which the FDA imposed in the fourth quarter last year, came after five patients enrolled in a Phase 1/2 trial experienced lower limb muscle weakness that left two unable to walk. According to an Oct. 26, 2020 statement, the patients' conditions "resolved within a few weeks of the dosing pause and implementation of treatment." The companies lowered the study dosage to secure the FDA's blessing to resume testing.
- Under the amended trial protocol, eight patients between ages 4 and 8 years will receive the drug, known as GTX-102, in 2 milligram doses. The companies previously received clearance to begin the trial in the U.K. and Canada under a separate amendment, in which the starting dose is permitted to be higher.
While the clinical hold lifting is encouraging news for the companies' partnership, questions still loom about safety in the genetic medicine field. Earlier this month, for instance, a committee of experts convened by the FDA examined several side effects associated with a certain type of gene therapy
GTX-102 is what's known as an antisense oligonucleotide, a type of medicine designed to modify gene expression rather than replace whole genes.
Last October, GeneTx and Ultragenyx reported that the patients taking GTX-102 experienced "a serious adverse event of lower extremity weakness believed to be related to local inflammation." The onset of these symptoms began one to four weeks after the last dose, and in two of the patients escalated to "an inability to walk or bear weight."
The drug, which is delivered via an injection through the spine, is meant to treat Angelman's syndrome, a rare genetic disorder typically detected in babies that causes delayed development, problems with speech and balance and oftentimes seizures. There is currently no approved therapy for Angelman's, leading a disease charity to set up GeneTx as a subsidiary.
GTX-102 is designed to reactivate expression in neurons of one form of a gene known as UBE3A that's inherited from fathers. As Angelman's is caused by loss of function in the form of the gene that's passed down from mothers, the companies' hypothesis is that such treatment could improve neurological symptoms for patients.
A GeneTx executive said in a statement that the trials will resume "in all three regions [U.S., UK and Canada] over the next several months."
While antisense oligonucleotides present different safety concerns than those triggered by AAV gene therapy, the FDA appears to be proceeding carefully when it comes to genetic medicine overall.
“Our enthusiasm for this field must be balanced by caution," said Wilson Bryan, director of the FDA's Office of Tissues and Advanced Therapies, during last month's FDA meeting on AAV gene therapy safety. "The greatest risks in drug development fall on the patients who receive an investigational product."