Ultragenyx asks FDA to review gene therapy for Sanfilippo A
If approved, UX111 would become 1st therapy cleared in US for Sanfilippo
Ultragenyx Pharmaceutical has submitted a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval of its gene therapy UX111 for Sanfilippo syndrome type A.
If approved, UX111 would become the first therapy to be cleared in the U.S. for Sanfilippo, a rare childhood form of dementia.
“The path to get a treatment to the point of a BLA filing has been long and perilous for the Sanfilippo community,” Emil D. Kakkis, MD, PhD, CEO and president of Ultragenyx, said in a company press release. “They have had to watch their children, once thriving, lose their ability to speak and walk, and eventually die, while research programs were shelved due to regulatory and funding hurdles.”
Under the accelerated approval pathway, the FDA can allow a treatment to be marketed based on preliminary clinical trial evidence indicating that it is likely to be of clinical benefit. However, that approval is conditional, and the transition to a traditional approval is contingent on further clinical trial data to confirm these benefits.
BLA supported by data from ongoing Phase 1/2/3 Transpher A clinical trial
UX111’s BLA was supported by data from the ongoing Phase 1/2/3 Transpher A clinical trial (NCT02716246) which showed the gene therapy led to reductions in levels of heparan sulfate (HS) in the cerebrospinal fluid (CSF), which is the fluid surrounding the brain and spinal cord, of Sanfilippo type A patients. These reductions in HS levels correlated with stabilizations or improvements in cognitive function.
Heparan sulfate is the sugar molecule that toxically accumulates and causes damage to brain cells in all forms of Sanfilippo caused by genetic mutations that lead to a lack of functional enzymes needed to break it down. In Sanfilippo type A, the faulty gene is SGSH, which leads to a deficiency in an enzyme of the same name.
The FDA had agreed last year that CSF heparan sulfate levels could be used as a reasonable endpoint to support a BLA for accelerated approval of UX111. Ultragenyx believes this could pave the way for the development of treatments for other diseases characterized by the buildup of heparan sulfate and related molecules, collectively called mucopolysaccharidoses (MPS).
“The FDA’s acceptance of CSF HS, which we define as a disease-cause biomarker since it measures the underlying disease, enabled us to file our BLA and may unlock the future accelerated approvals of a host of new therapies for these devastating MPS diseases that affect the brain,” Kakkis noted.
Ultragenyx acquired UX111, formerly known as ABO-102, from Abeona Therapeutics in 2022.
UX111 designed to deliver functional version of SGSH gene to patient’s cells
The gene therapy is designed to deliver a functional version of the SGSH gene to a patient’s cells, thereby enabling production of a healthy SGSH enzyme. It’s packaged into a viral carrier that helps it be taken up by the body’s cells when delivered via a one-time infusion into the bloodstream.
Ultimately, by enabling HS to be properly broken down, the treatment is expected to slow neurodegeneration and ease the symptoms of Sanfilippo type A.
In Transpher A, 28 children with Sanfilippo type A received a single infusion of UX111 at one of three doses and are being followed for up to two years. After completing the study, participants can enter a Phase 3 extension study (NCT04360265), where they’ll be followed for at least five years.
Last year, Ultragenyx presented data from the 17 trial participants in the study’s modified intent-to-treat population, all of whom received UX111 at its highest dose.
These participants were 2 years old or younger, or older than 2 with a cognitive development quotient (DQ) of 60 or above at study enrollment. DQ is an indicator of a child’s developmental status relative to normative values for children their age in the general population, with a score of 100 being about average.
Data showed HS levels rapidly decreased within the first month of treatment for all participants and that these reductions were sustained over a mean follow-up period of nearly 2.5 years.
All but one participant achieved stabilizations or improvements in cognitive function, with most being at an age where cognitive declines would usually be expected in Sanfilippo type A. There was a statistically significant correlation between reductions in HS levels and cognitive scores.
UX111 was generally well tolerated, with the most frequently reported treatment-related side effects being elevations in liver enzymes, most of which were mild or moderate in severity.
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