Ultragenyx’s Gene Therapy UX111 Improves Clinical Function in MPSIII
With regard to safety, Ultragenyx characterized the gene therapy as “generally well-tolerated."
Eric Crombez, MD
Ultragenyx’s UX111 (ABO-102), an adeno-associated virus (AAV) vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome),has improved clinical function in patients treated in the phase 1/2/3 Transpher A clinical trial (NCT02716246).1 Updated data from the study are being presented at the 21st Annual WORLDSymposium, held February 3 to 7, 2025, in San Diego, California.
Transpher A treated 28 patients with UX111 in total across 3 different dose levels, with 22 patients having received the highest dose of UX111 (3x1013 vg/kg). Among the 17 patients in Transpher A’s modified intention to treat (mITT) group, which includes patients who received the high dose and at the time of enrollment were either no more than 2 years of age or older than 2 years with a cognitive developmental quotient of 60 or above, an improvement of +16 points was recorded for the model-based mean Bayley-III cognitive raw score from 24 to 60 months of age. By contrast, a natural history group used for comparison showed a decline of –6.8 points for the model-based mean Bayley-III cognitive raw score from 24 to 60 months of age, thus resulting in a +22.7 point treatment effect (P < .0001). Furthermore, raw scores for model-based mean receptive and expressive communication (P < .05) and fine motor function (P = .05) also showed significant improvement for the mITT group in comparison to the natural history group. Numerical improvements for the mITT group were also seen in gross motor scores, but these were not statistically significant. Ultragenyx stated that gross motor function losses are generally seen later in disease progression and thus longer-term follow-up may be necessary to establish statistical significance in this area. The company also pointed out that for all 5 subdomains of Bayley-III, a statistically significant correlation was observed between levels of heparan sulfate in cerebrospinal fluid (CSF-HS) exposure and estimated yearly rate of change.
“When we compare the impact of UX111 to natural history in children 2 to 5 years of age, we see that as you correct the underlying enzymatic deficiency at a molecular level, you provide the ability to preserve neurons and for these children to gain new developmental skills,” Eric Crombez, MD, the chief medical officer at Ultragenyx, said in a statement.1 “For older patients with severe disease, we know from caregivers and clinicians that stabilizing the disease, so that a child can retain or even slow down the loss of key skills like walking independently, communicating and self-feeding, would have a profound impact on their quality of life.”
Ultragenyx also reported that as of the August 2024 data cut-off date, a 65% median decrease in CSF-HS exposure (P < .0001) was seen in the group of all patients who were treated at the study’s high dose, who had a mean posttreatment follow-up time of 34 months. For the mITT group, who had a mean posttreatment follow-up time of 36 months, a 66% median decrease in CSF-HS exposure(P < .0001) was recorded.
“These very promising results are particularly gratifying to me as an investigator because this program began at Nationwide Children’s Hospital in the lab of our former center faculty members, Doug McCarty and Haiyan Fu, more than a decade ago,” Kevin Flanigan, MD, the director of the Jerry R. Mendell, MD, Center for Gene Therapy at Nationwide Children’s, added to the statement.1 “This is a devastating disorder, and it is quite meaningful to see not only this vector’s impact on biologic markers of the disease but also to see its clinical impact on both younger and older treated patients."
For the 10 patients not included in the mITT group, whose ages ranged from 5.6 to 14.8 years at their most recent assessment, Ultragenyx stated that communication skills were retained in all patients, 3 of whom are verbal and 7 of whom are nonverbal. In 9 patients, ambulation was retained, with 8 patients having independent ambulation and 1 patient have supported ambulation. Nine patients retained the ability to eat and/or self-feed.
With regard to safety, Ultragenyx characterized the gene therapy as “generally well-tolerated" across 33 patients treated across all dose levels in Transpher A and a separate phase 1/2 clinical trial (NCT04088734). Elevations in liver enzymes, the majority of which grade 1 or grade 2 in severity and all of which resolved, constitute the most frequent treatment-emergent adverse events reported.
In December 2024, Ultragenyx submitted a biologics license application (BLA) to the FDA for UX111.2 Notably, Ultragenyx is seeking accelerated approval for the BLA based on the use of CSF-HS data from Transpher A, which will be used as a surrogate end point. In June 2024, Ultragenyx announced that it had participated in a meeting with the FDA in which the company and the agency came to an agreement that CSF-HS may be used as a surrogate end point for the accelerated approval.3 Although, at the time Ultragenyx stated that an additional meeting would be necessary to clarify further details with regard to BLA submission.
“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, chief executive officer and president of Ultragenyx, said in the press release announcing the BLA submission.2 “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. We commend the FDA’s detailed evaluation and acceptance of CSF-HS as a well-characterized biomarker to support an accelerated approval pathway for MPS disorders, including Sanfilippo syndrome. 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.”
