Ultragenyx Announces New Data Demonstrating that Treatment with UX111 AAV Gene Therapy Significantly Improved Clinical Function Across Multiple Developmental Domains in Children with Sanfilippo Syndrome Type A (MPS IIIA) Correlated with Sustained Reductions in CSF-HS
Ultragenyx Pharmaceutical (NASDAQ: RARE) announced significant clinical improvements in children treated with UX111 AAV gene therapy for Sanfilippo Syndrome Type A. The modified intent-to-treat group showed a +22.7 point treatment effect in Bayley-III cognitive raw scores compared to untreated patients, with a p-value <0.0001.
The treatment demonstrated substantial reductions in heparan sulfate levels in cerebrospinal fluid, with a median reduction of 65% across all patients (N=27) and 66% in the modified intention to treat group (N=17). The mean follow-up duration was 34 months for all patients, with the longest being 77 months.
In older patients with advanced disease, 9 out of 10 children retained abilities in ambulation and self-feeding, while all 10 maintained communication skills. The therapy was generally well-tolerated, with mostly mild to moderate liver enzyme elevations that resolved. A BLA submission was filed with the FDA in December 2024, with a PDUFA decision expected in H2 2025.
Ultragenyx Pharmaceutical (NASDAQ: RARE) ha annunciato significativi miglioramenti clinici nei bambini trattati con la terapia genica UX111 AAV per la Sindrome di Sanfilippo Tipo A. Il gruppo modificato per l'intento di trattamento ha mostrato un effetto del trattamento di +22,7 punti nei punteggi cognitivi grezzi Bayley-III rispetto ai pazienti non trattati, con un p-value <0.0001.
Il trattamento ha dimostrato riduzioni sostanziali nei livelli di eparan solfato nel liquido cerebrospinale, con una riduzione mediana del 65% in tutti i pazienti (N=27) e del 66% nel gruppo modificato per l'intento di trattamento (N=17). La durata media del follow-up è stata di 34 mesi per tutti i pazienti, con la massima durata di 77 mesi.
Nei pazienti più grandi con malattia avanzata, 9 bambini su 10 hanno mantenuto abilità di deambulazione e autosomministrazione, mentre tutti e 10 hanno mantenuto le capacità comunicative. La terapia è stata generalmente ben tollerata, con principalmente lievi a moderati aumenti degli enzimi epatici che si sono risolti. Una domanda di BLA è stata presentata alla FDA nel dicembre 2024, con una decisione PDUFA prevista per il secondo semestre del 2025.
Ultragenyx Pharmaceutical (NASDAQ: RARE) anunció mejoras clínicamente significativas en niños tratados con terapia génica UX111 AAV para el Síndrome de Sanfilippo Tipo A. El grupo modificado por intención de tratar mostró un efecto del tratamiento de +22.7 puntos en las puntuaciones cognitivas brutas de Bayley-III en comparación con pacientes no tratados, con un p-valor <0.0001.
El tratamiento demostró reducciones sustanciales en los niveles de heparán sulfato en el líquido cefalorraquídeo, con una reducción mediana del 65% en todos los pacientes (N=27) y del 66% en el grupo modificado por intención de tratar (N=17). La duración media del seguimiento fue de 34 meses para todos los pacientes, siendo la más larga de 77 meses.
En pacientes mayores con enfermedad avanzada, 9 de 10 niños retuvieron habilidades de deambulación y autoalimentación, mientras que los 10 mantuvieron habilidades de comunicación. La terapia fue generalmente bien tolerada, con principalmente elevaciones leves a moderadas de las enzimas hepáticas que se resolvieron. Se presentó una solicitud de BLA a la FDA en diciembre de 2024, con una decisión de PDUFA esperada en el segundo semestre de 2025.
울트라제닉스 제약 (NASDAQ: RARE)는 AAV 유전자 치료 UX111로 치료 받은 산필리포 증후군 A형 아동에서 상당한 임상 개선을 발표했습니다. 수정된 치료 의도 그룹은 치료받지 않은 환자에 비해 Bayley-III 인지 원점수에서 +22.7점의 치료 효과를 보였으며, p-value는 <0.0001이었습니다.
치료는 모든 환자(N=27)에서 65%, 수정된 치료 의도 그룹(N=17)에서 66%의 중간 감소와 함께 뇌척수액의 헤파란 황산염 수치에서 상당한 감소를 보여주었습니다. 모든 환자의 평균 추적 관찰 기간은 34개월이었으며, 최장 기간은 77개월입니다.
진행된 질병이 있는 고령환자에서 10명 중 9명의 아동이 보행 및 자가 급식 능력을 유지했으며, 10명 모두 의사 소통 능력을 유지했습니다. 이 치료는 일반적으로 잘 견뎌졌으며, 대부분 경미한 알프아마이나 간 효소 상승이 있었습니다. 2024년 12월에 FDA에 BLA가 제출되었으며, 2025년 하반기에 PDUFA 결정이 예상됩니다.
Ultragenyx Pharmaceutical (NASDAQ: RARE) a annoncé des améliorations cliniques significatives chez des enfants traités par thérapie génique UX111 AAV pour le syndrome de Sanfilippo de type A. Le groupe modifié par intention de traiter a montré un effet de traitement de +22,7 points dans les scores cognitifs bruts de Bayley-III par rapport aux patients non traités, avec une valeur p <0,0001.
Le traitement a démontré des réductions substantielles des niveaux de sulfate d'héparane dans le liquide céphalorachidien, avec une réduction médiane de 65% chez tous les patients (N=27) et de 66% dans le groupe modifié par intention de traiter (N=17). La durée moyenne de suivi était de 34 mois pour tous les patients, la plus longue étant de 77 mois.
Chez les patients plus âgés atteints d'une maladie avancée, 9 enfants sur 10 ont conservé leurs capacités de déambulation et d'auto-alimentation, tandis que les 10 ont maintenu des compétences en communication. La thérapie a été généralement bien tolérée, avec principalement des élévations d'enzymes hépatiques légères à modérées qui se sont résolues. Une demande de BLA a été soumise à la FDA en décembre 2024, avec une décision PDUFA prévue pour le second semestre 2025.
Ultragenyx Pharmaceutical (NASDAQ: RARE) gab bedeutende klinische Verbesserungen bei Kindern bekannt, die mit der UX111 AAV-Gen-Therapie für das Sanfilippo-Syndrom Typ A behandelt wurden. Die modifizierte Intention-to-Treat-Gruppe zeigte einen Behandlungseffekt von +22,7 Punkten in den rohen kognitiven Bayley-III-Werten im Vergleich zu unbehandelten Patienten, mit einem p-Wert von <0,0001.
Die Behandlung zeigte erhebliche Reduktionen der Heparansulfatwerte in der cerebrospinalen Flüssigkeit, mit einer medianen Reduktion von 65% bei allen Patienten (N=27) und 66% in der modifizierten Intention-to-Treat-Gruppe (N=17). Die durchschnittliche Nachbeobachtungsdauer betrug 34 Monate für alle Patienten, wobei die längste 77 Monate betrug.
In älteren Patienten mit fortgeschrittener Erkrankung behielten 9 von 10 Kindern die Fähigkeiten zur Fortbewegung und Selbstversorgung, während alle 10 Kommunikationsfähigkeiten beibehielten. Die Therapie wurde im Allgemeinen gut vertragen, mit überwiegend milden bis moderaten Erhöhungen der Leberenzyme, die sich zurückbildeten. Im Dezember 2024 wurde ein BLA-Antrag bei der FDA eingereicht, mit einer PDUFA-Entscheidung, die für das zweite Halbjahr 2025 erwartet wird.
- Significant +22.7 point improvement in cognitive scores vs natural history (p<0.0001)
- 65% median reduction in CSF-HS levels across all patients (p<0.0001)
- Strong retention of key functions in 90% of advanced-disease patients
- BLA submission completed with FDA decision expected H2 2025
- Gross motor scores only showed numerical improvements, requiring longer follow-up
- Some patients experienced liver enzyme elevations as adverse events
Insights
The latest UX111 clinical data represents a significant breakthrough in treating Sanfilippo Syndrome Type A, with compelling evidence of both biological and functional improvements. The 65% median reduction in CSF-HS levels demonstrates robust target engagement, while the +22.7 point treatment effect in cognitive function provides clear evidence of clinical benefit.
Several aspects make these results particularly noteworthy:
- The sustained response duration (median follow-up of 34-36 months) suggests durable therapeutic effects, critical for gene therapy commercialization
- The positive outcomes in older patients with advanced disease indicate a broader potential market than initially anticipated
- The correlation between CSF-HS reduction and clinical improvements validates the mechanism of action and strengthens the regulatory case
With a BLA submission completed and PDUFA expected in H2 2025, UX111 could become Ultragenyx's first commercial gene therapy. The retention of key functions in older patients (communication, ambulation, self-feeding) addresses an urgent unmet need and could support premium pricing. The favorable safety profile, with primarily mild and manageable liver enzyme elevations, should facilitate regulatory approval.
The multi-domain efficacy and strong safety profile position UX111 as a potential first-line therapy for MPS IIIA, representing a significant market opportunity. While the addressable patient population is due to the rare disease status, the potential for premium pricing and long-duration benefit could make this a meaningful revenue driver for Ultragenyx.
Modified intent-to-treat group demonstrated +22.7 point (p<0.0001) treatment effect in the mean Bayley-III cognitive raw score compared to natural history data (ages 24-60 months)
Older children with more advanced disease demonstrated retention of clinically meaningful functional abilities, including communication, ambulation and self-feeding
The latest data from the pivotal Transpher A and long-term follow-up studies will be presented at WORLDSymposium™ 2025
NOVATO, Calif., Feb. 05, 2025 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced new data demonstrating treatment with UX111 (ABO-102) AAV gene therapy led to a statistically significant improvement in the Bayley-IIIi raw scores for the subdomains of cognition, receptive communication and expressive communication in patients with Sanfilippo syndrome type A (MPS IIIA) compared to natural history data from untreated patients. These clinical endpoints were correlated with substantial and sustained reduction in levels of heparan sulfate (HS) in cerebrospinal fluid (CSF). These data will be presented at the WORLDSymposium™ 2025 21st Annual Research Meeting, taking place February 3-7 in San Diego.
“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. 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,” said Kevin Flanigan, M.D., director of the Jerry R. Mendell, M.D. Center for Gene Therapy at Nationwide Children’s.
Following treatment with UX111 (3x1013 vg/kg), levels of CSF-HS decreased within the first month post-treatment in all patients (N=27) irrespective of age or stage of disease progression at the time of treatment. As of the August 2024 cutoff date, the median reduction in CSF-HS exposure was
Function improved in mITT group compared to natural history
Cognitive function, expressive and receptive communication and fine and gross motor skills were measured using Bayley-III and compared to natural history data from untreated patients with reported rapid progressor phenotypes.ii Mean observed raw scores on the Bayley-III domains improved compared to natural history. The model-based mean Bayley-III cognitive raw score from ages 24 to 60 months in the mITT group improved by +16 points compared to natural history patients who declined by -6.8 points, demonstrating a +22.7 point (p<0.0001) treatment effect.
The raw scores were also significantly improved for model-based mean receptive and expressive communication (p<0.05) and fine motor function (p=0.05), while gross motor scores achieved numerical improvements. Gross motor function is generally lost later in the disease progression, and longer-term follow-up is needed to establish significant separation from the natural history data in untreated patients.
Furthermore, there was a statistically significant correlation between CSF-HS exposure and estimated yearly rate of change (EYC) for all five Bayley-III subdomains.
“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,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “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.”
Children who are older or with more advanced disease at the time of treatment retained functional abilities
In a pre-specified analysis, all 10 patients that were outside of the mITT group due to older age or having more advanced disease at the time of treatment showed retention of meaningful functional abilities at the time of last assessment. All 10 children, who were between the ages of 5.6 and 14.8 years old at the time of last assessment, retained communication skills (3 verbal and 7 non-verbal), 9 retained ambulation (8 independent and 1 supported) and 9 retained the ability to eat and/or self-feed. These findings are clinically significant as these functions significantly worsen and are eventually lost in late childhood and early adolescence.iii
Safety profile remains favorable
UX111 was generally well tolerated across all doses (N=33), including the highest dose of 3x1013 vg/kg. The most frequently reported treatment-emergent adverse events (TEAEs) to date were elevations in liver enzymes and the majority of these events were mild (Grade 1) or moderate (Grade 2) in severity and all resolved.
These data were included in the Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for UX111 that was filed by the company in December 2024. A Prescription Drug User Fee Act (PDUFA) decision on the application and potential U.S. launch are expected in the second half of 2025.
About the UX111 Clinical Program
The Transpher A study (NCT02716246) has enrolled and treated 28 patients across 3 dose Cohorts at 5 sites in 3 countries. The high dose Cohort 3 (3x1013 vg/kg) consists of 22 patients, and 17 are in the mITT group. The mITT group is defined as patients who were either up to age 2 years old, or patients older than 2 years with a cognitive developmental quotient of 60 or above at time of enrollment. These patients received the highest dose of UX111.
A separate study (NCT04088734) enrolled five patients. All participants received the highest dose of 3x1013 vg/kg.
Subjects who participated in either clinical study were invited to enroll into a long-term follow-up study (NCT04360265). The Transpher A and long-term follow-up studies are ongoing, and patients will continue to be followed for a minimum of 5 years following treatment with UX111.
About UX111
UX111 is a novel in vivo gene therapy in Phase 1/2/3 development for Sanfilippo syndrome type A (MPS IIIA), a rare fatal lysosomal storage disease with no approved treatment that primarily affects the brain. UX111 is designed to be dosed in a one-time intravenous infusion using a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to cells. The therapy is designed to address the underlying SGSH enzyme deficiency responsible for abnormal accumulation of heparan sulfate, a glycosaminoglycan, in the brain that results in progressive cell damage and neurodegeneration. The UX111 program has received Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug designations in the U.S., and PRIME and Orphan medicinal product designations in the EU.
About Sanfilippo Syndrome Type A (MPS IIIA)
Sanfilippo syndrome type A (MPS IIIA) is a rare, fatal lysosomal storage disease with no approved treatment that primarily affects the brain and is characterized by rapid neurodegeneration, with onset in early childhood. Children with MPS IIIA present with global developmental delay which eventually leads to progressive cognitive, language and motor decline, behavioral abnormalities and early death. MPS IIIA is estimated to affect approximately 3,000 to 5,000 patients in commercially accessible geographies with a median life expectancy of 15 years. MPS IIIA is caused by biallelic pathogenic variants in the SGSH gene that lead to a deficiency in the sulfamidase (SGSH) enzyme responsible for breaking down heparan sulfate, a glycosaminoglycans, which accumulate in cells throughout the body resulting in the observed rapid neurodegeneration that is associated with the disorder.
About Ultragenyx
Ultragenyx is a biopharmaceutical company committed to bringing novel therapies to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved medicines and treatment candidates aimed at addressing diseases with high unmet medical need and clear biology, for which there are typically no approved therapies treating the underlying disease.
The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.
For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com.
Forward-Looking Statements and Use of Digital Media
Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, business plans and objectives for UX111, expectations regarding the tolerability and safety of UX111, and future clinical and regulatory developments for UX111 are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, the ability of the company to successfully develop UX111, the company’s ability to achieve its projected development goals in its expected timeframes, risks related to adverse side effects, risks related to reliance on third party partners to conduct certain activities on the company’s behalf, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements.
For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 6, 2024, and its subsequent periodic reports filed with the SEC.
In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/mycompany/).
Contacts
Ultragenyx Pharmaceutical Inc.
Investors
Joshua Higa
+1-415-475-6370
ir@ultragenyx.com
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Carolyn Wang
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media@ultragenyx.com
i Bayley-III is the Bayley Scales of Infant and Toddler Development 3rd edition (BSITD III)
ii Shapiro et al., 2016; Wijburg et al., 2022
iii Delgaldillo et al., 2013
FAQ
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