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High-Cost Therapy Profile: July 2025

Rebisufligene etisparvovec Intravenous (IV)

Metabolic gene therapy 
July 3, 2025

Proposed indications 

Sanfilippo A syndrome (Mucopolysaccharidosis III type A [MPS-IIIA]) 

FDA approval timeline

Aug. 18, 2025

  • Fast Track
  • Orphan Drug
  • Priority Review
  • Rare Pediatric Disease (RPD)
  • Regenerative Medicine Advanced Therapy (RMAT)
  • Seeking Accelerated Approval 

Place in therapy 

Rebisufligene etisparvovec (UX111) is an in vivo gene therapy using a self-complementary adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the N-sulfoglucosamine sulfohydrolase (SGSH) gene to cells.  

  • If approved, UX111 will be the first pharmacological treatment for patients with Sanfilippo A syndrome. 
  • UX111 is a one-time gene therapy designed to correct the sulfamidase enzyme deficiency by delivering a working copy of the defective SGSH gene to the cells of the central nervous system (CNS) and peripheral organs, thus decreasing heparan sulfate levels. 
  • Cerebral spinal fluid (CSF) heparan sulfate data is being used as a surrogate endpoint to obtain accelerated approval. Patients with reduced levels of heparan sulfate in the CSF showed improvement in cognitive function after treatment with UX111. 
  • UX111 is being evaluated in younger patients who are higher-functioning and most likely to benefit from treatment. 
  • Study data also suggested that UX111 may improve communication and fine and gross motor skills compared to the non-treated historical control group. 
  • Patients are being evaluated in a long-term Phase 3 extension study for a minimum follow-up of 5 years after treatment. 
  • Other agents in the pipeline under evaluation for Sanfilippo A syndrome include OTL-201, a lentiviral-based stem cell gene therapy which uses a patient’s own genetically modified stem cells to insert a functional copy of the SGSH gene into the patient’s cells and DNL126, an SGSH replacement therapy that crosses the blood brain barrier. 

Understanding your data

UX111 is a one-time gene therapy that uses a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to the cells. The SGSH gene provides instructions for making the enzyme responsible for breaking down heparan sulfate. Mutations in the gene causes enzyme deficiency that results in accumulation of heparan sulfate. Studies evaluating UX111 are limited and include the following: 

  • NCT02716246: Phase 1/2/3 gene transfer clinical trial of UX111 for Sanfilippo A syndrome. 
  • NCT04360265: A long-term follow-up study of patients with Sanfilippo A syndrome from gene therapy clinical trials involving the administration of UX111.  
  • NCT04088734: A Phase 1/2 open label, single-dose, gene transfer study of UX111 in patients with middle and advanced phases of Sanfilippo A syndrome. 

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others: 

Common measurable inclusion criteria: 

  • Diagnosis of Sanfilippo A Syndrome 

Common measurable exclusion criteria: 

  • History of hepatitis B or C, human immunodeficiency virus (HIV), or human T-lymphotropic virus 1 (HTLV-1)
  • History of uncontrolled seizure disorder
  • History of cardiomyopathy or significant congenital heart abnormalities
  • Previous treatment by HSCT
  • Pregnant or breastfeeding 

Appendix

Category Procedure codes
Sanfilippo A Syndrome International Classification of Diseases, Tenth Revision (ICD-10): E76.3, E76.22
Hepatitis B ICD-10: B16.0, B16.1, B16.9, B16.2, B17.0, B18.0, B18.1, B19.10, B19.11
Hepatitis C ICD-10: B18.2, B19.20, B19.21
HIV ICD-10: B20, B97.35, Z21
HTLV-1 ICD-10: B97.33
Uncontrolled seizure disorder ICD-10: G40.111, G40.319, G40.813, G40.911, G40.211, G40.119, G40.311, G40.419, G40.814, G40.823, G40.824, G40.411, G40.804, G40.919, G40.833, G40.A11, G40.219, G40.A19, G40.803, G40.011, G40.834, G40.B11, G40.B19
Cardiomyopathy ICD-10: I42.0, I42.5, I25.5, O90.3, B33.24, I42.2, I43, I42.9, I42.1, A36.81, I42.6
Congenital heart abnormalities ICD-10: Q24.4, Q24.9, Q25.0, Q25.46, Q25.5, Q25.72, Q25.9, Q26.8, Q27.1, Q24.6, Q25.3, Q22.8, Q25.21, Q28.3, Q20.1, Q21.2, Q23.2, Q23.4, Q25.40, Q26.4, Q27.9, Q24.1, Q22.1, Q25.79, Q21.8, Q22.5, Q25.48, Q25.8, Q26.9, Q27.8, Q28.8, Q25.47, Q26.0, Q23.3, Q24.3, Q26.3, Q28.0, Q24.8, Q25.29, Q25.44, Q27.39, Q28.2, Q28.9, Q21.1, Q20.5, Q20.8, Q22.9, Q23.1, Q23.9, Q25.1, Q21.4, Q23.0, Q20.4, Q21.3, Q24.0, Q25.41, Q26.6, Q27.0, Q25.43, Q20.9, Q23.8, Q26.1, Q20.0, Q20.2, Q20.3, Q20.6, Q21.0, Q26.2, Q26.5, Q27.2, Q27.30, Q27.32, Q27.34, Q27.4, Q28.1, Q22.4, Q24.5, Q25.49, Q25.71, Q22.0, Q22.2, Q22.3, Q22.6, Q27.31, Q27.33, Q24.2, Q25.6, Q21.9, Q25.42, Q25.45
HSCT ICD-10: Z94.84, T86.5, M31.11
Current Procedural Terminology (CPT): Z94.84, T86.5, M31.11
ICD-10- Procedure Coding System (PCS): 30230G2,30230G3, 30230Y2, 30230Y3, 30233G2, 30233G3, 30233Y2, 30233Y3, 30240G2, 30240G3, 30240Y2, 30240Y3, 30243G2, 30243G3, 30243Y2, 30243Y3, 30230C0, 30230G0, 30230Y0, 30233G0, 30233C0, 30233Y0, 30240C0, 30240G0, 30240Y0, 30243C0, 30243G0, 30243Y0, 30233Y1, 30243Y1, 30233Y1, 30263Y0, 30263Y1
Pregnant or breastfeeding ICD-10: Z34.00, Z34.8, Z34.90, Z33.1, O09.00, O09.10, O09.291, O09.40, O09.211, O09.30, O09.511, O09.521, O09.611, O09.621, O09.819, O09.821, O09.822, O09.823, O09.829, O36.80x0, O09.891, O09.892, O09.893, O09.899, Z39.0, Z39.1, Z39.2, Z36, Z37, Z37.1, Z37.2, Z37.3, Z37.4, Z37.59, Z37.69, Z37.7, Z37.9, Z64.0, Z32.01, O30.009, O30.019, O30.039, O30.049, O30.099, O30.109, O30.119, O30.129, O30.199, O30.209, O30.219, O30.229, O30.299, O30.809, O30.819, O30.829, O30.899, O20.0, O44.01, O44.02, O44.03, O10.011, O10.012, O10.013, O10.02, O10.911, O10.912, O10.913, O10.92, O10.03, O21.0, O60.12X0, O60.13X0, O60.14X0, O48.0, O31.01X0, O31.02X0, O31.03X0, O98.111, O98.112, O98.113, O98.12, O98.13, O24.32, O24.911, O24.912, O24.913, O24.92, O24.93, O99.331, O99.332, O99.333, O99.334, O99.335, O80, O30.001, O30.002, O30.003, O32.0XX0, O33.0, O34.01, O34.02, O34.03, O34.01, O34.02, O34.03, O35.0XX0, O43.011, O36.0110, O36.0120, O36.0130, O36.0910, O36.0920, O36.0930, O36.1110, O36.1120, O36.1130, O36.1910, O36.1920, O36.1930, O68, O36.5110, O36.5120, O36.5130, O36.5910, O36.5920, O36.5930, O36.61X0, O36.62X0, O36.63X0, O43.101, O43.102, O43.103, O43.811, O43.812, O43.813, O43.91, O43.92, O43.93, O36.8910, O36.8920, O36.8930, O68, O77.0, O36.91X0, O36.92X0, O36.93X0, O40.1XX0, O40.2XX0, O40.3XX0, O41.01X0, O41.02X0, O41.03X0, O61.1, O64.9XX0, O62.0, O63.0, O70.0, O71.02, O71.03, O72.0, O43.211, O43.212, O43.213, O43.221, O43.222, O43.231, O43.232, O43.233, O73, O74.1, O89.09, O75.0, O86.89, O22.01, O22.02, O22.03, O87.4, O86.4, O88.011, O88.012, O88.013, O88.02, O88.03, O99.411, O99.412, O99.413, O99.42, O99.43, O91.011, O91.012, O91.013, O91.02, O92.011, O92.012, O92.013,O92.03, O35.8XX0, O36.8210, O36.8220, O36.8230, O75.89, Z37.0, Z37.2, Z37.3, Z37.59, Z37.69, O86.12, O85, O86.81, O86.89

Clinical deep dive 

Disease state overview

Sanfilippo A syndrome is a rare, autosomal recessive, lysosomal storage disease. There are four types of Sanfilippo A syndrome (IIIA, IIIB, IIIC, IIID), differentiated by gene mutations that cause varying enzyme deficiencies. The subtype IIIA is the most common form and is known to rapidly progress. It is due to a mutation in the SGSH gene resulting in a deficiency of sulfamidase, causing an accumulation of the glycosaminoglycan heparan sulfate in lysosomes, which leads to cellular dysfunction, primarily in the CNS. In Sanfilippo A syndrome, developmental delay becomes evident by 2–5 years of age and results in deterioration of intellectual and motor skills and causes disturbances in behavior. The average life expectancy of individuals with Sanfilippo A syndrome is about 15 years. 

Epidemiology 

The estimated prevalence of Sanfilippo A syndrome for subtype IIIA, in the U.S., is 0.52 per 1,000,000 live births. The Genetic and Rare Diseases Information Center (GARD) with the National Institutes of Health (NIH) estimates less than 5,000 persons in the U.S. are living with Sanfilippo A syndrome. 

Treatment

There is no cure for Sanfilippo A syndrome and there are no approved treatments. Current treatment is supportive.  

Drug and clinical trial overview 

The ongoing, open-label Phase 1/2/3 Transpher A trial is evaluating UX111 in patients ≥ 6 months of age with Sanfilippo A syndrome. The modified intention-to-treat (mITT) group (n=17) included patients ≤ 2 years of age and patients > 2 years of age with a Bayley-III cognitive developmental quotient ≥ 60. In the trial, patients in the mITT group received a one-time IV infusion of UX111 at a dose of 3 x10¹³ vector genome per kilogram (vg/kg). At a mean follow-up of 36 months (range, up to 77 months), the study reported a 66% (p<0.0001) reduction in the primary endpoint of heparan sulfate exposure in the CSF in the mITT group. Furthermore, a significant improvement in cognitive function was reported with UX111 compared to natural history of untreated patients (Bayley-III score raw cognitive score in patients 24–60 months of age, +16 points versus -6.8 points, respectively; p<0.0001). Numerical improvement in fine and gross motor scores was also reported. In addition, retention of meaningful functional abilities (e.g., communication, ambulation, feeding) were observed among 10 patients who received UX111 but were not in the mITT population due to older age or having more advanced disease. UX111 was generally well tolerated. Transient, mild to moderate elevations in liver enzymes were reported. 

Pipeline (late-stage development)

Name Manufacturer Route of administration Mechanism of action Proposed / studied indication Status
DNL126 Denali Therapeutics  IV SGSH RT using ETVto deliver SGSH gene across the BBB Sanfilippo A syndrome Phase 1/2
OTL-201 Orchard IV Lentiviral-based stem cell gene therapy delivering the SGSH gene to the cells Sanfilippo A syndrome Phase 1/2
JR-441 JCR Pharmaceuticals IV A recombinant fusion protein heparan N-sulfatase ERT Sanfilippo A syndrome Phase 1/2
Enzyme replacement therapy (ERT); replacement therapy (RT); enzyme transport vehicle (ETV); blood brain barrier (BBB)

The information provided has been developed based on available information as of July 2, 2025. This therapy is NOT FDA approved, and content may change as more information becomes available. Caution should be used when developing formulary and utilization management strategies.

The information contained in this report is intended for educational purposes only and is not intended to define a standard of care or exclusive course of treatment, nor be a substitute for treatment.

All brand names are property of their respective owners. 

References 

  1. ClinicalTrials.gov. NCT02716246: Phase 1/2/3 gene transfer clinical trial of scAAV9.U1a.hSGSH for MPS-IIIA. Available at: https://clinicaltrials.gov/study/NCT02716246?term=abo-102&city=&rank=3. Accessed June 5, 2025. 
  2. ClinicalTrials.gov. NCT04360265: A long-term follow-up study of patients with MPS-IIIA from gene therapy clinical trials involving the administration of ABO-102 (scAAV9.U1a.hSGSH). Available at: https://clinicaltrials.gov/study/NCT04360265?term=abo-102&city=&rank=2. Accessed June 5, 2025. 
  3. ClinicalTrials.gov. NCT04088734. A Phase 1/2 open label, single-dose, gene transfer study of scAAV9.U1a.hSGSH (ABO-102) in patients with middle and advanced phases of MPS IIIA disease. Available at: https://clinicaltrials.gov/study/NCT04088734. Accessed June 5, 2025. 
  4. Denali Therapeutics announces FDA has selected DNL126 (ETV:SGSH) for MPS-IIIA (Sanfilippo Syndrome Type A) for START pilot program intended to accelerate development of rare disease therapies. Available: Denali Therapeutics Announces FDA Has Selected DNL126. Accessed June 5, 2025.  
  5. FDA grants priority review to gene therapy for Sanfilippo type A. March 5, 2025. Available at:  https://sanfilipponews.com/news/fda-priority-review-granted-ux111-gene-therapy-sanfilippo-a/. Accessed June 13, 2025. 
  6. Fu H, Meadows AS, Pineda RJ, et al. Differential prevalence of antibodies against adeno-associated virus in healthy children and patients with mucopolysaccharidosis III: perspective for AAV-mediated gene therapy. Hum Gene Ther Clin Dev. 2017 Dec;28(4):187-196. DOI: 10.1089/humc.2017.109. Epub 2017 Oct 24. 
  7. JCR Pharmaceuticals Initiates First Dosing in Phase I Clinical Trial of JR-441 for Mucopolysaccharidosis Type IIIA. Available at: JCR Pharmaceuticals Initiates First Dosing in Phase I Clinical Trial of JR-441 for Mucopolysaccharidosis Type IIIA - BioSpace. Accessed June 5, 2025. 
  8. Mucopolysaccharidosis type III. National Institutes of Health. Available at: https://rarediseases.info.nih.gov/diseases/3807/mucopolysaccharidosis-type-3. Accessed June 9, 2025.  
  9. Mucopolysaccharidosis: How the different types affect patients and treatment approaches? March 19, 2025. Available at: https://www.delveinsight.com/blog/mucopolysaccharidosis-types-and-treatment-strategies#:~:text=Enzyme%20replacement%20therapy%20(ERT)%20has,patients%20with%20this%20devastating%20condition. Accessed June 13, 2025.  
  10. Mucopolysaccharidosis type III. Available at: https://medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-iii/. Accessed June 13, 2025.  
  11. National Organization for Rare Disease. Mucopolysaccharidosis Type III. Updated January 23, 2024. Available at: https://rarediseases.org/rare-diseases/mucopolysaccharidosis-type-iii/. Accessed June 13, 2025. 
  12. Orchard Therapeutics’ stem cell gene therapy OTL-201 reduces heparan sulphate levels in patients with MPS-IIIA. Available: Orchard Therapeutics’ Stem Cell Gene Therapy OTL-201 Reduces Heparan Sulphate Levels in Patients With MPSIIIA. Accessed June 5, 2025. 
  13. Sanfilippo awareness day: a peek into the CGT pipeline. November 16, 2025. Available at: https://www.cgtlive.com/view/sanfilippo-mpsiii-awareness-peek-cgt-pipeline . Accessed June 13, 2025. 
  14. Sanfilippo Syndrome - Market insight, epidemiology and market forecast – 2032. Available at: https://www.delveinsight.com/report-store/sanfilippo-syndrome-market. Accessed June 5, 2025.  
  15. The latest data from the pivotal Transpher A and long-term follow-up studies will be presented at WORLDSymposium™ 2024. Available at: https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-data-demonstrating-treatment-ux111-results. Accessed June 13, 2025. 
  16. UX111 (rebisufligene etisparvovec and formerly ABO-102) gene therapy for the potential treatment of Sanfilippo syndrome (MPS-IIIA). Available at: https://www.ultragenyx.com/our-research/pipeline/ux111-for-mps-iiia/. Accessed June 9, 2025.  
  17. Ultragenyx announces data demonstrating treatment with UX111 results in significant reduction in heparan sulfate exposure in cerebrospinal fluid correlated with improved long-term cognitive function in patients with Sanfilippo syndrome type A (MPS-IIIA). February 6, 2024. Available at: https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-data-demonstrating-treatment-ux111-results. Accessed June 13, 2025.  
  18. Ultragenyx acquires global rights to AAV gene therapy ABO-102 for Sanfilippo syndrome type A (MPS IIIA) from Abeona Therapeutics. Available at: https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-acquires-global-rights-aav-gene-therapy-abo-102. Accessed June 13, 2025.  
  19. Ultragenyx announces data demonstrating treatment with UX111 results in significant reduction in heparan sulfate exposure in cerebrospinal fluid correlated with improved long-term cognitive function in patients with Sanfilippo syndrome type A (MPS IIIA). Available at: https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-data-demonstrating-treatment-ux111-results. Accessed June 13, 2025.
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