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High-Cost Therapy Profile: November 2025

Tividenofusp alfa Intravenous (IV) | Denali Therapeutics 

Metabolic
November 14, 2025

Proposed indications 

Mucopolysaccharidosis type II (MPS II), also known as Hunter Syndrome 

FDA approval timeline

April 5, 2026 (review extended) 

  • Breakthrough Therapy
  • Fast Track
  • Orphan Drug
  • Priority Review
  • Rare Pediatric Disease (RPD)
  • Seeking Accelerated Approval

Place in therapy 

Tividenofusp alfa (DNL310) is an enzyme replacement therapy (ERT) composed of iduronate-2-sulfatase (I2S) enzyme, which breaks down heparan sulfate and dermatan sulfate in the lysosome to maintain cellular homeostasis. Tividenofusp alfa is fused to an enzyme transport vehicle, which is engineered to cross the blood brain barrier (BBB). 

  • If approved, tividenofusp alfa will be the first ERT that crosses the BBB, potentially addressing the central nervous system (CNS) symptoms experienced by patients diagnosed with MPS II. 
  • Cerebrospinal fluid (CSF) heparan sulfate levels are being used as a surrogate endpoint to seek accelerated approval. 
  • Tividenofusp alfa will be the second agent approved to treat MPS II, following idursulfase (Elaprase). Elaprase is an ERT that requires weekly weight based IV infusions but is not known to cross the BBB.  
  • Tividenofusp alfa is being evaluated in a Phase 2/3 confirmatory clinical trial comparing its efficacy to Elaprase in patients 2 to < 6 years of age with neuronopathic MPS II (cohort A) or 6 to < 26 years of age with non-neuropathic MPS II (cohort B). Study completion is expected in December 2025. 
  • Clemidsogene lanparvovec (RGX-121), a one-time intracisternal gene therapy, is being evaluated to treat the neurocognitive decline in MPS II cases. If approved, it will address both the neurodevelopmental and systemic effects of MPS II. 

Understanding your data

MPS II is caused by mutations in the IDS gene which controls the production of the I2S enzyme. The I2S enzyme is necessary to break down glucosaminoglycans also known as large sugar molecules such as heparan sulfate and dermatan sulfate. The deficiency in the IS2 enzyme results in accumulation of glucosaminoglycans within the cells, leading to health problems. Tividenofusp alfa works by delivering IS2 enzyme to the brain and body, thus potentially addressing the behavioral, cognitive and physical symptoms of MPS II. Studies evaluating tividenofusp alfa in MPS II include the following: 

  • NCT05371613 COMPASS (DNLI-E-0007): A Phase 2/3, multicenter, double-blind, randomized study to determine the efficacy and safety of tividenofusp alfa vs Elaprase in pediatric and young adult participants with neuronopathic or non-neuronopathic MPS II.  
  • NCT04251026 (DNLI-E-0002): A Phase 1/2, multicenter, open-label study to determine the safety, pharmacokinetics and pharmacodynamics of tividenofusp alfa in pediatric participants with MPS II. 
  • NCT06075537: An open-label extension to investigate the long-term safety, tolerability and efficacy of tividenofusp alfa in patients with MPS II from study DNLI-E-0002 or study DNLI-E-0007. 

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 MPS II. 

Common Measurable Exclusion Criteria: 

  • History of stem cell therapy. 
  • Received any CNS-targeted MPS ERT within the last 6 months. 

Appendix


Category Procedure codes
MS II International Classification of Diseases, Tenth Revision (ICD-10): E76.1, E76.3
CNS-targeted MPS ERT Health care Common Procedure Coding System (HCPCS): none available
Stem cell therapy ICD-10: Z94.84, T86.5, M31.11 

Current Procedural Terminology (CPT): 38241, 38240 

ICD-10-procedural 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  

Clinical deep dive 

Disease state overview

MPS II is a rare inherited progressive lysosomal storage disorder that results from deficiency or absence of the lysosomal enzyme, I2S, caused by mutations in the IDS gene. The lack of I2S enzyme results in the accumulation of toxic substances (dermatan sulfate and heparan sulfate) in tissues and organs leading to their dysfunction. Patients can present with either severe, early-onset or less severe, late-onset. These two forms of MPS II are based on neurologic impact and rate of progression. The neuronopathic form is more severe and accounts for about two-thirds of cases; it is characterized by cognitive impairment and CNS involvement. The non-neuronopathic form has no neurological symptoms or has less severe symptoms and mental function is usually normal. Symptoms can include coarse facial features, a large head, joint stiffness, skeletal abnormalities, respiratory issues, hearing loss, cardiovascular issues and neurological issues (e.g., seizures). Developmental delays become apparent around ages 18 to 24 months. Death due to upper airway disease or cardiovascular failure occurs between 10 to 20 years of age. 

Epidemiology 

MPS II usually affects only boys and occurs in about 1 in 100,000 to 1 in 170,000 male births. It has been seen in girls on rare occasions. There are about 500 boys diagnosed with MPS II in the U.S. 

Treatment

There is no cure for MPS II and there is no treatment available to address the neurodevelopmental decline. Current treatment options include weekly IV Elaprase, hematopoietic stem cell transplant (HSCT) in younger patients and symptomatic management. Current ERT manages some physical symptoms and slows the progression of disease (reducing liver volume, increasing mobility and reducing respiratory infection frequency) but it does not cross the BBB and therefore does not impact the neurodegeneration associated with MPS II. 

Drug and clinical trial overview 

An open-label, Phase 1/2 study evaluated tividenofusp alfa in 43 patients ≤ 18 years of age with MPS II. Patients were stratified into multiple cohorts depending on age, MPS II type (neuronopathic, non-neuronopathic) and other patient demographics. Patients receiving standard of care ERT at baseline switched to tividenofusp alfa without a washout period. During the 24-week treatment period, various cohorts received doses ranging from 3–30 mg/kg. In the open-label extension, all patients received tividenofusp alfa 15 mg/kg via weekly IV infusions with or without prior dose escalation. Interim data demonstrate a 90.9% mean reduction in CSF heparan sulfate level from baseline at week 24 with all participants having normal or near normal levels at week 24, which was sustained through week 153 (-89.3%). The mean urine heparan sulfate was reduced by 84.6% from baseline to week 24 and sustained through week 129 (-80.1%). There was also a significant increase in the proportion of patients with normal total urine glucosaminoglycans from baseline (5–77%) at week 24, which was sustained through week 129. The study also demonstrated a significant reduction from baseline to week 61 (-41.1%) in serum neurofilament light chain (NfL) with continued reduction seen through week 129 (-81.5%, all within normal range), which suggests a decrease in neuronal injury. In addition, adaptive behavior and cognitive scores improved or stabilized. The most common treatment emergent adverse events were infusion-related reactions, anemia, vomiting, pyrexia, upper respiratory tract infection and rash; the majority being mild to moderate in severity.  

The double-blind, active-controlled, Phase 2/3 COMPASS study has been initiated to evaluate IV-administered tividenofusp alfa compared to Elaprase in patients 2 to < 6 years of age with neuronopathic MPS II (cohort A) or 6 to < 26 years of age with non-neuropathic MPS II (cohort B). Coprimary outcome measures are the percent change from baseline in CSF heparan sulfate concentration and change from baseline in the Vineland Adaptive Behavior Scale, Third Edition (Vineland-3) in cohort A. Study completion is anticipated in December 2025.  

Pipeline (late-stage development)

Name Manufacturer Route of administration Mechanism of action Proposed / studied indication Status
Clemidsogene lanparvovec (RGX-121) Regenxbio Intracisternal Adeno-associated virus gene therapy MPS II Prescription Drug User Fee Act (PDUFA) 2/8/2026
Pabinafusp alfa (JR-141) JCR Pharmaceuticals IV ERT MPS II Phase 3

The information provided has been developed based on available information as of Oct. 30, 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. Burton B, Muenzer J, Harmatz P, et al.(2025). P026: Interim analysis of the efficacy and safety of weekly intravenous tividenofusp alfa in mucopolysaccharidosis type II: A phase 1/2 study. Abstract 102870. Genetics in Medicine 3, supplement 2, 2025. https://doi.org/10.1016/j.gimo.2025.102870.   
  2. ClinicalTrials.gov. NCT05371613: A Phase 2/3, multicenter, double-blind, randomized study to determine the efficacy and safety of tividenofusp alfa (DNL310) vs idursulfase in pediatric and young adult participants with neuronopathic or non-neuronopathic MPS II.  
  3. ClinicalTrials.gov. NCT04251026: A Phase 1/2, multicenter, open-label study to determine the safety, pharmacokinetics, and pharmacodynamics of DNL310 in pediatric participants with Hunter syndrome. 
  4. ClinicalTrials.gov. NCT06075537: An open-label extension to Investigate the long-term safety, tolerability, and efficacy of DNL310 in patients with MPS II from study DNLI-E-0002 or study DNLI-E-0007.  
  5. ClinicalTrials.gov. NCT04573023: A Phase 3 study of JR-141 in patients with MPS II (STARLIGHT). 
  6. ClinicalTrials.gov. NCT03566043 CAMPSITE. A Phase 1/2/3 multicenter, open-label study to evaluate the efficacy, safety, tolerability, and pharmacodynamics of RGX-121 in pediatric subjects with MPS II (Hunter Syndrome). 
  7. Denali Therapeutics Announces U.S. FDA Breakthrough Therapy Designation Granted to Tividenofusp Alfa for the Treatment of Hunter Syndrome (MPS II). January 9, 2025. Available at: https://www.biospace.com/press-releases/denali-therapeutics-announces-u-s-fda-breakthrough-therapy-designation-granted-to-tividenofusp-alfa-for-the-treatment-of-hunter-syndrome-mps-ii. Accessed October 10, 2025. 
  8. Denali Therapeutics announces initiation of BLA filing for Accelerated Approval of tividenofusp alfa for the treatment of Hunter syndrome (MPS II) and positive ongoing interactions with FDA on DNL126 through START program. April 2, 2025. Available at: https://www.biospace.com/press-releases/denali-therapeutics-announces-initiation-of-bla-filing-for-accelerated-approval-of-tividenofusp-alfa-for-the-treatment-of-hunter-syndrome-mps-ii-and-positive-ongoing-interactions-with-fda-on-dnl126-through-start-program. Accessed October 10, 2025. 
  9. Denali Therapeutics announces FDA review extension of BLA for tividenofusp alfa for the treatment of MPS II (Hunter Syndrome). October 13, 2025. Available at: https://www.globenewswire.com/news-release/2025/10/13/3165786/0/en/Denali-Therapeutics-Announces-FDA-Review-Extension-of-BLA-for-Tividenofusp-Alfa-for-the-Treatment-of-MPS-II-Hunter-Syndrome.html. Accesses October 15, 2025.  
  10.  Elaprase [package insert]. Lexington, MA; Shire; November 2018. 
  11. Kang J. Tividenofusp alfa gets Priority Review for Hunter Syndrome. July 23, 2025. Available at: https://www.neurologyadvisor.com/news/tividenofusp-alfa-gets-priority-review-for-hunter-syndrome/. Accessed October 10, 2025.
  12. Hunter syndrome overview. Available at: What is Hunter syndrome | Project Alive. Accessed August 25, 2025. 
  13. Meglio M. FDA grants Priority Review, sets Prescription Drug User Fee Act (PDUFA) Date for Hunter syndrome treatment tividenofusp alfa. July 7, 2025. Available at: https://www.neurologylive.com/view/fda-grants-priority-review-sets-pdufa-date-hunter-syndrome-treatment-tividenofusp-alfa. Accessed September 1, 2025. 
  14. Muenzer J, Bodamer O, Burton B, et al. The role of enzyme replacement therapy in severe Hunter syndrome-an expert panel consensus. Eur J Pediatr. 2012;171(1):181-8. DOI: 10.1007/s00431-011-1606-3.  
  15. National Organization for Rare Disorders. Mucopolysaccharidosis Type II. Available at:  https://rarediseases.org/rare-diseases/mucopolysaccharidosis-type-ii-2/. Accessed August 20, 2025.  
  16. National Library of Medicine. IDS gene iduronate 2-sulfatase. Available at: https://medlineplus.gov/genetics/gene/ids/. Accessed August 20, 2025. 
  17. Scarpa M, Almássy Z, Beck M, et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis. 2011;6:72. DOI: 10.1186/1750-1172-6-72. 
  18. Scarpa M, Lampe C. Mucopolysaccharidosis Type II. 2007 Nov 6 [Updated 2025 Jan 16]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1274/. Accessed February 2025. 
  19. Shapiro EG, Eisengart JB. The natural history of neurocognition in MPS disorders: A review. Mol Genet Metab. 2021;133(1):8-34. DOI: 10.1016/j.ymgme.2021.03.002.   
  20. Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008;167(3):267-77. Epub 2007 Nov 23. 
  21. Zhou J, Lin J, Leung WT, Wang L. A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management. Intractable Rare Dis Res. 2020;9(1):1-9. DOI: 10.5582/irdr.2020.01011.  
  22. Żuber Z, Kieć-Wilk B, Kałużny Ł, et al. Diagnosis and management of mucopolysaccharidosis Type II (Hunter Syndrome) in Poland. Biomedicines. 2023;11(6):1668. DOI: 10.3390/biomedicines11061668. 
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