Advances in Hunter Syndrome Therapeutics: Overviewing the Pipeline

The recent FDA approval of tividenofusp alfa (Denali Therapeutics) marks a meaningful inflection point for the Hunter syndrome community. For clinicians managing patients with mucopolysaccharidosis type II (MPS II), the approval represents the first CNS-penetrant enzyme replacement therapy (ERT) cleared in the United States — a long-sought advance given that conventional ERT has never adequately addressed the progressive neurological deterioration that defines the severe form of the disease. Yet the approval of a single agent, however significant, does not close the chapter on unmet need in MPS II. The disease remains life-limiting, its neurological burden is substantial, and the therapeutic landscape is still evolving rapidly across multiple modalities.

With that context, the pipeline for Hunter syndrome warrants close attention. Gene therapies, next-generation ERTs engineered to cross the blood-brain barrier, and genome-editing approaches are all in active development — spanning Phase 1 through late-stage regulatory review. Some of these programs have posted compelling biomarker and neurocognitive data; others have encountered significant regulatory or clinical hurdles that have reshaped their trajectories. Below is a round-up of six of the most notable investigational agents currently in development for MPS II, offering clinicians a focused look at what may be coming next.

Emerging Agents

Clemidsogene Lanparvovec (RGX-121) - REGENXBIO

Clemidsogene lanparvovec (RGX-121) is one of the most closely watched gene therapy programs in the MPS II space. It is designed as a potential one-time AAV9 therapeutic that delivers the iduronate-2-sulfatase (IDS) gene directly to the central nervous system, with the goal of providing a permanent source of secreted I2S protein beyond the blood-brain barrier — enabling long-term cross-correction of cells throughout the CNS.

The therapy has been evaluated in the Phase I/II/III CAMPSIITE trial (NCT03566043), which met its primary endpoint with statistical significance, and data presented at the SSIEM Annual Symposium 2024 showed a median CSF heparan sulfate D2S6 reduction of 85% among patients who received the pivotal dose level, with biomarker levels approaching normal and sustained for up to two years.

Despite this clinical momentum, RGX-121 hit a significant regulatory setback in early 2026. The FDA issued a complete response letter (CRL) in February 2026, outlining multiple concerns, including questions about whether the trial's eligibility criteria adequately differentiated neuronopathic from attenuated disease, whether the external natural history control group was sufficiently comparable to the treated population, and whether CSF heparan sulfate D2S6 levels used as a surrogate endpoint were reasonably likely to predict clinical benefit.¹

Complicating matters further, the pivotal CAMPSIITE trial was placed on clinical hold in January 2026 following an intraventricular CNS tumor in a patient treated with a separate REGENXBIO product, RGX-111 — with a suspected AAV vector genome integration event associated with overexpression of the PLAG1 protooncogene. REGENXBIO has indicated plans to work with the FDA on a resubmission path.

Pabinafusp Alfa (JR-141/IZCARGO) — JCR Pharmaceuticals

Pabinafusp alfa is a brain-penetrant ERT developed by Japan-based JCR Pharmaceuticals that has already achieved approval in Japan under the brand name IZCARGO, making it one of the most clinically mature agents in this space globally. It is a recombinant fusion protein combining an antibody against the human transferrin receptor (hTfR) and iduronate-2-sulfatase; using JCR's proprietary J-Brain Cargo® technology, pabinafusp alfa is designed to cross the blood-brain barrier and deliver ERT directly to the CNS to address the neurological symptoms of the disease.

The clinical evidence base is substantial. A Phase 2/3 multicenter, single-arm, open-label trial in 28 Japanese patients showed CSF heparan sulfate concentrations significantly decreased from baseline to week 52 (p < 0.001), and neurocognitive evaluations showed positive changes in 21 of the 28 patients.² More recently, a pooled, post hoc analysis of 63 patients across five open-label trials, presented at ICIEM 2025, showed rapid and sustained decreases in CSF HS levels by week 13 that were maintained through end of follow-up and were evident regardless of prior ERT exposure.³ JCR has stated plans for regulatory submissions beyond Japan, with the five-year data bolstering the case for broader global approval.

HMI-203 - Homology Medicines

HMI-203 is an investigational in vivo gene therapy being developed by Homology Medicines for adult patients with Hunter syndrome. It is designed as a one-time therapy, using one of the company's human hematopoietic stem cell-derived adeno-associated virus vectors (AAVHSCs) to deliver functional copies of the IDS gene to multiple organs, with the goal of enabling I2S enzyme production and reducing pathological GAG accumulation. A key differentiator of Homology's approach is the systemic reach of its AAVHSC platform. HMI-203 is designed to reach organs throughout the body, including the nervous system, by crossing the blood-brain and blood-nerve barriers — addressing both the peripheral organ and CNS manifestations that standard-of-care ERT does not adequately treat.⁴

The Phase 1 juMPStart trial (NCT05238324) is an open-label, dose-escalation study evaluating a single intravenous administration of HMI-203 in adult males with MPS II who are currently being treated with standard-of-care idursulfase ERT. Three planned dose cohorts of three participants each are being assessed, with entry intervals built in to allow safety and efficacy review prior to advancing.⁵ The trial evaluates peripheral endpoints including liver and spleen volume, cardiac and pulmonary function, and range of motion, as well as CNS-directed endpoints including CSF enzyme activity and GAG levels.

SB-913 - Sangamo Therapeutics

SB-913 holds a notable distinction in the broader field of gene medicine: it was used in the first-ever evaluation of an in vivo genome-editing treatment in humans. Developed by Sangamo Therapeutics, the therapy employs zinc finger nuclease (ZFN) genome editing technology rather than a conventional gene therapy approach. SB-913 inserts a corrective IDS gene into a precise location in the DNA of liver cells, with the intention of enabling the liver to produce a lifelong, stable supply of the IDS enzyme lacking in Hunter syndrome patients. The ZFNs and the corrective gene are delivered as a single intravenous infusion via AAV6 vectors targeting the liver.

The Phase 1/2 CHAMPIONS study (NCT03041324) enrolled up to nine adult males with MPS II across three dose cohorts. At 16 weeks post-dosing in Cohort 2, mean reductions were observed in total urinary GAGs, dermatan sulfate, and heparan sulfate of 51%, 32%, and 61%, respectively. However, according to clinical records, the CHAMPIONS study's Phase 1 trial was completed in March 2017 with no outcomes formally reported, and the program has not advanced to later-stage trials.⁶ All nine subjects dosed in the study have rolled over to a long-term follow-up study (NCT04628871), and the program's current development trajectory remains under evaluation. SB-913 had previously received orphan drug, fast track, and rare pediatric disease designations from the FDA.

Tividenofusp Alfa (DNL310) - Denali Therapeutics

Tividenofusp alfa was the most advanced CNS-penetrant ERT in the MPS II pipeline before its recent FDA approval, and its clinical development arc offers important context for understanding the current treatment paradigm shift. DNL310 is a recombinant form of the IDS enzyme engineered to cross the blood-brain barrier using Denali's proprietary ETV (enzyme transport vehicle) technology, and is administered intravenously. The ETV platform attaches the IDS enzyme to a transferrin receptor-binding moiety, enabling active transport across the BBB — a fundamental redesign of how ERT is delivered to the CNS.

Phase 1/2 data demonstrated a 90% mean reduction in CSF heparan sulfate after 24 weeks, sustained through week 104, along with normalization of urinary GAGs and improvements or stabilization in adaptive behavior, cognition, hearing, liver volume, and growth.⁷ Importantly, most patients in those trials were already on standard-of-care ERT, suggesting the improvements reflected an additive treatment benefit. The therapy was subsequently evaluated in the Phase 2/3 PEARL trial (NCT05476380), a randomized, double-blind, active-controlled study comparing tividenofusp alfa to idursulfase. The FDA granted breakthrough therapy designation, and Denali submitted a BLA in early 2025 under the accelerated approval pathway, leading to the approval that now positions the therapy as the first CNS-penetrant ERT for Hunter syndrome available in the US.

AGT-182 - ArmaGen

AGT-182 is an investigational BBB-penetrant ERT developed by ArmaGen in collaboration with Takeda (formerly Shire). It is engineered by fusing the replacement IDS enzyme to an antibody that targets the receptor on the blood-brain barrier that transports insulin to all cells of the body, including the brain — allowing the IDS enzyme to be carried through the BBB attached to that antibody. The therapy holds orphan drug designation from both the FDA and the EMA, and remains one of the earlier examples of a receptor-mediated transcytosis approach applied to lysosomal storage disease.

AGT-182 was evaluated in the Phase 1/2a Breaking Barriers trial (NCT02262338). The trial was an open-label, sequential, multi-dose study designed to determine a safe and well-tolerated dose in adult males with Hunter syndrome.⁸ Data from the first cohort of four adult patients showed clinically significant decreases in liver and spleen volumes in two of four patients, and clinically significant decreases in urinary GAGs in all four patients, leading an independent DMC to recommend advancing to the 3 mg/kg dose cohort. However, clinical records indicate the Phase 1 trial was completed in March 2017 with no outcomes formally reported, and the program's subsequent path forward has remained uncertain.⁹

REFERENCES
1. REGENXBIO Presents Positive Twelve-Month Pivotal Data from Phase I/II/III CAMPSIITE® Trial of RGX-121 for Treatment of MPS II. News release. REGENEXBIO. September 5, 2026. Accessed April 2, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-presents-positive-twelve-month-pivotal-data-phase/
2. Okuyama T, et al. A Phase 2/3 Trial of Pabinafusp Alfa in MPS-II. Molecular Therapy. 2021;29(2):671–679. PMC7854283.
3. JCR Pharmaceuticals Presents Long-Term Clinical Data on Pabinafusp Alfa for the Treatment of Mucopolysaccharidosis Type II (MPS II) at ICIEM 2025. News release. September 8, 2025. Accessed April 2, 2026. https://finance.yahoo.com/news/jcr-pharmaceuticals-presents-long-term-170300633.html
4. Homology Medicines Initiates Clinical Trial for HMI-203, a One-Time Investigational Gene Therapy Candidate for Adults with MPS II (Hunter Syndrome). News release. October 18, 2021. Accessed April 2, 2026. https://www.biospace.com/homology-medicines-initiates-clinical-trial-for-hmi-203-a-one-time-investigational-gene-therapy-candidate-for-adults-with-mps-ii-hunter-syndrome
5. Shioshita G. P007: juMPStart: Phase 1, open-label, dose-escalation safety and efficacy gene therapy study evaluating HMI-203 in adults with MPS II. Genetics Medicine. 2023;1(1):100017. doi:10.1016/j.gimo.2023.100017
6. Sangamo Announces Interim Results Of Phase 1/2 CHAMPIONS Study Showing Preliminary Evidence Of In Vivo Genome Editing In Patients With MPS II Treated With SB-913. News release. Sangamo Therapeutics. February 7, 2019. Accessed April 2, 2026. https://investor.sangamo.com/news-releases/news-release-details/sangamo-announces-interim-results-phase-12-champions-study
7. Denali Therapeutics announces primary analysis and long-term follow-up of phase 1/2 study in Hunter syndrome (MPS II) with tividenofusp alfa. News release. Denali Therapeutics. February 6, 2025. Accessed April 2, 2026. https://www.globenewswire.com/news-release/2025/02/06/3022238/0/en/Denali-Therapeutics-Announces-Primary-Analysis-and-Long-Term-Follow-Up-of-Phase-1-2-Study-in-Hunter-Syndrome-MPS-II-with-Tividenofusp-Alfa.html
8. ArmaGen Presents Data from First Cohort of Phase 1/2a of AGT-182 for Treatment of Hunter Syndrome. News release. ArmaGen. July 14, 2016. Accessed April 2, 2026. https://www.prnewswire.com/news-releases/armagen-presents-data-from-first-cohort-of-phase-12a-of-agt-182-for-treatment-of-hunter-syndrome-300299036.html
9. Zanetti A, Tomanin R. Targeting Neurological Aspects of Mucopolysaccharidosis Type II: Enzyme Replacement Therapy and Beyond. BioDrugs. 2024;38:639-655. doi:10.1007/s40259-024-00675-0