REGENXBIO to resubmit application for Hunter gene therapy after FDA’s most recent pivot

FDA Reverses Stance on REGENXBIO's Hunter Syndrome Gene Therapy

REGENXBIO announced that the FDA has reversed its previous stance on the Biologics License Application (BLA) for its Hunter syndrome gene therapy, RGX-121 (NAVSUNLI). Following an appeal of a February rejection, the agency now deems REGENXBIO's existing clinical data sufficient for consideration under the accelerated approval pathway, negating the need for additional patient enrollment or studies, including a previously recommended untreated control arm. REGENXBIO plans to resubmit the BLA in the third quarter, with a Type A meeting expected in July to review longer-term biomarker and clinical data. This decision reflects a broader trend of FDA flexibility for rare diseases under new leadership.

• The FDA has significantly altered its position on REGENXBIO's gene therapy, RGX-121, for Hunter syndrome. After initially rejecting the BLA in February, the agency now acknowledges that the existing clinical data are sufficient to support an accelerated approval pathway. This reversal means REGENXBIO will not need to enroll additional patients or conduct further studies, including the previously recommended untreated control arm, streamlining the path to potential market approval.
• The initial complete response letter for RGX-121 cited concerns regarding eligibility criteria in the registrational study and the comparability of external controls. The FDA had recommended an appropriate untreated control arm. However, through collaborative discussions and an appeal, the agency has now confirmed that these previous requirements are no longer necessary, allowing REGENXBIO to proceed with a resubmission based on its current data set.
• This decision for REGENXBIO, alongside a similar reversal for uniQure's Huntington's disease gene therapy, signals a more flexible regulatory environment at the FDA for rare diseases under acting commissioner Kyle Diamantas. The agency appears committed to leveraging accelerated approval pathways and supporting innovative clinical trial designs, such as externally-controlled trials, to expedite transformative therapies for unmet medical needs.

RGX-121: The Data Behind the FDA's Accelerated Approval Pivot

The clinical evidence base for Hunter syndrome (MPS II) spans a range of study designs, from large multinational registries to prospective observational cohorts and retrospective chart reviews. The Hunter Outcome Survey (HOS), a multi-centre, worldwide, observational long-term follow-up registry open to all diagnosed MPS II patients, has served as a foundational data source. A key HOS analysis included 639 patients who received idursulfase for ≥6 months, with a median age at first treatment of 6.2 years and a median treatment duration of 56.3 months. Endpoints assessed at three years included urinary glycosaminoglycan (uGAG) levels, 6-minute walk test (6MWT) distance, left ventricular mass index (LVMI), absolute forced vital capacity (FVC) and FEV₁, and palpable liver and spleen size. A complementary 2024 systematic literature review analysed 33 eligible articles and evaluated short- and long-term clinical and patient-centred outcomes, rating evidence according to GRADE criteria. A 2019 systematic review — searching from inception to August 2017 — identified one randomised clinical trial, four observational studies, and five case reports, evaluating outcomes including uGAG levels, organ size, anti-ERT antibody development, infusion-related reactions, respiratory and cardiac function, joint mobility, sleep-disordered breathing, and quality of life.

Prospective and retrospective studies have further refined understanding of functional and neurocognitive trajectories. A 2-year prospective observational study (NCT01822184) enrolled 55 boys with MPS II aged ≥2 and <18 years, all receiving intravenous idursulfase at baseline. Cognitive function was assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) score and adaptive function using the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) score, with subgroup analyses stratified by age (<7 vs. ≥7 years) and baseline DAS-II GCA (≤70 vs. >70). A 2024 retrospective medical chart review at 19 US sites examined 140 male MPS II patients diagnosed between 1997 and 2017, stratifying disease manifestations and healthcare resource utilisation by age at ERT initiation and cognitive impairment status, with a focused subgroup analysis on patients diagnosed before age 6 years.

Health-related quality of life (HRQL) has been formalised as an endpoint in dedicated MPS II trials. A clinical study enrolled 96 male patients and their parents, administering four validated instruments — the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS), CHAQ, CHQ, and HUI3 — prior to ERT initiation, with Spearman rank-order correlations used to examine associations between questionnaire scores and clinical function parameters. An ADL questionnaire study of 74 Japanese patients (51 severe, 23 attenuated phenotype) assessed three domains — movement, movement with cognition, and cognition — each with four subcategories rated on a 5-point assistance scale, yielding a 60-point composite across 12 MPS-specific subcategories. Collectively, these studies reflect a methodological evolution toward capturing both somatic and neurocognitive burden, though the inability of intravenous idursulfase to cross the blood-brain barrier remains a consistent and critical limitation across all trial designs.

FDA's Evolving Stance: Addressing Unmet Needs in Rare Diseases

Over the past three years, research and clinical consensus efforts have substantially clarified the populations most affected by Hunter syndrome (MPS II) and the gaps that remain inadequately addressed by current standard of care. The unmet need landscape spans neurological, somatic, diagnostic, economic, and care-delivery dimensions, with particular urgency around CNS disease and the growing adult patient population.

• Neurological disease remains the critical treatment gap: Intravenous idursulfase ERT improves somatic symptoms and extends life expectancy by approximately 12 years, but cannot cross the blood-brain barrier, leaving CNS pathology unaddressed in the approximately two-thirds of patients with neuronopathic MPS II. Supraphysiological neurofilament light chain (NfL) levels correlate with accelerated cognitive decline, and baseline cerebrospinal NfL corresponds to IDS genotype severity and primary substrate burden—underscoring the need for CNS-directed therapies. Although intrathecal idursulfase (idursulfase-IT) showed caregiver-reported cognitive and behavioral improvements in pediatric trials, clinical trial data were ultimately deemed insufficient to support regulatory filing.

• High somatic burden persists in the growing adult population: Analysis of 373 adult male patients in the Hunter Outcome Survey found cardiovascular signs and symptoms in 71.6%, oxygen dependency in 27.3%, hearing aid use in 38.6%, and hernia repair as the most common surgery (17.8%); approximately 50.9% experienced at least one serious adverse event in adulthood, most commonly respiratory disorders. This expanding adult cohort—driven by improved survival from ERT—represents a population with complex, multisystem needs that require continued multidisciplinary management and regular assessments.

• Transition of care lacks standardization across healthcare systems: As more patients survive into adulthood, the transition from pediatric to adult care services has emerged as a structured unmet need. Transition pathways show high variability within and between countries (including Canada, Colombia, Germany, Mexico, the UK, and the USA), with no common international standards in place. Key deficits include absence of a designated key contact person, insufficient psychological support, and lack of standardized protocols—with additional complexity for patients with neuronopathic MPS II.

• Diagnostic delays and misdiagnosis remain prevalent, particularly in under-resourced settings: In Turkish cohorts, mean diagnostic delay was 19.7 ± 40.4 months; in China, MPS II is frequently misdiagnosed. Newborn screening (NBS) was added to the US Recommended Uniform Screening Panel (RUSP) in 2022, but evidence from NBS programs outside Taiwan and the USA remains limited. False-positive rates are elevated due to pseudodeficiency alleles and methodological variability. In low- and middle-income countries (LMICs) such as Kenya, absent genetic counseling infrastructure and social stigmatization of affected families compound diagnostic gaps.

• Economic burden is substantial and inadequately supported by health policy: In China, 124 patients accrued approximately 14.79 million yuan in direct and indirect costs over a single year, with direct costs comprising 87.19% of total burden. Hospitalizations, length of stay, outpatient visits, and HSCT were the principal cost drivers. Existing treatment options are considered insufficient in both efficacy and affordability, and the absence of adequate policy guarantees places severe financial pressure on patients and families.

• Mitochondrial and cellular pathology represent emerging mechanistic gaps: Preclinical data from 6-month-old MPS II mice indicate disrupted mitochondria-lysosome crosstalk in brain and cardiac tissue, evidenced by reduced TBC1D15, elevated Rab7 in the heart, decreased Drp1 (reduced fission), and increased VDAC1 and COX IV. Reduced activities of citrate synthase, malate dehydrogenase, isocitrate dehydrogenase, creatine kinase, and pyruvate kinase—alongside diminished mitochondrial respiration and disrupted mitophagy—highlight bioenergetic failure as an underaddressed pathophysiological axis not targeted by current ERT.

• Newborn screening programs and registry infrastructure remain underdeveloped globally: Birth prevalence estimates from NBS initiatives are higher than historically reported, with figures of approximately 1 in 15,000 in Japan versus approximately 1 in 73,000 in the USA, and 0.45 per 100,000 male live births in Malaysia. Despite this, prospective population screening data outside Taiwan and the USA remain minimal. Expert consensus in Turkey has formally recommended the establishment of a national MPS II registry and annual patient-reported outcome assessments to close longitudinal data gaps.

Hunter Syndrome: Persistent Challenges in Current Treatment Approaches

Current treatment approaches for Hunter syndrome (MPS II) face substantial efficacy and safety limitations that leave significant unmet medical needs, particularly with respect to neurological disease progression. Enzyme replacement therapy (ERT) with idursulfase remains the only FDA-approved pharmacological intervention, yet its clinical utility is constrained by several well-documented shortcomings. Hematopoietic stem cell transplantation (HSCT), the other principal therapeutic modality, similarly fails to deliver durable neurological benefit.

• Inability to cross the blood-brain barrier: Intravenously administered idursulfase cannot cross the blood-brain barrier (BBB), resulting in no measurable improvement in central nervous system function in patients with the severe disease phenotype. This limitation extends to gene therapy approaches — AAV9.hIDS administered intravenously achieved only 4–50% of wild-type IDS enzyme activity in the CNS despite producing supraphysiological levels in peripheral organs (up to 560-fold above wild-type) and circulation (up to 9,100-fold above wild-type).

• Absence of neurocognitive benefit with ERT: ERT alleviates select somatic manifestations — including organomegaly, respiratory impairment, and glycosaminoglycan (GAG) accumulation — but confers no neurocognitive benefit. Responses across clinical parameters are heterogeneous; while cardiac manifestations and facial features may stabilize, neurological deterioration continues in severe-phenotype patients.

• Immunogenicity and infusion-related reactions: Up to 50% of ERT-treated patients develop anti-IDS antibodies, and IgG antibodies have been detected in up to 46.9% of patients across treatment cohorts. Infusion-associated reactions, including serious anaphylactic events, represent a clinically significant safety concern, as documented in individual case reports and broader registry data.

• Failure of HSCT to provide long-term neurological benefit: Although HSCT achieves successful engraftment and reduces urinary GAG excretion, its clinical impact on neurological outcomes has been consistently disappointing. Cerebral white matter abnormalities remain unchanged over time, and HSCT has not demonstrated long-term effectiveness on neurological symptoms — likely due to insufficient IDS enzyme production from donor cells engrafting in the brain. Dysostosis multiplex and cardiovascular involvement also continue to progress.

• Limited efficacy data in young and pediatric patients: Safety and efficacy data from clinical studies are available only for patients 1.4 years of age and older, with particularly limited information on ERT effects in children under 5 years. Given that early intervention is critical to modifying disease trajectory, this evidence gap presents a meaningful clinical challenge.

• Persistent underdiagnosis and access inequities: Many complications of Hunter syndrome remain underdiagnosed and undertreated in routine clinical practice. Access to ERT is markedly unequal across geographies — for example, ERT was not initiated in the Philippines until 2017, with only 8 of 40 identified male patients receiving treatment. Delayed initiation (mean age at ERT start of 14.03 years in one Filipino cohort) further limits therapeutic outcomes.

• Ongoing cardiovascular risk despite treatment: Close cardiac monitoring remains mandatory in all patients, including those receiving ERT, due to the high incidence of hypertension and valvular heart disease. Mortality data underscore this risk — within one year of ERT initiation, documented deaths included myocardial infarction with severe coronary artery disease, pneumonia, and sleep apnea-related complications.