REGENXBIO Inc.

We have invested in innovative manufacturing process development and analytical capabilities and use a suspension cell culture-based manufacturing process. We have deep in-house knowledge of biologics and gene therapy manufacturing, which has enabled us to scale manufacturing of our AAV therapeutics while ensuring product quality for patients and improving cost-of-goods. We have developed systems which we believe will provide robust manufacturing and global supply of AAV therapeutics to meet quality requirements and anticipated research, clinical and future commercial demand. Our Good Manufacturing Practices (cGMP) production facility, the REGENXBIO Manufacturing Innovation Center (RMIC), is located in our corporate headquarters in Rockville, Maryland. The RMIC was designed to support clinical and future commercial production of AAV therapeutics and has been in operation since mid-2022. In 2025, the FDA completed a pre-license inspection (PLI) and bioresearch monitoring (BIMO) inspection as part of the RGX-121 Biologics License Application (BLA) with no observations.

We have developed a proprietary, high-yielding manufacturing process platform for NAV vector production (NAVXpress®) that can be applied across multiple AAV therapeutics. This manufacturing process platform approach improves development efficiency and shortens timelines by leveraging data across multiple programs. The suspension-based manufacturing platform has demonstrated robust scalability from bench-scale to 500 liter and 1,000-liter cGMP batches with consistent yield and product purity demonstrated via comparability studies. At the RMIC facility, we have demonstrated the ability to scale the manufacturing process up to 2,000 liters.

We believe NAVXpress enables consistent, rapid, and reliable manufacturing across programs, addressing key challenges in advancing gene therapies to market and at scale. The NAVXpress manufacturing process is fully characterized, and we have completed full-scale process validation across three of our late-stage programs to support the RGX-121 BLA and future BLA submissions.

We have designed custom starting materials for use in the NAVXpress platform, including plasmids and cell lines, that increase the efficiency and productivity of NAV vectors. We have demonstrated that these cell lines, named NAVXcell®, enable high-yielding production processes while allowing for efficient purification.

We have developed product formulations specific to our different delivery devices and routes of administration. We aim to ensure that our formulations are designed and assessed to ensure product stability can be maintained for numerous years and that our AAV therapeutics can be exposed to a variety of handling and delivery procedures.

We have endeavored to design our platform manufacturing process, formulations and devices to enable efficient transition from research to clinical trials to commercial readiness, while minimizing changes during product development. To support our platform, we have developed a comprehensive set of analytical methods to assess quality and characterize the product. We continue to expand and enhance internal analytical lab capabilities with the aim of improving quality and control and supporting accelerated development of AAV therapeutics.

The close collaboration of our research and manufacturing teams allows us to evaluate the manufacturability of AAV therapeutics early in the discovery process and move quickly from candidate selection to the manufacturing of clinical-grade material. We believe this allows us to accelerate the process of developing AAV therapeutics.

AAV Therapeutic Delivery Devices

We believe that a critical component of AAV Therapeutic development is to deliver treatments safely, effectively and efficiently to the right part of the body. We leverage the differentiated characteristics of NAV Vectors to target different tissues and cells. To further enhance the profile of AAV therapeutics, we have developed a platform of different devices to assist in the delivery of AAV therapeutics using multiple routes of administration to tissues and cells.

We have developed significant expertise in designing delivery device systems for use with AAV therapeutics and have also developed and in-licensed relevant intellectual property, including know-how, related to delivery devices. Our research and development activities have involved several delivery device advancements for AAV therapeutics. We focus research on designing features and implementing delivery device solutions that we believe have the potential to improve the effect, patient safety and caregiver usability of AAV therapeutics.

We leverage and support the advancement of innovative devices to deliver our investigational gene therapies using multiple routes of administration, including to the central nervous system and subretinal and suprachoroidal regions of the eye. As part of our delivery device expertise, we have created teams of experts to support and train physicians to deliver AAV therapeutics in operating room and physician office settings.

In recent years, a tremendous amount of progress has been made in the development of gene therapies, and we believe we are a leader in these advancements.

Our Investigational AAV Therapeutics

We are currently focusing our internal development pipeline in three areas: retinal diseases, neuromuscular diseases and neurodegenerative diseases.

Sura-vec (ABBV-RGX‑314) for the Treatment of Wet AMD and DR

We are developing surabgene lomparvovec (sura-vec, ABBV-RGX‑314) in collaboration with AbbVie as a potential one-time treatment for wet AMD and DR. These diseases are characterized by loss of vision due to excess fluid accumulation from new blood vessel formation and treated with anti-vascular endothelial growth factor (anti-VEGF) therapies.

Wet AMD is the leading cause of vision loss in people over 60, affecting more than two million patients in the United States, Europe and Japan. The risk for developing wet AMD increases with age and we anticipate that the incidence of new cases will continue to increase significantly with the growth of an aging population. In patients with wet AMD, fluid accumulation can result in physical changes in the structure of the retina and adverse changes in vision. As this process progresses, blindness can result from atrophy and scar formation.

DR is a complication of diabetes and is the leading cause of blindness in adults between 24 and 75 years of age worldwide. It is a progressive retinopathy, and the spectrum of DR severity ranges from non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR). As DR progresses, a large proportion of patients develop vision-threatening complications, including diabetic macular edema (DME) and neovascularization that can lead to blindness. An estimated 27 million patients are affected with DR across the U.S., Europe and Japan, and of those, there are more than 23 million DR patients without center-involved DME. DR is the leading cause of vision loss in working-age adults and the incidence is expected to continue to grow significantly with the prevalence of diabetes.

Frequent anti-VEGF injections in the eye have been shown to reduce the risk of blindness in randomized controlled clinical trials and are approved for the treatment of wet AMD and DR. The current standard-of-care anti-VEGF treatments require patients to receive injections in the eye every four to 16 weeks for the duration of the disease. Real world evidence shows that patients with wet AMD are severely undertreated, and DR patients with early non-proliferative disease are often not treated due to the unsustainable treatment burden of administering frequent injections required with currently approved anti-VEGF therapies. As a result, the majority of wet AMD patients experience significant vision loss over time and most patients with early non-proliferative DR progress to more severe forms of the proliferative disease, developing common vision-threatening complications such as center-involved DME and proliferative DR.

Sura-vec is being developed as a novel, one-time treatment that includes the NAV AAV8 vector containing a gene for a monoclonal antibody fragment designed to inhibit VEGF activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation. After delivery of sura-vec, we believe retinal cells will continue to produce the anti-VEGF protein. Two separate routes of administration of sura-vec to the eye are being evaluated: a subretinal delivery procedure as well as a targeted, in-office administration to the suprachoroidal space. We have licensed certain exclusive rights to the SCS Microinjector® from Clearside Biomedical, Inc. (Clearside) to deliver gene therapy treatments to the suprachoroidal space of the eye.

Sura-vec is currently being evaluated in multiple clinical trials, including two pivotal trials (ATMOSPHERE and ASCENT), one Phase II bridging study, one long-term follow-up study and a fellow eye sub-study in patients with wet AMD, all utilizing subretinal delivery. Additionally, two Phase II clinical trials in patients with wet AMD (AAVIATE) and DR (ALTITUDE) are ongoing along with two corresponding long-term follow-up studies, all utilizing in-office suprachoroidal delivery. Within the Phase II study in DR, we are also evaluating ABBV-RGX-314 in diabetic macular edema (DME). Additionally, we are planning a Phase IIb/III program in DR and expect to dose the first patient in a two-part Phase IIb/III study (NAAVIGATE) in the second quarter of 2026.

Clinical Development of Sura-vec Subretinal Delivery for the Treatment of Wet AMD

We have two ongoing pivotal trials, ATMOSPHERE® and ASCENT®, for the treatment of wet AMD using sura-vec (ABBV-RGX-314) delivered subretinally.

ATMOSPHERE and ASCENT are multi-center, randomized, active-controlled pivotal trials to evaluate the efficacy and safety of a single-administration of sura-vec versus standard of care in patients with wet AMD. Enrollment in both trials completed in October 2025. To support future commercialization of sura-vec, the cGMP material produced by our NAVXpress platform process has been incorporated in the ongoing pivotal trials, ATMOSPHERE and ASCENT, for the treatment of wet AMD using sura-vec delivered subretinally.

These trials are expected to support global regulatory submissions, including with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Over 1,200 participants enrolled in ATMOSPHERE and ASCENT combined. We expect topline data from these trials to be shared in the fourth quarter of 2026.

In October 2022, we announced data from the Phase I/IIa long-term follow-up study of sura-vec for the treatment of wet AMD using subretinal delivery (n=37). Results show that sura-vec demonstrated to be generally well-tolerated (nine SAEs were reported in four patients, none of which were considered related to sura-vec) and patients treated with sura-vec demonstrated a durable treatment effect up to four years in Cohort 3 and up to three years in Cohort 4. Stable to improved visual acuity was observed, with a mean BCVA of +12 letters from baseline at four years for Cohort 3 patients and -5 letters from baseline at three years for Cohort 4 patients following sura-vec administration.

Two-year findings from this study were published in The Lancet in March 2024, in a paper titled "Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study".

In July 2025, we presented final one-year data at the American Society of Retinal Specialists annual meeting from the Phase II pharmacodynamic study designed to evaluate the same dose levels being used in the two pivotal trials. Results support the dose levels demonstrated similar clinical profiles. As of October 21, 2024, sura-vec manufactured using REGENXBIO's NAVXpress platform process was well tolerated at both dose levels with no drug-related serious adverse events (SAEs). At one year, at both dose levels, participants receiving sura-vec demonstrated stable to improved best corrected visual acuity and central retinal thickness, as well as meaningful reductions in anti-VEGF burden in participants with high treatment burden, with the majority remaining injection-free.

In June 2025, we reported one-year results from the Phase II fellow eye sub-study Clinical Trials at the Summit. The sub-study evaluated subretinal delivery of sura-vec in patients who received sura-vec in the Phase I/IIa or bridging studies and elected to receive treatment in their second eye. As of May 26, 2025, sura-vec was well tolerated in the treated second eye with no drug-related serious adverse events and no cases of intraocular inflammation observed. At 12 months post-administration, patients saw a 93% reduction in anti-VEGF treatment burden and sustained vision and anatomy. We believe these data demonstrate the potential of sura-vec to preserve vision long-term for patients with wet AMD as a one-time treatment for both eyes. Bilateral disease impacts a significant number of patients with wet AMD.

Clinical Development of Sura-vec Suprachoroidal Delivery for the Treatment of Wet AMD

We are also evaluating the efficacy, safety and tolerability of suprachoroidal delivery of sura-vec through AAVIATE®, a multi-center, open label, randomized, controlled, dose-escalation Phase II trial of sura-vec for the treatment of wet AMD.

In January 2024, we announced data from the AAVIATE trial demonstrating that patients treated with sura-vec continue to demonstrate stable BCVA and CRT at six months. In addition, a meaningful reduction in anti-VEGF treatment burden was observed following administration of sura-vec. The highest reduction was seen in dose level 3, demonstrating an 80% reduction in annualized injection rate with 50% of patients remaining injection-free.

As of July 29, 2024, sura-vec at dose level 3 with short course prophylactic steroid eye drops continued to be well tolerated with no drug-related serious adverse events (SAEs) and no cases of intraocular inflammation, endophthalmitis, vasculitis, retinal artery occlusion, choroidal effusion, or hypotony. Mild episcleritis occurred in three patients, all resolved and completed treatment with topical steroids. There were no cases of elevated intraocular pressure. Based on this favorable safety profile, the Phase II AAVIATE trial also enrolled a cohort to evaluate sura-vec at dose level 4 (1.5x10e12 GC/eye). Patients in this cohort also received short course prophylactic steroid eye drops.

Clinical Development of Sura-vec Suprachoroidal Delivery for the Treatment of DR

We are evaluating the efficacy, safety and tolerability of suprachoroidal delivery of sura-vec for the treatment of DR. In August 2025, we announced 2-year results from ALTITUDE®, a multi-center, open label, randomized, controlled, dose-escalation Phase II trial evaluating patients with non-proliferative DR (NPDR) who received a single, in-office injection of sura-vec.

As of June 9, 2025, sura-vec was well tolerated at dose levels 1, 2 and 3, with no drug-related SAEs. No intraocular inflammation was observed through two years at dose level 3 (1.0x10e12 GC/eye) (n=15) with short-course topical prophylactic steroids. Additionally, NPDR patients that received sura-vec demonstrated durable, long-term efficacy. Sura-vec demonstrated a dose-dependent increased rate of meaningful improvement as measured by the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale, with 50% of dose level 3 patients achieving at least a two-step improvement without the need for any supplemental treatment. We also reported that dose level 3 patients achieved an over 70% reduction in the risk of vision threatening events compared to historical control.

Based on these results, we announced we will initiate a pivotal Phase IIb/III trial evaluating sura-vec in subjects with NPDR without center-involved DME, and a corresponding amendment to our eyecare collaboration with AbbVie. We are activating clinical sites for a Phase IIb/III double-masked sham injection controlled trial. We expect to dose the first patient in the second quarter of 2026.

The Phase II ALTITUDE trial also includes a cohort of patients with center-involved DME. Enrollment completed in this cohort in June 2025. DME is a vision-threatening complication of DR. Patients will receive a one-time, in-office injection of sura-vec dose level 4 (1.5x10e12 GC/eye) with short course prophylactic steroid eye drops.

RGX-202 for the Treatment of Duchenne

We believe that RGX-202 has the potential to serve as a second-to-market, differentiated gene therapy treatment for Duchenne.

RGX-202 is our investigational AAV Therapeutic for the treatment of Duchenne, a rare disease caused by mutations in the gene responsible for making dystrophin, a protein of central importance for muscle cell structure and function. Without dystrophin, muscles throughout the body degenerate and become weak, eventually leading to loss of movement and independence, required support for breathing, cardiomyopathy and premature death. There is presently no cure for Duchenne, and there is a significant unmet need for disease modifying treatment options. Duchenne is one of the most common fatal genetic disorders affecting children, primarily boys. Duchenne is estimated to occur in approximately one in every 3,500-5,000 live male births and has an estimated prevalence of more than 30,000 cases in the U.S., Europe and Japan.

RGX-202 is designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-Terminal (CT) domain found in naturally occurring dystrophin. Presence of the CT domain has been shown in preclinical studies to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice. Additional design features may potentially improve gene expression, increase translational efficiency and reduce immunogenicity. RGX-202 is designed to support the delivery and targeted expression of the transgene throughout skeletal and heart muscle using the NAV AAV8 vector, and a well-characterized muscle-specific promoter (Spc5-12).

We have received orphan drug product, Fast Track designation and rare pediatric disease designation from the FDA for RGX‑202.

Clinical Development of RGX-202

AFFINITY DUCHENNE® is a multicenter, open-label Phase I/II/III trial evaluating two dose levels (1x1014 GC/kg and 2x1014 GC/kg) of RGX-202 in ambulatory patients aged one and older. The pivotal phase of the trial, evaluating dose level 2, is fully enrolled (n=30) and expected to support a BLA submission using the accelerated approval pathway in 2026.

In November 2024, we reported positive interim safety and efficacy data from the Phase I/II portion of the trial. This included a favorable safety profile at both dose levels among the first eleven patients, with no adverse events (AEs) or series adverse events (SAEs) reported, positive RGX-202 microdystrophin expression results for the first nine patients, with all patients exceeding 10% expression, and positive functional outcomes from the first five Phase I/II participants. Functional results included 12-month data from three dose level 1 patients aged 4-10 and nine-month data from two dose level 2 (pivotal dose) patients aged 8 and 12. In all five participants, across both dose levels, RGX-202 demonstrated evidence of positively impacting disease trajectory, with patients demonstrating stable or improved function on NSAA and timed function tests including time to stand, 10 meter walk/run and time to climb. Results were measured against external natural history controls matched for age and baseline function.

Through January 2026, subsequent interim data from the Phase I/II study was presented and was generally consistent with the positive initial findings. Results reported in June 2025 demonstrated a continued favorable safety profile with no SAEs or adverse events of special interest (AESI) reported (n = 13), positive safety data including consistent, robust microdystrophin expression and transduction across all treated ages (n = 12) and positive interim functional results from all dose level 2 recipients at 9 and 12 months (all dose level 2 participants exceeded external natural history controls on all functional measures). Additional positive data evaluating individual patient North Star Ambulatory Assessment (NSAA) using the established cTAP disease progression model results at 12 months were presented in October 2025 (at the 2025 International Congress of the World Muscle Society) and at 18 months in January 2026 (via a company announcement). As of January 5, 2026, RGX-202 was well tolerated in the Phase I/II trial, with no SAEs or AESIs.

The pivotal portion of AFFINITY DUCHENNE is ongoing and we expect to report topline data from the ongoing pivotal study of AFFINITY DUCHENNE in early second quarter of 2026. To support potential accelerated approval, the primary endpoint of the pivotal trial is the proportion of participants whose RGX-202 microdystrophin expression is ≥ 10% at Week 12. Secondary endpoints include change from baseline on timed function tests including time to stand, 10 meter walk/run and time to climb in participants ages 4 and older. Participants aged 1 to < 4 years will be evaluated using the Peabody Developmental Motor Scale-Third Edition and stride velocity 95 th centile. Patients will be assessed on the North Star Ambulatory Assessment (NSAA) as an exploratory endpoint. We expect to request a pre-BLA meeting with the FDA based on this data in mid-2026. Additional regulatory interactions with the FDA and European Medical Association (EMA) are planned for the first half of 2026. We are recruiting patients (n=30) in the confirmatory portion of the AFFINITY DUCHENNE trial of RGX-202.

Additionally, preclinical results comparing a microdystrophin gene therapy construct that included the C-terminal (CT) domain, which is included in the RGX-202 construct, to a microdystrophin construct without the CT domain which were published in Molecular Therapy Methods and Clinical Developmentin July 2025. The results showed that the microdystrophin with the CT domain improved functional benefit compared to the microdystrophin without, supporting the potential of RGX-202 to drive functional improvements in patients with Duchenne Muscular Dystrophy.

RGX-202 is manufactured using our proprietary, high-yielding NAVXpress platform process. This suspension-based manufacturing process has demonstrated scalability up to 2,000 liters with consistent yield and product purity. The RMIC has the capacity and yields to produce up to 2,500 doses of RGX-202 per year to support future commercialization. We began manufacturing the first batches of RGX-202 intended for commercial supply at the RMIC and completed the Process Performance Qualification (PPQ) campaign in the fourth quarter of 2025.

Additionally, we are recruiting patients in the AFFINITY BEYOND® trial, an observational screening study. The primary objective of AFFINITY BEYOND is to evaluate the prevalence of AAV8 antibodies in patients with Duchenne up to 12 years of age. Information collected in this study may be used to identify potential participants for the AFFINITY DUCHENNE trial and potential future trials of RGX-202.

RGX‑121 for the Treatment of MPS II

RGX‑121 (clemidsogene lanparvovec) is our investigational AAV Therapeutic for the treatment of MPS II, which we are developing in collaboration with Nippon Shinyaku in the U.S. and certain countries in Asia. MPS II, also known as Hunter syndrome, is a rare disease caused by mutations in the gene responsible for making iduronate-2-sulfatase (IDS), which encodes the I2S enzyme. The I2S enzyme is responsible for the breakdown of the polysaccharides heparan sulfate (HS) and dermatan sulfate in lysosomes, structures that dispose of waste products inside cells. These polysaccharides, called glycosaminoglycans (GAGs), accumulate in tissues of MPS II patients, resulting in diverse clinical signs and symptoms. HS is a key biomarker of I2S enzyme activity and high amounts of HS accumulate in the central nervous system (CNS) of neuronopathic MPS II patients, which has been shown to correlate with neurocognitive manifestations of the disease. In severe forms of the disease, early developmental milestones may be met during the first year after birth, but developmental delay is readily apparent by 18 to 24 months. Developmental progression begins to plateau between three and five years of age, with regression reported to begin around six and a half years. By the time of death, most patients with CNS involvement are severely mentally handicapped and require constant care. MPS II is estimated to occur in approximately 1 in 100,000 to 1 in 170,000 births worldwide. Based on global population, this equates to approximately 500 to 1,000 MPS II patients born each year worldwide.

Enzyme replacement therapy (ERT), the current standard of care for patients with MPS II, does not treat CNS manifestations of the disease because the enzyme cannot cross the blood-brain barrier. We believe that specific treatment to address the neurological manifestations of MPS II and prevent or stabilize cognitive decline remains a significant unmet medical need.

RGX‑121 is designed to use the NAV AAV9 vector to deliver the human IDS gene to cells in the CNS. Delivery of the gene therapy and expression of the enzyme that is deficient within cells in the CNS could provide a permanent source of secreted I2S enzyme on the CNS side of the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS. We believe this strategy could provide rapid I2S enzyme delivery to the brain, potentially preventing the progression of cognitive deficits that otherwise occur in MPS II patients.

We have received orphan drug product designation, rare pediatric disease designation, regenerative medicine advanced therapy (RMAT) and Fast Track designation from the FDA, as well as orphan designation and advanced therapy medicinal products (ATMP) classification from the EMA for RGX‑121.

Clinical Development of RGX‑121 for the Treatment of MPS II

CAMPSIITE® is a Phase I/II/III multicenter, open-label trial enrolling boys with MPS II, aged 4 months up to 5 years of age.

In February 2024, we reported that the pivotal phase of the CAMPSIITE trial achieved its primary endpoint, proportion of patients with cerebrospinal fluid (CSF) D2S6 below maximum attenuated level at W16. Accurate and sensitive measurements of CSF GAGs, such as HS D2S6, have the potential to be considered a surrogate endpoint that is reasonably likely to predict clinical benefit in MPS II disease under the accelerated approval pathway, as buildup of GAGs in the CSF of MPS II patients correlates with clinical manifestations including neurodevelopmental deficits. MPS II patients treated with RGX-121 achieved decreased CSF levels of D2S6 below maximum attenuated disease levels at 16 weeks (p value of 0.00016). Patients receiving RGX-121 demonstrated an 86% median reduction in D2S6, approaching normal levels. Initial pivotal results were consistent with data from the dose-finding phase of CAMPSIITE, in which the majority of patients were shown to be exceeding expectations in neurodevelopmental function compared to natural history data up to four years.

In June 2024, we announced the completion of a successful pre-BLA meeting for RGX-121, where we finalized details of our BLA with FDA. In that announcement, we shared that the FDA continued to be aligned with our plan to use CSF levels of HS D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit to support accelerated approval of RGX-121.

In September 2024, we reported long term data showing that patients receiving RGX-121 at the pivotal dose level demonstrated an 85% median reduction of CSF levels of HS D2S6 approaching normal levels and sustained for up to two years. In the dose-finding part of the trial, investigators chose to discontinue standard-of-care intravenous enzyme replacement therapy (ERT) or to remain ERT-naïve for a majority of patients. At the pivotal dose level (dose level 3), 80% of patients were ERT-free at last time point, up to more than 18 months post-dosing. At dose level 2, 71% of patients were ERT-free at last time point, up to almost three years.

In January 2025, we announced a strategic partnership with Nippon Shinyaku to develop and commercialize RGX-121 and RGX-111 in the United States and certain countries in Asia. For more information, refer to "Nippon Shinyaku Partnership for MPS Diseases" below.

In March 2025, we submitted a BLA for RGX-121 seeking accelerated approval to the FDA, which we believe is likely to be eligible for priority review. In August 2025, the FDA completed a pre-license inspection and bioresearch monitoring information inspection for the RGX-121 BLA with no observations. Also in August 2025, we announced the FDA had extended its review timeline of the RGX-121 BLA following the Company's submission of longer-term clinical data for all patients in the pivotal study of RGX-121 (n=13) in response to an FDA information request, resulting in an extension of the Prescription Drug User Fee Act (PDUFA) date from November 9, 2025 to February 8, 2026. These positive 12-month clinical data, which were consistent with biomarker and neurodevelopmental data previously submitted on the same patients in the BLA, were presented during the International Congress of Inborn Errors of Metabolism (ICIEM) in September 2025.

In January 2026, we announced that the FDA placed the RGX-121 program on clinical hold in relation to a serious adverse event in a patient treated in the Phase I/II trial of RGX-111. The FDA cited the similarities in products, study populations, and shared risk between the clinical studies. For more information, refer to the “Clinical Development of RGX-111 for the Treatment of MPS I” below.

In February 2026, we announced that the FDA issued a Complete Response Letter (CRL) for the RGX-121 BLA. The FDA stated in the CRL that it had agreed to the study protocol in principle and outlined several reasons for not approving the gene therapy, including uncertainty regarding the study eligibility criteria to adequately define a population with neuronopathic disease (vs. attenuated disease), the comparability of the natural history external control to the study population, and the appropriateness of CSF HS D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit. The CRL lists several potential paths forward, including a new study, treating additional patients and conducting longer-term follow up, and using an untreated control arm. Throughout active discussions during the BLA process, we believed we had addressed the points raised in the CRL through the submission of additional data and responses to numerous information requests. The FDA did not agree the data set provided substantial evidence of effectiveness to support approval of RGX-121 for the treatment of MPS II. We plan to request a Type A meeting with the FDA.

As of March 2026, we plan to work with the FDA to address the clinical holds and CRL, and discuss potential paths forward for the program. Potential approval of the BLA for RGX-121 could result in receipt of a Rare Pediatric Disease Priority Review Voucher, assuming the statutory criteria are met. If approved, RGX-121 is expected to be the first approved gene therapy and one-time treatment for MPS II.

RGX‑111 for the Treatment of MPS I

RGX-111 is our investigational AAV Therapeutic for the treatment of MPS I, a rare disease caused by deficiency of IDUA, an enzyme required for the breakdown of polysaccharides in lysosomes. Like RGX-121, this program is included our strategic partnership with Nippon Shinyaku to develop and commercialize RGX-121 and RGX-111 in the United States and certain countries in Asia.

Similar to MPS II, many MPS I patients develop symptoms related to GAG accumulation in the CNS, which can include excessive accumulation of fluid in the brain, spinal cord compression and cognitive impairment. MPS I patients span a broad spectrum of disease severity and extent of CNS involvement. The severe form of MPS I is also referred to as Hurler syndrome. Hurler patients have two mutations in the IDUA gene, resulting in no active enzyme. These patients typically present with symptoms before two years of age and universally exhibit severe cognitive decline after an initial period of normal development. MPS I is estimated to occur in approximately 1 in 100,000 births worldwide. Based on global population, this equates to more than 1,000 MPS I patients born each year worldwide. The current standard of care for patients with an attenuated form of MPS I is a recombinant form of human IDUA, given as a weekly ERT infusion. This has demonstrated improvement in hepatosplenomegaly, growth, mobility and respiratory function. However, as the enzyme cannot cross the blood-brain barrier, ERT does not treat the CNS manifestations of MPS I. Patients are also often treated with hematopoietic stem cell transplantation (HSCT). Although this approach has demonstrated improvements in survival, growth, cardiac and respiratory function, mobility and intellect, it is also associated with clinically relevant morbidity and an estimated 10% to 20% mortality. Accordingly, the procedure is reserved for patients with severe disease before two years of age because the risk-benefit ratio is thought to be more favorable in younger patients who have not yet experienced advanced cognitive decline. Another critical limitation of HSCT is that cognitive decline continues for up to a year after transplant before stabilizing, leaving permanent cognitive deficits.

Overall, we believe the limitations of HSCT and ERT leave a significant unmet need for a method to safely achieve long-term IDUA reconstitution in the CNS for MPS I patients experiencing neurological complications. RGX-111 is designed to use the NAV AAV9 vector to deliver the human IDUA gene to the CNS. Delivery of the enzyme that is deficient within cells in the CNS could provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS. We believe this strategy could also provide rapid IDUA delivery to the brain, potentially preventing the progression of cognitive deficits that otherwise occurs in MPS I patients. We have received orphan drug product designation, rare pediatric disease designation and fast track designation from the FDA, as well as orphan designation and ATMP classification from the EMA for RGX-111.

Clinical Development of RGX‑111 for the Treatment of MPS I

A Phase I/II study evaluating RGX-111 initiated in 2017 and enrollment for that study completed in 2023. The multi-center, open-label, dose escalation trial evaluated the safety, tolerability and pharmacodynamics of RGX-111 delivered via single injection to the CNS to patients with MPS I. Interim results from the study, reported in February 2023, showed RGX-111 to be well tolerated across two dose levels in the eight patients enrolled in the Phase I/II trial as of January 17, 2023 and in the single-patient IND as of December 12, 2021, with no drug-related SAEs. Biomarker and neurodevelopmental assessments indicated an encouraging CNS profile in patients dosed with RGX-111.

In November 2023, future development of RGX-111 was largely halted as a result of a strategic pipeline prioritization and corporate restructuring. Efforts to continue development of RGX-111 are set to be reinitiated following our announcement in January 2025 of a strategic partnership with Nippon Shinyaku to develop and commercialize RGX-111 in the United States and Asia. For more information, refer to "Nippon Shinyaku Partnership for MPS Diseases" below.

In January 2026, we announced that the FDA placed the RGX-111 program on clinical hold following preliminary analysis of a single case of neoplasm (intraventricular CNS tumor) in a participant treated in the Phase I/II study. The case was identified during a routine brain MRI of an asymptomatic five-year-old participant who received intracisternal RGX-111 four years prior. Preliminary genetic analysis of the resected tumor detected an AAV vector genome integration event associated with overexpression of a proto-oncogene (PLAG1), which is known to be susceptible to chromosomal rearrangements. Final analysis of the resected tumor was conducted by an independent third-party lab, and, as previously reported, detected an AAV vector genome integration event associated with overexpression of a PLAG1. Clonal integration of AAV vector elements into the PLAG1 gene was detected in the tumor tissue. Analyses supported classification as a PLAG1‑family neuroepithelial tumor and are consistent with the hypothesis that AAV vector integration at the PLAG1 site contributed to tumor formation. Of note, this participant had a background of factors that could have contributed to risk of oncogenic transformation. This child underwent unsuccessful stem cell transplant at 4 months of age, with loss of donor chimerism, and he received chemotherapeutics that may have contributed to DNA damage. The report concludes, based on formal neuropsychologic testing and developmental pediatrician assessment, that the patient’s neurocognitive development is above average, which indicates mitigation of MPS I disease, and the patient continues to do well. We anticipate the analysis will be published in a peer-reviewed journal this year.