The U.S. Food and Drug Administration (FDA) has placed two Regenxbio gene therapy programs on clinical hold, just weeks before a key regulatory decision was expected for one of the treatments. The decision followed the identification of a central nervous system (CNS) tumor in a pediatric trial participant, triggering heightened regulatory scrutiny. In response to the announcement, Regenxbio’s stock dropped sharply, falling approximately 32% in premarket trading to $9.16.
The clinical holds affect RGX-111 and RGX-121, two adeno-associated virus (AAV)–based gene therapies under development for rare lysosomal storage disorders. One of the holds was imposed less than two weeks before the FDA was scheduled to rule on the approval of RGX-121, significantly delaying the regulatory timeline.
CNS Tumor Identified in RGX-111 Trial Participant
Regenxbio disclosed that abnormal cellular growth was detected in a patient who had received RGX-111, an investigational gene therapy designed to treat mucopolysaccharidosis type I (MPS I), also known as Hurler syndrome. MPS I is a rare, inherited metabolic disorder that can lead to severe developmental delays, organ damage, neurological impairment, and premature death if left untreated.
RGX-111 is intended to improve neurological outcomes by delivering the IDUA gene directly to the central nervous system using an AAV9 vector, allowing for enzyme expression within the brain. The therapy was administered via intracisternal delivery, targeting the space near the brain.
The safety signal emerged after a routine MRI scan revealed a previously undetected intraventricular CNS tumor in an asymptomatic 5-year-old child. The patient had received RGX-111 approximately four years prior to the imaging finding.
FDA Extends Clinical Hold to RGX-121 Due to Shared Risk Profile
Although the adverse event occurred in a recipient of RGX-111, the FDA extended the clinical hold to RGX-121 due to similarities between the two programs. According to the agency, the treatments share overlapping technologies, trial populations, and potential safety risks associated with CNS-directed AAV gene therapy.
RGX-121 is being developed to treat mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, another rare genetic disorder that affects primarily young boys and leads to progressive neurological and physical decline. Regenxbio had submitted RGX-121 for FDA approval last year, and the agency had previously set a decision date in early February. That approval decision has now been postponed until at least February 8, pending further safety evaluation.
Genetic Analysis Reveals AAV Vector Genome Insertion
Initial genetic testing of the surgically resected brain tumor revealed the presence of an AAV vector genome insertion. Further analysis indicated that the insertion was associated with overexpression of PLAG1, a known proto-oncogene that is susceptible to chromosomal rearrangements and has been implicated in tumor formation.
Regenxbio stated that a comprehensive investigation is underway to determine whether the serious adverse event is causally related to RGX-111 or represents a coincidental finding. Regulatory authorities are expected to closely examine whether the AAV-based delivery method played a role in tumor development.
Company Response and Safety Record Emphasized
The company confirmed that the affected patient remains clinically asymptomatic, and the treating physician has reported favorable developmental progress following continued monitoring. Importantly, Regenxbio noted that none of the other nine RGX-111 trial participants have shown any evidence of neoplasm or abnormal growth to date.
Strategic Shift and Partnership with Nippon Shinyaku
In 2023, Regenxbio deprioritized RGX-111 as a standalone asset and began exploring strategic partnerships. This effort resulted in a collaboration agreement with Nippon Shinyaku, finalized approximately one year ago. The partnership includes both RGX-111 and RGX-121, with Regenxbio continuing to invest more heavily in RGX-121 due to its advanced development stage and regulatory momentum.
Despite the current setback, RGX-121 remains a key component of Regenxbio’s rare disease portfolio, and the company has reiterated its commitment to working closely with the FDA to address safety concerns and resume clinical development.
Broader Implications for AAV Gene Therapy Development
The FDA’s decision underscores ongoing regulatory caution surrounding CNS-targeted AAV gene therapies, particularly with respect to long-term safety and genomic integration risks. As gene therapy platforms move closer to commercialization, regulators are increasingly focused on rare but serious adverse events that may emerge years after treatment.
For Regenxbio, the coming months will be critical as investigators determine whether the CNS tumor is directly linked to RGX-111 or represents an isolated incident. The outcome of this review will not only shape the future of RGX-111 and RGX-121 but may also influence regulatory expectations across the broader gene therapy landscape.
FDA Places Clinical Hold on Regenxbio Gene Therapies Ahead of Approval Decision
Regenxbio said the U.S. Food and Drug Administration (FDA) has placed a clinical hold on two of Regenxbio’s investigational gene therapy programs, RGX-111 and RGX-121, just weeks before an expected approval decision for one of the therapies.
The clinical hold was triggered after a brain tumor was detected in a child who received Regenxbio’s RGX-111 gene therapy for mucopolysaccharidosis type I (Hurler syndrome) during a routine follow-up, prompting the FDA to review whether Regenxbio’s AAV-vector therapy contributed to the finding.
The FDA extended the hold to Regenxbio’s RGX-121 program, which targets mucopolysaccharidosis type II (Hunter syndrome), because of similarities in the design and risk profile of the two therapies — delaying Regenxbio’s impending regulatory decision that had been expected soon.
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