Two investigational gene therapies for rare paediatric diseases have been put on hold by the US Food & Drug Administration (FDA) after a child treated in a clinical trial developed a brain tumour, according to RegenXBio last week.
MedPage Today reports that the holds affect RGX-111 and RGX-121, therapies designed to treat mucopolysaccharidosis (MPS) type I and type II, also known as Hurler and Hunter syndromes. Both disorders involve a lysosomal enzyme deficiency that causes cells to become severely dysfunctional, leading to cognitive, functional and cardiac complications and death.
The tumour was discovered during a routine MRI of a five-year-old child who had received RGX-111 four years earlier to treat MPS I.
The FDA also suspended trials of RGX-121, which is being tested in MPS II, citing similarities in products, study populations and shared risks between the clinical studies.
A preliminary analysis of the resected tumour detected an adeno-associated vector (AAV) genome integration that was associated with over-expression of the proto-oncogene PLAG1, which is known to be susceptible to chromosomal rearrangements, RegenxBio said.
“The causality has not been established,” the company wrote in a press release. “The participant continues to be asymptomatic, with positive developmental advancements noted by the treating physician.’
No evidence of neoplasm was reported in nine other participants treated with RGX-111, nor in 32 participants treated with RGX-121.
In MPS I, a deficiency in alpha-L-iduronidase (IDUA) leads to an accumulation of glycosaminoglycans like heparan sulfate in tissues. RGX-111 is designed to deliver a functional copy of the IDUA gene to the central nervous system (CNS) using an AAV9 vector.
The treatment was evaluated in a phase 1/2 study.
MPS II also leads to accumulation of glycosaminoglycans, but it is caused by a deficiency in iduronate-2-sulfatase (I2S). RGX-121 is intended to deliver a functional copy of the I2S (IDS) gene to the CNS using an AAV9 vector.
“We are surprised by the FDA’s decision to place our RGX-121 programme on hold while the investigation of this single, inconclusive incident in RGX-111 continues,” RegenxBio President and CEO Curran Simpson said in a statement.
“These are separate therapies, and the positive safety profile of RGX-121 in more than 30 patients treated, including those dosed nearly seven years ago, remains unchanged. Patient safety is our top priority, and we, our investigators, and the patient community. remain confident in the benefit-risk ratio of RGX-121 and are highly encouraged by the meaningful efficacy profile demonstrated in the pivotal trial.”
In September 2025, RegenxBio announced positive pivotal data from the CAMPSIITE study, in which RGX-121, also known as clemidsogene lanparvovec, met the primary endpoint of reducing cerebrospinal fluid values of heparan sulfate D2S6 (HS D2S6) in paediatric patients with MPS II. HS D2S6 has been shown to correlate with neurocognitive manifestations of MPS II.
The FDA was scheduled to decide whether to approve RGX-121 for MPS II on 8 February. RegenxBio said it had not yet received the full clinical hold letter from the FDA and awaits further details from the agency.
An enzyme replacement therapy known as tividenofusp alfa has also shown positive outcomes in MPS II recently.
A phase 2/3 trial of tividenofusp alfa is under way.
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