As reported on drugs.com, REGENXBIO has disclosed that the U.S. Food and Drug Administration has halted clinical testing of its investigational gene therapies RGX‑111 and RGX‑121, both being developed for ultra‑rare mucopolysaccharidosis (MPS) disorders. The decision follows early findings of a brain tumor in a child previously treated with RGX‑111, a therapy aimed at MPS I (Hurler syndrome).
Tumor Identified in Long‑Term Follow‑Up
The safety signal emerged during a routine MRI in an asymptomatic five‑year‑old who had received RGX‑111 via intracisternal administration four years earlier. Surgical samples from the intraventricular CNS tumor revealed an adeno‑associated virus (AAV) vector integration event linked to elevated expression of PLAG1, a proto‑oncogene known to be vulnerable to chromosomal changes.
Investigators emphasized that the causal connection to the gene therapy remains undetermined. The child continues to show normal development and no clinical symptoms. No other cases of neoplasm have been reported among the remaining participants—nine treated with RGX‑111 and 32 treated with RGX‑121.
RGX‑121 Halted Due to Shared Risk Considerations
Although the event involved only RGX‑111, the FDA also suspended dosing of RGX‑121, a potential one‑time CNS‑directed therapy for MPS II (Hunter syndrome). Regulators cited overlap in patient populations, therapeutic design, and theoretical risk profiles.
REGENXBIO expressed disappointment with the broader hold. CEO Curran Simpson noted that RGX‑121 has shown a consistent safety record across more than 30 treated patients—including some followed for nearly seven years—and emphasized the significant unmet need in MPS II, where neurological decline progresses rapidly without effective intervention. The company awaits further detail in the FDA’s formal clinical hold communication.
About the Gene Therapy Programs
RGX‑121 (clemidsogene lanparvovec)
This program uses an AAV delivery system to introduce the iduronate‑2‑sulfatase (IDS) gene into CNS cells, with the aim of restoring continuous production of the I2S enzyme in boys with MPS II. The therapy has received multiple regulatory designations, including Orphan Drug, Rare Pediatric Disease, Fast Track, and RMAT status, as well as ATMP classification in Europe.
RGX‑111
Designed for MPS I, RGX‑111 delivers the α‑L‑iduronidase (IDUA) gene to the CNS using an AAV9 vector. The goal is long‑term enzyme expression capable of slowing or preventing cognitive decline. It has also received Orphan Drug, Rare Pediatric Disease, and Fast Track designations.
Background on MPS Disorders
MPS I and II are inherited lysosomal storage diseases caused by deficiency of critical enzymes responsible for breaking down glycosaminoglycans (GAGs). Accumulation of GAGs—particularly heparan sulfate—leads to widespread organ and neurologic dysfunction.
- MPS II (Hunter syndrome) primarily affects boys due to its X‑linked inheritance pattern. Neurological involvement remains an area of unmet medical need, as current enzyme replacement therapies do not cross the blood‑brain barrier.
- MPS I (Hurler syndrome) affects approximately 1 in 100,000 births. While stem cell transplantation and intravenous enzyme therapy can address systemic disease, CNS manifestations persist because existing therapies provide limited enzyme delivery to the brain.
What’s Next
REGENXBIO reports that investigations into the tumor’s origin are ongoing, and the company continues to work with regulators to resolve the clinical holds. Further updates are expected once the FDA issues its complete findings.
