FDA has placed clinical holds on REGENXBIO’s gene therapies RGX-111 (MPS I) and RGX-121 (MPS II) after a reported CNS tumor case in an RGX-111 trial participant, with investigations ongoing and causality not yet established.
Written By: Pharmacally Medical News Desk
REGENXBIO Inc. announced that the U.S. Food and Drug Administration (FDA) has placed a clinical hold on its investigational gene therapy RGX-111 (NCT03580083) for mucopolysaccharidosis type I (MPS I), also known as Hurler syndrome, following preliminary findings from a single reported case of neoplasm in a study participant.
The agency also issued a clinical hold on RGX-121 (NCT03566043), the company’s gene therapy program for mucopolysaccharidosis type II (MPS II), or Hunter syndrome, citing shared product and population similarities between the two trials.
The hold was initiated after routine monitoring identified an intraventricular central nervous system (CNS) tumor in an asymptomatic five-year-old child enrolled in the Phase I/II RGX-111 study. The participant had received intracisternal administration of RGX-111 approximately four years earlier.
Preliminary genetic evaluation of the resected tumor detected an adeno-associated virus (AAV) vector genome integration event linked to overexpression of the proto-oncogene PLAG1, a gene known to be vulnerable to chromosomal rearrangements. REGENXBIO noted that the investigation into whether the serious adverse event is related to treatment is still ongoing, and causality has not been established.
The notable part is that the participant remains asymptomatic and has shown positive developmental progress according to the treating physician. No additional neoplasm cases have been reported among the other nine participants treated with RGX-111 or among the 32 participants treated with RGX-121.
Company Responds to FDA Decision
REGENXBIO President and CEO Curran Simpson expressed surprise that the FDA extended the clinical hold to RGX-121 while the RGX-111 case remains inconclusive.
“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,” Simpson said. He emphasized that patient safety remains the company’s top priority while also highlighting the urgent unmet need for neurological treatment options in boys with MPS II.
The company stated that it has not yet received the full clinical hold letter and is awaiting additional details from the FDA.
Overview of RGX-121 in MPS II (Hunter Syndrome)
RGX-121 (clemidsogene lanparvovec) is being developed as a one-time gene therapy for boys with MPS II. The therapy is designed to deliver the iduronate-2-sulfatase (IDS) gene directly to the CNS, enabling long-term production of the I2S enzyme beyond the blood-brain barrier.
RGX-121 has received multiple regulatory designations from the FDA, including Orphan Drug Product, Rare Pediatric Disease, Fast Track and Regenerative Medicine Advanced Therapy (RMAT).
It has also received advanced therapy medicinal products (ATMP) classification from the European Medicines Agency.
MPS II is a rare X-linked recessive lysosomal storage disorder caused by I2S deficiency, resulting in accumulation of glycosaminoglycans and progressive CNS dysfunction. Severe forms often show developmental delays beginning around 18–24 months, and there remains a significant unmet medical need for therapies targeting neurological decline.
Overview of RGX-111 in MPS I (Hurler Syndrome)
RGX-111 uses an AAV9 vector to deliver the alpha-L-iduronidase (IDUA) gene to the CNS, aiming to provide permanent enzyme expression and prevent progression of cognitive impairment in MPS I patients.
RGX-111 has received Orphan Drug, Rare Pediatric Disease, and Fast Track designations from the FDA.
MPS I is a rare autosomal recessive disorder caused by IDUA deficiency and is estimated to occur in approximately 1 in 100,000 births. Current disease-modifying options include hematopoietic stem cell transplant (HSCT) and enzyme replacement therapy, but neither adequately addresses CNS involvement, and HSCT carries significant risk.
Next Steps
REGENXBIO stated that it will continue working with regulators as the investigation progresses. Both clinical programs remain paused until further FDA review clarifies the relationship, if any, between AAV vector integration and tumor development in the reported case.
References
REGENXBIO Announces Regulatory Update on Ultra Rare MPS Programs, Regenxbio via PR Newswire, 28 January 2026, https://www.prnewswire.com/news-releases/regenxbio-announces-regulatory-update-on-ultra-rare-mps-programs-302672061.html
RGX-121 for MPS II (Hunter Syndrome), REGENXBIO, https://www.regenxbio.com/therapeutic-programs/rgx-121/
RGX-111 Gene Therapy in Patients with MPS I, ClinicalTrials.gov ID NCT03580083, https://clinicaltrials.gov/study/NCT03580083
CAMPSIITE™ RGX-121 Gene Therapy in Subjects with MPS II (Hunter Syndrome), ClinicalTrials.gov ID NCT03566043, https://clinicaltrials.gov/study/NCT03566043
