REGENXBIO's MPS II Gene Therapy RGX-121 Hit With CRL

REGENXBIO's biologics license application (BLA) for clemidsogene lanparvovec (RGX-121), an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat mucopolysaccharidosis type 2 (MPS II, also known as Hunter syndrome), has received a complete response letter (CRL) from the FDA.¹

According to REGENXBIO, the FDA’sCRL, which it received on February 7, 2026, covered several reasons that the gene therapy product was not approved—despite the agency’s agreement with the study protocol in principle—including concerns about the ability of the clinical trial eligibility criteria to distinguish between neuronopathic disease and attenuated disease adequately, whether the external natural history control population used is sufficiently comparable to the trial population, and if there is reasonable likelihood that the surrogate end point used—heparan sulfate (HS) D2S6 levels in the cerebrospinal fluid (CSF)—can predict clinical benefit in an appropriate manner. Notably, the CRL contained several suggested pathways to a potential approval for the product, such as a new clinical trial, carrying out dosing of additional patients with longer follow-up, and implementation of an untreated control group on-study. Although, REGENXBIO stated that it has concerns about the difficulty of these pathways considering the ultrarare nature of MPS II.

"This decision is devastating for the families of boys living with this progressive, life-threatening disease," Curran M. Simpson, the president and chief executive officer of REGENXBIO, said in a statement.¹ "We are concerned about FDA's feedback regarding the overall development path and evaluation of the data in the context of the urgent need for this irreversible ultra-rare disease. We remain confident in the quality and volume of evidence demonstrating the long-term potential of RGX-121 to positively change the trajectory of Hunter syndrome. This program has been in development for over 10 years. We are incredibly grateful to all the patients, their families, investigators, and site staff who have supported this program and our continued efforts to bring a much-needed new treatment option to the Hunter syndrome community. We will continue those efforts."

REGENXBIO stated its intent to pursue a Type A meeting with the FDA to discuss a planned resubmission of the BLA, which it noted could include longer-term clinical data and “additional evidence from global MPS II experts to further clarify the neuronopathic patient population.”¹ The company noted that it believed it had already addressed the FDA’s concerns through data updates and responses to information requests during the BLA review period and that analyses and reviews had been held between the FDA and “leading global MPS and biomarker experts” during this period.¹

"MPS II is a very complex disease, but its impact is well established, resulting in irreversible brain damage for the majority of patients; without appropriate treatments stopping this neurocognitive decline, the neuronopathic MPS II child will die prematurely, usually in their mid-teens," Joseph Muenzer, MD, PhD, the director of Muenzer MPS Research and Treatment Center and a Bryson Distinguished Professor in the Division of Genetics and Metabolism in the Department of Pediatrics Genetics at University of North Carolina at Chapel Hill, added to the statement.¹ "I remain encouraged by the clinical data behind RGX-121. New innovations like gene therapy could make a significant impact for these patients, and time is precious for these families."

Notably, the pivotal phase 1/2/3 CAMPSIITE clinical trial (NCT03566043) evaluating RGX-121 was placed on clinical hold by the FDA in January 2026.² The hold was related to an intraventricular central nervous system tumor that occurred in 1 patient who was treated with RGX-111, a separate REGENXBIO AAV vector-based gene therapy product under evaluation for severe mucopolysaccharidosis Type I (MPS I, also known as Hurler syndrome) in a phase 1/2 clinical trial. The patient has not experienced symptoms, but the neoplasm was identified on a routine brain MRI 4 years after the patient was treated with the gene therapy product, and preliminary analysis indicated an AAV vector genome integration event associated with overexpression of PLAG1, a protooncogene. REGENXBIO noted that the tumor was resected, that the patient has shown positive developmental advancements, and that whether the serious AE was related to RGX-111 has not yet been determined. Although the event occurred in an RGX-111 trial, according to the company the FDA placed a hold on the RGX-121 program in addition to the RGX-111 program because of “similarities in products, study populations, and shared risk between the clinical studies.”²

"We are surprised by FDA's decision to place our RGX-121 program on hold while the investigation of this single, inconclusive incident in RGX-111 continues," Simpson said in a January 2026 statement.² "These are separate therapies, and the positive safety profile of RGX-121 in more than 30 patients treated, including those dosed nearly 7 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. RGX-121 presents an opportunity to address the urgent, significant unmet medical need in this ultrarare disease community, and continued delay means continued neurodevelopmental decline in boys with MPS II."

REFERENCES
1. REGENXBIO announces regulatory update on RGX-121 BLA for MPS II. News release. REGENXBIO Inc. February 9, 2026. Accessed February 9, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-presents-positive-twelve-month-pivotal-data-phase
2. REGENXBIO announces regulatory update on ultra rare MPS programs. News release. REGENXBIO Inc. January 28, 2026. Accessed January 28, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-regulatory-update-ultra-rare-mps-programs/