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

This article was originally published on our sister site, NeurologyLive®.

The FDA has issued a complete response letter (CRL) to REGENXBIO’s biologics license application (BLA) for clemidsogene lanparvovec (RGX-121), an investigational adeno-associated virus (AAV) vector–based gene therapy being developed for the treatment of mucopolysaccharidosis type 2 (MPS II), also known as Hunter syndrome.¹

REGENXBIO reported that it received the CRL on February 7, 2026. In the letter, the FDA outlined multiple reasons for not approving the gene therapy at this time, despite noting general agreement with the study protocol. These included concerns about whether the clinical trial eligibility criteria adequately differentiate neuronopathic from attenuated disease, whether the external natural history control group was sufficiently comparable to the treated population, and whether cerebrospinal fluid (CSF) heparan sulfate (HS) D2S6 levels, used as a surrogate end point, are reasonably likely to predict clinical benefit. The CRL also described several potential paths toward approval, including conducting a new clinical trial, dosing additional patients with longer follow-up, and incorporating an on-study untreated control group. REGENXBIO noted, however, that these approaches present challenges given 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."

The company stated that it plans to request a Type A meeting with the FDA to discuss a potential BLA resubmission. This resubmission could include longer-term clinical data as well as additional evidence from MPS II experts to further define the neuronopathic patient population. REGENXBIO added that it believes it addressed the FDA’s concerns during the review period through data updates, responses to information requests, and discussions involving FDA reviewers and MPS and biomarker experts.

"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/