FDA Issues CRL for REGENXBIO’s RGX-121 in Hunter Syndrome

FDA Issues CRL for REGENXBIO’s RGX-121 in Hunter Syndrome

By, Admin 10 February 2026

The US FDA has issued a Complete Response Letter (CRL) for RGX-121 (clemidsogene lanparvovec), REGENXBIO’s gene therapy for Mucopolysaccharidosis II (MPS II).

MPS II, also called Hunter syndrome, is an ultra-rare, progressive neurodegenerative disease affecting boys.

What the FDA Said?

The FDA did not approve the BLA under the accelerated approval pathway. The agency raised concerns around clinical definition, controls, and endpoints.

Key issues cited in the CRL:

  • Uncertainty in defining neuronopathic vs attenuated MPS II
  • Questions around comparability of the natural history external control
  • Lack of confidence that CSF HS D2S6 predicts clinical benefit

While the FDA agreed with the study protocol in principle, it concluded the data did not provide substantial evidence of effectiveness.

Why This Is a Big Setback?

RGX-121 targets the central nervous system, an area of critical unmet need in MPS II. The CRL suggests several possible paths forward:

  • A new clinical study
  • Treating additional patients
  • Longer-term follow-up
  • Inclusion of an untreated control arm

All of these are extremely challenging in an ultra-rare pediatric disease.

REGENXBIO’s Response

REGENXBIO plans to request a Type A meeting with the FDA. The company aims to:

  • Clarify the neuronopathic patient population
  • Submit additional long-term clinical data
  • Work toward BLA resubmission as quickly as possible

CEO Curran Simpson called the decision “devastating” for affected families.

Expert and Patient Advocacy Reactions

Clinical and patient leaders expressed strong concern. Dr. Joseph Muenzer, UNC Chapel Hill:

  • Emphasized the irreversible neurocognitive decline
  • Highlighted the urgency for CNS-targeted therapies

National MPS Society leadership urged:

  • Faster regulatory pathways for ultra-rare diseases
  • Immediate FDA engagement to identify a viable path forward

About RGX-121

RGX-121 is a one-time AAV gene therapy designed to deliver the IDS gene directly to the CNS. Its goal is long-term production of iduronate-2-sulfatase beyond the blood-brain barrier. The BLA was supported by data from the CAMPSIITE I/II/III trials, with follow-up through 12 months.

RGX-121 has shown:

  • Favorable safety profile
  • Biomarker reductions
  • Functional signals

But these were not sufficient for FDA approval.

Regulatory Context Matters

RGX-121 holds multiple FDA designations:

  • Orphan Drug
  • Rare Pediatric Disease
  • Fast Track
  • RMAT

Yet the CRL highlights a broader issue. Biomarker-driven approvals in ultra-rare CNS diseases remain a high bar.

Big Picture Takeaway

This CRL is not about safety. It’s about proof of clinical benefit, population definition, and endpoint acceptance. For gene therapies in ultra-rare neurodegenerative diseases, regulatory uncertainty remains the real bottleneck.

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