Second Clinical Hold Based on Long-Term MRI Findings

On August 24, 2026, the FDA placed REGENXBIO's clinical trial for RGX-121, a gene therapy for Hunter syndrome, on hold again. This decision followed the observation of asymptomatic spinal lesions in five patients who had received the treatment 3–6 years earlier in the CAMPSIITE study. While the company reported that the patients' clinical conditions remained stable and their neurocognitive and neurobehavioral assessments showed improvement or stability, the FDA prioritized a long-term safety evaluation to determine the nature of the lesions and their potential link to the treatment. As a result, further dosing and the company's short-term plan to resubmit the Biologics License Application (BLA) were suspended, causing the company's stock to drop more than 25% in early trading on the day of the announcement.

Safety Evaluation of IDS Gene Delivery Strategy Under Scrutiny

RGX-121, currently under development without a brand name, is also known by its generic name clemidsogene lanparvovec. It is a one-time investigational Phase 1/2 therapy that uses the NAV AAV9 vector to deliver a functional iduronate-2-sulfatase gene to the central nervous system. The goal is to enable the brain to continuously produce the IDS enzyme, thereby reducing heparan sulfate accumulation and inhibiting neurodegeneration. However, in January 2026, a brain tumor was observed in a patient treated with RGX-111, another therapy using the same platform, leading to the simultaneous hold of both RGX-111 and RGX-121. The recent spinal findings have once again highlighted the need for long-term monitoring of AAV-based therapies. Although no brain tumors were observed, the FDA and the company's ongoing review of imaging, pathology, and causality will determine the path to resuming development and finalizing the regulatory strategy.

Post-CRL Resubmission Path Also Delayed

The FDA issued a Complete Response Letter (CRL) for RGX-121's BLA on February 9, 2026, with the primary issue being the justification for using cerebrospinal fluid heparan sulfate reduction as a surrogate endpoint for accelerated approval. REGENXBIO had agreed to resubmit based on existing data after a Type A meeting and a formal objection, with plans to file again in June. However, this safety signal has led the company to withdraw its short-term submission plans. This delay indicates that the regulatory issue is not merely about supplementing efficacy data, but also requires an explanation of the natural incidence rate of imaging findings, vector biodistribution, and long-term tissue risks. There has been no AdCom vote history to date, and the current stage involves addressing the clinical hold and CRL.

Pressure from Approved Competitors and an 81-Million-Dollar Agreement

The Hunter syndrome treatment market is projected to reach USD 1.05 billion in 2025 and USD 1.12 billion in 2026. The current standard of care is Takeda's Elaprase (idursulfase), a recombinant IDS enzyme replacement therapy. Denali Therapeutics' Avlayah (tividenofusp alfa-eknm), a transferrin receptor-based enzyme delivery system that crosses the blood-brain barrier, received FDA accelerated approval on March 24, 2026, and has already entered the neurologic indication market ahead of RGX-121. REGENXBIO's agreement with Nippon Shinyaku includes an upfront payment of USD 110 million, development and regulatory milestone payments of USD 40 million, and sales milestones of USD 660 million, along with double-digit royalties tied to net sales. The delay in RGX-121 not only postpones the realization of unclaimed milestones and the value of priority review vouchers but also reduces the opportunity for the one-time dosing convenience to offset Avlayah's first-mover advantage.