> ## Content Index
> Fetch the complete content index at: https://www.fdaweb.com/llms.txt
> Use this file to discover other available public pages before exploring further.

# Regenxbio’s Complete Response Letter Released
- URL: https://www.fdaweb.com/regenxbios-complete-response-letter-released/
- Published: 2026-03-03T12:00:00.000Z
- Updated: 2026-09-14T13:34:41.000Z
- Author: David McFarland
- Tags: Biologics, #legacy-id-D5160755

A just-released [complete-response letter](https://download.open.fda.gov/crl/CRL%5FBLA125840%5F20260207.pdf?ref=fdaweb.com) is shedding light on FDA’s rejection last month of Regenxbio’s BLA for its gene therapy clemidsogene lanparvovec, citing fundamental concerns about the study population, choice of control, and use of a novel cerebrospinal fluid biomarker as the basis for accelerated approval. The therapy is intended to treat mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome

The company’s application sought a broad indication covering both neuronopathic and attenuated forms of MPS II. The rare genetic disorder, caused by mutations in the iduronate-2-sulfatase (IDS) gene, leads to the accumulation of glycosaminoglycans in tissues and progressive multi-organ dysfunction. The neuronopathic form is marked by neurological impairment.

Although FDA officials said they had previously agreed in principle to the study design and acknowledged regulatory flexibility given the rarity of the condition, they repeatedly raised concerns during development about the eligibility criteria, the comparability of the external control, and whether the biomarker could reasonably predict clinical benefit. In its letter, the agency said those concerns remained unresolved at the time of review.

“The data from the RGX-121-101 Part 2 study are insufficient to provide substantial evidence of effectiveness,” the FDA wrote, concluding that the trial did not qualify as an adequate and well-controlled study.

A central issue was how patients were classified as having neuronopathic disease. The trial allowed enrollment if patients met just one of four eligibility criteria — two based on specific IDS mutations and two based on neurodevelopmental testing using the Bayley Scales of Infant Development. FDA reviewers said that approach introduced heterogeneity and uncertainty about whether the enrolled children truly represented the intended neuronopathic population.

FDA also rejected the company’s proposed use of CSF HS D2S6 as a surrogate endpoint reasonably likely to predict clinical benefit. The biomarker has not previously supported a regulatory decision and is not part of routine clinical practice. The company defined responders as patients whose CSF HS D2S6 levels fell below 100 ng/mL, a threshold derived from a small dataset that included only seven external MPS II patients.

Regulators said the threshold lacked external validation and scientific consensus, and noted that some treated patients had pre-treatment levels below 100 ng/mL, complicating interpretation. Two patients in the pivotal cohort had baseline levels that made them effectively unevaluable for treatment effect under the proposed definition.

Moreover, most patients were followed for only 52 weeks, a duration FDA said was insufficient to assess deviations from natural cognitive decline in neuronopathic MPS II, which often manifests later in childhood.

Separately, the agency referenced a reported case of a malignant brain tumor in a separate gene therapy program (RGX-111 for MPS I) using a similar AAV vector platform. Because vector integration was identified in tumor tissue in that case, FDA said similar safety risks could exist for clemidsogene lanparvovec and signaled that a post-marketing safety requirement could be necessary in the future.

Potential paths forward include conducting a new clinical study or enrolling additional patients with longer neurodevelopmental follow-up, demonstrating meaningful biomarker normalization, and incorporating a more appropriate untreated control group. FDA also recommended use of an adjudication committee to better define the target population.

The company said last month after receiving the letter that the options FDA spelled out are particularly challenging in an ultra-rare disease population like MPS II. “This decision is devastating for the families of boys living with this progressive, life-threatening disease,” company CEO **Curran Simpson** is quoted in a release as saying. He added that the company remains confident in the long-term potential of RGX-121 and plans to work with FDA to clarify the neuronopathic patient population and provide additional clinical data. Regenxbio intends to request a Type A meeting to discuss next steps and aim for a BLA resubmission as quickly as possible.

The RGX-121 program has been in development for more than a decade, according to the company. The therapy is designed to deliver the IDS gene) to the central nervous system (CNS), potentially providing a permanent source of the enzyme and enabling long-term correction of affected cells. Across the CAMPSIITE I/II/III trials, RGX-121 has been well-tolerated and supported by biomarker, functional, and safety data, including outcomes through 12 months, it said.