FDA Rejects Regenxbio’s MPS II Gene Therapy

Rare Daily Staff

The U.S. Food and Drug Administration rejected Regenxbio’s application for accelerated approval of RGX-121, the company’s gene therapy for the rare lysosomal storage disorder mucopolysaccharidosis II (MPS II), or Hunter syndrome.

Regenxbio shares fell more than 13 percent on the news.

The FDA told the company in a letter that it had agreed to the study protocol in principle and outlined several reasons for not approving the gene therapy, including uncertainty about whether the study’s eligibility criteria adequately defined a population with neuronopathic disease, the comparability of the natural history external control to the study population, and the appropriateness of its surrogate endpoint as reasonably likely to predict clinical benefit.

The letter from the agency listed several potential paths forward, including conducting a new study, treating additional patients with longer-term follow-up, and using an untreated control arm. Regenxbio said each of these approaches would be 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,” said Curran Simpson, president and CEO of Regenxbio. “We are concerned about the 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.”

MPS II, or Hunter syndrome, is caused by a deficiency of the lysosomal enzyme I2S, which leads to an accumulation of glycosaminoglycans (GAGs), including heparan sulfate (HS), in tissues. This buildup ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system (CNS). In severe forms of the disease, early developmental milestones may be met, but developmental delay typically becomes apparent by 18 to 24 months. Specific treatment to address the neurological manifestations of MPS II remains a significant unmet medical need. Key biomarkers of I2S enzymatic activity in MPS II patients include its substrate, CSF HS D2S6, which has been shown to correlate with the neurocognitive manifestations of the disorder.

RGX-121 is a potential one-time gene therapy designed to deliver the iduronate-2-sulfatase (IDS) gene to the CNS. Delivery of the IDS gene within CNS cells could provide a permanent source of secreted iduronate-2-sulfatase (I2S) protein beyond the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS. The RGX-121–expressed protein is structurally identical to normal I2S.

RGX-121 has received orphan drug, rare pediatric disease, fast track, and regenerative medicine advanced therapy (RMAT) designations from the FDA, as well as advanced therapy medicinal products (ATMP) classification from the European Medicines Agency.

The company said that throughout active discussions during the application process, it believed it had addressed the points raised in the agency’s letter through the submission of additional data and responses to numerous information requests. Independent, leading global MPS and biomarker experts conducted analyses and reviews with the FDA as well. Ultimately, the FDA did not agree that the data set provided substantial evidence of effectiveness to support approval of RGX-121 for the treatment of MPS II.

Regenxbio said it plans to request a Type A meeting to discuss the letter and the planned application resubmission. The company intends to provide additional evidence from global MPS II experts to further clarify the neuronopathic patient population and share longer-term clinical data to support evidence of effectiveness. Regenxbio said it aims to identify a path forward as quickly as possible with the goal of resubmitting the application.

Photo: Curran Simpson, president and CEO of Regenxbio.