The FDA has placed a clinical hold on RGX-121 after small nodules or cystic masses were detected in the spines of five patients enrolled in REGENXBIO’s registrational trial. The biotech no longer plans to resubmit the candidate—which was rejected in February—in the near term.
REGENXBIO was down 22% in premarket trading Monday after the FDA placed a clinical hold on its embattled Hunter syndrome gene therapy—eschewing the biotech’s plans to refile for approval of the asset in the third quarter.
The FDA implemented the hold after the discovery of asymptomatic MRI findings in the spines of five participants in the Phase 1/2/3 CAMPSIITE study—the basis of REGENXBIO’s biologics license application (BLA) for RGX-121, which was rejected by the agency in February.
“All five participants continue to do well clinically and have demonstrated overall stability to improvement on neurocognitive and neurobehavioral assessments,” according to the company’s press release on Monday. Nevertheless, REGENXBIO “does not expect to resubmit the RGX-121 Biologics License Application (BLA) in the near term.”
In its complete response letter for RGX-121, the FDA recommended that REGENXBIO run a new study, treat more patients and include a placebo arm to support a resubmission. The program got new life in June when the agency—now under the leadership of acting commissioner Kyle Diamantas—determined the existing data to be sufficient to support a resubmission under the accelerated approval pathway.
Now, however, the program has hit yet another bump in the regulatory road.
The safety signals were identified through an “expanded MRI monitoring plan,” which the biotech implemented after another gene therapy program, RGX-111, was placed on clinical hold in January following the discovery of a tumor in a patient with Hurler syndrome, or mucopolysaccharidosis type 1 (MPS1). Hunter syndrome is also known as MPS2.
In the case of RGX-111, a genetic analysis of a tumor sample showed that an AAV vector, which is used to deliver RGX-111, had integrated into its genome, leading to a mutation in a known cancer-causing gene.
Brain and spine MRIs for the RGX-121 program identified either a small nodule or a small cystic mass in the spines of five out of the 48 CAMPSIITE participants receiving intracisternal or intraventricular RGX-121 approximately three to six years ago, according to REGENXBIO.
“Investigators deemed these findings to be nonserious and radiologists believe they are likely benign,” the company said in its Monday statement. “There is no clinical or pathological evidence to confirm the nature or causation of the spine MRI findings.”
REGENXBIO added that because spine MRI is not typically performed for Hunter syndrome in either clinical practice or trials, “the underlying prevalence and clinical significance of these types of asymptomatic findings in this patient population is unknown.”
“Boys with neuronopathic MPS II experience a multitude of neurodevelopmental and systemic effects,” Roberto Giugliani, professor of genetics at the Federal University of Rio Grande do Sul in Brazil, said in a statement alongside the press release. “While imaging natural history is limited for this ultra-rare disease, I believe that asymptomatic, likely benign findings like these may be inherent to the impact of Hunter Syndrome throughout the body.”
REGENXBIO CEO Curran Simpson stressed in the same press release his belief that the MRI findings are isolated to RGX-121.
“We believe these findings are unique and limited to our Hunter Syndrome program, and require longer-term follow-up and additional data analysis to assess the benefit-risk profile of RGX-121,” he said.
