FDA Places Clinical Hold on Regenxbio’s MPS1 Gene Therapy

The U.S. Food and Drug Administration has placed a clinical hold on Regenxbio’s experimental gene therapy, RGX-111, for the treatment of the rare lysosomal storage disorder MPS I, also known as Hurler syndrome.

Shares of Regenxbio were down about 15 percent on the day after falling as much as 30 percent at the opening.

The clinical hold came after a preliminary analysis of a single case of an intraventricular CNS tumor in a participant treated in its phase 1/2 study. The FDA also placed a clinical hold on RGX-121, for the treatment of MPS II, also known as Hunter syndrome, citing the similarities in products, study populations, and shared risk between the clinical studies.

The case was identified during a routine brain MRI of an asymptomatic five-year-old participant who received intracisternal RGX-111 four years prior. Preliminary genetic analysis of the resected tumor detected an AAV vector genome integration event associated with overexpression of a proto-oncogene (PLAG1), which is known to be susceptible to chromosomal rearrangements.

The investigation to determine if this serious adverse event is drug-related is ongoing. Causality has not been established. The participant continues to be asymptomatic, with positive developmental advancements noted by the treating physician. No evidence of neoplasm has been reported in the nine other participants treated with RGX-111 nor in the 32 participants treated with RGX-121.

MPS I is caused by a deficiency in the lysosomal enzyme alpha-L-iduronidase (IDUA), leading to an accumulation of glycosaminoglycans (GAGs), including heparan sulfate (HS), in tissues, which ultimately results in cell, tissue, and organ dysfunction, including in the central nervous system. This can include excessive accumulation of fluid in the brain, spinal cord compression, and cognitive impairment. Current disease-modifying therapies for MPS I include hematopoietic stem cell transplant (HSCT) and enzyme replacement therapy with a recombinant form of human IDUA administered intravenously. However, intravenous enzyme therapy does not treat the CNS manifestations of MPS I, and HSCT can be associated with clinically significant morbidity and mortality.

RGX-111 is designed to use the AAV9 vector to deliver the α-L-iduronidase (IDUA) gene to the central nervous system. Delivery of the IDUA gene within the cells in the central nervous system could provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS. By providing rapid IDUA delivery to the brain, RGX-111 could potentially help prevent the progression of cognitive deficits that otherwise occurs in MPS I patients. RGX-111 has received orphan drug product, rare pediatric disease, and Fast Track designations from the FDA.

“We are surprised by the FDA’s decision to place our RGX-121 program on hold while the investigation of this single, inconclusive incident in RGX-111 continues,” said Curran Simpson, president and CEO of Regenxbio. “These are separate therapies, and the positive safety profile of RGX-121 in more than 30 patients treated, including those dosed nearly seven years ago, remains unchanged. Patient safety is our top priority, and we, our investigators, and the patient community remain confident in the benefit-risk ratio of RGX-121 and are highly encouraged by the meaningful efficacy profile demonstrated in the pivotal trial.”

Photo: Curran Simpson, president and CEO of Regenxbio