FDA pause over spine MRI results hampered the Regenxbio gene therapy refiling plan

A clinical hold by the FDA on RGX-121 has halted the biotech’s efforts to re-file the gene therapy candidate that it once abandoned due to asymptomatic findings on MRIs of the spine.

Regulatory Obstacles and Approval Setbacks

The fortunes of RGX-121 seemed to rise and fall this year as Regenxbio pursued its hopes of taking the drug to market. In February, the FDA turned down the request for approval of the asset in mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome. At the time, the agency told Regenxbio to enroll more patients and incorporate an untreated control arm. The FDA dropped those demands in June and said it would consider a filing informed by the studies already conducted.

However, the biotech, which had expected to resubmit this year in the third quarter, does not have the application in mind for resubmission in the near future. The revised prospects for RGX-121 come after Regenxbio began expanded monitoring after receiving a prior clinical hold.

Safety Concerns Trigger Dual Program Suspensions

The FDA put both RGX-121 and RGX-111, a gene therapy in development for MPS I, on clinical hold in January. The regulatory move comes in the wake of a central nervous system tumor being found in an RGX-111 patient. The agency has suspended both programs after it observed the same safety signal in an RGX-111 trial, but similarities in the gene therapies, their study populations and the risks involved prompted the agency to put both on hold.

In turn, Regenxbio started to intensively monitor RGX-121 patients, including brain and spine MRI scans. Five of the participants in Regenxbio’s Campsiite trial presented with small nodules or cystic structures in their spine in images taken as part of the enhanced monitoring program, but no symptoms were reported. The patients received intracisternal or intraventricular RGX-121 about three to six years ago.

The results were not considered to be serious, according to investigators, and are thought to be benign by radiologists, Regenxbio said. The findings of the spine MRI are not clinically or pathologically definitive, and no nodules or mass of the brain were found. Because of the infrequent use of routine spine MRIs, it is not known how common or important spine abnormalities are in asymptomatic MPS patients.

Roberto Giugliani, Professor, Federal University of Rio Grande do Sul, Brazil, says in a statement, “Boys with neuronopathic MPS II have many neurodevelopmental and systemic effects”. Although imaging natural history is limited for this rare, ultra-rare disease, I think that this is more likely a normal part of the body’s reaction to the impact of Hunter syndrome in the absence of symptoms.

Next Steps and Long-Term Strategy

Investigators plan to keep periodically imaging the five patients. Regenxbio and its partner NS Pharma are examining further imaging and longer-term follow-up data from patients. The evidence, combined with the clinical hold letter and other feedback from FDA, will guide the next steps for RGX-121.

The future for RGX-121 remains unclear, but Regenxbio is pushing forward with RGX-202 for approval in Duchenne muscular dystrophy and surabgene lomparvovec for approval in wet age-related macular degeneration. The other gene therapies use a different capsid and routes of administration than RGX-121, informing Regenxbio’s belief that the spine findings are limited to RGX-121.

Regenxbio has delayed plans to resubmit its application for RGX-121, an experimental gene therapy for Hunter syndrome, after the U.S. Food and Drug Administration placed the program on clinical hold. The decision follows the discovery of asymptomatic spine MRI findings in five participants in the CAMPSIITE study.

Regenxbio and the FDA Clinical Hold

The FDA’s clinical hold affects Regenxbio’s RGX-121 program, also known as clemidsogene lanparvovec. The therapy is being developed for mucopolysaccharidosis type II, or MPS II, a rare genetic disorder commonly known as Hunter syndrome.

The MRI findings involved small nodules or cystic masses in the spines of five participants who had received treatment approximately three to six years earlier. According to Regenxbio, the participants remain clinically well, and investigators considered the findings nonserious.