After facing a delayed decision deadline and a clinical hold, Regenxbio’s Hunter syndrome gene therapy has been rejected by the FDA.
In rejecting RGX-121, the FDA raised concerns about its clinical trial’s ability to properly define a patient population, the use of a natural history control arm and the use of a biomarker as a surrogate endpoint, according to a Feb. 9 release from Regenxbio.
The Feb. 8 Prescription Drug User Fee Act (PDUFA) date for RGX-121 was already delayed by the agency from a previous deadline of Nov. 9, 2025. The FDA accepted the one-time treatment for accelerated approval consideration last May.
“This decision is devastating for the families of boys living with this progressive, life-threatening disease,” Curran Simpson, Regenxbio’s president and CEO, said in the release. “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.”
During RGX-121’s approval submission process, Regenxbio provided additional data and responded to queries from the FDA that the biotech believed addressed the concerns raised in the CRL, according to the release. The company now plans to resubmit for approval with longer-term data as quickly as possible.
The FDA-flagged biomarker is heparan sulfate, which is widely accepted by the research community as an endpoint for accelerated approval. The regulator completed its pre-license and bioresearch monitoring information inspections for RGX-121 with no objections in August, Regenxbio said at the time, and at that point had also not raised any safety concerns about the Hunter syndrome candidate.
Vinay Prasad, M.D., head of the FDA’s Center for Biologics Evaluation and Research, which oversees gene therapies, has previously expressed ire over the use of biomarkers for approvals rather than placebo-controlled trials that measure clinical outcomes. Under Prasad’s leadership, the FDA has also dealt surprise blows to uniQure’s Huntington’s disease gene therapy and Capricor Therapeutics’ heart disease cell therapy.
Meanwhile, the recent hold on RGX-121 came after a patient developed a brain tumor after being given a different gene therapy from Regenxbio. The tumor was discovered in a five-year-old patient who received the biotech’s Hurler syndrome candidate RGX-111, which was also hit by a hold, four years prior. The child had no symptoms and the tumor has been removed, with the patient now doing well.
The FDA letter acknowledges the clinical hold and the brain tumor found in a patient who received RGX-111, a Regenxbio spokesperson told Fierce on Feb. 9, but does not cite them as reasons for the rejection.
Vexing vector
The RGX-111 patient’s brain tumor was found over the summer, and a genetic analysis last December found that the viral vector used to deliver RGX-111 had inserted part of its DNA into a known cancer-causing gene, Regenxbio’s Chief Medical Officer Steve Pakola, M.D., told Fierce last week, before the biotech received the FDA’s rejection.
While it’s known that the integration caused increased activity of the oncogene, Pakola added, more investigation is needed to determine how big a role this played in forming the patient’s brain tumor.
“What isn’t known definitively is whether there were any other potentially causative events,” Pakola said, especially since the gene where the integration happened, called PLAG1, is known to be unstable.
Integration of vector DNA into oncogenes has been a long-held fear for gene therapies, which is why the FDA warns of “the potential for insertional mutagenesis” on their labels, Pakola said. The other nine patients in the RGX-111 trial, as well as the 32 in the separate RGX-121 study, have shown no signs of a similar event, he added.
When the FDA announced the hold would extend to RGX-121 in addition to RGX-111, Regenxbio was baffled. RGX-121 is “a separate drug for a separate indication” that was “on the doorstep of a PDUFA date for potential approval via the accelerated approval pathway,” Pakola said.
Hurler syndrome and Hunter syndrome are more technically known as mucopolysaccharidosis type I (MPS I) and mucopolysaccharidosis type II (MPS II), respectively. While they have similar names, they are in fact quite different, Pakola said.
“Each of the MPSs, even though they share that name, are different in their baseline demographics, their prognosis, the different comorbidities and sequelae,” the executive explained.
The conditions “are distinct disorders caused by deficiencies in different enzymes that affect different metabolic pathways,” leaders of the National MPS Society said in a statement after the clinical holds were announced. “We are profoundly troubled by the FDA’s decision to place RGX-121 on clinical hold.”
Both diseases involve genetic mutations that cause the lack of an enzyme critical for breaking down large sugars. In Hurler syndrome, patients are missing alpha L-iduronidase, while in Hunter syndrome the lost enzyme is iduronate 2-sulfatase.
Both Regenxbio gene therapies are meant to deliver functional copies of the genes that code for these respective enzymes to the brain, and both use the same adeno-associated viral vector for delivery and promoter to kickstart the gene’s expression once it arrives inside the patient’s cells.
This same viral vector, called AAV9, is used across many other gene therapies as well, Pakola noted. “AAV9-based gene therapies have been given to thousands of patients, over 6,000 patients based on what’s publicly available,” he said. “AAV integration into the host cell DNA has always been recognized to occur, albeit rarely.”
Jim Wilson, M.D., Ph.D., a gene therapy pioneer with extensive experience working on viral vectors, also told Fierce that much remains to be learned about the integration event.
Wild AAVs are also known to integrate into the cell’s genome during natural infection, Wilson said, but not in a way that causes cancer. There are also ways that the patient’s underlying disease could have made the emergence of the tumor more likely, he said.
“Integration would be necessary but not sufficient,” Wilson speculated. “There’d have to be something else that would contribute to that integration event leading to a tumor.”
Wilson cofounded Regenxbio back in 2009 and led animal studies of the gene therapies that became RGX-111 and RGX-121, he said, but has not worked on any of the clinical trials.
In work with dog and cat models of MPS I, as well as with four non-human primates injected with the same AAV9 vector and monitored for close to four years, Wilson never saw any integration, he told Fierce.
Wilson currently leads gene therapy outfit Gemma Biotherapeutics, which he founded after wrapping up a 30-year career as head of the University of Pennsylvania’s gene therapy program.
Related
The extremely rare risk of integration causing cancer should be balanced against the benefits of the gene therapy itself, Pakola said. Hurler syndrome and Hunter syndrome historically caused patients to die during childhood, and while life can now be somewhat prolonged using enzyme replacement therapy, there’s currently no way to stop the cognitive decline seen in both diseases.
“If the neurodevelopmental decline advances too far, it likely becomes irreversible, and you miss your chance to benefit these children in need,” Pakola said. “These children, just a few years after birth, are going to clearly decline, and this is devastating for families.”
Wilson agreed that MPS diseases are marked by extreme unmet need, which makes them ideal candidates for gene therapy. He worries that investors may respond to the Regenxbio integration event in a broadly negative way.
“I do think and expect that there will be a reaction feeding the narrative that gene therapy is unsafe,” Wilson said. Genome tinkering always comes with the risk of unforeseen long-term consequences, he added.
“We do need a practical way for long-term follow-up, there’s no question about it,” Wilson said, noting that when MPS patients receive bone marrow transplants—not accessible in all countries and complete with their own set of deadly risks, including cancer—they are followed by their physicians for a long time afterward.
The potential for far-off side effects is why the field should focus on developing gene therapies for rare diseases, Wilson said, where the benefits of treatment easily outweigh the risks.
While the future of both RGX-111 and RGX-121 is still up in the air, the FDA’s rejection of the latter will further delay a new treatment that the patient community has pinned its hopes on.
“I’ve seen the severe impact of MPS II on patients and their families firsthand and am extremely disheartened by today’s news,” Terri Klein, president and CEO of the National MPS Society, said in Regenxbio’s Feb. 9 release. “Families know the devastating trajectory of this disease all too well and have waited 20 years for new treatment options. They cannot wait any longer.”
