In a complete response letter published by the FDA on Monday, the agency said a resubmission for REGENXBIO’s Hunter syndrome gene therapy should provide evidence of normalized or improved biomarker levels or neurodevelopmental outcomes.
The rejection of REGENXBIO’s Hunter syndrome gene therapy, delivered to the biotech early last month, was driven by issues with the study’s population, controls and use of surrogate markers to measure efficacy.
The FDA dove into these problems in its complete response letter, which was made public on Monday. The regulator conceded that it “agreed in principle” to REGENXBIO’s proposed protocol but nevertheless consistently “expressed concerns throughout your development program” regarding the study’s design.
In particular, the agency flagged the “heterogeneity” of the patient population in REGENXBIO’s study. The company had requested a broad label for its gene therapy, dubbed RGX-121, to cover patients with various levels of disease severity.
But, according to the FDA, the pivotal study enrolled a sample with “uncertain phenotype,” in turn “raising uncertainty that the enrolled population is representative of the target population.”
The regulator also took issue with REGENXBIO’s use of external controls, which it said “lack the comparability” with the trial patients. This issue has been at the center of uniQure’s recent discussions with the agency, which recently told the biotech it would need to conduct a sham surgery–controlled Phase 3 study for the Huntington’s gene therapy instead of filing a biologics license application on the basis of its externally controlled Phase 1/2 trial as planned.
Finally, FDA took issue with REGENXBIO’s use of cerebrospinal fluid levels of the D2S6 protein as a surrogate endpoint, saying there is “insufficient evidence” to suggest that this marker is “reasonably likely to predict clinical benefit.”
For these reasons, the FDA concluded: “Despite exercising regulatory flexibility, given the breadth of uncertainties, we are unable to conclude that the RGX-121-101 study is an adequate and well-controlled study.”
For a resubmission, REGENXBIO should show the normalization of or a meaningful change in a relevant disease biomarker or in neurodevelopmental outcomes, the regulator wrote in its letter. The company could run a completely new late-stage study or enroll additional patients in its current trial. The agency also recommends that REGENXBIO use “an appropriate untreated control.”
The FDA’s rejection of RGX-121 last month has left the door open for Denali Therapeutics to potentially overtake REGENXBIO in the Hunter syndrome race. In a note to investors on Monday, analysts at William Blair called RGX-121’s approvability issues “program-specific,” suggesting that Denali’s tividenofusp alfa could make it to the market first.
“Tivi seems better positioned for an FDA approval,” the analysts continued, noting that Denali has more selectively defined its study population and used a broader biomarker surrogate, rather than just focusing on D2S6. “We remain 70-80% confident in Tivi’s approval for Hunter syndrome.” An FDA decision is expected on April 5.
The FDA’s publication of the REGENXBIO rejection letter follows a “radical transparency” push by the agency last year, which it kicked off by releasing more than 200 complete response letters. In an interview last month with CNBC, Commissioner Marty Makary conceded that the move, while giving the public a clear view of what went into a regulatory decision, has led to “a bit of an effort to find a bogeyman” behind drug rejections.
