In another sign that the FDA is easing its stance toward rare disease drug candidates under new leadership, the agency will reconsider Regenxbio’s gene therapy for an ultra-rare childhood disease, a reversal coming just about four months after a rejection.
The Maryland biotech announced Monday that the FDA has agreed that existing clinical data are sufficient to support an accelerated approval filing for Navsunli (clemidsogene lanparvovec), a one-time gene therapy for Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome.
The agency has reversed its previous demand that Regenxbio enroll more patients and incorporate an untreated control arm rather than relying on natural history data, requirements that the company had flagged as difficult for an ultra-rare disease population.
In handing down its rejection back in February, the FDA also questioned Regenxbio’s novel use of a biomarker measuring heparan sulfate (CSF HS D2S6), saying it lacks support from published literature and “lacks sufficient evidence to support the proposed threshold to differentiate disease phenotypes and predict clinical outcomes,” according to the agency’s complete response letter.
Since that rebuff, the FDA has approved Denali Therapeutics’ enzyme replacement therapy, Avlayah, for Hunter syndrome. The accelerated approval was based on heparan sulfate in cerebrospinal fluid as a biomarker, although analysts have noted that Denali’s data included more forms of heparan sulfate and longer-term results than Regenxbio’s filing for Navsunli.
Now, backtracking on its demands, the FDA has asked for a meeting with Regenxbio to review existing longer-term biomarker and clinical data, and will review a resubmission “on an expedited basis,” according to the company.
Hunter syndrome is an inherited disorder caused by a missing or faulty enzyme, leading to abnormal accumulation of certain sugar molecules, including heparan sulfate, in tissues throughout patients’ bodies. Symptoms typically begin to appear in children around the age of 2 and may include delayed growth and cognitive declines. About 2,000 patients worldwide live with Hunter syndrome, with more than 500 babies born each year with the disease, according to Regenxbio.
The change of tune on Regenxbio’s case serves as another example of an apparently more lenient stance toward rare disease therapeutics after a radical regime change at the FDA.
Just last week, uniQure announced that the FDA made a similar U-turn, agreeing that phase 1/2 data for the company’s Huntington’s disease gene therapy, AMT-130, would suffice for an accelerated approval filing. The agency also backed off its demand for a sham control and instead is working with the biotech to consider concurrent control on standard-of-care therapy.
“We are encouraged by recent signals from the new FDA leadership reinforcing a commitment to address the unique nature of rare diseases and use the accelerated approval pathway to bring transformative therapies to patients with serious, unmet medical needs,” Regenxbio CEO Curran Simpson said in a June 22 statement.
“The MPS community urgently needs new treatment options, and we appreciate the FDA’s willingness to use the accelerated approval pathway for rare diseases and expedite the review of Navsunli so that the Hunter syndrome community may soon have access to a potentially transformative one-time treatment,” Scott Loiler, Ph.D., chief scientific officer at the National MPS Society said in a statement.
The regulatory shifts around Regenxbio and uniQure followed a June 3 meeting between rare disease advocacy groups and the current FDA leadership, including Acting Commissioner Kyle Diamantas, Acting CDER Director Mike Davis, M.D., Ph.D., and Acting CBER Director Karim Mikhail.
The National MPS Society was reportedly present at the meeting. Following Regenxbio’s rejection and before Denali’s Avlayah go-ahead, the organization and other patient advocates staged a mock funeral outside the FDA, accusing the agency of “playing politics with treatments that science has proven safe and effective.”
The FDA’s complete response letter for Navsunli also noted a brain tumor case following treatment with Regenxbio’s MPS1 candidate, RGX-111, which uses a similar viral vector. The agency argued that because viral vector integration happened in the tumor issue, “potentially similar safety risks may exist” for Navsunli. In the letter, the agency asked that any future resubmission should include updated safety summary and a benefit-risk assessment, including vector integration analysis in MPS programs.