Days after FDA Commissioner Marty Makary appeared to malign uniQure’s AMT-130 in an interview with CNBC, the agency confirmed to the biotech that a sham surgery–controlled study is needed before submitting the gene therapy for approval.
After Marty Makary’s interview with CNBC last week, in which the FDA Commissioner appeared to criticize uniQure’s investigational gene therapy for Huntington’s disease, the biotech sustained another blow on Monday, revealing that it will likely need to conduct a Phase 3 trial rather than go directly to the FDA for approval.
The FDA “stated that it cannot agree that data from [uniQure’s] Phase I/II studies, compared to an external control, are sufficient to provide the primary evidence of effectiveness required to support a marketing application for AMT-130,” according to the biotech’s announcement of final minutes from its Type A meeting with the regulator.
Analysts were quick to express their concerns regarding this decision. “FDA’s comments are inconsistent with regulatory flexibility the FDA professes it will exercise in reviewing rare disease drugs for high unmet diseases,” Truist analysts pointed out in a Monday morning note.
UniQure and AMT-130 have been at the center of a trend that has seen the FDA seemingly reverse its own guidance. The company had aligned with the agency on the protocols and statistical analyses used—specifically, comparing AMT-130 to a natural history external control—according to its Nov. 3 announcement, and all signs had pointed to uniQure being on track to file a biologics license application (BLA) for AMT-130 following highly positive three-year data from a pivotal Phase 1/2 study of AMT-130. However, uniQure’s announcement continued, the agency “no longer agrees” that the study was sufficient “to provide the primary evidence in support of a BLA submission.”
In its most recent communication, the agency “strongly recommended” that uniQure conduct a prospective, randomized, double-blind, sham surgery–controlled study of the gene therapy, the company said. After a back-and-forth regarding the product’s path, uniQure now seems resigned to this FDA guidance.
However, H.C. Wainwright appears to believe the company has other options.
"[W]e believe an alternative path forward may be negotiated given the strong AMT-130 data generated to-date,” they wrote in a Monday morning note. "[W]e believe that the deepening clinical benefit demonstrated beyond 3 years post-treatment is the strongest dataset generated in HD and should support discussions for an alternative path forward.”
However, any alternate suggestions may face pushback from the FDA. In an interview with CNBC on Thursday, Makary appeared to refer to the therapy. “There was a product where the researchers drilled a burr hole, literally a hole, in people’s skulls” to directly inject a drug candidate into patients’ brains, Makary said. “At the end of the randomization period, it was found no benefit, and yet this is one of the drugs that we were pressured to approve.”
AMT-130 is delivered to the brain through an intracranial surgery that involves drilling a small number of holes into the skull in order to inject the gene therapy, according to uniQure’s website. A sham surgery would also involve drilling into the skull.
UniQure CEO Matt Kapusta addressed the FDA’s guidance in a statement on Monday, saying, “While we did not reach alignment on a submission pathway based on the Phase I/II data, we believe the totality and durability of our data warrant continued substantive dialogue regarding how the FDA’s stated commitment to regulatory flexibility may be appropriately applied in this setting.”
Stifel analysts, meanwhile, expressed their disappointment with the regulator’s decision in a note to investors Monday morning, noting that a “sham-controlled study introduces meaningful risk.”
“We had been hopeful that QURE would be able to reverse the agency’s stance given the unmet need in this fatal neurodegenerative disease and the support from HD advocacy groups,” they wrote.
Truist analysts agreed. “[I]n the setting of this devastating disease, we think the risk/benefit is skewed in favor of AMT-130.”
But Stifel noted that while they were disappointed, they weren’t surprised, both because of Makary’s comments to CNBC and because of “a string of negative [FDA] decisions in the rare disease space.”
Indeed, Disc Medicine last month received a complete response letter (CRL) for bitopertin, which it was proposing to treat a rare disease characterized by extreme, painful sunlight sensitivity. This followed a rejection for REGENXBIO’s Hunter syndrome gene therapy RGX-121 on February 9.
To ensure smoother sailing moving forward, uniQure said in its Monday update that it “intends to continue engaging with the FDA regarding Phase III development considerations” and plans to request a Type B meeting in the second quarter of this year “to further discuss potential study design approaches.”
