FDA requests additional clinical trial of Huntington’s gene therapy AMT-130
Agency wants more data before uniQure submits application seeking approval
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The U.S. Food and Drug Administration (FDA) has asked uniQure to conduct an additional clinical trial before submitting an application seeking approval of its experimental gene therapy, AMT-130, for Huntington’s disease.
That’s according to a press release from uniQure announcing the final minutes of a Type A meeting held with the agency on Jan. 30 to discuss the therapy’s regulatory pathway.
Late last year, the company announced that the FDA no longer considered the positive data from two ongoing AMT-130 Phase 1/2 clinical trials — one in the U.S. (NCT04120493) and the other in Europe (NCT05243017) — suffcient to support the therapy’s approval.
Those trials are evaluating the safety and efficacy of the therapy in early-stage Huntington’s patients. Results showed that AMT-130 treatment slowed disease progression by 75% when compared with no treatment in an external group of patients participating in natural history studies.
We remain committed to engaging with the FDA to determine a clear, scientifically grounded, and efficient path forward for AMT-130.
However, the FDA raised concerns about reliance on comparisons with an external control group, stating that the available data do not provide sufficient primary evidence of the therapy’s effectiveness.
The agency has therefore strongly recommended that uniQure conduct a Phase 3 trial that includes a sham-surgery control group. In such a trial, participants would be randomly assigned to either receive AMT-30 or to undergo the same surgical procedure used to deliver AMT-130, but without the active therapy.
“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,” said Matt Kapusta, uniQure’s CEO. “We remain committed to engaging with the FDA to determine a clear, scientifically grounded, and efficient path forward for AMT-130.”
The company intends to request a Type B meeting in the coming months to further discuss potential Phase 3 study design options.
AMT-130 prevents production of mutant, healthy huntingtin proteins
Huntington’s is caused by mutations in the HTT gene, which result in the production of a longer-than-normal huntingtin protein that is thought to be toxic to nerve cells in the brain. The resulting neurodegeneration leads to a wide range of motor, behavioral, and psychiatric symptoms.
AMT-130 is a one-time gene therapy designed to prevent the production of both mutant and healthy huntingtin proteins. By reducing mutant huntingtin levels, the therapy is expected to slow or prevent Huntington’s progression. The single dose is administered directly into the brain via a surgical procedure.
The two ongoing Phase 1/2 trials are evaluating two doses of AMT-130 in adults ages 25 to 65 with early-stage Huntington’s disease. Participants are being followed for up to five years after treatment.
Consistent with two-year findings, three-year data from 24 AMT-130-treated participants showed slower disease progression than would be expected if the disease had followed its natural course. Such analyses compared data from AMT-130-treated patients in the two trials with those from an external group of untreated, matched patients in observational studies.
Three years after treatment, patients receiving the higher dose showed a 75% slower score worsening on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) — a standard measure of overall disease progression — relative to the external control group.
Those results had supported uniQure’s plan to submit an application seeking accelerated approval of AMT-130 for Huntington’s. Accelerated, or conditional, approval allows experimental therapies to reach the market based on early clinical evidence suggesting clinical benefit. Full approval depends on additional trial data confirming such benefits.
However, during a pre-submission meeting last year, the FDA concluded that the available clinical data were insufficient to proceed with the application submission. A subsequent Type A meeting was held to clarify the regulatory path forward, during which the agency recommended that uniQure conduct a sham procedure-controlled Phase 3 trial before approval could be considered.
“We are deeply grateful for the resilience and support of the Huntington’s disease community and remain committed to standing with patients and their families as we advance this potentially transformative therapy for a community in need,” Kapusta said.
