Gene therapy tied to slower functional decline in Huntington’s at 4 years

Up to four years after a single dose of the experimental gene therapy ifezuntirgene inilparvovec (formerly AMT-130), people with Huntington’s disease who received the high dose showed slower disease progression than would be expected without treatment.

That’s according to data from two long-term Phase 1/2 clinical trials, one in the U.S. (NCT04120493) and one in Europe (NCT05243017), that are testing two doses of the therapy in adults with early Huntington’s disease. The treatment results were compared with matched untreated patients from a natural history study.

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Four-year data show continued slowing of Huntington’s progression

“Four years after a single administration, ifezuntirgene inilparvovec continues to show meaningful slowing of disease progression, further strengthening our conviction in its benefit for people living with Huntington’s disease,” Walid Abi-Saab, MD, chief medical officer of uniQure, said in a company press release.

Previously announced data after three years of follow-up showed that ifezuntirgene inilparvovec slowed disease progression in high-dose patients compared with matched untreated controls.

“What I find particularly notable in the expanded data is the consistently meaningful treatment effect at 36 months [three years], and the apparent stability of the functional capacity benefit through Month 48,” said Victor Sung, MD, professor of neurology at the University of Alabama at Birmingham.

One of the measures used to track disease progression was Total Functional Capacity (TFC), which assesses how well people with Huntington’s can function independently in daily life. It “tracks things that matter the most to patients and families – ability to work, perform household chores and handle daily self-care activities,” Sung said. “Seeing that treatment difference maintained at four years is meaningful for people living with this relentlessly progressive degenerative disease.”

Huntington’s is caused by mutations in the gene that encodes the huntingtin protein. Ifezuntirgene inilparvovec is a one-time gene therapy designed to reduce the production of both normal and mutated huntingtin protein, which is expected to slow Huntington’s progression. The therapy is administered directly into the brain during surgery.

Gene therapy under review for accelerated FDA approval

Based on the trials’ three-year data, uniQure recently filed an application with the U.S. Food and Drug Administration (FDA) asking for the therapy’s accelerated approval.

The accelerated approval pathway can allow a therapy to reach patients sooner based on evidence reasonably likely to predict clinical benefit, while requiring additional testing to confirm that benefit. Plans for a confirmatory trial are already underway.

The FDA had previously requested that an additional trial be run before uniQure submitted a regulatory application, but the agency later agreed that the existing three-year data could serve as the primary basis for the application.

An application seeking the gene therapy’s approval in the U.K. has also been submitted to the country’s Medicines and Healthcare products Regulatory Agency (MHRA).

The newly announced analyses involve 17 patients treated with the high dose of ifezuntirgene inilparvovec. Of those, 15 were included in the three-year analysis and 12 in the four-year analysis. The new analyses were completed after uniQure submitted its application to the FDA, so these updated data were not included in the application.

Updated three-year data showed that scores on the composite Unified Huntington’s Disease Rating Scale (cUHDRS), a measure of Huntington’s disease severity, fell by an average of 0.28 points, indicating worsening, while TFC scores fell by an average of 0.27 points. Among matched untreated patients from the natural history dataset, cUHDRS scores fell by an average of 1.39 points and TFC scores by an average of 0.82 points.

Compared with matched untreated controls, high-dose patients had 80% slower decline on cUHDRS and 67% slower decline on TFC.

“The updated 36-month analysis, which now includes three additional high-dose patients, showed a substantial effect on cUHDRS and TFC, further reinforcing the data included in our license applications,” Abi-Saab said.

Functional decline remained slower at 4 years with high dose

Four-year data showed that TFC scores declined by an average of 0.37 points in high-dose patients, compared with an average decline of 0.94 points among matched untreated controls. That amounted to a 61% slower decline with the gene therapy.

“We see this even as the rate of decline in the updated comparator dataset slowed, an anticipated shift which appears to reflect some attrition in the longitudinal external control data, and which does not reflect the typical clinical presentation of accelerating decline over time,” Sung said.

cUHDRS scores at four years also showed 44% slower decline in high-dose patients compared with matched untreated controls, but the difference did not reach statistical significance. According to the company, missing data in the natural history dataset may have understated the treatment effect; four-year data were missing for 53% of matched controls.

Available four-year data for both doses, with 12 patients in each dose group, indicated slower disease progression in the high-dose group.

“At 48 months [four years], [TFC], the primary measure of our confirmatory study, demonstrated consistent slowing of functional decline, with the absolute treatment benefit maintained in Month 48,” Abi-Saab said. “Furthermore, the observed differences between the high and low doses on both [cUHDRS] and TFC are consistent with a dose-dependent treatment effect.”

The therapy continues to show a manageable safety profile with longer follow-up, with the most commonly reported adverse events related to the surgical procedure and all resolved.

“We believe these data are clinically meaningful for Huntington’s disease patients, and we look forward to presenting them at a future scientific meeting,” Abi-Saab added.