Mixed results from Huntington's gene therapy trial after four years

A gene therapy for Huntington's disease failed to show statistically significant slowing of disease progression after 48 months, according to newly released data.

Dutch biopharmaceutical company uniQure had recently reapplied for an accelerated Biological Licence Application (BLA) from the Food and Drugs Administration (FDA) for their Huntington's disease gene therapy fezuntirgene inilparvovec, or AMT-130. The application relied on three-year results from phase 1/2 clinical trials in 12 patients (see BioNews 1344). However, updated results showing 44 percent slowing of disease progression in 12 high-dose individuals four years after treatment did not reach statistical significance. Still, uniQure maintains that these results remain worthwhile for Huntington's disease patients, who have limited treatment options.

'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,' said Dr Walid Abi-Saab, chief medical officer at uniQure. 'At 48 months, Total Functional Capacity (TFC), the primary measure of our confirmatory study, demonstrated consistent slowing of functional decline, with the absolute treatment benefit maintained in month 48.'

Huntington's disease is a rare genetic condition caused by too many repeating sequences of CAG bases in the Huntingtin gene, leading to the production of a faulty protein. It causes progressive neurodegeneration, leading to physical and mental impairments. AMT-130 is a single-dose microRNA gene therapy that aims to lower abnormal Huntingtin protein levels over time (see BioNews 1308).

The four-year results of the clinical trial, shared in a recent press release, indicate a dose-dependent effect of AMT-130. This is evidenced by differences in mean change from baseline between low- and high-dose patients on both TFC, which measures a patient's ability to perform daily tasks, and the composite Unified Huntington's Disease Rating Scale (cUHDRS), a standardised score tracking disease progression.

Data for three new individuals was also added to existing three-year datasets, with statistically significant results showing that disease progression slowed by 80 percent based on the cUHDRS and by 67 percent based on the TFC across all 15 high-dose individuals after 36 months.

'Huntington's disease does not slow on its own; the biology is one of inevitable progressive decline,' said Professor Victor Sung, professor of neurology at the University of Alabama at Birmingham (UAB) and director of the UAB Huntington's Disease Clinic. 'What I find particularly notable in the expanded data is the consistently meaningful treatment effect at 36 months, and the apparent stability of the functional capacity benefit through month 48.'

Survivorship bias may explain disappointing primary endpoints after four years, suggested uniQure. Their trial assesses disease progression in Huntington's disease patients who have received their gene therapy compared to matched controls who have not. Over half the matched controls data was missing after four years, with patients whose condition had deteriorated faster being more likely to have discontinued follow-up.  

UniQure's current BLA relies only on the three-year data from the first 12 patients. UniQure intends to present the new findings to the FDA at a future meeting.