Markets punish Uniqure for Huntington’s vagueness

Lack of clarity on safety and efficacy causes shareholders to decamp.

Results from the phase 1/2 trial of Uniqure’s Huntington’s disease gene therapy AMT-130 have painted a confusing safety picture, and with data on key efficacy endpoints largely absent investors assumed the worst.

An unclear outcome was always possible, the data coming from just two patients on treatment, but Uniqure’s shares still slid 30% yesterday. It clearly did not help that Uniqure did not spell out the actual measurements of total and mutant huntingtin protein in the patients treated with AMT-130, saying only that these were “highly variable and inconclusive”.

Uniqure has also not been helped by the currently dismal biotech market sentiment. It said there were no serious adverse events related to AMT-130 in the US trial. But the two treated patients, both in the low-dose cohort, receiving a 6x1012vg/kg did have increased levels of neurofilament light chain, a marker of neuronal injury.

Stil, NfL levels had returned to baseline by the one-year readout. AMT-130 is injected directly into the striatum, the brain region affected in Huntington’s, which necessitates drilling into the skull. 

Sustained NfL elevations were also seen in the phase 1/2 trial of Roche and Ionis’s antisense candidate tominersen. 


Investors were clearly seeking data on efficacy markers as well as on safety. In addition to the lack of data on huntingtin protein levels, Uniqure also made what SVB Leerink analysts called a “last-minute decision” to omit volumetric MRI data. 

Trial subjects are to have their striatal volume measured via imaging, as this area of the brain shrinks in untreated Huntington’s patients. A signal of striatal volume preservation with AMT-130 could be considered compelling evidence of efficacy.

And that seems to be it for now. According to Stifel analysts, Uniqure blamed a faulty assay used by a contract research organisation for the uneven HTT protein results, and said it was possible to reanalyse cerebrospinal fluid samples taken from the patients, allowing HTT data to be released in the future. 

Uniqure has also promised an update on all 10 patients in the low-dose cohort in the second quarter of next year, but this too will be largely focused on safety. Full safety and efficacy data from both dose groups, including volumetric MRI changes, are due in the first half of 2023, after the 16 patients in the 6x1013vg/kg high-dose cohort reach a year of follow-up.

Skip phase 3? 

Waiting to release volumetric MRI data until all patients reach the one-year timepoint would allow blinding to be maintained throughout the trial, something analysts say could allow the current study to be considered registrational. 

In the interim, the group is to add a third cohort. Recruitment of 18 patients is to begin towards the end of 2022, to explore simpler methods of infusing AMT-130. AMT-130 is also in a European phase 1/2 trial in 15 patients that should yield topline data in 2023.

Ultimately Uniqure is gambling twice over: first, that the US study reads out positively when the full data emerge in in more than a year’s time, and secondly that this hit is enough to allow it to go straight to the regulators.

Share This Article