uniQure’s Huntington’s disease gene therapy has failed to significantly slow disease progression after 48 months, sending the biotech’s stock down 41% when trading began. But mitigating circumstances and the ongoing strength of a secondary endpoint kept analysts optimistic about AMT-130’s path to approval.
One year ago, uniQure linked AMT-130 to a 75% slowing of disease progression, as measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS), at Month 36 of a phase 1/2 trial. Tuesday, the biotech shared updated data on the 12 patients. At month 48, uniQure linked AMT-130 to a 44% slowing of disease progression on cUHDRS. The result fell short of statistical significance.
Investors reacted badly to the news. Yet, while the biotech’s share price fell to $23.15 when the market opened, analysts and uniQure executives were more positive about the update. The trends seen in the data “are positive and meaningful” for patients, uniQure CEO Matt Kapusta said on a conference call with investors. Guggenheim Securities analysts voiced optimism about AMT-130 in a note to investors.
The optimism reflects questions about the implications of the missed primary endpoint and confidence provided by a secondary endpoint. More than half of the external control data used in the month 48 primary endpoint analysis are missing, Kapusta said.
“While missingness is inherent to long-term natural history datasets, the patients who left the control were declining markedly faster than those who remained,” Kapusta said. “Over time, the comparator increasingly reflected a healthier population than at baseline. This bias cuts against AMT-130, not for it. It understates treatment benefit.”
The external comparator “may have several methodological flaws,” Guggenheim analysts said. Notably, a single outlier “contributed approximately one third of the overall cUHDRS degradation” between month 36 and month 48, the analysts said. The biotech reported a 54% slowing of cUHDRS disease progression in a post hoc analysis using the prior external control.
The impact of the weakening of the cUHDRS data, regardless of external control, was offset by the steady performance of a secondary endpoint. Total functional capacity (TFC) showed a 61% slowing of disease progression at month 48, replicating the 60% result reported at Month 36. Kapusta framed TFC, the primary endpoint of uniQure’s confirmatory trial, as a critical measure for Huntington’s patients.
“TFC is the most direct measure we have of what patients and families care about,” Kapusta said. “It captures whether someone can hold a job, manage their own finances and perform the daily tasks that allow them to live independently.”
uniQure filed for accelerated FDA approval based on month 36 AMT-130 data compared to the prior external control. It is difficult to speculate on whether the FDA will “rerun the analysis with the new data cut or not,” Walid Abi-Saab, M.D., chief medical officer of uniQure, said on the conference call. “That is something that we will deal with if the FDA asks us to run it or if they run it themselves,” Abi-Saab said.
AMT-130 has already endured a tumultuous journey to the FDA. In March, the FDA rejected uniQure’s plan to file for accelerated approval based on the phase 1/2 data. Months later, the agency reversed its opposition to the submission, leading uniQure to file for accelerated approval early this month.