Roche abandons two Huntington's drug candidates

Roche has scrapped the development of two drugs for Huntington's disease – tominersen and RG6496 – after seeing disappointing results in clinical trials.

Both drugs come from an alliance between the Swiss pharma group and Ionis, which dates back nearly a decade, spanning multiple candidate therapies for the devastating neurodegenerative disorder.

Roche broke the news of its decision in a letter to patient organisations, which revealed that tominersen (IONIS-HTTRx/RG6042) failed to meet its efficacy objectives in the phase 2 GENERATION HD2 study.

The disappointing efficacy came even though the drug – an antisense oligonucleotide designed to reduce the production of all forms of the huntingtin protein (HTT), including the mutated variant involved in Huntington's disease – met the biomarker objectives of the study.

Tominersen had already missed the mark in the phase 3 GENERATION HD1 trial, which was abandoned in 2021. Rather than scrap tominersen entirely, Roche started GENERATION HD2 to see if the drug could perform better in a younger patient population with less advanced disease.

With that hope now dashed, Roche said it had taken the "difficult decision" to discontinue the programme.

Meanwhile, it has also terminated development of RG6496, a follow-up antisense candidate designed to affect the mutated form of HTT alone, which was in the first-in-human POINT-HD trial.

After only three subjects were dosed in the single-dose study, Roche found evidence in an animal study that it would not be possible to offer multiple doses, so there would be no possibility of using it for long-term treatment.

"These are independent, data-driven events, which have coincided by chance," wrote the company in the letter. "While this news is deeply disappointing, promptly communicating about the findings is the most responsible way for us to honour the contribution of study participants and allow the HD community to focus efforts on other avenues of research."

The demise of the two programmes still leaves Roche with one Huntington's candidate, the gene therapy RG6662, which is in a phase 1/2 trial and came from the group's acquisition of Spark Therapeutics for $4.8 billion in 2019.

It is the second R&D setback for Ionis in quick succession, coming after AstraZeneca-partnered Wainua (eplontersen) failed a highly anticipated phase 3 trial in ATTR cardiomyopathy.

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