On 18 January, Ionis Pharmaceuticals announced that its partner Roche would begin a new Phase II trial to reassess its pipeline antisense therapy, tominersen, in Huntington’s disease (HD). Roche’s decision to bring back tominersen in a newly designed trial marks a surprising twist in the drug’s story, as its development had been halted last March due to failure to show evidence of clinical benefit in the Phase III GENERATION HD1 (NCT03761849) study. Based on positive findings from an exploratory post-hoc analysis of the GENERATION HD1 trial, Roche’s new trial will assess tominersen’s efficacy in a younger group of adult early-manifest HD patients with a lower disease burden. GlobalData believes that Roche’s bid to revive tominersen is justifiable given the acute unmet needs in the HD market and the fact that the company still has the opportunity to bring one of the first disease-modifying treatments to this market.

Tominersen is an antisense therapy that acts by reducing the production of all forms of the huntingtin protein (HTT), including its mutated variant (mHTT), which is believed to be the main cause of HD. The therapy is administered by injection through the spine into the cerebrospinal fluid (CSF). Due to its novel mechanism of action and data showing a significant reduction in CSF mHTT in an earlier Phase I/II trial (NCT02519036), tominersen’s development initially instilled great hope for the treatment of patients with early manifest HD. The drug’s prospects plummeted, however, after the independent data monitoring committee decided to discontinue dosing in the Phase III GENERATION HD1 study due to a poor risk-benefit profile. Interim results from the GENERATION HD1 study, which assessed the effect of the treatment on Composite Unified Huntington’s Disease Rating Scale (cUHDRS) scores, showed that the scores of patients who were given tominersen every eight weeks actually worsened more rapidly over time compared with those given placebo. Patients who were given the less-frequent dosing of tominersen (every 16 weeks) had comparable cUHDRS scores to patients who were given placebo.

On 20 January, Roche representatives presented an update on new tominersen data as part of the Huntington’s Disease Society of America Research Webinar Series. Roche representatives noted that the new Phase II trial will evaluate the safety and efficacy of different doses of tominersen in younger adult patients with a low disease burden, which is assessed using the CAG-repeat Age Product (CAP) score. Beyond this, specific details on the trial design and start date will be announced at a later date. During the webinar, Roche presented new clinical endpoints from the hypothesis-driven, post-hoc exploratory analyses of GENERATION HD1 that support the company’s decision to continue the development of tominersen. The data showed that treatment with tominersen every 16 weeks in the low age, low CAP subgroup resulted in better overall outcomes compared with placebo, as measured by the cUHDRS, total functional capacity (TFC) and total motor score (TMS), as well as comparable overall adverse events.

GlobalData believes that although Roche’s new tominersen trial will focus on a smaller subset of HD patients than were studied previously, the drug still has the potential to address a patient segment with significant unmet need. If tominersen can score an approval in this patient group, it is highly likely to see strong uptake as no disease-modifying drug has yet been approved for HD patients. GlobalData forecasts the HD market in the US, Germany and the UK to reach sales of $917.7m by 2030, while the addition of tominersen to this market would likely bring overall sales of more than $1bn.