Dosing Stopped in Phase 3 Trial of Tominersen for Huntington’s, Roche Says

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

Share this article:

Share article via email
Tominersen trial stopped

Roche has discontinued dosing in the Phase 3 GENERATION HD1 trial of its investigational therapy tominersen in adults with Huntington’s disease.

The decision was made after a pre-planned review of trial data by an independent data monitoring committee, which issued a “no go” recommendation based on tominersen’s potential benefit/risk profile.

While the basis for this recommendation was not disclosed, Roche noted that no new or emerging safety concerns were identified in this review. The company will continue to follow study participants for safety and efficacy measures without any further dosing of the investigational therapy or a placebo.

“This is very unfortunate news to deliver on the tominersen Phase 3 study and we know it will be especially difficult for people with Huntington’s disease to hear,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development, said in a press release.

“We would like to thank all of the individuals and families participating in the study for their contribution, as well as the broader HD [Huntington’s disease] community for their commitment and collaboration,” he added.

Garraway also said that “GENERATION HD1 is the largest clinical trial in Huntington’s disease to date and we do know that the data generated will significantly advance our understanding of huntingtin-lowering as a potential treatment approach.”

Roche intends to share further updates on its plans for tominersen once the study’s full data are available and analyzed. Meanwhile, tominersen dosing will also be paused in an open-label extension study for participants of other tominersen trials, called GEN-EXTEND (NCT03842969).

For now, other Roche trials in Huntington’s disease will continue as planned.

Initially developed by Ionis Pharmaceuticals and licensed to Roche in 2017, tominersen was designed to suppress the production of all forms of the huntingtin protein (HTT), including the mutated variant that leads to Huntington’s.

It is administered directly into the spinal canal (intrathecal injection) so to reach the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord.

Data from a previous Phase 1/2 trial (NCT02519036) showed that tominersen significantly reduced the levels of mutant HTT protein in the CSF of early stage patients, prompting the launch of the Phase 3 GENERATION HD1 study (NCT03761849).

The trial, which had enrolled 791 adults (25 to 65 years), was evaluating tominersen’s long-term safety and effectiveness.

Participants, recruited at sites across 18 countries, were randomly assigned to either an intrathecal injection of tominersen once every two or four months, or to a placebo injection once every two months, each given for up to two years.

Among the trials Roche plans to continue without changes is the open-label, Phase 1 GEN-PEAK study (NCT04000594), set to assess tominersen’s pharmacokinetics (movement into, through, and out of the body) and pharmacodynamics (effects on the body) in up to 20 Huntington’s adult patients.

The trial was temporarily placed on hold in March 2020 due to two cases of infection, which were later found to be linked to the device used to take samples of patients’ CSF, rather than to tominersen itself.

Roche also plans to continue its Huntington’s disease natural history study (NCT03664804), assessing the association between mutant HTT protein in the CSF and clinical measures and biomarkers of Huntington’s in up to 100 adults with early stage disease over 15 months.

The fully enrolled trial also will evaluate wearable devices to measure disease burden. No therapy will be given during the study, as the goal is to understand the natural progression of the disease. Its results are expected to provide valuable information for other trials of investigational therapies targeting mutant HTT.

With last year’s acquisition of the gene therapy company Spark Therapeutics, Roche also expanded its gene therapy program to likely include Huntington’s disease.

In a separate press release, Brett Monia, PhD, Ionis’ CEO, said that “we are very disappointed by this news,” and this was “not the outcome we have been working towards or hoped for, as we have grown quite close to the HD patient community over the years.”