New Phase 2 trial of tominersen enrolling people at early stages
Up to 360 early manifest, prodromal patients sought for study at lower doses
Enrollment is underway in a Phase 2 clinical trial testing Roche’s therapeutic candidate tominersen in people with early manifest Huntington’s disease and those in the prodromal phase of the disease, when hallmark disease symptoms are not yet present.
The study, dubbed GENERATION HD2 (NCT05686551), aims to enroll up to 360 patients, ages 25 to 50, across 15 countries in North America, Europe, South America, and Oceania, according to a previous announcement from Roche.
For now, the trial is recruiting eligible patients at the Dent Neurological Institute in New York, and the Hospital Universitario de Badajoz and Hospital Ramón y Cajal, both in Spain. Additional study sites will be posted on the trial’s webpage once they receive approval from local health authorities and begin recruiting.
Tominersen aims to lower huntingtin and mutant protein levels in the brain
Huntington’s is caused by mutations in the HTT gene, leading to the production of a faulty version of the huntingtin (HTT) protein that forms toxic clumps up in nerve cells.
Tominersen, a treatment called an antisense oligonucleotide, is designed to reduce levels of the huntingtin protein, including its mutant version, in the brain. It is administered, via an intrathecal injection into the spinal canal, to reach the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord.
Tominersen was initially developed by Ionis Pharmaceuticals, which licensed the therapy to Roche in 2017.
Its clinical development began in 2015, with a Phase 1/2 trial (NCT02519036) demonstrating the treatment significantly lowered mutant HTT levels in the CSF of adults with early manifest Huntington’s.
A global Phase 3 trial called GENERATION HD1 (NCT03761849) followed, testing the safety and efficacy of tominersen against a placebo in 791 adults with manifest Huntington’s. Participants were randomly assigned to either tominersen at 120 mg or a placebo once every two or four months for up to two years.
The trial’s main goal was to evaluate changes in disease severity, as assessed with the composite Unified Huntington’s Disease Rating Scale (cUHDRS) that accounts for cognition, motor skills, and the ability to function independently in daily life (total functional capacity or TFC).
During an interim analysis, an independent data monitoring committee found that patients given tominersen every two months had consistently poorer cUHDRS scores — indicating more severe disease — than those on a placebo. Patients treated every four months showed no significant differences in cUHDRS scores relative to the placebo group.
While no significant safety findings were noted with nearly a year and a half of treatment, the committee considered that tominersen did not provide any benefit over a placebo and recommended against further testing.
GENERATION HD1 stopped dosing patients in March 2021 — a decision that disappointed the Huntington’s community.
Subsequent exploratory analyses, however, suggested that younger patients with less severe disease and who were on less frequent tominersen dosing may have benefited from the treatment.
New trial testing 60 or 100 mg given every 16 weeks against placebo
The GENERATION HD2 trial was launched to further explore that possibility by testing 16 months of lower doses of tominersen — 60 or 100 mg given every 16 weeks or four months — in adults with prodromal or early manifest Huntington’s. The prodromal period is characterized by the presence of early signs and nonspecific symptoms of Huntington’s.
Of note, participants must never have used an antisense oligonucleotide therapy or other mutant huntingtin-lowering treatment. As such, GENERATION HD1 participants may be eligible for the new trial only if they were on a placebo in the earlier trial.
Roche noted that this criteria decision was made in consultation with experts in the field and recognized that it may be “disappointing news” for some patients.
“As we learn more about tominersen through the GENERATION HD2 study, we will evaluate if additional clinical trial opportunities may be possible,” the company noted in the trial announcement.
GENERATION HD2’s main goals are to assess the safety and changes with treatment in CSF levels of mutant HTT, as well as changes in cUHDRS and TFC scores.
Secondary outcomes include various measures of cognitive and motor function, and changes in CSF levels of neurofilament light chain, a nerve cell damage biomarker. The development of antibodies against the therapy also will be monitored.
As in the earlier GENERATION HD1 study and other trials, a data monitoring committee will review safety, clinical, and biomarker data every four to six months.
GENERATION HD2 is expected to finish in January 2027.