Dosing will be paused in the open-label extension study (GEN-EXTEND) of tominersen while data are carefully analyzed to inform next steps on this study.
The phase 3 GENERATION HD1 study (NCT03761849) evaluating tominersen, the first agent to successfully target and reduce levels of mutant huntingtin (mHTT) protein in patients with Huntington disease (HD), will discontinue dosing, according to a recent announcement from Roche.1
The decision, informed by an unblinded Independent Data Monitoring Committee (IDMC), stems from a pre-planned review of the results of the phase 3 study. Despite no new or emerging safety signals in treatment with tominersen, the recommendation was based on the investigational therapy’s potential benefit/risk profile for study participants.
"This is very unfortunate news to deliver on the tominersen phase 3 study and we know it will be especially difficult for people with HD to hear,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Roche, said in a statement. “The HD community currently has no treatments to stop or slow the progression of this rare neurodegenerative disease that impacts families across generations.”
Roche noted that they will still follow participants for safety and clinical outcomes, without the dosing of the investigational agent or placebo. Following complete analysis of the available data from the phase 3 study, the company will present the research to the HD community as well as detail their future plans.
In May 2019, results from a phase 1/2 trial published in the New England Journal of Medicine demonstrated that the investigational antisense oligonucleotide was the first therapeutic to successfully target and reduce levels of mHTT protein in patients with HD.2 A total of 46 patients with early HD were enrolled into the trial. Treatment with tominersen showed dose-dependent reductions of mHTT protein in the cerebrospinal fluid (CSF), with the greatest reductions recorded in the 2 highest-dose groups (90 mg: 42% reduction; 120 mg: 38% reduction). Although nearly all patients experienced mild to moderate adverse events (AEs), investigators reported no serious AEs in patients who received the study drug.
Those results then provided the confidence for Roche to continue the drug into the phase 3 GENERATION HD1 trial. Patients included in the study were randomized 3:1 to tominersen 120 mg every 2 months, tominersen 120 mg every 4 months, or placebo.3
Primary end points of the study were change from baseline to week 101 in Composite Unified Huntington’s Disease Rating Scale and Total Functional Capacity Score. Other secondary outcome measures included a change from baseline in Total Motor Score, Symbol Digit Modalities Test, Stroop Word Reading Test, and Clinical Global Impression.
The global trial included 791 participants from 18 countries aged 25 to 65 years with manifest HD, defined as having a diagnostic confidence level score of 4 as well as an Independence Scale score greater than 70.
GEN-PEAK, a phase 1 study aiming to better understand the pharmacokinetics of tominersen, will continue despite the termination of GENERATION HD1. Researchers will also evaluate how the drug affects mHTT protein levels and other markers in the spinal fluid and blood, across a dosing range from 30 mg to 120 mg over 2 administrations.1 Additionally, the observational Roche HD Natural History study will continue as well.
The company also noted that dosing will be paused in the open-label extension study (GEN-EXTEND) of tominersen while data are analyzed to inform next steps on this study.
"GENERATION HD1 is the largest clinical trial in HD to date and we do know that the data generated will significantly advance our understanding of huntingtin-lowering as a potential treatment approach,” Garraway added. “We would like to thank all of the individuals and families participating in the study for their contribution, as well as the broader HD community for their commitment and collaboration.”