Examining Tominersen as a Potential Treatment for Huntington Disease: The GENERATION HD2 trial

Author(s):

Isabella Ciccone, MPH

Fact checked by:

Marco Meglio

Key Takeaways

Huntington disease is caused by a mutation in the huntingtin gene, leading to toxic protein production and progressive neurological decline.
Tominersen, an investigational therapy, targets mutant huntingtin protein reduction, with potential to alter HD progression.
The phase 2 GENERATION HD2 trial assesses tominersen's safety and efficacy, focusing on early-stage HD patients and two dosing regimens.
Interim results prompted a focus on the higher dose, with no safety concerns, and the trial is set to conclude in 2026.

The phase 2 trial tests Roche’s investigational antisense oligonucleotide therapy tominersen in patients with early stages of Huntington disease, a disease with no FDA-approved therapies available.

Huntington disease (HD) is a rare, inherited neurological condition that progressively impacts movement, cognitive abilities, and behavior. Early signs can include subtle changes in mood, thinking, and behavior, which may not immediately interfere with daily functioning. As the disease advances, individuals may experience involuntary, jerky movements that interfere with basic tasks such as walking and eating, a stage known as early manifest HD. HD is caused by a mutation in the huntingtin gene (HTT), which leads to the production of a toxic form of the huntingtin protein (mHTT).

Tominersen (Roche) is an investigational antisense oligonucleotide (ASO) therapy designed to reduce the production of the mutant huntingtin protein. Previous clinical trials have shown that the drug can lower levels of mHTT, suggesting a potential to alter the course of the disease. However, tominersen is still under study and has not been approved for clinical use.

Nicki Niemann, MD

(Credit: Barrow Neurological Institute)

The phase 2 GENERATION HD2 trial (NCT05686551) is currently underway to assess the safety and efficacy of 2 different doses of the ASO compared with placebo.¹ This study, being conducted by principal investigator Nicki Niemann, MD, a neurologist in the Muhammad Ali Parkinson Center and assistant professor of neurology at Barrow Neurological Institute, is focused on patients in the early stages of HD, with the goal of identifying a dose that could provide therapeutic benefit.

Key outcomes of the trial include the number and severity of any adverse effects, changes in levels of the mHTT protein in cerebrospinal fluid (CSF), brain changes observed through MRI scans, and changes in participants’ ability to move, think, and carry out daily activities. Additional measures being evaluated by investigators include biomarkers of nerve damage in CSF and the drug’s impact on the immune system. In the study, participants will be randomly assigned to be given 60 mg of tominersen or a higher dose of 100 mg of tominersen, or a placebo every 4 months for at least 16 months administered by intrathecal injection.

To qualify for the trial, participants must be between 25 and 50 years old at the start of the study and have a CAP score between 400 and 500, a calculation that combines age and the number of CAG repeats in the huntingtin gene. Eligible participants must have been diagnosed with early manifest HD or be carriers of the mutated gene showing subtle early symptoms, which may be identified through detailed clinical evaluation. They must also be able to undergo procedures such as blood draws, lumbar punctures, and MRI scans, and have a reliable study companion to support them throughout the study.

Certain factors may disqualify individuals from participating in the trial including previous or ongoing treatments for HD that could influence huntingtin protein levels, a history of gene therapy, cell transplantation, or brain surgery, and specific medical conditions such as hydrocephalus, chronic migraines, certain psychiatric disorders, or infections. Additionally, individuals who are pregnant, breastfeeding, or planning to become pregnant during or shortly after the study may not be eligible.

In April 2025, Roche noted in a community letter that it amended GENERATION HD2 to include only a higher dose of tominersen after interim data revealed this dosage may be more likely to show benefit in patients with HD. The independent data monitoring committee (iDMC), those who helped make the decision, did not find any safety concerns with the agent, and the trial remains on track to conclude in 2026.²

Those previously assigned to the 60 mg dose will be switched to the 100 mg dose, and those in other treatment groups (100 mg and placebo) will remain in their assigned groups. Roche noted that the iDMC will continue to review study data every 4-6 months to recommend whether to continue, modify, or stop the study. Although it was concluded that the 100 mg dose may be best for clinical benefit, the company claimed it cannot draw final conclusions at this time, and will wait for the study be completed.

GENERATION HD2 is a follow-up to GENERATION HD1 (NCT03761849), a phase 3 trial of tominersen that was discontinued in early 2021. 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. Months later, GENERATION HD2 was decided upon after a post-hoc analysis from the original study showed a possible benefit for a subgroup of patients who are younger with less disease burden.³

GENERATION HD1 was the largest clinical trial in HD at the time, comprising 791 participants across 18 countries. Prior to that study, the therapy was tested in a phase 1/2 trial, with results published in the New England Journal of Medicine. In the study, treatment with tominersen successfully targeted and reduce levels of mutant huntingtin protein in patients with HD, becoming the first such agent to achieve this feat. Overall, dose-dependent reductions were observed, with the greatest changes observed in the 2 highest-dose groups (90 mg: 42% reduction; 120 mg: 38% reduction).⁴