Roche ends two Huntington’s disease drug programmes after disappointing results

Today, Roche announced in a community letter difficult news for the Huntington’s disease (HD) community, discontinuing two separate clinical programmes after new data emerged from ongoing studies. 

The larger announcement concerns GENERATION HD2, the Phase II clinical trial evaluating tominersen, a total huntingtin-lowering therapy, in people with early HD. The study found that tominersen did not appear to improve symptoms or slow disease progression and so did not meet one of its key primary endpoints.

Roche also announced it is discontinuing POINT-HD, a first-in-human study of the drug RG6496, designed to selectively lower expanded huntingtin. Animal studies indicated that the drug would not be suitable for the long-term dosing required for treatment in clinical trials.

Importantly, in neither case was the decision to close out the trial related to the safety of trial participants which is a silver lining to this sad news. Although the announcements happened at the same time, Roche emphasised that they are unrelated decisions based on different datasets. Let’s get into what we learned from this update and what information is still to come. 

Tominersen – the first drug shown to lower huntingtin in people

First, a quick recap about the drug being tested in GENERATION-HD2. Tominersen is a huntingtin-lowering drug given by spinal tap. It is a type of drug called an anti-sense oligonucleotide, or ASO, that lowers levels of both the regular and expanded huntingtin proteins, also referred to as total huntingtin lowering. It was the first drug to show that lowering huntingtin was possible in people but has had its fair share of challenges as it progressed through clinical testing. 

Clinical trials are among the largest, longest, and most expensive scientific experiments ever undertaken, requiring an enormous commitment from both the researchers who run them and the families who take part.

A Phase 3 study, called GENERATION HD1, tested tominersen but was halted early in 2021 after an independent data review committee found that the safety risks outweighed potential benefits in the group of trial participants being assessed. However, an after-the-fact investigation of the data generated in this trial, known as a post hoc analysis, suggested that certain groups of participants, particularly younger individuals with less advanced disease and lower CAG numbers, might benefit from a lower or less frequent dose. 

The best way to prove that the findings from the subgroup analysis were real was to do another trial. So even though this trial didn’t give us the results we had hoped for, this important finding sparked renewed interest in studying tominersen and the launch of a new trial called GENERATION HD2.

The GENERATION-HD2 trial was a Phase 2 placebo-controlled study initially testing 2 doses of tominersen, but later honed in on just the higher 100 mg dose compared to placebo. The trial sought to figure out if tominersen was able to influence HD biomarkers including huntingtin and neurofilament light (NfL), the latter of which is an indicator of brain health. Critically, this trial was also designed to work out if tominersen could slow down disease progression, as measured by the clinical metrics composite Unified Huntington’s Disease Rating Scale (cUHDRS) and Total Functional Capacity (TFC), important measures of many different signs and symptoms of HD. 

Tominersen lowers huntingtin, but does not appear to slow disease progression 

The headline result from this latest update about GENERATION HD2 is disappointing but there are some encouraging findings in the update from Roche.

Importantly, the drug appeared to do exactly what it was designed to do biologically. Participants receiving tominersen had significant reductions in levels of the expanded huntingtin protein in the cerebrospinal fluid (CSF) that bathes the brain, alongside reductions in NfL in both CSF and blood plasma, indicating brain health seemed to be improving. We did not learn the specifics yet of exactly how much each of these biomarkers changed but hopefully we will learn that in forthcoming updates.

Roche also reported no new safety concerns during the study, which is good news. 

Every clinical trial, regardless of its outcome, teaches us something.

However, despite these encouraging biomarker changes, people receiving tominersen did not appear to experience a slowing of disease progression compared with those receiving placebo during the span of the study. The study’s clinical endpoints, including the hoped for improvements in cUHDRS and TFC at 16 months, were not met. As a result, Roche has decided to discontinue development of tominersen.

Ultimately, this is a complete termination of this drug for testing and treatment of HD by Roche, meaning there will be no open label dosing or compassionate use of this drug. Anyone who has or is participating in a trial for tominersen and has additional questions should reach out to their study centre and their neurologist for support and to discuss a transition plan. 

What does this mean for other huntingtin lowering approaches?

This is disappointing news, particularly for the hundreds of families who participated in the study and the many more who have followed the tominersen story over the past decade. However, it’s important that we are careful about what these results do, and do not, tell us.

This study suggests that the degree of lowering of expanded huntingtin and changes to NfL achieved in approximately 16 months in this trial was perhaps not sufficient to meaningfully slow HD progression. But this does not necessarily mean that huntingtin lowering cannot slow HD.

There are still many unanswered questions. 

• Was the amount of huntingtin lowering sufficient in the brain regions that matter most? 
• Was treatment started early enough? 
• Is 16 months long enough to detect changes in a disease that progresses very slowly? 
• Some participants have been treated for much longer – how has this drug worked for them over a longer time period?
• Could a different huntingtin-lowering approach, like a splice modulator or gene therapy, produce different results? 

These questions remain open.

Several other huntingtin-lowering therapies currently in development use different technologies, dosing strategies, or delivery methods. Some studies, including uniQure’s AMT-130 gene therapy programme, have suggested that any clinical effects may take several years to emerge.

For that reason, and with the sparse information we have so far, we are interpreting the GENERATION HD2 results in the context of this specific drug, dose, and study design rather than as a verdict on huntingtin lowering as a whole. The full dataset has not yet been released, and Roche says further analyses will be presented at future scientific meetings.

POINT-HD also comes to an end

Roche’s community letter also announced today that it is stopping development of RG6496, an experimental drug designed to selectively lower only the expanded copy of the huntingtin gene in people carrying a particular SNP – a small DNA letter change that some people with HD have in their expanded gene. Like tominersen, RG6496 was also an ASO delivered by spinal tap. A small phase 1 safety study had begun to test this drug, dosing its first participants at the end of 2025. 

A big difference between tominersen and RG6496 is that the decision to end this programme was not based on results from people in the trial. POINT-HD had only recently begun enrolling participants, with just three people receiving a single dose so far, none of whom had experienced any bad side effects to date. 

In parallel to this study in people, Roche was conducting longer-term animal studies to determine whether long term treatment with repeated dosing would be safe. Animal studies are often done by companies while trials are conducted to continue learning about a drug while also getting it out to the community as quickly as possible. If they learn more that would impact their approach, they can adjust or halt the trial the drug is being tested in. In this instance, those concurrent animal studies identified findings that Roche concluded would prevent the drug from being developed as a treatment that could be given with long term dosing. 

Although Roche stated that there are no major safety concerns for people receiving a single dose, the company decided to stop the programme because repeated treatment would no longer be possible. Participants already enrolled will continue to receive follow-up monitoring. Roche has not yet released detailed information about the animal study findings.

A huge contribution from the HD community

Clinical trials are among the largest, longest, and most expensive scientific experiments ever undertaken, requiring an enormous commitment from both the researchers who run them and the families who take part. They require years of work from researchers, clinicians, industry partners and, most importantly, hundreds of volunteers and their families who choose to participate despite there being no guarantee that a treatment will work.

These results do not necessarily mean that huntingtin lowering cannot slow HD.

More than 1,500 HD families have contributed to Roche’s huntingtin-lowering programmes since the first tominersen studies began over a decade ago. Although today’s news is deeply disappointing, it’s important to remember as we all digest this news that those contributions have fundamentally advanced the field. These studies proved that the huntingtin protein can be safely measured and lowered in people, supported the development and validation of biomarkers that are now used across HD research, and generated an enormous amount of knowledge that will influence the design of future therapies.

Every clinical trial, regardless of its outcome, teaches us something. Sometimes the lessons are exactly what researchers hoped to find; sometimes they reveal that a promising approach needs to be refined or that a different strategy may be needed. While this news is very disappointing, there’s no such thing as a failed study. Researchers are gaining valuable knowledge from each study, each trial participant, and each datapoint. So no effort is wasted. Every study brings the HD field one step closer to understanding how to develop treatments that truly modify the course of the disease.

The HDBuzz team, and the wider HD community, owe an enormous debt of gratitude to every participant, family member, study coordinator, and clinician who made these programmes possible. Progress in HD research is built on your generosity, courage, and commitment.

Looking forward

While this marks the end of two programmes, it is not the end of HD therapeutic development at Roche. The company says its gene therapy programme, RG6662 (formerly developed by Spark Therapeutics), continues unchanged, and the company remains committed to exploring multiple therapeutic approaches for HD.

Roche has committed to sharing full data at future medical meetings. HDBuzz will continue to follow this story as more data and news on this update become available.

Summary: 

• Roche has discontinued development of huntingtin-lowering drugs, tominersen and RG6496.
• In the GENERATION HD2 trial, tominersen lowered huntingtin and improved biomarker measures, but did not appear to slow disease progression.
• The decision to stop RG6496 was unrelated to the tominersen results and was based on findings from longer-term animal studies, not safety or efficacy data from trial participants.
• These findings do not rule out huntingtin lowering as a therapeutic strategy. Many questions remain about timing, dose, delivery, and whether other huntingtin-lowering approaches could produce different outcomes.
• Although disappointing, these programmes transformed HD research by demonstrating that huntingtin can be lowered in people and by generating knowledge that will inform the next generation of clinical trials.
• Roche remain committed to developing therapeutic approaches for HD and their gene therapy program for RG6662 (formerly developed by Spark Therapeutics) is continuing unchanged.