Today Roche shared difficult news. After careful review of the data, they have decided to stop two of their Huntington's disease studies: GENERATION HD2 and POINT-HD. We've provided an overview along with further details provided in a community letter from Roche to help explain these recent decisions.

In Summary:

GENERATION HD2 was testing tominersen, the second time this drug has been studied in a large trial. An earlier study, GENERATION HD1, was stopped a few years ago, and this study was designed to try again at a lower dose in people at an earlier stage of HD. The results showed tominersen was safe and did lower both the normal and harmful form of the huntingtin protein, along with a marker of damage in the brain called NfL. Unfortunately, it did not slow the course of HD or improve how participants were doing, so the study is ending.

POINT-HD tested a newer drug, RG6496. It was designed to be more selective than tominersen, lowering mainly the harmful form of the huntingtin protein while sparing more of the normal form. It stopped early after animal data showed it could not be given safely long term. Everyone who received a dose is safe and will continue to be monitored.

From HDYO

News like this is hard for our whole community to process. We're deeply grateful to Roche for their years of dedication to HD, and we are especially grateful to everyone who took part in these trials. While it can be frustrating, a trial ending is not a door closing; every trial gives researchers information they need to get the next one right. We've seen setbacks become progress before, and we are confident we will again. The work continues, and so does our community. Our hope has never rested on one drug or one trial; it rests in each other, and in knowing you never carry this alone. HDYO is here for you through all of it.

More Details from Roche

These are independent, data-driven events, which have coincided by chance. While this news is deeply disappointing, promptly communicating about the findings is the most responsible way for us to honor the contribution of study participants and allow the HD community to focus efforts on other avenues of research.

GENERATION HD2/tominersen: Study Results

The GENERATION HD2 study was designed to validate a data trend found in adults with early or very subtle symptoms of HD after scientists analysed the results of a prior tominersen study (GENERATION HD1). Recently, the 16-month treatment period for all GENERATION HD2 participants was completed, data collected and initial analyses were conducted. Initial results of the primary analysis show:

• Safety: Tominersen was well tolerated and showed no new safety signals.
• Biomarkers: Tominersen significantly lowered mutant huntingtin protein and Neurofilament Light Chain (NfL) (a protein linked to neuronal damage that is elevated in people with HD), compared to people receiving placebo.
• Efficacy: There was no meaningful impact on clinical efficacy for the study participants receiving tominersen, compared to those on placebo.

POINT-HD/RG6496: New Findings from Non-clinical (Animal) Studies

The POINT-HD study is the first time RG6496 is being tested in people. The study’s main aims were evaluating the effects of a single dose of the drug in people with early HD. The study recently opened and has enrolled three participants.

In parallel to the POINT-HD study, Roche was conducting longer-term non-clinical (animal) research to support future plans to give multiple doses of the drug. Based on new data from one of these studies, our team has concluded that RG6496 cannot be given chronically with repeated doses. While there is no safety concern for people to receive one dose, we have chosen to stop the POINT-HD study early, because we can no longer offer participants the possibility of long-term treatment. Enrolled participants will continue to be monitored, per study protocol.

Next Steps

• Communications to Study Participants: Our immediate focus is supporting participants and sites regarding these announcements. Earlier this week, sites were notified so they could contact participants and discuss transition plans and support. Because these studies are running in multiple countries, we acknowledge that families may have received news at different times and in different channels. For further questions, families should contact their sites. Our team can also be reached at medinfo.roche.com.
• Sharing Data & Learnings: Data will continue to be analysed and presented at future medical meetings. We are committed to sharing learnings with the research and family communities to advance the understanding of drug development for HD.
• Further Research: Roche’s Phase I/II study of investigational gene therapy RG6662 (formerly from Spark Therapeutics; study SPK-101, NCT06826612) is ongoing as planned. Additionally our interest in exploring multiple HD therapeutic approaches remains, and we will continue to follow promising science.

With profound thanks to the HD community

We have been humbled and inspired by the 1,500+ HD families and broader community who contributed to both programmes - tominersen since clinical studies began in 2015 with our partner Ionis Pharmaceuticals, and RG6496 more recently. These contributions changed the history of HD drug development - proving the protein that causes HD could be lowered in humans, shaping new research and approaches, which will undoubtedly lead to future breakthroughs.

On behalf of all Roche HD team members over the years, we are deeply grateful to this incredible HD community. Progress is only possible together and built over years of partnership. We remain hopeful for the future of HD research.

About the GENERATION HD2 Study

The GENERATION HD2 study (NCT05686551) is a Phase II study that evaluated the safety, biomarker impacts, and clinical efficacy trends of tominersen, compared to placebo over a minimum of 16 months. It investigated whether a 100mg dose of tominersen administered via spinal fluid injection three times a year could offer clinical benefit to adults aged 25-50 years with early HD. In addition to safety and biomarker measures, tominersen was evaluated using composite Unified Huntington's Disease Rating Scale (cUHDRS) or Total Functional Capacity (TFC) scores - scales that are commonly used in HD studies to understand the impact on disease progression. The study enrolled 301 participants across 15 countries (Argentina, Australia, Austria, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, the UK and the USA).

About the POINT-HD Study

The POINT-HD study (NCT07246941) is a Phase I, first-in-human study that evaluated the safety and tolerability of RG6496 in adults aged 25-65 years with early HD. RG6496 was designed to selectively lower mutant huntingtin protein by targeting a specific SNP (a small variation in the DNA sequence) found in the expanded HD gene of some individuals. The study aimed to investigate safety, drug behaviour, and biomarker changes following one dose of RG6496 administered via spinal fluid injection. The study was open in New Zealand, Argentina, and Australia, and had planned to open in Canada and Europe.