HIGH IMPACT – During Roche’s HDSA presentation, the company discussed GENERATION-HD1 trial data and post-hoc analysis in subgroups of patients. The call was led by Peter McColgan (Roche) and Lauren Boak (Roche). The speaker mentioned that there were over 700 participants listening in to the talk.

The GENERATION HD-1 study is a randomized, multi-center double-blind placebo-controlled Phase III study performed in 18 countries across 100 sites.

  • There were 791 participants enrolled
  • Participants were clinically diagnosed with adult-onset manifest HD, aged 25-65 years of age, and with CAP scores of greater than 400
  • Participants received 120mg of tominersen either every 8 weeks or every 16 weeks or placebo every 8 weeks

The iDMC recommended to stop dosing while continuing to follow-up participants for safety and clinical outcomes in March 2021. The review was unblinded at week 69 (month 17).

Key findings of Generation HD-1 study at week 69 showed:

  • Tominersen 120 mg every 8 weeks was unfavorable compared to placebo
  • Benefit : Risk in 120mg every 16 week was not clear. Safety profile comparable to placebo however no apparent benefit was observed

Generation HD-1 Post Hoc Exploratory analysis

Objective was to determine whether there was a subgroup of patients that could benefit from tominersen, and whether outcomes were dependent on disease burden.

  • Performed univariate and multivariate analysis to determine whether there was a subgroup of patients in Generation HD1 that respond to tominersen, and whether there is a biological reason, as supported by biomarkers
  • Key results show potential benefit for low age, lower disease burden patients, as measured by CAP scores in tominersen every 16 week arm. In tominersen every 8 weeks arm, there were unfavorable outcomes, regardless of baseline characteristics

 Key Results

  • Whole group analysis showed unfavorable outcomes for tominersen 120mg every 8 weeks compared to placebo, and no apparent benefit for tominersen 120 mg every 16 weeks compared to placebo
  • There were four subgroups based on age and disease burden (CAP score)
    • Group 1: Low age, low CAP
    • Group 2: Low age, high CAP
    • Group 3: High age, low CAP
    • Group 4: High age, high CAP
  • Post Hoc analysis exploratory analysis showed that tominersen every 16 weeks Low age, Low CAP subgroup showed favorable outcomes compared to placebo for all UHDRS clinical endpoints at week 69. Confirmation in a prospectively designed randomized, placebo-controlled study is required
  • Analysis of UHDRS clinical endpoints for tominersen every 8 week subgroup analysis showed unfavorable outcomes compared to placebo, regardless of CAP scores
  • Whole group findings of CSF NfL and mHTT changes showed NfL increases from baseline at all time points with greatest increase at week 21 and trending toward baseline at week 69. Subgroup data is also consistent with this. Results showed lowering of CSF mutant Huntington, with greater lowering with more frequent dosing. Seen across all subgroups
  • There was dose dependent increase in ventricular volume, with 8-week tominersen data  showing larger increases in ventricular volume than tominersen every 16 weeks


  • Low age, Low CAP – comparable AEs to placebo in 8 and 16 week treatment group. Fewer SAEs observed in 8 and 16 week subgroups compared to placebo.
  • High Age, High CAP – AEs in 8 and 16 week tominersen groups were comparable to placebo

Next Steps

  • Roche is designing new Phase II trial to explore safety and efficacy of different doses tominersen in younger adult patient population with less disease burden
  • The last visit for participants in the GENERATION HD1 and GEN-EXTEND studies will be in March-April 2022. All participants have completed part 1 of the GEN-PEAK study and part 2 will not be conducted

Q & A

Are you able to reiterate timeline for unblinding people who participated in Gen HD 1 trial? Last patient will have last visit in March or Early April this year. Need to wait until last visit happens. Will have full dataset available and need to go through additional steps to make sure study is closed, hopefully in May. Information will be available to investigator at different sites hopefully in June.

Can you share information with us about upcoming trial? We’re in very early stages of designing it. Working hard and will let patients know as soon as they know more.

On continued access of tominersen to trial participants and compassionate use – Generation HD1 failed to reach primary outcome. Post-hoc analysis not statistically significant. While we have confidence to move forward, need trial specifically designed to see whether it’s good for patients who are younger with less disease burden. Wouldn’t meet criteria for compassionate use to happen. Safety is number one priority. Need confidence in positive benefit risk. At this point don’t have this information.

Lots of other things happening in HD research and clinical trials. What does that mean for potential for participants to engage in other studies? For each study that happens in Huntington’s sponsor will look at what type of patients to include etc. People exposed to Huntington-lowering agent may be excluded from other studies, however depends on which study it is. There are more studies coming up and will look at what recommendations are based on exposure to tominersen. Participants can reach out to site investigators to determine eligibility.

Is there any indication of what might have made tominersen toxic at higher dose? Also, any comments on ventricular volume data? It was seen across group and subgroups is that outcomes unfavorable for 8 week treatment group. Might be that the amount of drug might be too high for patients. Might be due to drug itself. It’s difficult to know whether it’s due to inflammation. Effects may be related to on-target effects and lowering of wildtype Huntington or might be off-target effect because drug dose too high. Phase II will not have Tominersen treatment every 8 weeks. When ventricles monitored, saw only three cases in treatment every 8 weeks, didn’t see it in every 16 weeks for hydrocephalus. Increase in ventricles didn’t manifest into symptoms in patients receiving treatment every 16 weeks so significance of it is unclear.

Why is NfL important in HD? It’s a measure of axonal loss. Higher NfL indicates a bad process. The natural history of Huntington disease will have NfL increases as they progress with disease of about 7-9% per year. Does NfL life seem to increase relative to drug? NfL level at week 37 is in line with baseline. Gives confidence that we can prevent it from rising and would give us confidence in potential clinical benefit. Will test in phase III.

Digital data – Does Roche have plans to share findings or change way type of data was collected? Digital monitoring tool in study took a lot of effort by participants and site staff and that. Are in process of analyzing and will be sharing the data. Have to finish reviewing and understanding before sharing. Use of monitoring tool is new to many people. Feedback is helpful and are thinking of ways to optimize it if it will be used in next study.

What have we learned about Huntington lowering and in general as a potential modality? Two messages – tominersen works lowers mutant Huntington proteins levels in CSF. On other hand patients didn’t get better. Just meant that with study, patient population and dose, it didn’t work. We have to sit back with news of this study and wave study of allele specific ASO not being able to lower mutant Huntington. What we’re hearing now is that there may be a benefit from tominerson and that Roche wants to move forward. We’ve learned a lot and there’s a clear difference in 8 week and 16 week. There’s much more data to come out and a lot of learning and not let failure stop us. Lots of approaches besides Huntington lowering. We’re glad there’s signal to go forward at this point.

Data suggests possibly younger patients with milder symptoms could benefit from tominersen. Does it support idea of preventative trials? Or does it rule out idea of tominersen being beneficial for other subgroups? Want to reiterate that just because benefit of this dose at frequency is in younger patients with less disease burden doesn’t mean can’t work for older patients with more disease burden. Seen in Alzheimer’s that earlier intervention shows more benefit but doesn’t mean you can’t benefit later patients. Hope is to treat whole HD community.

Potential length of study – would it be possible to see benefit if treatment longer period of time? Recommendation came from iDMC review of data. Safety needs to be number one priority. Saw in treatment every 8 weeks that outcomes were in unfavorable direction and recommendation was to stop dosing. Might have seen different outcomes if treatment continued, but safety needs to be most important thing for any study.

Is there any last bit of advice or words of encouragement to share with everyone? From a patient perspective, what’s the reason to believe?  Very disappointed that we had to stop dosing early in March. We’re encouraged by robustness of this study and how it was designed and conducted. We can learn a lot from it, even though we had to stop dosing, study is not a failure. Pleased to share what we learned in last 9 months. We were able to answer some questions, but we have many more questions. The field is still moving forward not just with tominersen, but with other trials working toward the same goal.

We see consistency across endpoints in subgroups and it’s supported by biomarker data. Confident in terms of safety and we can learn more in phase II by looking at lower doses. Will benefit community.

When conducting trials looking for treatment in HD, look at beneficial effect and safety. When trial fails, have to see what happened and what went wrong. In looking at how did we fail, it’s  important as an investigator, to look at trial, and people in trial. There’s still a potential that it could help people. Next study will be informed by everything we learned from this study and it’s important to go forward. Let’s take our time to see what plan will be from Roche about design of next trial.

inThought Analysis

As tominersen was the front-runner of HD treatment, its development has been closely watched by the Huntington’s Disease community. During the HDSA sponsored public discussion session, Roche did not disclose any information regarding the new design of the Phase II trial, but emphasized that the company believes post-hoc analysis showed enough signal that renders continue development of tominersen. However, looking closely, the post-hoc analysis was not statistically significant, and the signals were in points that only suggests small trends. Even though more frequent dosing of every 8-weeks showed more knockdown of mHTT, it led to unfavorable outcomes across all readouts. This may cause additional confusion regarding the efficacy of tominersen. We postulate that knockdown of both mHTT and wtHTT may be one explanation, or frequent dosing/great drug exposure can enhance brain atrophy as seen from ventricular enlargement. In addition, if tominersen is only beneficial for younger patients as Roche suggested, it will not be able to address the unmet needs where the most common age of onset of HD patients is mid-life. The momentum of tominersen to be the leading treatment for HD has waned over the past year. Roche has a long way to go before it can reinstate tominersen’s dominance in the HD field.


Source: HDSA Research Webinar