The Clinical Community Reaction to Roche’s Tominersen Turnaround in Huntington

SAP Partner | <b>Vanderbilt University Medical Center (VUMC)</b>

After discontinuing dosing in the phase 3 GENERATION HD1 study in 2021, Roche is designing a new phase 2 trial for tominersen, its investigational antisense oligomer for Huntington disease.

In mid-January 2022, Roche and Ionis announced that they were designing a new phase 2 clinical trial for the investigational Huntington disease (HD) treatment, tominersen.1

This news came nearly a year after its prior trial the phase 3 GENERATION HD1 study (NCT03761849) discontinued dosing after the Independent Data Monitoring Committee made a recommendation to do so based on the investigational therapy’s potential benefit/risk profile for study participants.2 Previously, the therapy had been assessed in a phase 1/2 trial that suggested it could successfully reduce levels of mutant hutingtin (mHTT) protein in patients with HD.3

This new phase 2 trial was decided upon after a post hoc analysis showed a possible benefit for subgroup of patients who are younger with less disease burden.1 Further details about the design are expected to be revealed at future scientific meetings. Beginning January 20, 2022, Roche noted it would participate in a series of webinars on the findings from the post hoc analysis of the GENERATION HD1 study and the next steps for the tominersen program for the scientific and patient communities.

Tominersen, previously known as IONIS-HTTRx or RG6042, is an investigational antisense medicine designed to reduce the production of all forms of HTT, including its mutated variant, mHTT, in individuals with HD. Roche licensed the investigational medicine from Ionis in December 2017.

To get an understanding of the clinical community’s reaction to the news, NeurologyLive® reached out to a pair of experts in the care of patients with HD: Daniel Claassen, MD, MS, director, Huntington’s Disease Clinic, and division chief, Behavioral and Cognitive Neurology, Vanderbilt University Medical Center (VUMC); and Victor Sung, MD, director, University of Alabama at Birmingham (UAB) Huntington's Disease Clinic, codirector, UAB School of Medicine Neuroscience Module, and director, Birmingham VAMC Deep Brain Stimulation Program.

Read their reactions below:

Victor Sung, MD: I think the news validates some of the strong data on the huntingtin-lowering efficacy that has been documented with tominersen, but I think we still have to approach it all with caution.

I think that while there may be criticism that this is just spinning or cutting the data, I think Roche's announcement is pragmatic and data-driven. Basically, what I take away is that in the low-age/low-CAP score subgroup of patients, the data show that there may be some benefit there. But since the study was not powered to detect a change in that subgroup, before we can conclude anything, we will have to conduct a larger study to know for sure whether that signal is real or not.

That approach is fair as long as we proceed with caution. I think Roche, investigators, and patients and their families will all proceed more carefully this time after the emotional letdown of the failure in 2021, but I remain cautiously optimistic.

Daniel Claassen, MD, MS: Investigators from Roche and Ionis recently announced an intent to design a phase 2 study assessing the antisense oligomer (ASO) tominersen in Huntington disease. To briefly remind everyone, this study was stopped due to futility, and patients appear to have poor outcomes from study drug with increased ventricular volume, neurofilament light chain levels, and worsening clinical severity—especially in the group treated at greater frequency (every 8 weeks versus every 16 weeks). The Roche team recently presented a post hoc analysis, suggesting that patients who are younger, with less disease exposure (defined using the CAG by age product score), and less frequent administration (every 16 weeks) may “benefit” from the compound.

It is worth remembering that post hoc analyses are fraught with difficulty. How are we to interpret a possible effect in a lower CAP and lower age subgroup? Many investigators are concerned that new trials of tominersen, which appear to have a detrimental effect on participants, may be difficult to justify. The existing concerns about the benefits of wildtype Huntington protein and potential detriments from lowering wildtype Htt remain—and these concerns are held across multiple current therapeutic initiatives in HD. What about exacerbated neuroinflammation, and disrupted CSF flow from tominersen? How do we account for these effects in patients who are given these treatments? So many questions.

Our team discussed these results, and we were reminded of a potential source of bias, that can often occur with post hoc analyses like these. Collider bias can distort purported associations between exposure and outcome relationships. In this case, restricting analyses to young participants with lower CAG repeats who have received intrathecal tominersen can result in false associations that do not exist in the general population. With an interest to the possible future trial, we need a clear and cogent hypothesis that gives the HD community confidence that we can go forward. Right now, there are too many questions that restrain ebullient excitement from the community. But it is encouraging that this research is continuing.

Transcript edited for clarity.

1. Ionis' partner to evaluate tominersen for Huntington's disease in new Phase 2 trial. News release. Ionis. January 18, 2022. Accessed January 19, 2022.
2. Roche provides update on tominersen program in manifest Huntington’s disease. News release. Roche. March 22, 2021. Accessed January 19, 2022.
3. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Phase 1-2a IONIS-HTTRx Study Site Teams. Targeting huntingtin expression in patients with Huntington’s disease. N Engl J Med. 2019;380(24):2307-2316. doi:10.1056/NEJMoa1900907