New Trial of Tominersen Possible in Younger, Milder Disease Patients

Certain people with Huntington’s disease — specifically, younger adults with milder disease — may have benefited from treatment with tominersen in the Phase 3 GENERATION HD1 clinical trial, according to a new analysis of study data.

Based on the results, its developer Roche is planning to launch a Phase 2 clinical trial to continue testing the investigational therapy, the company announced in a letter to the Huntington’s community.

“These findings suggest that lower-exposure tominersen may benefit younger adult patients with lower disease burden,” Peter McColgan, MD, PhD, clinical director of the Huntington’s program at Roche, said during a webinar hosted by the Huntington’s Disease Society of America.

“But importantly, this is a post hoc analysis; these findings are not definitive,” McColgan added. “That’s why we need to further investigate and evaluate them in a prospectively designed, randomized, controlled study.”

Additional details about the upcoming trial will be announced as they are available.

“We are in the very early stages of designing [the trial]. We completely understand that patients are really keen to learn more and, potentially, how they can get involved, so we are working extremely hard,” McColgan said. “As soon as we can share more about it, we will, but it’s very early days. … We will update the community as soon as we can.”

Wrapping up GENERATION HD1

Tominersen is an antisense oligonucleotide therapy designed to lower the amount of mutant huntingtin protein in the brain. It is administered via spinal (intrathecal) injection into the fluid around brain and spinal cord (cerebrospinal fluid, CSF).

Following promising early clinical data that tominersen could reduce mutant huntingtin levels as intended, Roche launched the Phase 3 study (NCT03761849) to test the therapy’s safety and clinical efficacy. GENERATION HD1 enrolled 791 adults with Huntington’s. Participants were randomly assigned to a placebo or tominersen at a dose of 120 mg, given either once every eight or 16 weeks.

The study’s main goal was to evaluate the effect of tominersen treatment on composite Unified Huntington’s Disease Rating Scale (cUHDRS) scores, a measure that takes into account two assessments of cognition and a motor function test, as well as changes in total functioning capacity (TFC, a person’s ability to function independently in their day-to-day life).

Roche announced that it was stopping dosing in GENERATION HD1, as well as the open-label extension study GEN-EXTEND (NCT03842969) in March 2021. This decision was based on a recommendation from the trial’s independent data monitoring committee (iDMC), a group of outside experts tasked with ensuring the safety of trial participants and who have access to unblinded data.

The iDMC analysis found that patients treated with tominersen every eight weeks had consistently worse scores on the cUHDRS, TFC, and other measures compared with those on placebo. Patients given tominersen every sixteen week had no significant difference from placebo. Overall, the results suggested that tominersen was not benefiting patients — an announcement that met with disappointment from the Huntington’s community.

Despite an end to trial dosing, participants were asked to continue in the trials for safety checks and to collect further data. According to Lauren Boak, PhD, global development leader at Roche, the majority of patients have continued with GENERATION HD1 and GEN-EXTEND since dosing stopped.

According to Boak, the last trial patient visits will be conducted in March or early April. After these visits, study sites will work to close the studies — a process that involves checking the quality of the data, getting samples sent to labs, and “a lot of paperwork,” Boak said.

Once all these processes are done, the trial will be unblinded — meaning participants will be able to find out which treatment group they had been in during the study, or if they were given a placebo. This is expected by June.

Participants who need to know their treatment status to determine their eligibility for other clinical trials can find out earlier by contacting their investigator, Boak said.

“We had hoped that GENERATION HD1 would meet its primary objectives … but we are encouraged that there is a path forward to continue tominersen research in a subset of [Huntington’s] patients. We recognise that this may still be disappointing news for some members of the [Huntington’s] community,” Roche stated in its letter. “However, GENERATION HD1 was the first-ever Phase III study testing the huntingtin-lowering theory and the vast amount of data from the study provides valuable information for all [Huntington’s] research.”

Roche also noted that the GEN-PEAK study (NCT04000594), testing how tominersen moves through and affects the body (its pharmacokinetics and pharmacodynamics), is now considered complete. Part 1 has finished and its optional Part 2 will not take place.

Analysis ‘gives confidence’ for new trial

Overall results from GENERATION HD1 had suggested that tominersen did not benefit patients compared with placebo.

“The next step for us was to try and understand, could there be a group of patients in the GENERATION HD1 study that may have benefited from tominersen?” McColgan said. “This is when we design a post hoc analysis.”

A post hoc analysis is designed and conducted after a trial’s data has already been collected. Since the original study was not designed to answer the question(s) asked in a post hoc analysis, the results are by definition not definitive — but they can provide insight and indicate avenues for future testing. Importantly, these results are not statistically significant, meaning that they could represent a chance result.

For their analysis, the researchers divided all study participants into two groups based on age — the oldest half and the youngest half. They similarly divided participants into two groups based on their CAP score, a measure of disease severity that looks at age in addition to number of CAG repeats in the HTT gene (broadly indicative of a more severe Huntington’s-causing mutation). The median age was 48, and the median CAP score was 500.

Based on age and CAP score, trial participants were distributed into four groups: low age/low CAP, high age/high CAP, low age/high CAP, and high age/low CAP.

The post hoc analysis revealed two key findings, according to McColgan. First, in patients given tominersen every eight weeks, TFC and cUHDRS scores were consistently worse than placebo across all groups.

“For treatment every eight weeks, point estimates were in the unfavorable direction [compared with placebo] at week 69, regardless of age or CAP score,” McColgan said.

Across most of the groups, scores for patients given tominersen every 16 weeks were not markedly different than placebo. However, in the low age/low CAP subset of patients, those on this less frequent tominersen dose tended to have better TFC and cUHDRS scores after 69 weeks of treatment. The same trend was found for the various components of the cUHDRS.

“For patients receiving [tominersen] treatment every 16 weeks in the low age/low CAP subgroup point estimates were in the favorable direction compared to placebo for all UHDRS clinical endpoints at week 69,” McColgan said.

Data for this low age/low CAP group covered 39 patients who received tominersen every eight weeks, 50 patients treated every 16 weeks, and 39 patients on placebo.

Safety data in the low age/low CAP subgroup generally were positive, McColgan noted. Rates of side effects were similar among treatment groups, with patients given tominersen every 16 weeks reporting fewer serious adverse events than those on placebo.

Biomarker data showed that both dosing regiments lowered the levels of mutant huntingtin protein. Tominersen at both doses was also tied to an increase in neurofilament light chain (NfL) levels, a marker of nerve damage, and to increases in the size of fluid-filled spaces in the brain (ventricular volume). Among patients given tominersen every 16 weeks, NfL levels increased in the weeks immediately after starting on tominersen, but had lowered to baseline levels by week 69.

The consequences of these biomarker changes are still being explored, McColgan said, but they broadly indicate that the therapy does lower huntingtin levels as intended, and generally suggest reasonable safety with dosing every 16 weeks.

“The results [of this post hoc analysis] are not definitive, they are not statistically significant, but they do give us confidence to proceed to a new Phase 2 study which is specifically designed to test this new hypothesis about this subgroup,” McColgan said.