GENERATION HD1 Trial Fails to Show Benefits of Tominersen

Treatment with tominersen failed to show evidence of clinical benefit in adults with Huntington’s disease during the Phase 3 clinical trial GENERATION HD1.

Roche, the company developing tominersen, decided to pause dosing in the clinical trial about a month ago, after a pre-planned review of trial data by an independent data monitoring committee found the treatment did not show a favorable benefits/risk profile. Dosing in GEN-EXTEND (NCT03842969), an open-label extension study for people who participated in other tominersen trials, also was paused.

During a webinar, hosted by the Huntington’s Disease Society of America, Lauren Boak, PhD, global development team leader, product development neuroscience at Roche, shared data from the trial that led to this decision.

What is the GENERATION HD1 trial?

Tominersen is an investigational therapy designed to lower levels of the mutant huntingtin protein in the brain that cause Huntington’s. Findings from a previous Phase 1/2 trial (NCT02519036) demonstrated that tominersen treatment significantly reduced the levels of this mutant protein.

“The very important data that came out of this study, was for the first time showing that an investigational agent can lower mutant huntingtin in Huntington’s patients. That was a great achievement,” Boak said.

These early positive results prompted the launch of the Phase 3 GENERATION HD1 study (NCT03761849), which set out to evaluate the clinical efficacy and safety of tominersen.

GENERATION HD1 enrolled 791 adults with Huntington’s, who were evenly divided into three groups: one group was given placebo; the other two received tominersen, at a dose of 120 mg, given either once every eight weeks or once every sixteen weeks. The therapy is administered by an injection through the spine into the fluid that bathes the brain and spinal cord (called the cerebrospinal fluid, or CSF).

The study’s main goal was to determine the effect of treatment on Composite Unified Huntington’s Disease Rating Scale (cUHDRS) scores. The cUHDRS is a composite score that takes into account two tests of cognition, a measure of motor function, and a test of functional capacity (TFC, a person’s ability to function independently and successfully day-to-day). GENERATION HD1 originally was designed to last 101 weeks (just over two years). Outside the U.S. and Japan, only TFC measures were designated as the primary outcome.

As is common practice for clinical trials, the GENERATION HD1 study had an independent data monitoring committee (iDMC) — a group of experts, independent of the study’s sponsor (Roche), who are tasked with reviewing data as the study is conducted, in order to ensure the safety of participants. Notably, unlike the sponsor, or the study’s investigators and participants, the iDMC has access to unblinded data, meaning they know which patients were given the experimental therapy.

“The iDMC plays a very critical role, having access to all of the information during the study, to assess the balance of the potential risks versus the potential benefits [of treatment to] study participants,” Boak said. “When they do this, on a regular basis, they then recommend whether or not the study should continue, based on their assessment.”

The decision to discontinue dosing of tominersen was made based on an interim analysis conducted by the iDMC in March.

What the iDMC analysis found

In their analysis, iDMC members specifically looked at data covering patients in the GENERATION HD1 study for 69 weeks (about a year-and-a-half). This included approximately 60% of participants in each of the three study groups.

Among participants given placebo, scores on the cUHDRS — as well as scores on its individual measures of functionality, mobility, and cognition — tended to worsen over time. That is expected in a progressive disease like Huntington’s, where symptoms usually become worse as time goes on.

Among participants given the less-frequent dosing of tominersen (every 16 weeks), scores on the cUHDRS and its individual measures were generally comparable to placebo at all timepoints. There was no evidence that the active treatment was easing symptoms or improving participants’ ability to function, relative to the placebo.

For those given tominersen every eight weeks, cUHDRS and related scores worsen over time more quickly than they did for participants given placebo. By 69 weeks of treatment, individuals given this more frequent dosage of tominersen consistently had worse scores than those given placebo or tominersen once every 16 weeks.

The same trend was found for the Montreal Cognitive Assessment (another measure of cognition not included in the cUHDRS) and for clinician-rated assessments.

Collectively, these data illustrate, “a very consistent pattern that we’ve observed across these multiple measures. … We do not see any benefit or favorable outcome for tominersen treatment versus placebo,” Boak said.

Data from GENERATION HD1 have so far not raised any new safety concerns related to the therapy. Commonly-reported adverse events (side effects) included falls, injection site pain, dizziness, headache, and the common cold.

Of note, serious adverse events occurred at a higher rate among participants given tominersen every eight weeks (15%), compared to those given tominersen every 16 weeks (8%) or those given placebo (11%).

Also of note, tominersen treatment was associated with increasing size of ventricles — fluid-filled cavities in the brain — in imaging studies. Most of these changes have not been associated with any clinical symptoms, according to Boak.

“The overall conclusion is not what we had hoped … In the 120 mg every eight weeks dosing arm, tominersen was considered unfavorable compared to placebo. In the less-frequent dosing arm, the 120 mg every 16 weeks, the safety profile appeared comparable to placebo, however … there was no apparent benefit observed,” Boak concluded. She noted that the overall lack of any sign of efficacy across the many measures is what ultimately led to the decision to discontinue dosing.

What happens now?

Boak stressed that, even though dosing of the trial has been stopped, the GENERATION HD1 study is still ongoing, with plans to continue to collect data on participants in order to evaluate clinical and safety outcomes. Participants will be asked to complete some further clinical assessments (though fewer than originally planned). The trial likely will be unblinded to participants early next year.

Boak noted that, by the time all data is collected, about 70% of participants are expected to have been treated for 69 weeks.

“We don’t expect the overall conclusions to change, but the individual numbers may,” Boak said.

Furthermore, many analyses — such as looking at levels of proteins in participants’ blood or CSF — have yet to be undertaken. Analyzing these samples will let researchers determine the effects of treatment on mutant huntingtin levels, and how levels of the mutant protein correspond to efficacy measures. Other biomarker analyses also will be conducted.

In the coming months and years, as more data is collected, researchers hope to better understand the effects of tominersen treatment on the body and why the trial’s results turned out the way they did. Such analyses could help to inform future research for Huntington’s treatments.

“None of us were hoping for these results; it is very disappointing … Obviously, though, [GENERATION HD1] is a clinical trial, and it set out to answer the questions. And we have interpretable data. It is not the data that we hoped for … but from this, we will be able to learn a lot,” Boak said.

Roche also is continuing its open-label Phase 1 trial GEN-PEAK (NCT04000594), which is testing how tominersen moves through and affects the body (its pharmacokinetics and pharmacodynamics).