Roche Designing New Phase 2 Trial of Tominersen in Huntington Disease


After a post hoc analysis revealed promising results in a subgroup of younger adults with less disease burden, Ionis has announced that Roche will develop a new phase 2 trial.

C. Frank Bennett, PhD, executive vice president, chief scientific officer and franchise leader for neurological programs, Ionis Pharmaceuticals

C. Frank Bennett, PhD

Almost a year after news that the phase 3 GENERATION HD1 study (NCT03761849) was discontinuing dosing of tominersen, an investigational agent for Huntington disease (HD), its developer Roche has begun designing a new phase 2 trial after a post hoc analysis showed a possible benefit for subgroup of patients who are younger with less disease burden, according to an announcement from partner company Ionis.1,2

Further details about the design of the new phase 2 trial are expected to be revealed at future scientific meetings. Beginning January 20, 2022, Roche is expected to 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 the huntingtin protein (HTT), including its mutated variant, mHTT, in individuals with HD. In December 2017, Roche licensed the investigational medicine from Ionis.

"These findings are promising and warrant a new study designed to test tominersen in this specific patient group. We are pleased that Roche has determined that there is a path to advance the tominersen development program," C. Frank Bennett, PhD, executive vice president, chief scientific officer and franchise leader for neurological programs, Ionis Pharmaceuticals, said in a statement.1 "This is an encouraging development for the HD community. We and Roche are grateful to the HD community's continued partnership, which has led to these important insights and a new scientific hypothesis."

Originally, the results from the phase 1/2a trial (NCT02519036) provided the confidence for Roche to move forward with tominersen into the phase 3 GENERATION HD1 trial.3 Patients included in the phase 3 study were randomized 3:1 to tominersen 120 mg every 2 months, tominersen 120 mg every 4 months, or placebo. All told, the global trial included 791 participants from 18 countries aged 25 to 65 years with manifest HD, defined as having a diagnostic confidence level score of 4 as well as an Independence Scale score greater than 70.

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Primary end points of GENERATION HD1 were change from baseline to week 101 in Composite Unified Huntington’s Disease Rating Scale and Total Functional Capacity Score. Other secondary outcome measures included a change from baseline in Total Motor Score, Symbol Digit Modalities Test, Stroop Word Reading Test, and Clinical Global Impression. The study is still ongoing without dosing for the collection of safety and clinical outcomes, with an anticipated completion date occurring as planned at the last patient visit, sometime in March or April 2022.

Daniel O. Claassen, MD, MS, Director, Level 1 HDSA Center of Excellence, Vanderbilt University Medical Center

Daniel O. Claassen, MD, MS

In reaction to this news, Daniel Claassen, MD, MS, director, Huntington’s Disease Clinic, and division chief, Behavioral and Cognitive Neurology, Vanderbilt University Medical Center (VUMC), told NeurologyLive® that it is important to remember that the Independent Data Monitoring Committee recommended stopping GENERATION HD1 because of futility—patients appeared to have poor outcomes from the study agent, including increased ventricular volume, increased neurofilament light chain levels, and worsening clinical severity, especially so in those treated at a 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 treated with less frequent drug administration (every 16 weeks) may ‘benefit’ from the compound,” Classsen said. “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.”

Claassen added that there are existing concerns in the community about the benefits of wild-type Huntington protein and the possible detriments from lowering wild-type Htt. “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,” he said.

He explained to NeurologyLive® that in post hoc analyses such as these, collider bias can “distort purported associations between exposure and outcome relationships,” making the analyses difficult to translate to a wider population—particularly in this case, where the analyses will take place only in a specific subgroup. “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,” Claassen said.

Also expected to complete around March/April 2022 is GEN-EXTEND, an open-label extension study for participants coming from any Roche HD study, where patients received 120-mg tominersen every 2-4 months. That study is also ongoing without dosing.

The results from the phase 1/2 trial of tominersen were published in the New England Journal of Medicine in May 2019, demonstrating that the investigational antisense oligonucleotide was the first therapeutic to successfully target and reduce levels of mHTT protein in patients with HD.2 A total of 46 patients with early HD were enrolled in the trial. Treatment with tominersen showed dose-dependent reductions of mHTT protein in the cerebrospinal fluid (CSF), with the greatest reductions recorded in the 2 highest-dose groups (90 mg: 42% reduction; 120 mg: 38% reduction). Although nearly all patients experienced mild to moderate adverse events (AEs), investigators reported no serious AEs in patients who received the study drug.3

The clinical development program also included GEN-PEAK, a phase 1 study aiming to better understand the pharmacokinetics of tominersen, which continued after dosing was halted in GENERATION HD1, evaluating how the drug affects mHTT protein levels and other markers in the spinal fluid and blood, across a dosing range from 30-120 mg over 2 administrations.2 GEN-PEAK is expected to now be completed as all patients have completed part 1 of the study and part 2 has been terminated.

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
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