After halting dosing in the historic Phase 3 clinical trial for its Huntington’s disease gene silencing drug tominersen last March, pharmaceutical giant Roche announced today that it will start a new, less ambitious Phase 2 trial, limited to younger adult patients with “less disease burden.” The goal is to measure tominersen’s efficacy against the progression of HD.
Disease burden is calculated using a person’s age and degree of genetic mutation: the higher the sum of those two factors, the higher the burden. Roche, after initial testing of the drug, skipped Phase 2, which typically tests safety and efficacy of different doses, to pursue a Phase 3 trial, which confirms safety and efficacy in a larger population. Now it is proceeding in a more typical manner.
Roche informed the global HD community about the new trial in a letter released today. Roche’s partner Ionis Pharmaceuticals, Inc., the original developer of tominersen, also issued a press release.
“New exploratory post hoc analyses of GENERATION HD1 suggest that low exposure (less frequent dosing) tominersen may benefit younger adult patients with lower disease burden,” the Roche letter stated.
Low dosing meant volunteers received the drug every 16 weeks, while high dosing was every eight weeks.
“These findings, together with safety data of low exposure tominersen, support the continuation of the development program with a new Phase II clinical trial in younger adult patients with lower disease burden,” the letter continued. “While the findings are encouraging, confirmation in a randomised, placebo-controlled study is important.”
Post hoc
analyses involve criteria set after data is seen, and “therefore they are
not definitive,” the letter said. Because the trial was not specifically designed to run these analyses, the number of patients in the subgroups are small and the differences to placebo are not "statistically significant" and "could represent a chance result."
Even so, “these findings are promising and warrant a new study designed to test tominersen in this specific patient group,” stated Frank Bennett, Ph.D., Ionis' executive vice president, chief
scientific officer and franchise leader for neurological programs, in the press release. “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 [about tominersen].”
Maximizing benefits for HD patients
“It’s very exciting,” said Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at the University of California San Diego.
One of the GENERATION HD1 trial investigators, Dr. Corey-Bloom participated in a Roche-sponsored videoconference about the GENERATION HD1 findings that are serving as the basis for plans for a Phase 2 trial.
“They’ve analyzed the data in a very thoughtful manner,” Dr. Corey-Bloom said. “They’re hoping to really maximize benefits for at least a specific group of patients with HD, based on the results of their post hoc analysis.”
Roche is still planning the new trial. Therefore, it has not yet announced a timeline, sites, eligibility criteria, or information about dosing.
“This is just the news that should instill hope – a clear demonstration of the researchers’ commitment to regroup, redirect, and bravely move forward with its work on tominersen even after the challenges of 2021,” Martha Nance, M.D., the Center of Excellence director at Hennepin Health Care in Minneapolis, MN, commented by e-mail. “HD families, research scientists, and clinicians will need to work together in the coming years to determine when, whether, and how this drug can be delivered safely, effectively, and ethically to people in the earliest stages of HD.”
Representatives of Roche will present public updates on tominersen in previously scheduled webinars on January 20 for the European Huntington’s Disease Network (click here to register) and HDSA (click here to register). Another webinar, hosted by the European Huntington Association, will take place on January 24 (click here to register).
Roche is “resurrecting” tominersen in the “right way,” wrote Evaluate Vantage biopharma analyst Madeleine Armstrong. “Instead of running another phase 3, or indeed seeking approval, Roche is now going back to phase 2, although details are scant.”
With “no approved therapies for Huntington’s,” Roche “looks justified in trying again,” she added.
More results at upcoming conference
In an initial trial completed in 2017, Ionis had demonstrated that tominersen had successfully lowered the amount of the mutant, purportedly toxic huntingtin protein in the cerebral spinal fluid of a small group of volunteers.
Those impressive results led Roche to skip the standard Phase 2 trial and enter directly into Phase 3 (click here to read more). The GENERATION HD1 trial started in early 2019, enrolled a total of around 800 participants globally, and was to end in 2022.
However, in March 2021 a monitoring board conducting a standard review of trial data recommended that all dosing of tominersen in GENERATION HD1 be stopped. Roche decided to also stop dosing in a supporting trial. The following month Roche confirmed that trial data indicated that tominersen was ineffective and, in some cases, actually caused volunteers to worsen.
Roche is expected to present a detailed scientific update on tominersen at the 17th Annual HD Therapeutics Conference February 28-March 3 in Palm Springs, CA.
(Disclosure: I hold a symbolic amount of Ionis shares.)
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