Roche confirms second, more focused, trial of Huntington’s disease drug will start early next year

 

As anticipated, the pharmaceutical firm Roche will retest its Huntington’s disease gene silencing drug, tominersen, by enrolling a more limited group of volunteers for a new clinical trial, which should start in early 2023.

 

Roche announced the new trial, GENERATION HD2, on September 18 at a meeting of the European Huntington’s Disease Network (EHDN) in Bologna, Italy. Roche also issued a letter to the HD community.

 

Roche halted the GENERATION HD1 trial of tominersen in March 2021 because of lack of efficacy against HD symptoms.

 

However, after months analyzing the GENERATION HD1 data, Roche reported in January that tominersen might benefit younger patients with less advanced symptoms. The new 16-month study, GENERATION HD2, will verify efficacy in that group.

 

GENERATION HD1 enrolled clinical trial volunteers ranging in age from 25-65 and included people with more advanced disease.

 

GENERATION HD2 will limit participation to people aged 25-50 who have “prodromal (very early subtle signs of HD) or early manifest HD,” the Roche letter stated.

 

“I am very excited about this new trial,” Jody Corey-Bloom, M.D., Ph.D., wrote me in a September 19 e-mail.

 

Dr. Corey-Bloom directs the Huntington’s Disease Society of America (HDSA) Center of Excellence  at the University of California San Diego, a site for GENERATION HD1 and again for GENERATION HD2.

 

“A lot of thought has gone into the new trial,” Dr Corey-Bloom observed. “I think this is a very well-planned trial!”

 

Roche world headquarters in Basel, Switzerland (photo by Norman Oder)

 

Key adjustments in dosing

 

According to the Roche statement, GENERATION HD2 aims to sign up approximately 360 participants in approximately fifteen countries (Argentina, Austria, Australia, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, the United Kingdom, and the United States). Additional locations might be added.

 

The study will have three cohorts. One third will receive placebo, one third 60 mg of tominersen, and one third 100 mg. To ensure the objectivity of the trial, neither the participant nor study team will know what the participant receives.

 

In contrast with GENERATION HD1, the new trial also will administer lower doses of tominersen. In GENERATION HD1, all volunteers receiving the drug took 120 mg. In GENERATION HD2, participants taking the drug will get either 60 mg or 100 mg.

 

Another key difference involves the frequency of dosing. GENERATION HD1 administered the drug every two or four months, whereas the new study will dose at only four months.

 

These adjustments are a major goal of the study: to determine whether lower or less frequent dosing can be beneficial. Such lower dosing or less frequent dosing potentially avoids some of the problems seen in GENERATION HD1. In that trial, the higher dose did not benefit volunteers (click here and here to read more).

 

As in the first trial, in GENERATION HD2 tominersen will be administered via lumbar puncture (spinal tap).

 

Renewed but cautious hope for preventing HD

 

The Roche letter reported that GENERATION HD1 and all other related tominersen studies have closed.

 

“These studies comprised the first-ever Phase III [efficacy] clinical program to test the huntingtin-lowering hypothesis,” the letter noted, referring to tominersen’s mechanism of lowering the amount the huntingtin protein involved in HD. “Additionally, it was because of the HD community’s commitment to research that the trials recruited faster than anticipated, and thus generated data faster than anticipated.”

 

That commitment, the letter observed, “inspires all researchers to continue pursuing potential options for people impacted by the disease.”

 

Roche will announce additional information about GENERATION HD2 in the coming months.

 

After the devastating news about tominersen 18 months ago, its potential seemed dead. Now, though enthusiasm about tominersen has perhaps diminished, a new, albeit less ambitious, path perhaps has emerged for the drug.

 

"Overall, the announcement of the new GENERATION HD2 trial at the EHDN meeting was well received by the audience in Bologna, which was a mix of clinicians, scientists, and families," HDSA CEO Louise Vetter, who attended the meeting, wrote me in an e-mail. "The fact that this trial is clearly a dose-finding study was notable, and it seem representative of the more conservative mood in the HD clinical science right now."

 

“While the results of GENERATION HD1 were certainly disappointing for everyone, they don’t mean that huntingtin-lowering isn’t a viable therapeutic approach,” Sarah Hernandez, Ph.D., the Director of Research Programs for the HD-focused Hereditary Disease Foundation, wrote me in an e-mail. “Targeting huntingtin directly targets the cause of HD and remains one of the strongest therapeutic hypotheses.”

 

GENERATION HD1’s results “also don’t mean that HTT lowering won’t eventually work for a broad population of people with HD,” Dr. Hernandez added. “They just mean that tominersen seems to require a more narrow patient group for efficacy. The new GENERATION HD2 trial seeks to define exactly what that patient group is, which could be very significant in moving the field forward.”

 

My hope is that GENERATION HD2’s aim to treat individuals earlier in the disease could generate valuable insights for a major goal in the science of HD and other neurodegenerative diseases: a therapy to prevent symptoms from appearing in disease gene carriers like me.

At Therapeutics Conference, landmark study of young gene carriers highlights how Huntington’s disease researchers seek to solve critical puzzles

Armed with ever more impressive data and a deeper understanding of Huntington’s disease, scientists and drug hunters convened at the 15th Annual HD Therapeutics Conference this week, facing the complex puzzles that still hinder the quest for treatments for this deadly neurological disorder.

One of those puzzles: how to not only treat symptoms, but to prevent them, especially in young presymptomatic carriers of the HD gene, so that they don’t have to spend their lives fearing the currently inevitable onset of this devastating disease.

On February 26, Sarah Tabrizi, FRCP, Ph.D., of University College London, answered key questions about what kinds of health consequences young presymptomatic gene carriers suffer decades before they’re likely to develop the disease in midlife.

Previous studies have demonstrated that brain shrinkage can occur as early as 15 to 18 years before predicted age of onset. Ranging in age from 18-40, the 64 gene carriers in Dr. Tabrizi’s HD Young Adult Study went through state-of-the art brain scans and cognitive testing, and also provided samples of blood and cerebrospinal fluid (CSF) for analysis. These at-risk volunteers are, on average, 24 years from estimated onset.

This study, in line with “The Path to Prevention” (one of five major themes of the 2020 conference), is aimed at helping identify the optimal time to treat gene carriers to slow or prevent their neurological decline.

“Comprehensive cognitive testing was normal,” as compared to 67 non-HD-affected individuals, reported Dr. Tabrizi in her presentation to the conference. “There were no significant psychiatric differences, which I found very interesting, because I would have predicted they would’ve been big differences.”

Dr. Tabrizi said that "there’s always been a thought that carrying the HD gene hard-wired you for psychiatric burden,” but the Young Adult Study suggests that such symptoms become more prominent closer to onset.

“I think that was – and I don’t say this lightly – a landmark presentation,” Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me today, adding that Dr. Tabrizi’s team carried out the study with “a high degree of rigor and granularity.”

“The participants seem to be remarkably well,” Dr. Pacifici observed. The absence of many of the neurological and other problems typical of HD is an encouraging prospect for developing safe and well-tolerated treatments that could “not just reverse, but actually prevent” HD, he said.

Dr. Pacifici lauded the study volunteers for their "unbelievably selfless participation," including submitting to the study's "incredibly rigorous battery."

Above, Dr. Sarah Tabrizi presenting her talk on the HD Young Adult Study at the 2020 HD Therapeutics Conference, February 26, 2020, and, below, a closeup of Dr. Tabrizi (photos by Gene Veritas, aka Kenneth P. Serbin)

Overall, ‘good news’ for young gene carriers

The young gene carriers in the study did appear to go through a small change in the area of the forebrain known as the striatum, consisting primarily of the putamen and the caudate, the deep brain regions that are most affected by HD. The striatum helps to control our movements and rewards system.

The study found a significant reduction in the size of the putamen, but an insignificant reduction in the caudate. Nevertheless, Dr. Tabrizi explained that, based on this study, these differences (in comparison with the normal subjects) were “not associated with predicted years to onset.”

“So what we now know, based on the data, is that the striatum never appears to be the same size as the control group,” she explained. 

The “very slightly smaller” striatum may suggest a “neurodevelopmental effect” (the way the brain develops) that is “well compensated for,” Dr. Tabrizi said, meaning that the brain adjusts without clear damage. She added that it “might be why the striatum is vulnerable later in life, because it has a double hit.” As mentioned by Dr. Tabrizi, this interpretation resonates with the research of Peg Nopoulos, M.D., who has studied the compromised development of the brains of people affected by juvenile HD.

Alternatively, neurodegeneration early on could be “too subtle and variable” to associate with predicated age of onset, Dr. Tabrizi noted.

Other imaging results showed no decrease in the white matter (the tissue in the brain made of nerve fibers and possibly involved in cognitive problems in HD) or any other aspect of the brain measured in the study, indicating that the subjects were still “very far from onset,” Dr. Tabrizi continued.

“This is really good news,” Dr. Tabrizi stated.

Douglas Langbehn, M.D., Ph.D., a psychiatrist and biostatistician at the University of Iowa who did the statistical analysis for the HD Young Adult Study, listens to Dr. Tabrizi at the Therapeutics Conference (photo by Gene Veritas).

The ongoing search for reliable biomarkers

The study also involved the ongoing search for reliable biomarkers (signs of disease and drug efficacy).

The study detected mutant huntingtin protein in the subjects’ cerebrospinal fluid. “CSF mutant huntingtin was higher in those closer to [predicted] onset, suggesting that some injury is releasing mutant huntingtin [from the brain], but very subtle,” Dr. Tabrizi said.

Several other biomarkers were elevated in the subjects’ CSF, again indicating an early, subtle injury, but most of those subjects had readings showing levels very close to those of the unaffected control subjects, Dr. Tabrizi continued. Furthermore, six other biomarkers were normal, she added.

The Young Adult Study points to the one CSF biomarker in particular, neurofilament light, a marker of brain damage, as potentially helpful in measuring disease progression and treatment response in people decades from onset, Dr. Tabrizi concluded.

A drug that kept neurofilament light at very low levels could prevent degeneration of the brain, she added.

You can watch Dr. Tabrizi’s presentation in the video below.

A moving keynote address

With a record attendance of 380, the conference opened on February 24 with a moving keynote speech by Amy Merkel, a 45-year-old nurse from Wisconsin and the founder of Starfish Yoga.

A small company, Starfish focuses on encouraging constructive coping skills, primarily for people affected by past imprisonment, sexual abuse, and neurological disorders, including HD.

Amy, who titled her talk “Life is Good,” belongs to a family deeply affected by HD. She recounted her extended family’s decades-long struggles with HD. Amy received a standing ovation.

Stay tuned to this blog for additional reporting on the conference, including an overview provided in my interview with Dr. Pacifici.

Above, HD advocate Amy Merkel addresses the 15th Annual Therapeutics Conference, and, below, poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (photos by Gene Veritas).