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The halted (GENHD1) study of the investigational antisense drug tominersen provided insights about Huntington's disease staging and informed future clinical trials, researchers said.

The phase III study involved 791 manifest Huntington's disease patients who received intrathecal tominersen 120 mg either every 8 weeks or every 16 weeks, or placebo. Based on an overall benefit-risk assessment by an independent data monitoring committee, the in March 2021.

An ad hoc analysis showed that at week 69, the mean change from baseline on one of the primary efficacy end points was significantly worse in the every-8-week tominersen group compared with placebo, reported Sarah Tabrizi, MD, PhD, of University College London in England, and co-authors in correspondence published in the .

GENERATION HD1 was the first phase III trial of an antisense oligonucleotide in adult Huntington's carriers, Tabrizi noted. It aimed to build on earlier research that showed tominersen (previously IONIS-HTTRx) was safe and effective in lowering huntingtin (HTT) protein levels in cerebrospinal fluid (CSF).

"There was great hope for the study in the Huntington's disease community -- and for those studying similar neurodegenerative disorders -- following the previous results from the phase Ib/IIa study, so the premature halting of dosing at 17 months on the recommendation of the independent data monitoring committee was devastating," Tabrizi told 木瓜直播.

"While the study was halted early when it became apparent that participants in the high dose group were doing worse than placebo on clinical measures, post hoc analysis indicated that a small subset of younger participants with less disease burden and receiving the drug less frequently had a positive exposure response against clinical measures, indicating that perhaps the drug needs to be administered earlier in the disease course to younger patients to have a benefit," she pointed out.

This hypothesis currently is being tested in a phase II dose-finding trial of tominersen in a cohort of younger participants at an earlier disease stage, Tabrizi noted.

Huntington's is an inherited neurodegenerative disease that leads to death about 20 years after symptom onset. Carriers of the mutated HTT gene with more than 40 cytosine-adenine-guanine (CAG) repeats inevitably develop the disease. That predictability may provide a window to lower mutant huntingtin protein before symptoms appear.

GENERATION HD1 findings suggested that treating Huntington's disease years after motor symptom onset may be too late to make a difference to the underlying neurodegenerative process, Tabrizi observed.

"The early stopping of GENHD1 informed the development of a new Huntington's disease staging system, the (HD-ISS)," she noted. "The staging system, similar to that used in cancer, defines Huntington's disease in four stages that cover the entire disease spectrum and will transform the development of therapeutic interventions at the very earliest stages of disease before any overt clinical signs, providing the best chance of substantially slowing disease progression."

GENERATION HD1 data also showed that higher exposure to the drug led to neuroinflammation, enlargement of the brain ventricles, and the release of neurofilament light (NfL) protein. "As a result of the trial, NfL increases in CSF are viewed as a safety biomarker in future antisense oligonucleotide therapeutic trials for Huntington's disease and other neurodegenerative disorders," Tabrizi said.

The primary end point in GENERATION HD1 was the change from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) or Total Functional Capacity (TFC) scale scores at week 101. Scores on the cUHDRS range from −8 to 25 and TFC scores range from 0 to 13; in both cases, higher scores indicate improvement.

An ad hoc analysis showed the mean change from baseline on the cUHDRS at week 69 was significantly worse with every-8-week tominersen compared with placebo (-0.54 points, adjusted P=0.001), but the mean change from baseline in the score on the TFC scale did not differ significantly (-0.40 points, adjusted P=0.09), Tabrizi and co-authors said. In the every-16-week tominersen group, mean changes from baseline on cUHDRS and TFC scores did not vary significantly from placebo.

Changes in mutant HTT levels in CSF were consistent with dose regimen-dependent decreases and concomitant increases in ventricular volume. At week 21, a transient increase in CSF NfL levels emerged in the every-8-week tominersen group; increased levels of leukocytes and total protein in CSF in some participants suggested an inflammatory component, the researchers noted. In addition, more adverse events occurred in the every-8-week tominersen group than in placebo or the every-16-week tominersen group.

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