Impact of Biological Sex Stratification on Clinical Outcomes in Progressive Supranuclear Palsy

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Summary of  Molecular Psychiatry  https://doi.org/10.1038/s41380-026-03709-x 
Dr. Guy Shapira  et al.

Points

Tel Aviv University researchers conducted a 52-week trial reanalysis of over 300 patients to evaluate Davunetide in progressive supranuclear palsy.
Reanalyzing cohort data using FDA-recommended PSPRS-10 metrics revealed that Davunetide significantly slowed disease progression specifically in female patients.
Treated female patients demonstrated preserved motor function, fine motor control, balance, and daily living capabilities compared to placebo cohorts.
Cognitive evaluations using the RBANS scale showed significant improvements in language performance and working memory among treated women.
Cerebrospinal fluid biomarker analysis revealed opposite sex-specific correlations between pathological tau levels and clinical symptom severity in men and women.

Summary

This study evaluated the sex-specific therapeutic efficacy and molecular mechanisms of the experimental tau-targeting agent Davunetide in patients with progressive supranuclear palsy (PSP). Progressive supranuclear palsy represents a fatal neurodegenerative tauopathy lacking approved disease-modifying therapies. Led by Illana Gozes at Tel Aviv University, the investigators reanalyzed longitudinal 52-week clinical data from a international trial of over 300 PSP patients by stratifying cohort outcomes by sex and applying the updated FDA-recommended 10-item PSP Rating Scale (PSPRS-10) alongside the traditional 28-item PSPRS primary endpoint.

Statistical analyses utilized linear mixed-effects models, including FDA-recommended Mixed Models for Repeated Measures (MMRM), while cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). While the original non-stratified trial demonstrated no overall drug effect, sex-stratified MMRM reanalysis revealed significant clinical efficacy restricted to female participants. Davunetide-treated women exhibited a marked slowing of motor and functional decline across balance, fine motor control, and daily living activities. Furthermore, treated females achieved statistically significant improvements in RBANS cognitive domains, including language performance and working memory, compared to placebo controls, whereas no therapeutic benefit occurred in male participants.

Mechanistic biomarker investigations revealed profound dimorphic molecular differences between biological sexes regarding cerebrospinal fluid pathological tau accumulation. Elevated pathological tau levels correlated negatively with linguistic performance in female patients, whereas male subjects demonstrated an opposite molecular trajectory. The authors conclude that Davunetide demonstrates sex-specific clinical efficacy for female PSP patients, emphasizing that sex-stratified trial design and FDA-recommended outcome metrics are essential for unmasking therapeutic efficacy in neurodegenerative tauopathies.

Link to the article: https://www.nature.com/articles/s41380-026-03709-x

References

Shapira, G., Blatt, J., Guz, L. S., Shomron, N., & Gozes, I. (2026). Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women. Molecular Psychiatry, 1–12. https://doi.org/10.1038/s41380-026-03709-x