Surprising sex differences indicate davunetide-mediated brain protection and clinical efficacy in women suffering from progressive supranuclear palsy

Abstract

Abstract Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, mixing men and women concluded no efficacy. In contrast, here, analyzing sex-dependency in a comprehensive 52-weeks PSP clinical trial (313 patients), showed clear baseline differences in brain ventricular volumes. Significant age/decreased ventricular volume correlations in davunetide-treated females, and highly significant baseline ventricular volume-dependent/volume increase correlations in placebo-treated females were observed, while males showed no effects. Using sophisticated statistics, female-specific davunetide-mediated protection of ventricular volume was directly correlated with primary trial-endpoints, Schwab and England Activities of Daily Living (SEADL), and PSP Rating Scale (PSPRS). Davunetide-treated females showed slower deterioration in SEADL, and in the bulbar domain of PSPRS including speaking and swallowing difficulties caused by brain damage. Together with slower disease progression seen in men, the results reveal gender-based drug efficacy, demonstrating the neuroprotective, disease-modifying impact of davunetide treatment in female PSP patients.