Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women

Abstract

Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females (r = 0.74, P = 2.36^-9), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 (P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progression and revealed significant protection according to the SEADL scale as early as at 39 weeks (P = 0.008), as well as protection of the bulbar and limb motor domains considered by the PSPRS, including speaking and swallowing difficulties caused by brain damage, and deterioration of fine motor skills, respectably (P = 0.01), at 52 weeks. Furthermore, at 52 weeks of trial, the exploratory Geriatric Depression Scale (GDS) significantly correlated with the SEADL scale deterioration in the female placebo group and demonstrated davunetide-mediated protection of females. Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients.

Fig. 1. Significant baseline sex differences in brain ventricular volumes.

The baseline demographics of the study cohorts are shown, namely, weight (A) and height (B), age (C), ventricular volumes (D), SEADL scale (E) and PSPRS (F). Placebo-treated subjects are in blue and davunetide-treated subjects are in red, with males (n = 55 placebo, n = 55 davunetide) and females (n = 48 placebo, n = 51 davunetide) being clearly separated. Means ± S.D. are denoted on the graphs. The GraphPad Prism 7.0 software was used to analyze the results. Following D’Agostino and Pearson normality distribution test, the datasets presented on (A, B, D, F) appeared to be lognormal distributed. Thus, for these data sets, log10 transformations were performed and were further analyzed by two-way ANOVA followed by the Sidak multiple comparisons test. Original data was plotted. For (C, E) data sets, normal distribution was found, hence, two-way ANOVA followed by Sidak multiple comparisons test was performed directly. Statistically significant differences are denoted as follows: *P < 0.05; **P < 0.01; ***P < 0.001; **** P < 0.0001.

Fig. 2. Davunetide treatment provides significant neuroprotection against baseline brain ventricular volume-dependent increases in female PSP patients.

Linear regressions (specifically, the Pearson correlation coefficient r) correlating absolute ventricular volume change (mm³) with baseline volume (mm³), as measured by MRI after 52 weeks of trial, are presented. Males (n = 55 placebo, n = 55 davunetide) and females (n = 48 placebo, n = 51 davunetide) are separately pictured. See the main text (“Data source”) and “Methods” for further details.

Fig. 3. Substantial sex differences indicate that davunetide-mediated neuroprotection is significantly correlated with multiple study endpoints and age.

A Shown are the Pearson correlation coefficient r values of plots reflecting percent change relative to baseline after 52 weeks of davunetide or placebo treatment, including the study primary endpoints (PSPRS and SEADL scale), the secondary endpoints of brain ventricular volume change and CGIC, the exploratory endpoints CGIds and CGD, as well as the demographic characteristics of age. Color-coded significance is denoted by *P < 0.05; **P < 0.01; ***P < 0.001. “.” denotes 0.05 < P < 0.1. Further variables including precise “n” for each variable and additional endpoint comparisons are delineated in Table S1, further correlations are shown in Table S2. B Linear regressions (depicting the Pearson correlation coefficient r) separating males and females according to davunetide or placebo treatment as measured by MRI are shown. The percent baseline change in ventricular volume at 52 weeks of treatment, correlating to age is presented. C Geriatric Depression Scale (GDS) values depicting the change from baseline of the overall scores in males (n = 52, placebo; n = 53, davunetide) and females (n = 57, placebo; n = 54, davunetide), as visualized by GraphPad Prism 7.0 software followed by a Wilcoxon test (Table S1).

Fig. 4. PSP develops significantly faster in females, as shown for SEADL scale and PSPRS measures, and is further accentuated in multiple PSPRS domains.

Linear regressions (depicting the Pearson correlation coefficient r) separating placebo-treated males and females, measuring percent change relative to baseline after 6, 13, 26, 39 and 52 weeks of twice daily placebo treatment. A PSPRS. B Limb-motor domain of PSPRS (fine motor skills, including tremor). C Bulbar domain data. D Gait midline results. E Daily activities. F SEADL scale results. Significance, comparing males to females (Wilcoxon test) for a time point (as indicated) is denoted by asterisks, following the same convention as in Figs. 1 and 3, “#” denotes 0.05 < P < 0.1. Males (n = 55 placebo, n = 55 davunetide) and females (n = 48 placebo, n = 51 davunetide).

Fig. 5. Significant protection against lumbar motor, bulbar and SEADL scale deterioration upon davunetide treatment in women.

Linear regression plots (depicting the Pearson correlation coefficient r) comparing percent change relative to baseline after 6, 13,26, 39 and 52 weeks in females receiving davunetide or placebo. A PSPRS, B the limb motor domain of PSPRS, C the bulbar domain of PSPRS, and D SEADL scale. Significance is denoted by asterisks, following the same convention as in Figs. 1, 3, and 4. Males (n = 55 placebo, n = 55 davunetide) and females (n = 48 placebo, n = 51 davunetide).