This paper reviews the efficacy, safety, and systemic absorption of
estradiol with
TX-004HR, an investigational, low-dose 17β-estradiol vaginal softgel
capsule, designed to treat vulvar and vaginal
atrophy (VVA) in postmenopausal women, with an improved user experience. In phase 2 (NCT02449902) and phase 3 REJOICE (NCT02253173) studies,
TX-004HR significantly improved the proportions of vaginal superficial and parabasal cells and vaginal pH, and in the phase 3 study decreased the severity of
dyspareunia, vaginal dryness, and vulvar and/or vaginal
itching or irritation. In two randomized, phase 1 trials,
estradiol Cmax and AUC0-24 were significantly lower with 10μg and 25μg
TX-004HR than with the same doses of an approved vaginal
estradiol tablet. A substudy (n=72) of the REJOICE trial showed that
estradiol Cavg and AUC0-24 with 4μg and 10μg
TX-004HR were not different from placebo on days 1 and 14. While
TX-004HR 25μg was associated with higher Cavg and AUC0-24 versus placebo on days 1 and 14, these levels remained within the postmenopausal range.
Estradiol day-84 values for all three doses were not different from placebo, demonstrating no
estradiol accumulation. All
TX-004HR doses were well tolerated and had an acceptable safety profile in all reviewed studies. The local vaginal efficacy of
TX-004HR was significantly better than that of placebo, while the overall safety profile was similar to that of placebo. Negligible to very low systemic
estradiol absorption was observed whether given at 4, 10, or 25μg. If approved,
TX-004HR may be an alternative option for women with symptomatic VVA without increasing mean systemic
estradiol absorption above postmenopausal levels.