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Abstract

Conjugated estrogen/bazedoxifene (CE/BZA) therapy represents a new, progestin-free treatment in the management of postmenopausal health. CE/BZA pairs CE with the selective estrogen receptor modulator, BZA. The rationale for the development of CE/BZA was that BZA, acting primarily as a selective estrogen receptor degrader in uterine and breast tissue, would sufficiently inhibit the proliferative effects of CE on the endometrium. The absence of a progestin would reduce the incidence of uterine bleeding, breast pain and increased breast density associated with progestin-containing hormone therapy. CE/BZA has been evaluated in five multicenter, randomized, double-blind, placebo-controlled, and active-controlled Phase III trials known as the SMART trials. CE/BZA has been shown to maintain the established benefits of estrogen therapy for treatment of vasomotor symptoms and prevention of a loss in bone mineral density (bone mass), while minimizing certain estrogenic effects, particularly in the uterine endometrium and breast.

Keywords

bazedoxifene conjugated estrogens hormone therapy menopause vasomotor symptoms

Menopause is associated with the loss of ovarian estrogen production that is associated with a constellation of symptoms, which may include the following: vasomotor symptoms (VMS), symptoms of vulvar vaginal atrophy, and a loss of bone mass often resulting in osteoporosis and associated fractures [1]. Postmenopausal women are also susceptible to difficulties with sleep, mood swings, memory loss and sexual dysfuntion. Menopause-related symptoms associated with estrogen deficiency commonly overlap and have a significant negative impact on a postmenopausal woman's quality of life (QoL) [2 –4].

VMS, such as hot flashes and night sweats, are considered to be the most common and disruptive symptoms associated with estrogen deficiency. VMS are experienced by approximately 60–90% of postmenopausal women and are the chief menopausal complaint that lead women in Western societies to seek medical treatment [5 –7]. Even though it has been suggested that in most women VMS will abate over time without any intervention, VMS can be severe enough to affect the QoL.

Recent studies reported that approximately 10% of postmenopausal women in Western societies reported symptoms for up to as long as 12 years after the onset of menopause [6,8,9]. Management of postmenopausal symptoms also requires greater healthcare resource [10]. It has been shown that as the severity of VMS increases, health status decreases, which may result in a loss of productivity at work resulting in an economic burden [n].

Overview of the market

For postmenopausal women with a uterus, progestin-containing hormone therapy (HT) has been the most commonly prescribed medication for the treatment of VMS [12]. The addition of a progestin to the estrogen component is required to prevent endometrial stimulation often associated with an increase in the incidence of endometrial hyperplasia that may lead to adenocarcinoma of the endometrium [13]. Progestin-containing HT has proven to be efficacious for the treatment of VMS. A meta-analysis based on clinical trials showed a reduction of 77% in the number of hot flushes in postmenopausal women [14].

There are a variety of dose combinations available both orally and transdermally. Among the doses typically used when initiating systemic progestin-containing HT are 0.3, 0.45 and 0.625 mg oral conjugated estrogen (CE) and 0.5–1.0 mg of oral micronized 17β-estradiol. There are also multiple progestogen dosing-regimen options for endometrial safety. The dose varies based on the progestogen used and the estrogen dose, typically starting at the lowest effective doses of 1.5 mg medroxyprogesterone acetate (MPA), 0.1 mg norethindrone acetate, 0.5 mg drospirenone or 100-mg micronized progesterone [15]. The availability of the range of dose regimens described allows for therapy to be tailored to the needs of individual women.

Treatment with progestin-containing HT is not without drawbacks and specific risks. Breast tenderness and uterine bleeding are major limitations to the use of progestin-containing HT and these side effects are the most common reasons for discontinuation of therapy [16,17]. Uterine bleeding leads to discontinuation of therapy in up to a third of women, and rates of discontinuation can be as high as 68% within the first year of treatment. Rates of discontinuation for breast tenderness/pain have been reported as high as 40% in some clinical trials [18]. As described previously, these common effects, as well as concerns regarding hormone-related changes in breast density, contribute to patient anxiety and distress, and also have an economic impact because of the need for additional testing or interventions, and loss of productivity at work [18].

Rare events reported with progestin-containing HT include an increased risk for venous thromboembolic events (VTEs), coronary heart disease and ischemic stroke [19]. In addition, progestin-containing HT has been linked to an increase in breast cancer [20,21]. The Women's Health Initiative (WHI) estrogen plus progestin substudy indicated that after a mean intervention time of 5.6 years and a mean follow-up of 7.9 years, breast cancer incidence was increased among women who received CE 0.625 mg/MPA 2.5 mg [20,22].

Nonhormonal therapies, which are potential alternatives for the treatment of VMS, include herbal products that contain or may have properties similar to estrogens (soy and herbs, e.g., black cohosh) and some antidepressants. However, clinical research for these products is limited and those studies that have been conducted have provided conflicting results concerning their effectiveness. While clinical trials of antidepressants, such as serotonin–norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitors (SSRIs), have demonstrated these drugs to be moderately effective for the treatment of VMS, they are not as effective as hormonal treatments and are also associated with side effects. Recently, the US FDA has approved the selective serotonin reuptake inhibitor, paroxetine, at a dose lower than that used for depression, for the treatment of hot flushes associated with menopause [23].

CE/bazedoxifene: a tissue-selective estrogen complex

CE/bazedoxifene (BZA) therapy represents a new treatment paradigm for the management of menopausal health in women with a uterus. CE/BZA pairs the selective estrogen receptor modulator (SERM), BZA, with CE (Premarin®, Pfizer, PA, USA; Figure 1). CE/BZA maintains the established benefits of estrogen therapy for menopausal symptoms of VMS, vulvar vaginal atrophy and prevention of osteoporosis, while preventing the estrogenic effects on the uterus and breast tissue that are considered to be adverse in a postmenopausal woman.

Figure 1.

Chemical structure of bazedoxifene acetate and the most abundant estrogens in Premarin® (Pfizer, PA, USA).

The rationale for the development of CE/BZA was that BZA, acting primarily as an estrogen receptor antagonist in uterine tissue, would inhibit the proliferative effects of CE on the endometrium in a manner mechanistically distinct from progestins. Importantly, subsequent clinical trials demonstrated that it also reduce the incidence of irregular uterine bleeding. While the addition of progestins to estrogens effectively inhibit endometrial proliferation and hyperplasia, they also lead to considerable morphologic modifications to the uterus, including an increase in blood supply, alteration of angiogenesis and thickening of the endometrium [24]. These morphological changes have been associated with irregular bleeding [24]. When BZA is combined with CE, in addition to BZA competing with CE binding to the estrogen receptors (α and β), BZA also induces estrogen receptor degradation primarily in the uterus and breast essentially eliminating the estrogenic effects of CE on the endometrium, such as increased endometrial hypertrophy and hyperplasia (Figure 2) [25].

Figure 2.

The mean daily number and severity of moderate-to-severe hot flushes over 12 weeks in the SMART-2 trial. (A) The mean daily number and (B) the mean daily severity of moderate-to-severe hot flushes.

BZA functions similarly in breast tissues. BZA alone demonstrates minimal effects on the breast and does not induce breast pain or changes in breast density [26]. Since BZA causes estrogen receptor degradation in the breast, when combined with CE as CE/BZA, morphologic changes in the mammary gland are minimized and it is hypothesized that this is the pharmacologic explanation for the lack of an increase in breast pain and density. In vitro and in vivo models demonstrate that BZA also inhibits the proliferative action of estrogens on breast cancer cells [27].

Pharmacokinetics of CE/BZA

The pharmacokinetic profile of CE administered via a CE/BZA tablet is consistent with these historical data [28]. Maximum plasma concentrations of the estrogens are achieved approximately 6–10 h after oral administration of CE/BZA tablets. The estrogens are metabolized and eliminated in near-parallel fashion, with terminal half-lives ranging from 10 to 20 h, when measured as exogenous estrogens or when corrected for endogenous concentrations, as needed for estrone and 17β-estradiol. Steady-state concentrations for BZA and CE are achieved by the second week of daily-dose administration.

BZA has an absolute oral bioavailability of approximately 6%. BZA is rapidly absorbed after oral administration, with a Tmax of approximately 2 h, and it exhibits a linear increase in plasma concentrations for single doses up to 120 mg and multiple doses up to 80 mg. BZA is eliminated with a half-life of approximately 30 h. A formal dose-proportionality study demonstrated that the pharmacokinetics of BZA are linear over the dose range of 5–40 mg and single-dose pharmacokinetics adequately predicted multiple-dose pharmacokinetics. BZA is highly bound (98–99%) to plasma proteins in vitro. BZA is extensively metabolized via glucuronidation and excreted in the feces with less than 1% eliminated in urine [26,27].

Pharmacodynamics of CE/BZA

Hot flushes

CE/BZA demonstrated that, similar to CE, a reduction in tail skin temperature (a surrogate for hot flushes) was seen in ovariectomized rats [29]. The mechanistic explanation for effects seen with estrogens, such as CE or CE/BZA, in the CNS are unclear. SERMs, when dosed alone, have been clearly shown to exacerbate VMS [26]. In fact, both tamoxifen and raloxifene (RLX) have been shown to cross the blood–brain barrier and induce hot flushes in postmenopausal women [26]. While there is currently no preclinical evidence to address the blood–brain barrier penetrance of BZA, clinical studies have shown that CE/BZA can effectively relieve VMS with minimal attenuation by BZA and with a similar efficacy as compared with HT [30,31].

Clinical efficacy on VMS

Phase II study: dose-ranging study

The efficacy and safety of CE/BZA was evaluated in a Phase II dose-ranging study of 84 days duration conducted in 408 generally healthy, nonhys-terectomized postmenopausal women [Mirkin S, Pers. Comm.]. The doses used for the combination were CE 0.3 and 0.625 mg in combination with 5, 10 and 20 mg of BZA. It was demonstrated that 20 mg of BZA was the lowest dose that provided acceptable endometrial protection when administered with CE 0.3 or 0.625 mg. BZA 20 mg plus CE 0.625 mg demonstrated a significant reduction in number and severity of VMS. Given these Phase II data, a lower dose of CE 0.45 mg/BZA 20 mg was added to the SMART trials along with the CE 0.625-mg dose [30].

Phase III studies

CE/BZA has been evaluated in a series of multicenter, randomized, double-blind, placebo-controlled, and active-controlled Phase III trials known as the SMART trials (Table 1) [30 –33]. The key efficacy results from the SMART trials are presented in Table 2 and presented elsewhere [30 –33]. This review only focuses on the effect of CE/BZA for the treatment of VMS and the key safety findings.

Table 1.

Summary of pivotal SMART trials.

Study (n)	Treatment duration	Treatment groups	Active comparator Key end points
SMART-1 (3544)	24 months	BZA 10 mg/CE 0.45 mgBZA 20 mg/CE 0.45 mgBZA 40 mg/CE 0.45 mgBZA 10 mg/CE 0.625 mgBZA 20 mg/CE 0.625 mgBZA 40 mg/CE 0.625 mg Placebo	Raloxifene 60 mg	Incidence of endometrial hyperplasiaChange in BMDEffect on vaginal atrophyEffect on vasomotor symptomsEffect on sleepEffect on breast density
SMART-2 (332)	12 weeks	BZA 20 mg/CE 0.45 mgBZA 20 mg/CE 0.625 mg Placebo	NA	Effect on vasomotor symptoms
SMART-3 (664)	12 weeks	BZA 20 mg/CE 0.45 mgBZA 20 mg/CE 0.625 mgBZA 20 mg Placebo	BZA 20 mg	Effect on vaginal atrophy
SMART-5 (1886)	12 months	BZA 20 mg/CE 0.45 mgBZA 20 mg/CE 0.625 mg Placebo	CE 0.45 mg/MPA 1.5 mgBZA 20 mg	Incidence of endometrial hyperplasia Effect on BMD Effect on sleep Effect on breast density

BMD: Bone mineral density; BZA: Bazedoxifene; CE: Conjugated estrogens; MPA: Medroxyprogesterone acetate; n: Number of subjects randomized; NA: Not applicable.

Table 2.

Key efficacy findings for conjugated estrogens/bazedoxifene from the SMART trials.

Study	Efficacy
SMART-1	Significant decreases in the mean daily number of moderate-to-severe hot flushes (p < 0.05 vs placebo) and mean daily hot flush severity from baseline to week 12 (p < 0.001 vs placebo) [30]Significant increase from baseline in superficial vaginal epithelial cells with BZA 20 mg/CE 0.625 mg (p < 0.01 vs placebo), and significant decrease in parabasal cells at 2 years with both doses (both p < 0.001 vs placebo) [30]Significant increase in lumbar spine BMD from baseline at 2 years (p < 0.001 vs placebo) [30]Increased efficacy on BMD compared with RLX [30]Significant improvements in sleep parameters (p < 0.05 vs placebo) [30]
SMART-2	Significant reduction from baseline in the mean number of hot flushes and hot flush severity at week 12 (p < 0.001 vs placebo) [31] Significant improvements in sleep parameters (including time to fall asleep, sleep disturbance, sleep adequacy, and sleep problems index I and II [composed of six and nine questions, respectively, that evaluate overall sleep quality], p < 0.05 vs placebo) [31]Significant improvements in treatment satisfaction and quality of life (p < 0.05 vs placebo) [31]
SMART-3	Significant increases in vaginal epithelial superficial and intermediate cells, and significant decreases in parabasal cells at week 12 (p < 0.01 vs placebo) [32]Significant decrease in vaginal pH at week 12 with BZA 20 mg/CE 0.625 mg (p < 0.001 vs placebo) [26]Significant improvement in most bothersome VVA symptom at week 12 with BZA 20 mg/CE 0.625 mg (p < 0.05 vs placebo) [32]Significant improvements in treatment satisfaction and vasomotor function, sexual function and total quality of life at week 12 (p < 0.05 vs placebo) [32]
SMART-5	Significant increase in lumbar spine BMD from baseline at 1 year (p < 0.001 vs placebo)Increased efficacy on BMD compared with BZA and comparable to CE/MPASignificant improvements in sleep parameters (p < 0.05 vs placebo)

BMD: Bone mineral density; BZA: Bazedoxifene; CE: Conjugated estrogens; RLX: Raloxifene; VVA: Vulvar vaginal atrophy.

Efficacy of CE/BZA for the treatment of VMS

The efficacy of CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg for the treatment of moderate-to-severe VMS was evaluated in SMART-1 and SMART-2. The full design of both trials was presented elsewhere [30,31]. Briefly, both SMART trials evaluated the efficacy of CE/BZA in a population of postmenopausal women (age 40–75 years for SMART-1 and 40–65 for SMART-2) experiencing at least 50 moderate-to-severe hot flushes per week at baseline [30,31].

CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg treatment were statistically and clinically significantly more effective than placebo in reducing the average daily number of moderate-to-severe hot flushes from baseline at week 4 and 12 [30,31].

In SMART-2, the CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20-mg dose strengths were associated with a significant decrease (p < 0.001) in the adjusted mean daily number of moderate-to-severe hot flushes reaching a 74 and 80% reduction, respectively, representing a reduction of approximately 7–8 hot flushes per day from baseline to week 12 compared with a 51% reduction, representing a reduction of approximately 5 hot flushes per day in the placebo group [31].

At week 4, a reduction of 5–6 hot flushes per day was observed in subjects in the CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg treatment groups, respectively, compared with a reduction of 3 hot flushes in the placebo group. This reduction represented a 58.5, 66 and 32.6% decrease in the number of average daily moderate-to-severe hot flushes in the CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg treatment groups and placebo group, respectively [31].

CE/BZA efficacy was associated with a rapid onset at week 2/3 and the effects continued through week 12. More CE/BZA-treated women responded at both the 75 and 50% level compared with placebo at weeks 4 and 12. At week 12, 61% of women taking CE 0.45 mg/BZA 20 mg and 73% of women taking CE 0.625 mg/BZA 20 mg had a decrease from baseline of at least 75% in the number of moderate and severe hot flushes compared with 27% of women in the placebo group [31].

Similarly, in SMART-1, significant reductions in the number of moderate-to-severe hot flushes were observed for the CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg treatment groups compared with the placebo group at weeks 4 and 12. Efficacy was maintained throughout 2 years of therapy where the CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg treatment groups were associated with 84 and 93% reductions, respectively, representing a decrease of 9–10 hot flushes per day from baseline at year 2 compared with a 57% reduction (representing a decrease of approximately 6 hot flushes per day) from baseline in the placebo group [30].

CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg demonstrated statistically and clinically significant reductions in the average daily severity score of hot flushes compared with subjects who received placebo at week 4 and 12 in SMART-2 [31].

Over the 12 weeks of therapy, significantly greater reductions were observed in the average daily severity scores of hot flushes in CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg treatment groups compared with the placebo group, beginning at week 3 and continuing through week 12. Reductions of 26, 29 and 5% in the average daily severity score of hot flushes were observed in the CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg treatment groups and placebo group, respectively. The CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg treatment groups demonstrated significant decreases (p < 0.001) in the severity of hot flushes reaching a 39 and 55% reduction, respectively, from baseline to week 12 compared with a 14% reduction in the placebo group. Similar results were demonstrated in SMART-1 [30].

A secondary analysis evaluated the effect of CE/BZA on days without hot flushes. CE/BZA (both doses) was effective at increasing the number of days without hot flushes in symptomatic postmenopausal women over 12 weeks of therapy in the SMART-2 trial. The increase in number of hot flush symptom-free days with CE/BZA compared with placebo was sustained from week 3 (moderate-to-severe hot flushes) or week 4 (any hot flushes) through to week 12 [34].

Effect on menopause QoL

The effect of CE/BZA on menopause-related QoL was prospectively evaluated in the SMART trials using the Menopause Quality-of-Life tool. Statistically and clinically significant improvements in total Menopause Quality-of-Life score were observed across all SMART trials, for both CE/BZA doses.

QoL was evaluated in a population of postmenopausal women with a minimum of 50 hot flushes per week at baseline in SMART-2 [35]. Treatment with CE/BZA provides clinically meaningful improvements in vasomotor domain, sexual domain and total score [35].

In SMART-5, in the population of postmenopausal women with bothersome moderate-to-severe VMS who were randomized to CE/BZA, improved QoL measurements [36].

Effect on sleep

The effect of CE/BZA was evaluated in SMART-1, −2 and −5. In SMART-1, CE/BZA provided evidence of a positive effect of CE/BZA on sleep [30]. Subjects were asked questions related to sleep quality and quantity. CE/BZA showed a significant difference over placebo in some sleep parameters [30].

In SMART-2 and SMART-5, sleep was measured using the Medical Outcomes Study [31,36]. In both trials, CE/BZA consistently improved most Medical Outcomes Study sleep parameters. The effect was comparable with the observed with CE/MPA. In SMART-2, the reduction in hot flush severity was significantly associated with improved sleep [31,36].

Overall safety

Pooled analyses of all SMART trials indicated that CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20-mg dose strengths demonstrated an acceptable safety and tolerability profile in postmenopausal women. Overall, the frequency of treatment-emergent adverse events was similar between subjects treated with CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg compared with the subjects who received placebo. treatment-emergent adverse events were reported in 84.2% of subjects in the CE 0.45 mg/BZA 20 mg group, 84.8% of subjects in the CE 0.625 mg/BZA 20 mg group and in 84.9% of subjects who received placebo. Box 1 shows the summary of key safety and tolerability attributes of CE/BZA.

Adverse events that differentiate CE/BZA over progestin-containing HT were evaluated over 1 year of therapy. Both CE/BZA doses demonstrated the same incidence of adverse events of breast pain and vaginal bleeding as compared with placebo. The inxcidence of adverse events of breast tenderness was lower in the CE 0.45 mg/BZA 20 mg group (1.7%) and the CE 0.625 mg/BZA 20 mg group (1.3%) compared with the CE/MPA group (10.9%). The incidence of adverse events of vaginal bleeding was also lower in the CE 0.45 mg/BZA 20 mg group (0.9%) and the CE 0.625 mg/BZA 20 mg group (1.1%) compared with the CE/MPA group (11.8%,) [30,31,37].

Endometrial protection without the use of a progestin

The endometrial protection and tissue selectivity exhibited by BZA make it a suitable SERM for pairing with CE. BZA acting as an estrogen receptor antagonist in uterine tissue inhibits the proliferative effects of CE on endometrium (Figure 3) [29]. Preclinical studies suggest that BZA as a selective estrogen receptor degrader induce estrogen receptor degradation, which effectively diminishes the molecular target of the CE activity in the endometrium [38]. The mechanism of interaction of BZA and CE in the endometrium that results in an overall neutral effect (i.e., no endometrial stimulation) appears to be unique and has not been observed with estrogen–progestin therapy or other estrogen/SERM combinations (Figure 2) [38].

Figure 3.

The differential effects of estrogen-progestin therapy and bazedoxifene/conjugated estrogen on the endometrium. EPT binds to ER- and PR-activating estrogen- and progesterone-regulated genes. Histologically, EPT induces a weak secretory pattern in the endometrium. Owing to its effect on the endometrial blood vessels, EPT is associated with endometrial spotting and bleeding. BZA and CE bind only to ER, activating estrogen-regulated genes. BZA induces ER degradation and downregulation of CE-regulated genes, which results in an atrophic pattern in the endometrial morphology. The incidence of amenorrhea with BZA/CE is similar to placebo and higher than with EPT.

CE/BZA in clinical studies (SMART-1 through to SMART-5) has demonstrated favorable endometrial safety and tolerability [30,33]. Histology data indicate a low incidence of endometrial hyperplasia (<1%) with CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg in the 2-year SMART-1 trial, similar to that observed with placebo [30]. BZA 20 mg/CE 0.45 and 0.625 mg also demonstrated a low incidence of endometrial hyperplasia (<1%), similar to placebo, in the 1-year SMART-5 trial [33]. There were no differences compared with placebo in endometrial proliferation for CE/BZA or CE 0.45 mg/MPA 1.5 mg in SMART-5 [30,33]

The incidence of endometrial polyps was 5.7, 2.6 and 1.5% for BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg and placebo, respectively, in the SMART-1 trial [30]. CE/MPA in SMART-5 was associated with a greater incidence of endometrial polyps compared with CE/BZA and placebo [33].

Box 1.

Summary of key safety and tolerability findings in the SMART trials.

SMART-1

Similar incidences of AEs, SAEs and AEs leading to discontinuation among BZA/CE and PBO groups

No increase in VTE incidence for BZA/CE groups compared with PBO

Low endometrial hyperplasia rates (<1 %) at 2 years

Minimal increases from baseline in endometrial thickness (<1 mm) at 2 years, similar to those for PBO

High rates of cumulative amenorrhea over 2 years, similar to that for PBO

No difference in change from baseline in mammographic breast density at 2 years

No increase in breast pain incidence for BZA/CE groups versus PBO

SMART-2

Similar incidences of AEs, SAEs and AEs leading to discontinuation among BZA/CE and PBO groups

No endometrial hyperplasia reported in any group

No difference in mean change from baseline in endometrial thickness at 12 weeks

No increase in breast pain incidence for BZA/CE groups versus PBO

SMART-3

Similar incidences of AEs, SAEs and AEs leading to discontinuation among BZA/CE and PBO groups

No endometrial hyperplasia reported in any group

No difference in mean change from baseline in endometrial thickness at 12 weeks

No increase in breast pain incidence for BZA/CE groups versus PBO

SMARTS-5

Similar incidences of AEs, SAEs and AEs leading to discontinuation among BZA/CE and PBO groups

Lower incidence of AE associated with bleeding and breast pain compared with CE/MPA

Low endometrial hyperplasia rates (<1 %) at 2 years

High rates of cumulative amenorrhea over 2 years, similar to that for PBO and higher than CE/MPA

No difference in change from baseline in mammographic breast density at 2 years and significantly lower than CE/MPA

No increase in breast pain incidence for BZA/CE groups versus PBO and significantly lower than CE/MPA

AE: Adverse event; BZA: Bazedoxifene; CE: Conjugated estrogens; MPA: Medroxyprogesterone acetate; PBO: Placebo; SAE: Serious adverse event; VTE: Venous thromboembolic event

Data obtained using transvaginal ultrasound have also shown neutral effects of CE/BZA on the endometrium. In the SMART-1 trial, BZA 20 mg/CE 0.45 and 0.625 mg were associated with minimal increases in endometrial thickness from baseline (<1 mm), which were similar to placebo. In the SMART-5 trial, CE/MPA was associated with an increase in endometrial thickness of >5 mm in more subjects than with CE/BZA or placebo [30,33].

Bleeding profile

The effects of CE/BZA on endometrial spotting and bleeding have also been evaluated in the SMART trials [30,33]. In SMART-1 and SMART-5, BZA 20 mg/CE 0.45 and 0.625 mg were associated with high rates of cumulative amenorrhea, similar to placebo [30,33]. The rates of cumulative amenorrhea were >83, >87 and >85% for BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg and placebo, respectively, in SMART-1 [30]. Higher rates of cumulative amenorrhea were observed with BZA 20 mg/CE 0.45 and 0.625 mg (>87 and >84%, respectively) and placebo (>83%) compared with CE/MPA (>54%) in SMART-5 [33].

Breast safety

Both components of CE/BZA have a well-characterized breast profile. The Women's Health Initiative demonstrated that treatment with CE 0.625-mg daily did not increase the risk of breast cancer [39]. After a mean follow-up of 7.1 years, the annualized incidence of invasive breast cancer was not significantly different with CE (0.28%) compared with placebo. Results from an extended follow-up of 11.8 years were recently published [30], reporting a lower incidence of invasive breast cancer in women who had received a median of 5.9 years of CE therapy compared with placebo [40].

BZA did not stimulate cell proliferation and potently inhibited estradiol-stimulated proliferation in Michigan Cancer Foundation-7 proliferation assays [41]. In a separate study evaluating the effects of BZA on the growth of breast cancer xenografts in mouse models, BZA effectively inhibited the growth of tamoxifen-sensitive and tamoxifen-resistant tumor xenografts [42]. The lack of estrogen receptor stimulatory activity observed with BZA in preclinical studies has been further reinforced by clinical data from Phase III, randomized, double-blind studies in postmenopausal women [43 –45]. A Phase III, randomized, double-blind, 3-year trial of BZA 20 mg, RLX 60 mg or placebo in women with osteoporosis (n = 7492) showed no significant difference in the incidence of breast carcinoma and breast cysts with BZA compared with placebo or RLX; however, there was a significantly lower incidence of fibrocystic breast disease with BZA (0.3 and 0.2%, respectively) versus RLX (0.8%; p < 0.05) [43]. Breast pain incidence was similar among groups, with rates ranging from 2.4 to 3.0% [44,45]. In a retrospective ancillary analysis of a subset of women (n = 444) from this study, mean percent changes in breast density from baseline were low and similar among groups [46].

Given the safe profile of both components a similar profile is anticipated in CE/BZA. The incidence of breast-related adverse events was low and similar for CE/BZA compared with placebo across the SMART trials [30 –33]. The incidence of abnormal mammograms was also similar to placebo. In addition, breast cancer rates were low across the SMART studies. In a pooled analysis of the SMART studies, the rate of breast cancer in the CE/BZA groups were low and similar to placebo [30 –33]. However, these results should be taken with caution, since the number of breast cancer events were small (n = 2) and the duration of these trials were too short to provide definitive evidence of breast safety.

Breast density appears to be unaffected by CE/BZA treatment. In an ancillary study of SMART-1 (n = 507), mammographic breast density changes at 2 years with BZA 20 mg/CE 0.45 mg (-0.39%) were similar to those with placebo (-0.42%) and RLX 60 mg (-0.23%) [47]. Similarly, in the breast density substudy of SMART-5, BZA 20 mg/CE 0.45 mg was not associated with increased breast density, and demonstrated noninferiority compared with placebo at 12 months [37]. By contrast, CE 0.45 mg/MPA 1.5 mg was associated with a significant increase in breast density at 12 months versus placebo [37].

There were no significant differences between the CE/BZA and placebo groups in the percentage of women reporting breast pain or tenderness in any of the SMART trials [30,31,33]. In SMART-1, there were no significant differences in the incidence of breast pain among the CE/BZA, RLX and placebo groups [30]. In SMART-2 and SMART-3 trials, there were no significant differences in the number of women reporting ≥1 day of breast pain between the CE/BZA and placebo groups [31]. In SMART-5, the incidence of breast tenderness with CE/BZA was similar to placebo and statistically significantly lower than with CE/MPA [33]. Taken together, these clinical data support the favorable breast-related safety and tolerability profile of CE/BZA in postmenopausal women with an intact uterus.

Cardiovascular safety

The incidence of VTE was low, as expected in this relatively healthy population and consistent with what was reported in the Women's Health Initiative study for the estrogen alone or the estrogen plus progesterone groups [39,48]. The risk does not appear to be any greater than CE alone or BZA alone or greater than CE/MPA [39,45,48]. The mechanism for the lack of an additive effect with BZA/CE with regard to VTEs is not known, but may be due in part to degradation of estrogen receptors by BZA [38], which may influence the effects of CE. The incidence of coronary heart disease and cerebrovascular accident were similar to placebo [30 –33]. These results should be taken with caution, since the number of events was small and the duration of these trials was not longer than 2 years.

Clinical laboratory tests demonstrated that the CE/BZA was associated with a favorable lipid profile (decreases in total cholesterol, low-density lipoprotein and increases in high-density lipoprotein), with the exception of an increase in triglyceride levels [30]. CE/BZA was associated with an increase from baseline in serum triglycerides, which was similar to that reported for estrogen progestin-containing HT [49].

No other clinically significant changes in clinical laboratory tests were noted, including nonclinical meaningful changes on coagulation variables such as protein C/S activity, prothrombin time and plasminogen activator inhibitor-1 antigen [30].

Regulatory affairs

CE/BZA is the first FDA-approved tissue selective estrogen complex (TSEC). It was approved for the indications of ‘treatment of moderate-to-severe hot flushes associated with menopause and prevention of osteoporosis’ on 3 October 2013.

CE/BZA is undergoing regulatory review worldwide and regulatory approvals in the EU, Latin America and Asia are expecting for 2014.

Conclusion

HT is the conventional and established therapy option for postmenopausal women, with progestin-containing HT recommended for women with an intact uterus. Progestin-containing HT have demonstrated efficacy in relieving VMS and symptoms associated with vulvar vaginal atrophy, as well as in preventing osteoporosis. However, it is associated with some safety and tolerability concerns.

Executive summary

Background

Conjugated estrogen/bazedoxifene (CE/BZA) is a TSEC and represents a new treatment option in the management of menopausal health in women with a uterus.

CE/BZA pairs CE (Premarin®, Pfizer, PA, USA) with the selective estrogen receptor modulator, bazedoxifene.

Overview of the market

Progestin-containing hormone therapy (HT) has been the gold-standard medication for the treatment of vasomotor symptoms; however, progestin-containing HT is associated with high-discontinuation rate due to tolerability issues.

Pharmacokinetics

The pharmacokinetic profile of CE and BZA administered via a CE/BZA tablet is consistent with the individual components. Maximum plasma concentrations of the estrogens are achieved approximately 6–10 h after oral administration of CE/BZA tablets.

Clinical efficacy

CE/BZA is associated with a clinically meaningful reduction in the number and severity of hot flushes.

The efficacy of CE/BZA to relieve hot flushes is similar to that reported for progestin-containing HT.

CE/BZA is associated with clinically meaningful improvements in health-related quality of life and sleep.

Tolerability (vaginal bleeding)

Progestin-containing HT induces vaginal bleeding and, therefore, creates a need for additional testing that causes concerns.

BZA/CE demonstrated high amenorrhea rates that were comparable to placebo and statistically significantly greater than progestin-containing HT.

Overall safety

The frequency of treatment-emergent adverse events, adverse events leading to discontinuation and serious adverse events, were similar between subjects treated with CE/BZA compared with the subjects who received placebo.

Endometrial protection without a progestin

CE/BZA has demonstrated favorable endometrial safety profile with a similar incidence of hyperplasia as placebo.

Breast safety

CE/BZA is associated with a safe breast profile with the same incidence of breast cancer, breast pain and effect on breast density as placebo.

Regulatory status

CE/BZA is US FDA-approved for the indications of ‘treatment of moderate-to-severe hot flushes associated with menopause’ and ‘prevention of osteoporosis‘, and is ongoing regulatory review worldwide.

Conclusion

CE/BZA has been shown to maintain the established benefits of estrogen therapy for the treatment of vasomotor symptoms and prevention of loss in bone mineral density (bone mass), while minimizing certain estrogenic effects particularly in the endometrium and breast.

The TSEC provides a novel approach to treating menopausal symptoms and preventing osteoporosis, while maintaining endometrial and breast safety through the pairing of a SERM with one or more estrogens. CE/BZA is the first FDA-approved TSEC. The properties that resulted from the pairing of CE and BZA appear to be unique and cannot be assumed for other SERM/estrogen combinations. In preclinical studies, the molecular and pharmacologic profiles of BZA/CE were distinct from that of RLX/CE and lasofoxifene/CE. In clinical trials, although RLX combined with estrogens reduced menopausal symptoms, evidence of endometrial stimulation argues against use in postmenopausal women with a uterus [50]. By contrast, CE/BZA displayed favorable effects, with significant reductions in vasomotor and vaginal symptoms, and prevention of bone loss, while protecting the breast and endometrium. Furthermore, although all SERMs and estrogens are associated with some degree of cardiovascular risk, the incidence of VTEs and cardiovascular events in the SMART studies does not appear to be additive for the combination of BZA and CE.

Future TSEC development may involve the investigation of new SERM/estrogen combinations. Such combinations may have the potential to perform as well or better than CE/BZA for the treatment of menopausal symptoms and prevention of osteoporosis. These investigations would require evaluation of the appropriate dose ratio for the SERM and estrogen components, as well as determination of an effective delivery method (e.g., oral, transdermal or implant), along with evaluation of endometrial, breast and cardiovascular safety in large, randomized, controlled trials, such as the SMART trials.

Financial & competing interests disclosure

S Mirkin was a Pfizer employee at the time of the study. B Komm is a Pfizer employee. JH Pickar was formerly an employee of Wyeth Research, and has consulted for Wyeth/Pfizer, Depomed, BHR Pharma, ASCEND Therapeutics, Therapeutics MD, Ausio Pharmaceuticals and Shionogi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Conjugated Estrogen/Bazedoxifene Tablets for the Treatment of Moderate-to-Severe Vasomotor Symptoms Associated with Menopause

Abstract

Keywords

Overview of the market

CE/bazedoxifene: a tissue-selective estrogen complex

Pharmacokinetics of CE/BZA

Pharmacodynamics of CE/BZA

Hot flushes

Clinical efficacy on VMS

Phase II study: dose-ranging study

Phase III studies

Efficacy of CE/BZA for the treatment of VMS

Effect on menopause QoL

Effect on sleep

Overall safety

Endometrial protection without the use of a progestin

Bleeding profile

Breast safety

Cardiovascular safety

Regulatory affairs

Conclusion

Financial & competing interests disclosure

References