Long-term treatment with pegvisomant: observations from 2090 acromegaly patients in ACROSTUDY.

Objectives ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant (PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016. Methods Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed. Results Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the upper limit of normal (ULN). The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8 mg (year 1) to 18.9 mg (year 10). A total of 4832 adverse events (AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3× ULN at any time point during their follow-up was reported in 3%. Conclusions This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.

Initial investigation into the optimal dose ratio of conjugated estrogens and bazedoxifene: a double-blind, randomized, placebo-controlled phase 2 dose-finding study.

OBJECTIVE: The aim of the study was to explore dose-related endometrial effects of conjugated estrogens/bazedoxifene (CE/BZA). METHODS: In this randomized, double-blind, phase 2 study, 408 nonhysterectomized, symptomatic (with hot flushes [HFs]) postmenopausal women received ≥1 dose of CE 0.3 or 0.625 mg alone or with BZA 5, 10, or 20 mg/d; placebo; BZA 5 mg/d alone; or CE 0.625 mg with medroxyprogesterone acetate 2.5 mg/d for 84 days. The primary outcome was endometrial thickness on transvaginal ultrasound. HF frequency and severity based on diaries were key secondary outcomes. RESULTS: CE 0.625 mg alone increased endometrial thickness compared with placebo (mean 5.5 vs 2.95 mm, P < 0.001); BZA countered this in a dose-related manner such that average thickness with the addition of BZA 5, 10, and 20 mg was 5.99, 4.33, and 3.54 mm, respectively. On average, endometrium was significantly less thick with CE 0.625 mg/BZA 20 mg than CE 0.625 mg (P < 0.001) and CE 0.3 mg/BZA 20 mg versus CE 0.3 mg (2.94 vs 3.92 mm, P < 0.05); endometrial thickness was similar to placebo with CE 0.625 mg/BZA 20 mg. Lower BZA doses failed to reduce endometrial thickness relative to the same dose of CE alone. Regimens containing CE 0.625 mg reduced HF frequency and severity versus placebo; CE 0.3 mg with BZA 10 or 20 mg was ineffective. CONCLUSIONS: BZA ≥20 mg is needed to counter endometrial growth resulting from treatment with CE 0.3 or 0.625 mg. CE 0.3 mg inadequately controls HFs if given with BZA 20 mg.

Gynecologic Safety of Conjugated Estrogens Plus Bazedoxifene: Pooled Analysis of Five Phase 3 Trials.

OBJECTIVE: To evaluate gynecologic safety of conjugated estrogens/bazedoxifene treatment for menopausal symptoms and osteoporosis prevention in nonhysterectomized women. MATERIALS AND METHODS: We pooled data from five randomized, placebo-controlled trials of conjugated estrogens 0.625 mg/bazedoxifene 20 mg (n = 1583), conjugated estrogens 0.45 mg/bazedoxifene 20 mg (n = 1585), and placebo (n = 1241). Gynecologic safety was evaluated by pelvic examination, Papanicolaou smear, endometrial biopsy, transvaginal ultrasound, mammogram, adverse events, and diary records of vaginal bleeding and breast pain/tenderness. Incidence rates and relative risks (RR) versus placebo were calculated with inverse variance weighting. Data for conjugated estrogens 0.45 mg/medroxyprogesterone acetate 1.5 mg, an active comparator in two trials (n = 399), are included for comparison. RESULTS: Endometrial hyperplasia occurred in <1% (n = 4 [0.3%], 2 [0.2%], 1 [0.5%], and 2 [0.2%] for conjugated estrogens 0.625 mg/bazedoxifene 20 mg, conjugated estrogens 0.45 mg/bazedoxifene 20 mg, conjugated estrogens/medroxyprogesterone acetate, and placebo). There was one endometrial cancer, which occurred with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (0.44/1000 woman-years [95% confidence interval (CI), 0.00-2.37]; RR versus placebo 0.91 [95% CI, 0.17-4.82]). There were seven cases of breast cancer: four with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (1.00/1000 woman-years [95% CI, 0.00-3.21] RR 1.11 [95% CI, 0.33-3.78]), two with placebo, and one with conjugated estrogens/medroxyprogesterone acetate. Unlike conjugated estrogens/medroxyprogesterone acetate, conjugated estrogens/bazedoxifene did not increase breast density, breast pain/tenderness, or vaginal bleeding versus placebo. No active treatment increased ovarian cysts. CONCLUSION: Conjugated estrogens/bazedoxifene provides endometrial protection without increasing breast pain/density, vaginal bleeding, or ovarian cysts in nonhysterectomized postmenopausal women studied up to 2 years.

Efficacy and tolerability of bazedoxifene in Mexican women with osteoporosis: a subgroup analysis of a randomized phase 3 trial.

OBJECTIVE: Bazedoxifene (BZA) is a selective estrogen receptor modulator that reduces fracture risk and bone turnover in postmenopausal women with osteoporosis. This analysis evaluated BZA's effects on bone mineral density (BMD) and bone turnover in Mexican women with osteoporosis from the global pivotal trial (Study Evaluating Bazedoxifene Acetate in Osteoporosis in Postmenopausal Women). METHODS: In this 3-year, phase 3, randomized, double-blind trial, healthy postmenopausal women with osteoporosis (N = 7,492) received BZA 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The subanalyses of Mexican women assessed serum concentrations of osteocalcin and collagen type 1 C-telopeptide, BMD, and tolerability with BZA 20 mg/d versus placebo. RESULTS: In the Mexican subgroup (BZA, n = 39; placebo, n = 37) at month 12, BZA 20 mg/d produced significant (P < 0.001) percentage decreases from baseline in osteocalcin (-40.5 vs -18.5) and C-telopeptide (-45.7 vs -29.4). For BZA versus placebo, percentage change in BMD from baseline to month 36 was 3.3 versus 0.64 for lumbar spine, -0.18 versus -1.8 for total hip, 0.21 versus -2.6 for femoral neck, and -0.55 versus -1.4 for femoral trochanter; differences were not statistically significant. Results were comparable to the overall study population in which differences were statistically significant. Common adverse events (≥20%) included arthralgia, back pain, gastritis, headache, influenza, and pain; none led to study withdrawal. CONCLUSIONS: In Mexican women with osteoporosis, BZA was well tolerated and seems to produce BMD changes comparable to the global phase 3 population, although differences versus placebo were not statistically significant in this smaller subgroup.

A Pooled Analysis of the Effects of Conjugated Estrogens/Bazedoxifene on Lipid Parameters in Postmenopausal Women From the Selective Estrogens, Menopause, and Response to Therapy (SMART) Trials.

CONTEXT: Menopausal lipid profile changes may increase cardiovascular risk. The effects of conjugated estrogens (CE)/bazedoxifene (BZA), an approved menopausal therapy, on lipids have not been fully characterized. OBJECTIVE: The purpose of this study was to determine the effects of CE/BZA on lipids in the Selective estrogens, Menopause, And Response to Therapy (SMART) trials for ≥ 1 year. DESIGN: This was a pooled analysis of 3 randomized, double-blind, placebo (PBO)-controlled phase 3 trials (SMART-1, -4, and -5). SETTING: The study was conducted in North America, Europe, Asia-Pacific Region, and Latin America. PARTICIPANTS: Participants were nonhysterectomized postmenopausal women aged 40 to 75 years, not taking lipid-lowering medications (N = 2796). INTERVENTIONS: Treatments were CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, and PBO. MAIN OUTCOME MEASURES: The adjusted mean percentage changes from baseline in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and the LDL-C/HDL-C ratio at 12 and 24 months were measured. RESULTS: At 12 months, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg produced significant (P < .001) improvements vs PBO in TC (-4.20% and -4.37% vs -0.88%), LDL-C (-9.33% and -10.78% vs -1.08%), HDL-C (4.59% and 6.21% vs 1.30%), and the LDL-C/HDL-C ratio (-11.59% and -14.00% vs -0.84%). Triglycerides were significantly (P < .001) increased from baseline with both doses vs PBO (15.13% and 15.74% vs 4.43%). Similar trends (all P < .001) were seen at 24 months when SMART-1 and SMART-4 were pooled (TC: -3.25% and -3.13% vs 0.95%; LDL-C: -7.47% and -8.08% vs 2.95%; HDL-C: 5.91% and 7.19% vs 1.72%; triglycerides: 18.87% and 18.82% vs 6.49%; and the LDL-C/HDL-C ratio: -10.05% and -12.82% vs 2.56%). CONCLUSIONS: CE/BZA was associated with mostly favorable changes in lipid parameters for up to 2 years in nonhysterectomized postmenopausal women.

Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial.

OBJECTIVE: This phase 3 study evaluated the endometrial safety of bazedoxifene (BZA)/conjugated estrogens (CE) and bone mineral density (BMD) effects vs BZA alone, hormone therapy, and placebo (PBO). METHODS: The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, PBO- and active-controlled study in postmenopausal women with an intact uterus (N = 1843; aged 40-65 years) seeking treatment for menopausal symptoms. Subjects received daily oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or PBO. Primary endpoints were incidence of endometrial hyperplasia and percent change in lumbar spine BMD at 12 months. Secondary endpoints included additional osteoporosis parameters and assessments of tolerability and safety. RESULTS: At 12 months, endometrial hyperplasia incidence was low (<1%) and similar among groups. The BZA/CE group showed significantly greater increases in lumbar spine and total hip BMD vs decreases with PBO (P < .001); the CE/MPA group had increased lumbar spine BMD compared with that in the BZA/CE group. The BZA 20 mg/CE 0.45 and 0.625 mg groups had cumulative amenorrhea rates similar to those with PBO and BZA and significantly higher than those with CE 0.45 mg/MPA 1.5 mg (P < .001). The incidence of breast tenderness with BZA/CE was similar to that with PBO and BZA and significantly lower than with that with CE/MPA (P < .01). Although adverse event (AE) rates were similar among the groups, the incidence of serious AEs overall and AE-related discontinuation rates were higher with CE/MPA than with BZA/CE, BZA, or PBO. CONCLUSIONS: BZA/CE showed low rates of endometrial hyperplasia and improved lumbar spine and total hip BMD and was generally safe and well tolerated.

Breast effects of bazedoxifene-conjugated estrogens: a randomized controlled trial.

OBJECTIVE: To evaluate the effects of bazedoxifene-conjugated estrogens on mammographic breast density and other breast parameters in nonhysterectomized postmenopausal women enrolled in a randomized, double-blind, placebo-controlled, and active-controlled phase 3 study. METHODS: The 1-year Selective estrogens, Menopause, And Response to Therapy-5 trial estimated the efficacy and safety of bazedoxifene-conjugated estrogens in 1,843 postmenopausal women seeking vasomotor symptom treatment. A substudy enrolled 940 women with technically acceptable digital mammograms at screening and at 1 year. Treatments included bazedoxifene 20 mg and conjugated estrogens 0.45 or 0.625 mg, placebo, bazedoxifene 20 mg, and conjugated estrogens (0.45 mg) and medroxyprogesterone acetate (1.5 mg). Mammograms were centrally read by a single radiologist blinded to treatment and time sequence; percent breast density was determined using validated software. Noninferiority was based on a predefined margin of 1.5% for comparison of adjusted mean differences in breast density at 12 months. RESULTS: Bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg demonstrated noninferiority to placebo in breast density. Mammographic breast density decreased from baseline with bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg and placebo (mean -0.38% and standard error [SE] 0.22%, mean -0.44% and SE 0.22%, mean -0.32% and SE 0.23%, respectively). Conjugated estrogens-medroxyprogesterone acetate significantly increased breast density from baseline (mean 1.60%, SE 0.35%; P<.001) compared with placebo. Both bazedoxifene-conjugated estrogens doses showed rates of breast tenderness similar to placebo and significantly (P<.001) lower than conjugated estrogens-medroxyprogesterone acetate. No differences in incidence of breast-related adverse events were identified. CONCLUSION: Bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg did not increase mammographic breast density or breast tenderness over the course of 1 year with a favorable breast-related safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00808132. LEVEL OF EVIDENCE: I.

A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women.

OBJECTIVES: The primary objective of the Selective estrogen Menopause And Response to Therapy 3 (SMART-3) trial was to compare the efficacy and safety of two doses of bazedoxifene (BZA)/conjugated estrogens (CE) versus placebo for the treatment of moderate to severe vulvar/vaginal atrophy (VVA) associated with menopause. METHODS: This was a phase 3, multicenter, double-blind, randomized, placebo-controlled, and active comparator-controlled study. Healthy postmenopausal women (n = 664; aged 40-65 y) were randomized to BZA 20 mg/CE 0.625 mg, BZA 20 mg/CE 0.45 mg, BZA 20 mg, or placebo once daily for 12 weeks. Changes in vaginal maturation, vaginal pH, and severity of the most bothersome symptom of VVA from baseline were assessed at screening and at weeks 4 and 12. Adverse events were recorded throughout the study. RESULTS: BZA 20 mg/CE 0.625 or CE 0.45 mg significantly (P < 0.01) increased superficial cells and decreased parabasal cells compared with placebo. Vaginal pH and most bothersome symptom significantly improved with BZA 20 mg/CE 0.625 mg compared with placebo (P < 0.05). Improvements in vaginal dryness were also observed with both BZA/CE doses (P G 0.05). The incidence of treatment-related adverse events were similar across treatment groups. CONCLUSIONS: BZA/CE is effective in treating moderate to severe VVA and vaginal symptoms. These data further support the use of a tissue-selective estrogen complex containing BZA/CE as a new menopausal therapy for postmenopausal women.