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Summary Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. Introduction Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. Methods Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. Results At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs − 0.8% (0.43%) with PBO/ALN (P

Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture.Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463).After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p 0.001) and 1.54 percentage points greater for abaloparatide compared with teriparatide (95% CI 0.64, 2.45, p 0.001). At 18 months, 1/3 radius BMD losses (versus baseline) were similar for abaloparatide compared with placebo (-0.42; 95% CI -1.03, 0.20; p = 0.19) but losses with teriparatide exceeded those of placebo (-1.66%; 95% CI -2.27, -1.06; p 0.001). The decline with abaloparatide was less than that seen with teriparatide (group difference 1.22%; 95% CI 0.57, 1.87; p 0.001). The radius BMD findings, at both ultradistal and 1/3 sites, are consistent with the numerically lower incidence of wrist fractures observed in women treated with abaloparatide compared with teriparatide (HR = 0.43; 95% CI 0.18, 1.03; p = 0.052) and placebo (HR = 0.49, 95% CI 0.20, 1.19, p = 0.11).Compared with teriparatide, abaloparatide increased BMD at the ultradistal radius (primarily trabecular bone) and decreased BMD to a lesser extent at the 1/3 radius (primarily cortical bone), likely contributing to the numerically lower wrist fracture incidence observed with abaloparatide.

Context The ACTIVE study demonstrated the antifracture efficacy of abaloparatide in postmenopausal women with osteoporosis. ACTIVExtend demonstrated sustained fracture risk reduction with alendronate in abaloparatide-treated participants from ACTIVE. A direct comparison of the efficacy of abaloparatide and antiresorptive therapies has not been performed. Objective The objective of this analysis is to compare the antifracture efficacy of abaloparatide in ACTIVE with that of alendronate in ACTIVExtend. Design In this post hoc analysis, the rate of new vertebral fractures for women in ACTIVExtend (N = 1139) was calculated based on baseline and endpoint radiographs for placebo or abaloparatide in ACTIVE and alendronate in ACTIVExtend. Vertebral fracture rates between abaloparatide and alendronate were compared in a Poisson regression model. Fracture rates for nonvertebral and clinical fractures were compared based on a Poisson model during 18 months of abaloparatide or placebo treatment in ACTIVE and 18 months of alendronate treatment in ACTIVExtend. Results The vertebral fracture rate was lower during abaloparatide treatment in ACTIVE (0.47 fractures/100 patient-years) than alendronate treatment in ACTIVExtend (1.66 fractures/100 patient-years) (relative risk reduction 71%; P = .027). Although the comparisons did not meet statistical significance, after switching from placebo (ACTIVE) to alendronate (ACTIVExtend), the rate of new vertebral fractures decreased from 2.49 to 1.66 fractures per 100 patient-years, and after switching from abaloparatide to alendronate from 0.47 to 0.19 fractures per 100 patient-years. The rates of nonvertebral fractures and clinical fractures were not significantly different. Conclusion Initial treatment with abaloparatide may result in greater vertebral fracture reduction compared with alendronate in postmenopausal women with osteoporosis.

Summary Glucorticoid (GC) therapy is the commonest cause of secondary osteoporosis. Ovariectomized rabbits receiving the GC methylprednisolone for 6 weeks exhibited relatively lower vertebral and femoral bone mass. Treatment with the PTH receptor agonist abaloparatide for 12 weeks during ongoing methylprednisolone administration increased cortical and trabecular bone mass and femur bending strength. Introduction Abaloparatide, an osteoanabolic PTHrP analog, increases bone mineral density (BMD) and reduces fracture risk in women with postmenopausal osteoporosis. This study assessed abaloparatide effects on BMD and bone strength in ovariectomized (OVX) rabbits with glucocorticoid (GC)-induced osteopenia. Methods Thirty-two rabbits underwent OVX and 8 underwent sham surgery. One day later, 24 OVX rabbits began daily s.c. GC injections (methylprednisolone, 1 mg/kg/day) for 6 weeks, while 8 OVX and 8 sham controls received no GC. GC-challenged rabbits (8/group) then received GC (0.5 mg/kg/day) along with daily s.c. vehicle (GC-OVX), abaloparatide 5 μg/kg/day (ABL5), or 25 μg/kg/day (ABL25) for 12 weeks, and the no-GC OVX and sham controls received daily vehicle. Results GC-OVX rabbits showed significant deficits in vertebral and proximal femur areal BMD, lower cortical area, thickness and volumetric BMD of the femur diaphysis, and reduced trabecular bone volume and volumetric BMD in the vertebra and distal femur versus sham controls. These deficits were significantly reversed in the ABL25 group, which also showed enhanced trabecular micro-architecture versus GC-OVX controls. Destructive bending tests showed significantly lower femur diaphysis ultimate load and bending rigidity of the femoral diaphysis in the GC-OVX group versus sham controls, whereas these parameters were similar in the ABL25 group vs sham controls. Conclusions Abaloparatide 25 μg/kg/day mitigated the adverse effects of GC administration on cortical and trabecular bone and improved femoral strength in OVX rabbits. These results suggest potential promise for abaloparatide as an investigational therapy for glucocorticoid-induced osteoporosis.

Fractures typically heal via endochondral and intramembranous bone formation, which together form a callus that achieves union and biomechanical recovery. PTHrP, a PTH receptor agonist, plays an important physiological role in fracture healing as an endogenous stimulator of endochondral and intramembranous bone formation. Abaloparatide, a novel systemically-administered osteoanabolic PTH receptor agonist that reduces fracture risk in women with postmenopausal osteoporosis, has 76% homology to PTHrP, suggesting it may have potential to improve fracture healing. To test this hypothesis, ninety-six 12-week-old male rats underwent unilateral internally-stabilized closed mid-diaphyseal femoral fractures and were treated starting the next day with daily s.c. saline (Vehicle) or abaloparatide at 5 or 20 µg/kg/d for 4 or 6 weeks (16 rats/group/time point). Histomorphometry and histology analyses indicated that fracture calluses from the abaloparatide groups exhibited significantly greater total area, higher fluorescence scores indicating more newly-formed bone, and higher fracture bridging scores versus Vehicle controls. Callus bridging score best correlated with callus cartilage score (r = 0.64) and fluorescence score (r = 0.67) at week 4, and callus area correlated with cartilage score (r = 0.60) and fluorescence score (r = 0.89) at Week 6. By micro-CT, calluses from one or both abaloparatide groups had greater bone volume, bone volume fraction, bone mineral content, bone mineral density, and cross-sectional area at both time points versus Vehicle controls. Destructive bending tests indicated greater callus maximum load and stiffness in one or both abaloparatide groups at both time points versus Vehicle controls. These results provide preliminary preclinical evidence for improved fracture healing with systemically-administered abaloparatide. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Purpose Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture. Methods Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463). Results After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p

Male osteoporosis can occur with advanced age and with hypogonadism, with increased bone resorption and/or inadequate bone formation contributing to reduced bone mass and increased fracture risk. Abaloparatide is a selective PTH receptor agonist that increases bone formation and bone mass in postmenopausal women with osteoporosis and in estrogen-deficient animals. The current study evaluated the effects of abaloparatide in orchiectomized (ORX) rats, a model of male osteoporosis. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery; 8 weeks later the ORX groups exhibited relative osteopenia vs sham controls, based on dual X-ray absorptiometry (DXA) and/or peripheral quantitative computed tomography (pQCT) assessments at the total body, lumbar spine, femur, and tibia. ORX rats (n = 10/group) were then injected daily (s.c.) for 8 weeks with vehicle or abaloparatide at 5 (ABL5) or 25 μg/kg/d (ABL25). Sham controls (n = 10) received s.c. vehicle. DXA and pQCT showed that one or both abaloparatide groups gained more areal and volumetric BMD at all sites analyzed compared with vehicle controls, leading to substantial or complete reversal of ORX-induced BMD deficits. pQCT also indicated greater gains in tibial cortical thickness in both abaloparatide groups versus vehicle controls. Tibial bone histomorphometry showed greater trabecular bone formation and bone volume and improved micro-architecture with abaloparatide, with no increase in osteoclasts. Abaloparatide also led to significant improvements in the balance of biochemical bone formation markers versus bone resorption markers, which correlated with BMD changes. These findings suggest that abaloparatide may have therapeutic benefits in men with osteoporosis.

Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal or increased BMD. Abaloparatide reduces fracture risk in patients with postmenopausal osteoporosis (PMO); however, its efficacy in women with T2DM is unknown. This post hoc analysis evaluated the efficacy and safety of abaloparatide in patients with T2DM. The analysis included patients with T2DM from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), a phase 3, double‐blind, randomized, placebo‐ and active‐controlled trial. In ACTIVE, participants were randomized 1:1:1 to daily s.c. injections of placebo, abaloparatide (80 μg), or open‐label teriparatide (20 μg) for 18 months. A total of 198 women with PMO and T2DM from 21 centers in 10 countries were identified from ACTIVE through review of their medical records. The main outcomes measured included effect of abaloparatide versus placebo on BMD and trabecular bone score (TBS), with secondary outcomes of fracture risk and safety, in patients from ACTIVE with T2DM. Significant (p

Abaloparatide (ABL) is a 34-amino acid peptide designed to be a selective activator of the parathyroid hormone receptor type 1 signaling pathway. In the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), subcutaneous ABL reduced the risk of new vertebral, nonvertebral, clinical, and major osteoporotic fracture compared with placebo and of major osteoporotic fracture compared with teriparatide. To further evaluate the effectiveness of ABL, we calculated the number needed to treat (NNT) to prevent one fracture using ACTIVE data. To estimate the potential effectiveness of ABL in populations at higher fracture risk than in ACTIVE, we calculated NNT for vertebral fracture using reference populations from historical placebo-controlled trials, assuming an 86% relative risk reduction in vertebral fracture with ABL treatment as observed in ACTIVE. NNT was calculated as the reciprocal of the absolute risk reduction in ACTIVE. The projected NNT for ABL in other populations was calculated based on incidence rate (IR) for vertebral fractures in the placebo arms of the FREEDOM (placebo IR 7.2%), FIT-1 (placebo IR 15.0%), and FIT-2 (placebo IR 3.8%) trials. NNT for ABL in ACTIVE was 28 for vertebral, 55 for nonvertebral, 37 for clinical, and 34 for major osteoporotic fracture. NNT for these fracture types for teriparatide in ACTIVE were 30, 92, 59, and 75, respectively. Using placebo IRs from FREEDOM, FIT-1, and FIT-2, projected NNTs for vertebral fracture with ABL were 17, 8, and 31. These data are useful for further evaluating ABL for the treatment of osteoporosis in postmenopausal women.

Summary Abaloparatide, a novel PTH1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. Abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality. Introduction Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos). Methods Sixty-five 9–18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n = 17) or abaloparatide (0.2, 1, or 5 μg/kg/day; n = 16/dose level), while Sham controls received s.c. vehicle (n = 15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed. Results At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass-strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams. Conclusions Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters. Electronic supplementary material The online version of this article (10.1007/s00198-017-4323-6) contains supplementary material, which is available to authorized users.

Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities.

Purpose: Estrogen receptor–positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models. Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations. Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793–804. ©2017 AACR.

Abaloparatide is a novel 34 amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor 1 (PTHR1) signaling pathway. The effects of 12months of abaloparatide treatment on bone mass, bone strength and bone quality was assessed in osteopenic ovariectomized (OVX) rats. SD rats were subjected to OVX or sham surgery at 6months of age and left untreated for 3months to allow OVX-induced bone loss. Eighteen OVX rats were sacrificed after this bone depletion period, and the remaining OVX rats received daily s.c. injections of vehicle (n=18) or abaloparatide at 1, 5 or 25μg/kg/d (n=18/dose level) for 12months. Sham controls (n=18) received vehicle daily. Bone changes were assessed by DXA and pQCT after 0, 3, 6 or 12months of treatment, and destructive biomechanical testing was conducted at month 12 to assess bone strength and bone quality. Abaloparatide dose-dependently increased bone mass at the lumbar spine and at the proximal and diaphyseal regions of the tibia and femur. pQCT revealed that increased cortical bone volume at the tibia was a result of periosteal expansion and endocortical bone apposition. Abaloparatide dose-dependently increased structural strength of L4-L5 vertebral bodies, the femur diaphysis, and the femur neck. Increments in peak load for lumbar spine and the femur diaphysis of abaloparatide-treated rats persisted even after adjusting for treatment-related increments in BMC, and estimated material properties were maintained or increased at the femur diaphysis with abaloparatide. The abaloparatide groups also exhibited significant and positive correlations between bone mass and bone strength at these sites. These data indicate that gains in cortical and trabecular bone mass with abaloparatide are accompanied by and correlated with improvements in bone strength, resulting in maintenance or improvement in bone quality. Thus, this study demonstrated that long-term daily administration of abaloparatide to osteopenic OVX rats led to dose-dependent improvements in bone mass, geometry and strength.

Objective To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis). Patients and Methods ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients. Results Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P Conclusion Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis. Trial Registration clinicaltrials.gov Identifier: NCT01657162.

Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 mu g, placebo, or open-label teriparatide 20 mu g daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) = 90 mL/min, 1276 had 60 to

Abaloparatide is a novel 34-amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor (PTH1R) signaling pathway with 41% homology to PTH(1-34) and 76% homology to PTHrP(1-34). A 12-month treatment study was conducted in osteopenic ovariectomized (OVX) rats to characterize the mechanisms by which abaloparatide increases bone mass. Sprague-Dawley (SD) rats were subjected to OVX or sham surgery at age 6 months and left untreated for 3 months to allow OVX-induced bone loss. Ten OVX rats were euthanized after this bone depletion period, and the remaining OVX rats received daily subcutaneous injections of vehicle (n = 18) or abaloparatide at 1, 5, or 25 μg/kg/d (n = 18/dose level) for 12 months. Sham controls (n = 18) received vehicle daily. Bone densitometry and biochemical markers of bone formation and resorption were assessed longitudinally, and L3 vertebra and tibia were collected at necropsy for histomorphometry. Abaloparatide increased biochemical bone formation markers without increasing bone resorption markers or causing hypercalcemia. Abaloparatide increased histomorphometric indices of bone formation on trabecular, endocortical, and periosteal surfaces without increasing osteoclasts or eroded surfaces. Abaloparatide induced substantial increases in trabecular bone volume and density and improvements in trabecular microarchitecture. Abaloparatide stimulated periosteal expansion and endocortical bone apposition at the tibial diaphysis, leading to marked increases in cortical bone volume and density. Whole-body bone mineral density (BMD) remained stable in OVX-Vehicle controls while increasing 25% after 12 months of abaloparatide (25 μg/kg). Histomorphometry and biomarker data suggest that gains in cortical and trabecular bone mass were attributable to selective anabolic effects of abaloparatide, without evidence for stimulated bone resorption. © 2016 American Society for Bone and Mineral Research.

Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p -2.5 and ≤-3.0 versus >-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (

Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20–21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass–strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis.

Androgen deficiency is a leading cause of male osteoporosis, with bone loss driven by an inadequate level of bone formation relative to the extent of bone resorption. Abaloparatide, an osteoanabolic PTH receptor agonist used to treat women with postmenopausal osteoporosis at high risk for fracture, increases bone formation and bone strength in estrogen-deficient animals without increasing bone resorption. This study examined the effects of abaloparatide on bone formation, bone mass, and bone strength in androgen-deficient orchiectomized (ORX) rats, a male osteoporosis model. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery. Eight weeks later, sham-operated rats received vehicle (saline; n = 10) while ORX rats (n = 10/group) received vehicle (Veh) or abaloparatide at 5 or 25 μg/kg (ABL5 or ABL25) by daily s.c. injection for 8 weeks, followed by sacrifice. Dynamic bone histomorphometry indicated that the tibial diaphysis of one or both abaloparatide groups had higher periosteal mineralizing surface, intracortical bone formation rate (BFR), endocortical BFR, and cortical thickness vs Veh controls. Vertebral trabecular BFR was also higher in both abaloparatide groups vs Veh, and the ABL25 group had higher trabecular osteoblast surface without increased osteoclast surface. By micro-CT, the vertebra and distal femur of both abaloparatide-groups had improved trabecular bone volume and micro-architecture, and the femur diaphysis of the ABL25 group had greater cortical thickness with no increase in porosity vs Veh. Biomechanical testing indicated that both abaloparatide-groups had stronger vertebrae and femoral necks vs Veh controls. These findings provide preclinical support for evaluating abaloparatide as an investigational treatment for male osteoporosis.

Purpose In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results Five hundred fifty-eight women from ACTIVE’s ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan–Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures., In ACTIVExtend, reductions in fracture risk and increases in BMD achieved with 18 months of abaloparatide for postmenopausal osteoporosis were sustained through 24 months of subsequent alendronate.

Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE.Proportions of patients experiencing BMD gains from baseline of0%,3%, and6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites.At months 6, 12, and 18, there were significantly more3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the0% and6% responder thresholds.In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.

Objective: Advanced age is an important risk factor for fracture. The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) trial showed that subcutaneous abaloparatide increased bone mineral density (BMD) and reduced the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. This study describes the effects of abaloparatide in the subgroup of women aged 80 or more years in ACTIVE. Methods: Post hoc analyses of BMD and fracture incidence in this subgroup of women who received abaloparatide or placebo in the 18-month, phase 3, double-blind, randomized controlled ACTIVE trial. Results: The mean ages of the women ≥80 years were 81.9 and 81.7 years in the placebo (n = 43) and abaloparatide (n = 51) groups, respectively. The increases in BMD from baseline to 18 months with abaloparatide treatment were 3.9% at the total hip (P

Summary In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score. Introduction Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS). Methods This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 μg), subcutaneous teriparatide (20 μg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed. Results After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 μg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p

Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.

Abaloparatide is a novel synthetic peptide analog of parathyroid hormone-related protein (PTHrP) that is currently being developed as a potential anabolic agent in the treatment of postmenopausal osteoporosis.This study sought to assess the effects of abaloparatide on bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck in postmenopausal women with osteoporosis.Multi-center, multi-national, double-blind placebo controlled trial in which postmenopausal women were randomly assigned to receive 24 weeks of treatment with daily sc injections of placebo, abaloparatide, 20, 40, or 80 μg, or teriparatide, 20 μg. A 24-week extension was also performed in a subset of subjects.Postmenopausal women with osteoporosis (n = 222).BMD by dual-x-ray absorptiometry and biochemical markers of bone turnover.At 24 weeks, lumbar spine BMD increased by 2.9, 5.2, and 6.7% in the abaloparatide, 20-, 40-, and 80-μg groups, respectively, and 5.5% in the teriparatide group. The increases in the 40- and 80-μg abaloparatide groups and the teriparatide group were significantly greater than placebo (1.6%). Femoral neck BMD increased by 2.7, 2.2, and 3.1% in abaloparatide, 20-, 40-, and 80-μg groups, respectively, and 1.1% in the teriparatide group. The increase in femoral neck BMD with abaloparatide, 80 μg was significantly greater than placebo (0.8%). Total hip BMD increased by 1.4, 2.0, and 2.6% in the abaloparatide, 20-, 40-, and 80-μg groups, respectively. The total hip increases in the 40- and 80-μg abaloparatide groups were greater than both placebo (0.4%) and teriparatide (0.5%).Compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. Moreover, the abaloparatide-induced BMD increases at the total hip are greater than with the marketed dose of teriparatide. These results support the further investigation of abaloparatide as an anabolic therapy in postmenopausal osteoporosis.

Despite advances in the treatment of metastatic breast cancer, many women eventually relapse with more aggressive forms of endocrine-resistant disease. Mutations in the ESR1 gene encoding the estrogen receptor (ER) have recently emerged as a potential mechanism for the development of clinical resistance to conventional anti-estrogen therapies, such as fulvestrant. To overcome some of the pharmacokinetic limitations and intramuscular administration challenges associated with fulvestrant endocrine therapy and to combat the development of resistance, there is a significant need for the development of more durable and more effective ER-targeted therapies. Here, we begin to describe and characterize the preclinical efficacy of RAD1901, a novel, orally bioavailable small-molecule SERD, with significant therapeutic potential for treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 demonstrated profound tumor growth inhibition in MCF-7 xenograft models when compared to fulvestrant and tamoxifen. Importantly, RAD1901 also demonstrated marked single agent efficacy in a primary patient-derived xenograft (PDx) model harboring the ESR1 Y537S mutation indicating the utility of this SERD against clinically relevant ER mutants. Further biochemical binding studies and co-crystallization experiments of RAD1901 bound to the ER further confirms the ability of RAD1901 to bind to both mutant and wild type forms of the ER. RAD1901 is currently undergoing clinical testing in postmenopausal women with ER-positive advanced breast cancer. Citation Format: Garner F, Brown J, Katzenellenbogen J, Lyttle CR, Hattersley G. RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-07.

Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in in vivo and in vitro models of AR/ER+ breast cancer. Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models. Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib. Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1. It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER+ breast cancer patients. Clin Cancer Res; 23(24); 7608–20. ©2017 AACR.

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed “selective androgen receptor modulators” (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.

Introduction In the ACTIVE phase III trial, 2463 postmenopausal women with osteoporosis were randomized 1:1:1 to abaloparatide (ABL; n=824), blinded placebo (PBO; n=821), or open-label teriparatide (n=818). During ACTIVE, ABL increased BMD and reduced vertebral, nonvertebral, clinical, and major osteoporotic fractures compared to PBO. Women who completed ABL or PBO treatment in ACTIVE were eligible to enroll in an extension study (ACTIVExtend) to receive up to 24 months of open-label alendronate (ALN). Objectives To provide additional safety information and to evaluate vertebral and nonvertebral fracture endpoints. Methods The ACTIVExtend study enrolled 558 women from the original ABL group and 581 from the PBO group of the ACTIVE study (92% of women who completed ABL or PBO treatment in ACTIVE). Pre-specified endpoints, including vertebral, nonvertebral, clinical, and major osteoporotic fractures, were assessed over the 43-month period from ACTIVE baseline to the end of ACTIVExtend (18 months of ABL or PBO treatment, 1 month for reconsent, and 24 months of ALN treatment). Nonvertebral fracture endpoints were assessed using the Kaplan-Meier (KM) method, proportional hazard model, and logrank test for patients enrolled in ACTIVExtend and for the full ITT population randomized to ABL or PBO treatment in ACTIVE. Results During the 43-month period, 5.6% (n=32) of evaluable women sustained a new morphometric vertebral fracture in the PBO followed by ALN (PBO/ALN) group compared to 0.9% (n=5) in the ABL/ALN group, an 84% relative risk reduction (p The Table shows the KM rates of nonvertebral fracture endpoints over 43 months from ACTIVE baseline through the end of ACTIVExtend for both the ACTIVExtend cohorts as well as the full ACTIVE ITT population. The incidence of adverse events (AEs) including severe and serious AEs during ALN treatment period was similar for both study groups. The most common AEs were arthralgia, URI, and back pain. No cases of atypical femoral fracture or osteonecrosis of the jaw were reported. Conclusions In the ACTIVExtend study, administration of ABL for 18 months followed by ALN for 24 months resulted in sustained vertebral and nonvertebral fracture reduction compared to PBO followed by ALN. In the full randomized ACTIVE ITT population, over 43 months, in the ABL + ABL/ALN groups, there was a significant reduction in the incidence of vertebral and nonvertebral fractures as well as hip fractures compared to the PBO + PBO/ALN groups.

Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.

Objective The aim of the study was to assess the efficacy and safety of RAD1901, an oral estrogen receptor ligand, for the treatment of moderate-to-severe vasomotor symptoms of menopause. Methods This was a randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial. Postmenopausal women with a minimum of 7 moderate-to-severe, diary-reported hot flashes per day, or 50 per week, were randomized to one of five blinded dose groups (0 [placebo], 10, 25, 50, or 100 mg RAD1901 daily for 28 d). Efficacy endpoints included frequency and severity of hot flashes over 4 weeks of treatment. Results One hundred participants were randomized across the five treatment regimens. The frequency of moderate-to-severe hot flashes decreased in all groups over the treatment period (mean percent change from baseline at 4 wk, -54.1%, -77.2%, -51.8%, -53.8%, and -67.0% for placebo, 10, 25, 50, and 100 mg groups). The response in the 10 mg group was significantly different from placebo at 4 weeks (P = 0.024). No other dose group was significantly different from placebo. There were no statistically significant differences in severity of hot flashes between placebo and any dose group. Treatment was well tolerated; most treatment-emergent adverse events were mild to moderate in severity. Conclusions Daily treatment with 10 mg RAD1901 over 4 weeks resulted in a statistically significant reduction in the frequency of moderate-to-severe hot flashes compared with placebo, with an acceptable safety profile. Further clinical trials are warranted to investigate RAD1901's utility as a potential treatment for vasomotor symptoms.

Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p -2.5 and ≤-3.0 versus >-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (

Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities.

Recent studies have shown that the androgen receptor (AR) is widely expressed across all subtypes of breast cancer, with AR detected in 75-95% of estrogen receptor (ER) positive tumors. Prior to the development of ER-targeted therapy, androgens were used to treat breast cancers with favorable clinical responses. The lack of tissue-selectivity and understanding of mechanism of action of classic androgens led to its declined use in this disease. Selective androgen receptor modulators (SARMs) are a class of molecules developed as tissue selective non-steroidal androgens that modulate AR signaling. However, the effect of SARMs on AR signaling in breast cancer cells is not well understood. RAD140 is an orally available SARM with potent anabolic activity in muscle and bone but a highly attenuated effect in seminal vesicles and prostate. Its efficacy is being evaluated in in vivo xenograft models of AR/ER+ breast cancer. To further our understanding of the mechanism of action of RAD140 in breast cancer cells, we examined the effects of RAD140 on AR and ER signaling pathways. The specificity and selectivity of RAD140 were examined using competitive binding assays for AR, ER, glucocorticoid receptor (GR) and progesterone receptor (PR), and using an AR reporter assay in AR/ER+ ZR-75 breast cancer cells and LNCaP prostate cancer cells. RAD140 was found to bind AR with high affinity and specificity, with 250-fold target selectivity over the next nuclear receptor PR. The AR reporter assay results demonstrated a potent AR agonist activity of RAD140 in ZR-75 breast cancer cells but not in LNCaP prostate cancer cells, in contrast to the full agonist activity of DHT seen in both cell types. RAD140 treatment led to substantial tumor growth inhibition in AR/ER+ breast cancer xenografts. Samples of RAD140-treated xenografts were analyzed by immunocytochemistry, western blotting and quantitative real-time PCR to evaluate the modulation of AR and ER pathways. It was found that the expression of known AR target genes including KLK2, FKBP5 and the tumor suppressor gene, ZBTB16, were potently induced in RAD140-treated tumors. Furthermore, RAD140 led to substantial suppression of known ER target genes including progesterone receptor (PR), TFF1 and GREB1. In conclusion, RAD140 is a potent tissue-selective AR agonist in AR/ER+ breast cancer cells with robust activation of AR targets genes, and a unique mechanism of action that leads to the suppression of ER signaling, and marked anti-tumor activity. Citation Format: Ziyang Yu, Suqin He, Dannie Wang, Jeffrey Brown, Jamal Saeh, Gary Hattersley. RAD140, a selective androgen receptor modulator, has a differentiated mechanism of action in AR/ER positive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3609. doi:10.1158/1538-7445.AM2017-3609

Breast cancer is the most frequently diagnosed malignancy for women in the US with 246,660 new cases predicted in 2016. Histological and molecular characterization of breast cancer has led to improved understanding of the heterogeneity of this disease and development of therapeutic modalities tailored for each disease subtype. Hormone receptor positive breast cancers, which represent 75% of breast cancer cases, are routinely treated with therapies targeting the estrogen receptor (ER) axis, including aromatase inhibitors or anti-estrogens, either alone or in combination with other agents. Recent studies have shown that the androgen receptor (AR) is widely expressed across all subtypes of breast cancer, with AR detected in 75-95% of ER positive tumors. Mounting preclinical evidence from has demonstrated that AR agonists can suppress AR and ER positive (AR/ER+) breast cancer cell growth. Furthermore, prior to the development of ER-targeted therapy, androgens were used to treat breast cancers with favorable clinical responses. RAD140 is an oral, nonsteroidal, nonaromatizable selective androgen receptor modulator (SARM) with a distinct tissue selectivity profile and mechanism of action. Here we examined the molecular activity of RAD140 in breast cancer cells and evaluated its efficacy using AR/ER+ breast cancer xenograft models. The tissue-specific activity of RAD140 was examined using androgen response element (ARE)-driven reporter assay in AR/ER+ ZR75 breast cancer cells and AR+ LNCaP prostate cancer cells. RAD140 was shown to be a potent AR agonist, comparable to dihydrotestosterone (DHT), in breast cancer cells, but did not induce AR activity in prostate cancer cells, while DHT demonstrated full AR agonist activity. In vivo anti-tumor efficacy of RAD140 as monotherapy, compared with fulvestrant, or in combination with a CDK4/6 inhibitor (palbociclib) or mTOR inhibitor (everolimus) was evaluated in AR/ER+ patient derived xenograft (PDX) models and cell line-derived xenograft (CDX) models. Tumor-bearing mice were randomized into treatment groups and received vehicle, RAD140, fulvestrant, palbociclib, everolimus or combinations of RAD140 with palbociclib or everolimus. Tumor volume and growth was measured to evaluate efficacy. At the end of the study, plasma and tumor samples were collected for pharmacokinetic and pharmacodynamic analysis. In AR/ER+ breast cancer PDX models, RAD140 treatment led to substantial tumor growth inhibition that was greater than that seen with fulvestrant. Furthermore, combination of RAD140 with palbociclib or everolimus produced further enhanced anti-tumor efficacy in these models. In summary, RAD140 demonstrated tissue-selective AR agonism with marked anti-tumor activity in AR/ER+ breast cancer CDX and PDX models, together with enhanced anti-tumor activity in combination with a CDK4/6 inhibitor or mTOR inhibitor. Citation Format: Ziyang Yu, Suqin He, Jeffrey Brown, Chris Miller, Jamal Saeh, Gary Hattersley. RAD140, an orally available selective androgen receptor modulator, inhibits the growth of AR/ER positive breast cancer cell line- and patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3608. doi:10.1158/1538-7445.AM2017-3608

Importance Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor. Objective To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture. Design, Setting, and Participants The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤−2.5 and >−5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤−2.0 and >−5.0 or without fracture criteria and a T score ≤−3.0 and >−5.0 could enroll. Interventions Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months. Main Outcomes and Measures Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants. Results Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred in 0.58% (n = 4) of the abaloparatide group, 4.22% (n = 30) of the placebo group (risk difference [RD] vs placebo, −3.64 [95% CI, −5.42 to −2.10]; relative risk, 0.14 [95% CI, 0.05-0.39]; P P = .049), and 3.3% for teriparatide. BMD increases were greater with abaloparatide than with placebo (all P P = .006). Conclusions and Relevance Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments. Trial Registration clinicaltrials.gov Identifier:NCT01343004

Breast cancer is subdivided into categories based on a patient's estrogen receptor (ER), progesterone receptor (PR) or Her2 expression status. Estrogen receptor positive (ER+) breast cancer makes up approximately 70% of all breast cancers diagnosed and given the dependence on ER signaling in this disease segment, most treatment modalities focus on inhibiting some aspect of this pathway. Indeed, preventing estrogen synthesis (e.g. with aromatase inhibitors) and modulating ER pathway activity (e.g. with tamoxifen) continue to be mainstays in the standard of care for ER+ breast cancer patients. While patients typically respond well to these agents, a majority of patients will relapse, emphasizing the need to understand the specific mechanisms that can contribute to clinical resistance. One such mechanism is the activation of compensatory or concurrent signaling pathways that can stimulate growth (eg. Her2, CDK4/6) and/or confer survival (eg. PI3K, AKT, mTOR). The recent approval of palbociclib (CDK4/6i) or everolimus (mTORi) in combination with an aromatase inhibitor for the treatment of advanced ER+ disease demonstrates the effectiveness of combining anti-hormonals with targeted agents. While these combinations have superior efficacy compared to the use of aromatase inhibitors alone, alterations in ER itself, such as amplification and mutations, have been described as a second mechanism that can drive resistance to aromatase inhibitors in patients. These findings highlight the need for a selective estrogen receptor downregulator (SERD) that can degrade both wild-type and aberrant forms of ER in order to more effectively treat this patient population. We have recently demonstrated that treatment with RAD1901, an orally bioavailable SERD, results in consistent and robust tumor growth inhibition of patient derived xenograft (PDx) models, regardless of ER status. We hypothesized that combining RAD1901 with agents that inhibit compensatory signaling pathways would mitigate both mechanisms of resistance in ER+ breast cancer patients, leading to greater efficacy. We performed an efficacy screen with RAD1901 in patient derived xenograft (PDx) models with varied genetic backgrounds, allowing us to mimic clinical phenotypes and to better represent the heterogeneity within the ER+ breast cancer patient population. These models harbored a wide range of ER expression levels, in addition to other genetic alterations, which accurately represented the patients’ diverse treatment history profiles. Based on results from the screen, models were selected for additional studies to determine which targeted agent, if any, can be combined with RAD1901 to achieve maximal efficacy. By doing this, we were able to correlate response with genetic background in clinically relevant models, potentially allowing us to predict treatment strategies that have a higher likelihood of success for specific patients. Citation Format: Teeru Bihani, Jeffrey L. Brown, Dinesh M. Purandare, Gary Hattersley, Fiona Garner. RAD1901, an orally available SERD, as an effective combination partner in ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1814.

Breast cancer is the most frequent type of cancer diagnosed in women, with over 200,000 new cases diagnosed in the US each year. Treatment strategies are typically based on the tumors receptor status; that is, whether a tumor expresses estrogen receptor (ER), progesterone receptor (PR), or Her2. Estrogen receptor positive (ER+) breast cancers comprise approximately two-thirds of all breast cancers. For decades the approach to treat ER+ disease revolved around altering the ligand interactions with the receptor; either by preventing estrogen binding (e.g., tamoxifen) or preventing estrogen biosynthesis (aromatase inhibitors). While patients typically respond well to these agents, estrogen-independent ER activity and recurrent ER mutations are increasingly being reported as contributing factors to endocrine resistance and continue to be a clinical hurdle. Given this growing unmet medical need, selective estrogen receptor downregulators, or SERDs, have gained widespread attention as new therapeutic treatment strategies for ER + disease. Indeed, fulvestrant has been shown to downregulate ER and cause tumor growth inhibition in many ER+ breast cancer models. However, in the clinic fulvestrant appears to be limited by PK exposure properties and this, combined with its intramuscular route of administration, underscores the need for novel orally available SERDs. Here, we describe RAD1901, an orally administered SERD that binds ER and targets it for degradation in a dose-dependent manner. Biochemical affinity binding studies and cocrystallization experiments revealed insights into RAD1901 complexes with both wild-type and mutant forms of ER. In addition, RAD1901 treatment resulted in decreased cell proliferation in in vitro breast cancer cell lines and had profound single agent tumor growth inhibition in in vivo xenograft models. Consistent with these findings, RAD1901 treatment resulted in decreased expression levels of ER target genes. Interestingly, the extent of tumor growth inhibition induced by RAD1901 in vivo was dependent on ER expression levels, demonstrating the specificity of RAD1901 and predicting its activity in ER-driven cancers. Importantly, RAD1901 was also able to induce significant tumor growth inhibition in clinically relevant and representative patient-derived xenograft models, at a level similar to or greater than fulvestrant. In conclusion, our preclinical data demonstrate that RAD1901 is an orally available SERD, with potent single agent antitumor activity. RAD1901 is currently under clinical investigation in post-menopausal women with advanced ER+ disease. Citation Format: Teeru Bihani, Jeffrey Brown, Gary Hattersley, Fiona Garner. RAD1901, an orally available selective estrogen receptor downregulator, has potent anti-tumor activity in in vitro and in vivo models of ER+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR10.

Background Early gains in total hip BMD are desirable to improve hip strength early in the treatment of osteoporosis. Objectives To determine if women treated with 18-months of abaloparatide (ABL) were more likely to increase BMD than those treated with either TPTD or placebo (PBO), we performed a responder analysis comparing the percentage of subjects experiencing BMD gains of >3% at all three anatomic sites (total hip (TH), femoral neck (FN), lumbar spine (LS)). Methods In an 18 month phase 3 study of postmenopausal women aged 50-85 with a T-score ≤-2.5 at the spine or hip with either a prior vertebral or non-vertebral fracture, subjects were randomized to receive the PTHrP analog, ABL (80-μg SC daily), TPTD (20-μg SC daily), or placebo. All subjects were also treated with calcium and vitamin D supplementation per local practice. Treatment comparisons were performed using a 2-sided Chi-square test. Results 18-months of treatment with ABL (N=824) resulted in significantly greater increases in BMD relative to placebo (N=821) at 6, 12 and 18 months at TH, FN and LS. There were also significantly greater increases in BMD with ABL relative to TPTD (N=818) at TH and FN at 6, 12 and 18 months and at LS at 6 and 12 months. Overall, a significantly higher percentage of patients experienced >3% BMD gain in the ABL group (54%) compared to the PBO group (3.38%, p Conclusions In postmenopausal women with osteoporosis, more subjects treated with ABL experienced BMD increases at all 3 sites compared to those treated with TPTD or PBO. Disclosure of Interest P. Miller Grant/research support from: Radius Health, G. Hattersley Employee of: Radius Health, E. Lau Grant/research support from: Radius Health, P. Alexandersen Grant/research support from: Radius Health, T. Hala Grant/research support from: Radius Health, S. Mustatea Grant/research support from: Radius Health, B. Nedergaard Grant/research support from: Radius Health, A. Krogsaa Grant/research support from: Radius Health, J. Slessinger Grant/research support from: Radius Health, C. Zerbini Grant/research support from: Radius Health, I. Valter Grant/research support from: Radius Health, Z. Visockiene Grant/research support from: Radius Health, B. Jendrych Grant/research support from: Radius Health, C. Kulak Grant/research support from: Radius Health, F. Marquez Grant/research support from: Radius Health, A. Harris Employee of: Radius Health, G. Williams Employee of: Radius Health, M.-Y. Hu Employee of: Radius Health, D. Black Consultant for: Radius Health, B. Riis Consultant for: Radius Health, L. Russo Grant/research support from: Radius Health, C. Christiansen Consultant for: Radius Health