Stephen L. Myers

Combination Teriparatide and Raloxifene Therapy for Postmenopausal Osteoporosis: Results From a 6-Month Double-Blind Placebo-Controlled Trial†‡

We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6‐month double‐blind, placebo‐controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline.

A Randomized, Double‐Blind Phase 2 Clinical Trial of Blosozumab, a Sclerostin Antibody, in Postmenopausal Women with Low Bone Mineral Density

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double‐blind, placebo‐controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T‐score –2.0 to –3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T‐score –2.8). Blosozumab treatment resulted in statistically significant dose‐related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest‐dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.

Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors

Objective To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors. Methods Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo). Results At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab. Conclusions At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies. Clinical trial registration number NCT00689728.

A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate

Objectives To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). Methods In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). Results At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50–69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. Conclusions A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. Clinical Trial # NCT00785928.

A Phase 2 Randomized Study Investigating the Efficacy and Safety of Myostatin Antibody LY2495655 versus Placebo in Patients Undergoing Elective Total Hip Arthroplasty.

BACKGROUND Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. OBJECTIVES To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. DESIGN Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period. SETTING Forty-two sites in 11 countries. PARTICIPANTS Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization. INTERVENTION Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24. MEASUREMENTS Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time. RESULTS Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected. CONCLUSION Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.