SAFETY AND EFFICACY OF BA058 1

SAFETY AND EFFICACY OF BA058 8

Study to Evaluate the Safety and Efficacy of BA058 for Prevention of Fracture in Postmenopausal Women

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Ciara Natasha S. Tan

CRA 6210

The George Washington University

Title:

Study to Evaluate the Safety and Efficacy of BA058 for Prevention of Fracture in Postmenopausal Women

Clinical Trials Identifier:

NCT01343004

Test Drug:

BA058 80 mcg. The drug has not received marketing approval and is currently under investigation.

Indication:

Osteoporosis; Postmenopausal osteoporosis

Study Design:

A Randomized, Double-Blind, Placebo-Controlled, Comparative Phase 3, Multicenter International Study to Evaluate the Efficacy and Safety of BA058 80 mcg in the Prevention of Fracture in Otherwise Healthy Ambulatory Postmenopausal Women with Severe Osteoporosis

Sponsor Name, Address, and Telephone Number:

Radius Health, Inc. 617-551-4700

201 Broadway, 6th Floor

Cambridge, MA 02139

Compliance:

The study will be conducted in accordance with standards of Good Clinical Practice, as defined by the International Conference on Harmonization and all applicable federal and local regulations.

Date of Protocol:

Protocol Author:

Study to Evaluate the Safety and Efficacy of BA058 for Prevention of Fracture in Postmenopausal Women

Uniqueness of the Problem for Postmenopausal Women and Its Prevalence

Osteoporosis in postmenopausal women remains a serious healthcare problem. Generally, it is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (Lippuner, 2012, p.1). The uniqueness of postmenopausal osteoporosis is justified by the changes facing women in this period of life. Statistically, 30% of postmenopausal women in the United States suffer from osteoporosis, and 40% of them will have one or several fragility fractures in the remaining lifetime (Reginster & Burlet, 2006). According to Sirola and Kroger (2011), hormonal changes in menopause make osteoporosis unique for postmenopausal women, as estrogen depletion during the menopause leads to the loss of the muscle and bone mass. Because the risks, incidence, and prevalence of osteoporosis grow exponentially with age, its costs are likely to exceed those of other chronic diseases, including cardiovascular events (Lippuner, 2012).

Current Treatment Modalities Available to Postmenopausal Women with Osteoporosis

The goal of osteoporosis treatment is to prevent fractures. Contemporary medicine uses a diversity of pharmaceutical, surgical, and preventive methodologies to decrease bone resorption or facilitate bone formation (Lippuner, 2012). Bisphosphonates exemplify the centerpiece of modern osteoporosis treatment, as they inhibit bone resorption and increase bone mass formation in postmenopausal women with confirmed osteoporosis (Lippuner, 2012). The efficacy of risedronate sodium, a new bisphosphonate, was tested in terms of reducing the risks of vertebral and nonvertebral fractures in postmenopausal women (Harris et al., 1999). In a randomized, double-blind clinical trial involving 2458 ambulatory women with the history of fracture, risedronate was proved to be effective for treating osteoporosis in postmenopausal women (Harris et al., 1999). However, the risks of using bisphosphonates in elderly patients should not be disregarded (Lippuner, 2012). Regardless of the mode of administration (orally or intravenously), bisphosphonates were shown to expose elderly patients to considerable health risks, ranging from esophageal irritation to acute-phase reactions (Lippuner, 2012). Reduced renal function is one of the chief contraindications for the use of biophosphonates in postmenopausal women (Lippuner, 2012).

Non-hormonal drugs, which help to prevent fractures in postmenopausal women, were also tested. The effects of Denosumab on fracture prevention in postmenopausal women with confirmed osteoporosis have been explored (Cummings et al., 2009). Denosumab is a monoclonal antibody to the nuclear factor-kB ligand, which inhibits the development of osteoclasts, reduces bone resorption and increases bone density (Cummings et al., 2009). Its mechanism of action differs considerably from that of biophosphonates. Baron, Ferrari and Russell (2011) suggest that, while Denosumab binds to and inhibits RANKL, biophosphonates bind bones' mineral components and change the mode of action in osteoclasts. The key difference between Denosumab and biophosphonates is in the way they are distributed within bones and interfere with mature osteoclasts (Baron et al., 2011). Denosumab has proved to be relatively effective in treating osteoporosis and reducing the risks of vertebral, nonvertebral, and hip fractures in postmenopausal women (Cummings et al., 2009).

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Lasofoxifene was also proposed as a new method of treating osteoporosis and preventing fractures in postmenopausal women. Cummings et al. (2010) conducted a randomized trial involving 8556 postmenopausal women with low bone density to test the effects of lasofoxifene on the risks of fractures, breast cancer, strokes and coronary heart disease. Cummings et al. (2010) reported the benefits of lasofoxifene as a means to reduce the risks of bone fractures in postmenopausal women, but no other studies confirm these results. Anecdotal evidence emerges that soy products can help prevent fractures in postmenopausal women, but soy food consumption alone will never suffice to reduce the scope of osteoporosis in the public health system (Zhang et al., 2005). At the same time, the mechanisms by which some women develop increased risks of bone fractures after the menopause are yet to be understood (Garnero et al., 2000).

Recent advancements in the professional knowledge of bone pathophysiology have led to the development of new experimental preparations with a strong therapeutic potential. BA058 is a synthetic alternative to hPTHrP, a novel analog that holds a promise to reduce the risks of bone fractures in postmenopausal women. The physiologic role of hPTHrP, a parathyroid hormone (PTH)-related peptide, has been at the center of major medical developments since the 1980s. hPTHrP was shown to participate in normal bone biology, through normal endochondral bone formation and controlled cartilage proliferation (Mundy & Edwards, 2008). BA058 exemplifies a postmodern pharmaceutical analog of hPTHrP (1-34), an effective bone anabolic substance with an exclusive efficacy profile (Lippuner, 2012).

Introduction and Trial Protocol

This interventional randomized double-blind placebo-controlled comparative phase 3 study is designed to evaluate the efficacy and safety of BA058 as a method of preventing fracture in ambulatory postmenopausal women with confirmed severe osteoporosis and high risks of fracture. The results of the placebo-controlled Phase 2 study showed that BA058, 80 mcg, administered subcutaneously on a daily basis, led to bone mass gains and was well tolerated by postmenopausal women (Hattersley et al., 2012).

BA058 is available in the dose of 80 mcg, and it will be administered subcutaneously on a daily basis. The active comparator to be used is teriparatide, also titled Forteo or Forsteo. The comparator is available as 20 mcg injections to be administered subcutaneously on a daily basis. The outcomes of the trial will be measured by estimating new vertebral fractures through X-ray. Bone mineral density of hip, lumbar spine, ad femoral neck, non-vertebral fractures, and the number and frequency of hypercalcemic events will be evaluated. All results in the BA058 group will be compared to the outcome measures in the placebo group.

The study involves only healthy postmenopausal women aged between 50 and 85 years, with confirmed severe osteoporosis. Only women with bone mineral density ?2.5 and >-5.0 are allowed to participate. Only women with normal laboratory tests are included, meaning the normal range for PTH (1-34) and alkaline phosphatase. Women with the history of thyroid, parathyroid, and similar disorders, including adrenal abnormalities, will be excluded from the sample.

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