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Home , Abaloparatide, Teriparatide

Long-Term Care Updates

May 2019

Kristina M. Nikl, PharmD and Tionna T. Trarbach, PharmD

Osteoporosis, the most common bone disease, affects 50% of Americans 50 years of age or older. This condition can result in fractures, which are associated with increased admissions to hospitals and long-term care facilities, decreased

independence, and decreased quality of life.1 This article will compare the safety, efficacy, and cost-effectiveness of two anabolic agents FDA-approved for treating : (Tymlos) and (Forteo).

Both agents are considered (PTH) analogs and have similar mechanisms of action. Endogenous PTH binds to the parathyroid hormone 1 receptor (PTH1R). The binding of PTH to PTH1R stimulates function, increases gastrointestinal absorption, and increases renal tubular reabsorption of calcium. Teriparatide is a recombinant PTH protein and has pharmacologic activity that is similar to the physiologic activity of PTH. Treatment

with teriparatide increases bone mineral density (BMD), bone mass, and bone strength.2 Abaloparatide is an analog of human parathyroid hormone related (PTHrP), which acts as an at PTH1R in a manner similar to PTH. However, despite binding to the same receptor, teriparatide and abaloparatide have slightly different pharmacologic

effects because PTH1R has two conformations: an R conformation and an RG conformation.3 Binding to the R conformation results in physiologic responses that favor bone resorption and calcium mobilization, as this conformation is more involved in calcium . Alternatively, binding to the RG conformation results in net increases in bone formation and less calcium mobilization. Unlike teriparatide, which binds to each conformation equally, abaloparatide is

selective for the RG conformation, leading to more potent anabolic activity and less hypercalcemia.1,4

Teriparatide was FDA-approved in 2002 and is indicated for the treatment of osteoporosis in postmenopausal women, osteoporosis in men, and glucocorticoid-induced osteoporosis. Abaloparatide, FDA-approved in 2017, is only indicated for treatment of osteoporosis in postmenopausal women. For each indication listed, patients must be at a high risk for fracture for these agents to be considered. Since abaloparatide is a newer agent, it is not addressed in the most recent guidelines from the American Association of Clinical Endocrinologists and American College of Endocrinology, the National Osteoporosis Foundation, the North American Society, the American College of Physicians, or the Society for Post-Acute and Long-Term Care Medicine. However, abaloparatide is commonly considered an alternative to teriparatide and subsequently, the two have a similar place in therapy. Guidelines do not list these agents as first-line options because, unlike other agents (e.g., alendronate, risedronate, , and ), evidence is lacking to demonstrate a reduced incidence of all types of fractures. PTH analogs are second-line options, considered for treatment if first-line options are not well-tolerated or if the patient is at a high fracture risk, as these agents help to build bone instead of just inhibiting bone resorption.5-9 Patients at a high risk for fractures include those who are are elderly, have a history of fractures, or have a very low T-score.5,8

Both PTH analogs are administered daily via subcutaneous injection and are available in prefilled pens containing 28-30 doses. Teriparatide must be stored in the refrigerator at all times, but abaloparatide may be kept at room temperature while in use (for 30 days). They are not recommended for patients with preexisting hypercalcemia, with severe renal impairment, or at risk of . Both agents have a Boxed Warning due to the potential risk of osteosarcoma and should not be used longer than two years due to this risk. They have similar rates of adverse effects, although hypercalcemia occurs at a significantly higher rate with teriparatide. Other common adverse effects of both agents include orthostatic hypotension, dizziness, headache, and nausea.2,3

Patients initiating therapy with one of these agents should be counseled as follows:2,3 ● Store pen in refrigerator (while in use, abaloparatide may be stored at room temperature). ● Do not use pen if the solution appears cloudy, colored, or contains solid particles. ● Administer into the subcutaneous tissue in the abdomen, rotating injection sites, and use at any time of day at the same time each day without regard to meals. ● Sit or lie down during first few injections to minimize the potential for orthostatic hypotension. ● Maintain adequate calcium and intake through diet and/or supplementation.

In addition to slight differences in their mechanisms and pharmacologic activity, the cost of these agents differs. For a 30-day-supply and not considering insurance coverage or facility-specific pricing, the average wholesale prices of abaloparatide and teriparatide are ~$2000 and ~$4000, respectively.10,11 The manufacturers of both agents offer a savings card for the first few pens. Depending on the patient’s pharmacy, a GoodRx coupon may bring the cost down to around

$1900 for abaloparatide and $3500 for teriparatide.12 The comparative safety and efficacy of abaloparatide and teriparatide were evaluated in a phase 3 randomized clinical trial called the ACTIVE study. Postmenopausal women aged 49-86 years were screened for inclusion (T-score -2.5 to -5.0 and 1 moderate or 2 mild vertebral or nonvertebral fractures in previous 5 years), and a total of 2483 subjects were randomized 1:1:1 into one of three study arms: blinded abaloparatide 80 mcg daily, blinded matching placebo daily, or open-label teriparatide 20 mcg daily for 18 months. The primary efficacy endpoint for this study was the percent of participants with one or more new morphometric vertebral fractures. Secondary endpoints and exploratory analyses included changes in BMD, nonvertebral fractures, clinical fractures, and major osteoporotic fractures. Safety monitoring included physical examinations, assessment of vital signs, clinical laboratory tests, and reporting of adverse events at each study visit.13

The primary and secondary efficacy endpoints of the ACTIVE study are detailed in the table below. After 18 months of treatment, abaloparatide and teriparatide decreased the relative risk of new vertebral fracture by 86% and 80%, respectively, compared to placebo. These results further suggest that for every 28 or 30 patients treated with abaloparatide or teriparatide, respectively, a new vertebral fracture would be prevented in one additional patient. Abaloparatide also decreased the risk for nonvertebral fracture and clinical fracture compared to placebo, while teriparatide did not. No statistically significant difference between abaloparatide and teriparatide was observed for these outcomes. However, the study was not adequately powered to detect differences between abaloparatide and teriparatide for any of the selected outcomes. Despite this, abaloparatide was found to significantly decrease the risk of major osteoporotic fracture (fracture of the upper arm, wrist, hip, or clinical spine) by 55% compared to teriparatide, suggesting that for every 63 patients treated with abaloparatide vs. teriparatide, major osteoporotic fracture would be prevented in one additional patient.13

While researchers did not provide a comparison of BMD changes with abaloparatide vs. teriparatide at 18 months, 6-month follow-up data were available. Increases in BMD after 6 months of treatment were higher with abaloparatide compared to teriparatide for total hip (2.32% vs 1.44%; p<0.001), femoral neck (1.72% vs 0.87%; p<0.001), and lumbar spine (6.58% vs 5.25%; p<0.001).13

Overall, daily subcutaneous injections of abaloparatide significantly reduced the risk of new vertebral and nonvertebral fractures when compared to placebo. More so, abaloparatide demonstrated a significantly lower incidence of nonvertebral, major osteoporotic, and clinical fractures, as well as improved BMD, when compared to teriparatide.13

With respect to safety outcomes, adverse event rates were similar among abaloparatide, teriparatide, and placebo, with the exception of hypercalcemia. At 18 months, abaloparatide and teriparatide had an 8.5-fold and 16-fold increased risk of hypercalcemia at any time point vs. placebo. Despite the increased risk vs. placebo, abaloparatide decreased the relative risk of hypercalcemia by 47% compared to teriparatide, suggesting that for every 33 women treated with teriparatide vs. abaloparatide, one additional patient would experience hypercalcemia.13

Osteoporosis is associated with significant morbidity and mortality, imposing a financial burden on the health care system in the United States. When treating osteoporosis, in addition to safety and efficacy, cost-effectiveness of available treatment options is an important factor to consider. Two recently published cost-effectiveness analyses have provided evidence as to which agent is the most cost-effective. Both analyses used data from the ACTIVE trial to determine whether treatment with teriparatide or abaloparatide for 18 months, followed by alendronate for 5 years, is more cost-effective. The major difference between these studies is the type of model used. One study used the Markov microsimulation model, while the other used a discrete-event simulation (DES) model. Both are acceptable, but the DES model may be preferred, as it is more flexible, better able to detect patient heterogeneity, and has increased precision. Both studies analyzed the total cost and the number of quality adjusted life years (QALY) gained with each treatment option. Both concluded that abaloparatide is more cost-effective than teriparatide. Compared to teriparatide followed by alendronate, abaloparatide followed by alendronate resulted in more QALY gained at a lower cost. More specifically, one study concluded that over a ten-year-period the total per-patient cost of abaloparatide treatment for 18 months followed by alendronate for 5 years is ~$26,800. This therapy adds an average of 6.79 QALYs to a patient’s life. This is more cost-effective than a similar teriparatide treatment regimen, which costs ~$46,800 and only adds an average of 6.78 QALYs to a patient’s life.14,15

Some patients with osteoporosis may not be candidates for first-line treatments, which is why the availability of PTH analogs fulfills an important therapeutic niche. Although teriparatide and abaloparatide have similar mechanisms of action and similar risks associated with their use, abaloparatide may pose greater benefits and fewer adverse effects compared to teriparatide. The ACTIVE trial showed that both agents are superior to placebo for increasing BMD and decreasing fracture risk. Additionally, this study demonstrated that abaloparatide has enhanced efficacy for reducing major osteoporotic fractures compared to teriparatide. Abaloparatide also demonstrated greater improvements in BMD at the total hip, femoral neck, and lumbar spine at various time points as compared to teriparatide. The one major advantage of teriparatide over abaloparatide is its approval for use in men with osteoporosis. Until abaloparatide obtains FDA-approval for use in this population, teriparatide should be the preferred agent for male patients who are candidates for PTH therapy. Additional clinical trials are needed to further establish the comparative safety and efficacy of abaloparatide to teriparatide, but considering the current clinical evidence along with favorable cost-effectiveness data, abaloparatide should be preferred over teriparatide for the treatment of osteoporosis in postmenopausal women at a high risk for fracture. 1. Boyce EG, Mai Y, Pham C. Abaloparatide: review of a next-generation parathyroid hormone agonist. 2018;52(5):462-72. 2. Tymlos [package insert]. Waltham, MA; Radius Health, Inc.; October 2018. 3. Forteo [package insert]. Indianapolis, IN: Eli Lilly and Co.; March 2012. 4. Leder BZ, O’Dea LS, Zanchetta JR, et al. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. 2015;100(2):697-706. 5. Camacho P, Petak S, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clini- cal practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. 2016;22(4):1-42. 6. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. 2014;25(10):2359-81. 7. The North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. 2010;17(1):25-54. 8. Qaseem A, Forciea MA, McLean R, et al. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. 2017;166(11):818-39. 9. American Medical Directors Association. Osteoporosis and Fracture Prevention in the Long-Term Care Setting. Columbia, MD: AM- DA 2009. 10. Lexi-Drugs Online Database. Lexicomp Web site. http://online.lexi.com [subscription required]. Accessed April 23, 2019. 11. AccessPharmacy Online Database. AccessPharmacy Web site. https://accesspharmacy.mhmedical.com/ [subscription required]. Ac- cessed April 23, 2019. 12. GoodRx Online Drug Price Database. GoodRx Web site. https://www.goodrx.com/. Accessed April 23, 2019. 13. Miller PD, Hattersley G, Riis BJ, et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. 2016;316(7):722-33. 14. Hiligsmann M, Williams SA, Fitzpatrick LA, Silverman SS, Weiss R, Reginster JY. Cost-effectiveness of sequential treatment with aba- loparatide vs. teriparatide for United States women at increased risk of fracture. 2019;(18):30562-6. 15. Le AQ, Hay JW, Becker R, Wang Y. Cost-effectiveness analysis of sequential treatment of abaloparatide followed by alendronate ver- sus teriparatide followed by alendronate in postmenopausal women with osteoporosis in the United States. 2019;53(2):134-43.

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