New FDA approval: Tymlos (abaloparatide) for Osteoporosis

In April 2017, FDA approved Tymlos/AbaloParatide for treatment of postmenopausal osteoporosis. Tymlos has potent bone anabolic properties (PTH1 receptors). It is administered once a day subcutaneously for up to 2 years. Side effect could be nausea and palpitations. The original study published in JAMA June 2016 suggests overall tymlos superiority over forteo in fracture reduction and bone density improvement during an 18 month observation.

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FDA Center Watch

General Information:

Tymlos (abaloparatide) is a PTH related peptide [PTHrP(1-34)] analog.

Tymlos is specifically indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

Tymlos is supplied as an injection for subcutaneous injection. The recommended dosage of Tymlos is 80 mcg subcutaneously once daily. Cumulative use of Tymlos and parathyroid hormone analogs (e.g., teriparatide) for > 2 years during a patient’s lifetime is not recommended. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. 

 

Clinical Results:

The FDA approved Tymlos was based on the results at 18 months from the landmark ACTIVE trial and first six months of ACTIVExtend trial. Subjects were randomized to receive Tymlos 80 mcg (N = 824) or placebo (N = 821) given subcutaneously once daily. Data demonstrated consistent significant and rapid reductions in the risk of vertebral and nonvertebral fractures regardless of age, years since menopause, presence or absence of prior fracture (vertebral or nonvertebral) and bone mineral density (BMD) at baseline.

Specifically, in the ACTIVE trial, Tymlos demonstrated significant reductions in the relative risk of new vertebral and nonvertebral fractures compared to placebo: 86% in new vertebral fractures and 43% in nonvertebral fractures. The absolute risk reductions were 3.6% and 2.0%, respectively.

 

 

Side Effects:

Adverse effects associated with the use of Tymlos may include, but are not limited to, the following:

  • hypercalciuria
  • dizziness
  • nausea
  • headache
  • palpitations
  • fatigue
  • upper abdominal pain
  • vertigo (hypotension?)

The Tymlos label comes with the following Black Box Warning:

Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma, a malignant bone tumor, in male and female rats. It is unknown whether Tymlos will cause osteosarcoma in humans. Use of Tymlos is not recommended in patients at increased risk for osteosarcoma. Cumulative use of Tymlos and parathyroid hormone analogs (e.g., teriparatide) for > 2 years during a patient’s lifetime is not recommended.

 

Mechanism of Action:

Tymlos (abaloparatide) is a human parathyroid hormone related peptide [PTHrP(1-34)] analog, which acts as an agonist at the PTH1 receptor (PTH1R). This results in activation of the cAMP signaling pathway in target cells. In rats and monkeys, abaloparatide had an anabolic effect on bone, demonstrated by increases in bone mass density (BMD) and bone mineral content (BMC) that correlated with increases in bone strength at vertebral and/or nonvertebral site.


 

More from the ORIGINAL work, JAMA June 2016:

Osteoporosis is associated with substantial social, economic, and public health burdens. Based on 2010 US Census data, Wright et al estimated the prevalence of osteoporosis among women aged 50-70 years at 3.4 million. Another 18.8 million US women in that age group were estimated to have low bone mass at the femoral neck or lumbar spine. Additionally, Cawthon et al have estimated that the lifetime risk of osteoporotic fracture for a 60-year-old woman is 44%. Fractures are associated with decreased quality of life, including reduced independence, and osteoporotic fractures are associated with increased morbidity and mortality.

Experiencing a major osteoporotic fracture increases the risk of subsequent fractures, and risk is highest in the first few years after the fracture. Osteoanabolic therapy is often recommended for women at risk of future fracture, including those with recent fracture or with multiple fractures, but evidence of rapid fracture protection is lacking.

Abaloparatide is a peptide that selectively binds to the RG conformation of the PTH-type 1 receptor. As a result of its mechanism of action, it was hypothesized that abaloparatide would have a more pronounced anabolic action on bone compared with teriparatide.

In this trial of postmenopausal women with osteoporosis, daily subcutaneous administration of abaloparatide for 18 months significantly reduced the risk of new vertebral and nonvertebral fractures compared with placebo. Treatment with abaloparatide was also associated with modestly higher BMD gains, especially at sites rich in cortical bone, compared with the placebo and teriparatide groups. The incidence of hypercalcemia was lower with abaloparatide than with teriparatide treatment, consistent with proportionally less bone resorption with abaloparatide. Overall, there were no differences in serious adverse events between the treatment groups.

Changes in bone turnover markers with abaloparatide vs teriparatide treatment are consistent with changes in BMD with abaloparatide. The similar early increase in s-PINP and the less prominent increase in s-CTX with abaloparatide compared with teriparatide support the hypothesis that abaloparatide might have an enhanced net anabolic effect compared with teriparatide. Despite being lower in the abaloparatide group vs the teriparatide group, bone formation, as measured by s-PINP, still remained 50% above baseline in the abaloparatide group at 18 months. Although the effect of increases in formation vs resorption on BMD and bone strength is not understood, it is possible that the smaller increases in formation, coupled with a lesser increase in markers of bone resorption, are consistent with larger early increases in BMD and earlier fracture protection. Further research is needed to clarify the effects of differing patterns of bone turnover markers to better understand the interplay of formation and resorption.

Differences in the effects of teriparatide and abaloparatide may be related to differing biologic effects. The differential binding of abaloparatide compared with teriparatide leads to parathyroid type 1 receptor conformation binding selectivity that favors anabolic activity. As a result, abaloparatide may provide more transient stimulation of osteoblast cyclic adenosine monophosphate production and may result in lower expression of osteoblast-derived RANK-ligand. This could result in less stimulation of bone resorption.

This study has limitations. 63% of participants had a prior fracture; it cannot be determined from these data whether abaloparatide would have similar preventive and osteoanabolic effects among participants at lower risk for fracture. In this study, only a small number of fracture events occurred across treatment groups, with the event rate in the placebo group being smaller than anticipated. Although the event rate was lower than anticipated in the sample size calculation, the reduction in risk was larger than anticipated. These data indicate a reduction of risk until 18 months of treatment; it is not clear how long the benefit associated with abaloparatide may endure. In addition, the open-label teriparatide group may have resulted in bias in reporting subjective measures, such as safety events or differences in adherence, because participants and investigators were aware of the treatment.

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 the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments.