FDA Approves Tymlos for Osteoporosis in Postmenopausal Women

The FDA has given the green light to abaloparatide subcutaneous injection (Tymlos, Radius Health) 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 on or are intolerant of other available osteoporosis therapy.

Abaloparatide is a human parathyroid hormone-related peptide (PTHrP[1-34)]) analog that acts as an agonist at the PTH1 receptor. This results in activation of the cAMP signalling pathway in target cells. In animals, abaloparatide had an anabolic effect on bone, demonstrated by increases in bone mineral density (BMD) and bone mineral content that correlated with increases in bone strength at vertebral and nonvertebral sites.

The FDA’s approval was based on 18-month results from the phase-3 Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) and on results from the first six months of the ACTIVExtend trial, which demonstrated significant reductions in the risk of vertebral and nonvertebral fractures regardless of age, the years since menopause, the presence or absence of a prior fracture (vertebral or nonvertebral), and BMD at baseline.

In the ACTIVE trial, postmenopausal women 49 to 86 years of age (mean age: 69 years) were randomly assigned to receive abaloparatide 80 mcg (n = 824) or placebo (n = 821) administered subcutaneously once daily. This efficacy study was continued as the open-label ACTIVExtend trial, in which patients were no longer treated with abaloparatide or placebo but were maintained in their original treatment group and given alendronate (70 mg weekly) with calcium and vitamin D supplements for six months. The ACTIVExtend trial enrolled 1,139 patients, representing 92% of the patients who completed the ACTIVE study.

The primary endpoint of the ACTIVE trial was the incidence of new vertebral fractures in patients treated with abaloparatide compared with those given placebo. Abaloparatide was associated with a significant reduction in the incidence of new vertebral fractures compared with placebo at 18 months (0.6% vs. 4.2%, respectively; P < 0.0001). The absolute risk reduction in new vertebral fractures was 3.6% and the relative risk reduction was 86% for abaloparatide compared with placebo. The incidence of new vertebral fractures at 25 months was 0.6% in patients treated with abaloparatide and alendronate compared with 4.4% in patients treated with placebo and alendronate (P < 0.0001). The relative risk reduction in new vertebral fractures at 25 months was 87% for patients treated with abaloparatide and alendronate compared with patients treated with placebo and alendronate, for an absolute risk reduction of 3.9%.

Treatment with abaloparatide also resulted in a significant reduction in the incidence of nonvertebral fractures after 18 months of treatment plus one month of follow-up, during which no drug was administered, compared with placebo (2.7% vs. 4.7%, respectively). The relative risk reduction in nonvertebral fractures for abaloparatide compared with placebo was 43% (P = 0.049), and the absolute risk reduction was 2.0%.

After six months of treatment with alendronate in the ACTIVExtend trial, the cumulative incidence of nonvertebral fractures at 25 months was 2.7% for women in the prior abaloparatide group compared with 5.6% for women in the prior placebo group. At 25 months, the relative risk reduction in nonvertebral fractures was 52% (P = 0.017), and the absolute risk reduction was 2.9%

Eighteen months of treatment with abaloparatide in the ACTIVE study resulted in significant increases in BMD compared with placebo at the lumbar spine, total hip, and femoral neck (each P < 0.0001). Similar findings were reported after six months of treatment with alendronate in the ACTIVExtend study.

The results from the ACTIVE trial were published in August 2016 in the Journal of the American Medical Association, and the results from the first six months of the ACTIVExtend trial were published in February 2017 in the Mayo Clinic Proceedings.

The labelling for abaloparatide includes a boxed warning regarding a potential risk for osteosarcoma, based on animal data.

Sources: Radius Health(link is external); April 28, 2017; and Tymlos Prescribing Information; April 2017.