Adverse Reactions from Clinical Trial in Postmenopausal Women with Osteoporosis

The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebo-controlled clinical trial in postmenopausal women with osteoporosis aged 49 to 86 years (mean age 69 years) who were randomized to receive 80 mcg of TYMLOS (N = 824) or placebo (N = 821), given subcutaneously once daily for 18 months [see Clinical Studies (14.1)].

In this study, the incidence of all-cause mortality was 0.4% in the TYMLOS group and 0.6% in the placebo group. The incidence of serious adverse events was 10% in the TYMLOS group and 11% in the placebo group. The percentage of patients who discontinued study drug due to adverse events was 10% in the TYMLOS group and 6% in the placebo group. The most common adverse reactions leading to study drug discontinuation in the TYMLOS group were nausea (2%), dizziness (1%), headache (1%), and palpitations (1%).

Table 1 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo, and occurred in at least 2% of the patients treated with TYMLOS.

Orthostatic Hypotension

In the clinical trial of women with postmenopausal osteoporosis, the incidence of orthostatic blood pressure decline ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 4% in the TYMLOS group and 3% in the placebo group. At later time points the incidence was generally similar between the treatment groups. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0.5% of patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (10%) compared to placebo (6%) [see Warnings and Precautions (5.2)].

Tachycardia

In women with postmenopausal osteoporosis, adverse reactions of tachycardia, including sinus tachycardia, were reported in 2% of patients receiving TYMLOS and 1% of patients in the placebo group. In 5 of the 13 patients receiving TYMLOS who experienced tachycardia, symptoms occurred within 1 hour of administration. TYMLOS has been associated with a dose-dependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours [see Clinical Pharmacology (12.2)].

Injection Site Reactions

During the first month of the trial, injection site reactions were assessed daily one-hour after injection. TYMLOS had a higher incidence than placebo of injection site redness (58% vs. 28%), edema (11% vs. 3%), and pain (10% vs. 7%). Severe redness, severe edema, and severe pain were reported among 2.9%, 0.4%, and 0.4% of the TYMLOS-treated patients.

Laboratory Abnormalities

Adverse Reactions from the Extension Study in Postmenopausal Women with Osteoporosis

Following 18 months of treatment with TYMLOS or placebo, 1139 women transitioned to treatment with alendronate 70 mg administered orally once weekly. The incidence of adverse events occurring during alendronate treatment was similar in patients with prior placebo or TYMLOS therapy [see Clinical Studies (14.1)].

Adverse Reactions from Clinical Trial in Men with Osteoporosis

The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebo-controlled clinical trial in men with osteoporosis aged 42 to 85 years (mean age 68 years) who were randomized to receive 80 mcg of TYMLOS (N = 149) or placebo (N = 79), given subcutaneously once daily for 12 months [see Clinical Studies (14.2)].

In this study, no patient from either treatment group had an adverse reaction with a fatal outcome during the trial. Serious adverse reactions were reported by 5.4% of subjects treated with TYMLOS and 5.1% of subjects in the placebo group. Adverse reactions leading to study drug discontinuation were reported for 6.7% of patients treated with TYMLOS and 5.1% of patients receiving placebo. The most common adverse reaction leading to study drug discontinuation in the TYMLOS group was dizziness (2%).

Table 2 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo and occurred in at least 2% of the patients treated with TYMLOS.

Orthostatic Hypotension

In the clinical trial of men with osteoporosis, the incidence of orthostatic blood pressure declines of ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 6% in the TYMLOS group and 3% in the placebo group. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0 patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (9%) compared to placebo (1%) [see Warnings and Precautions (5.2)].

Laboratory Abnormalities

Risk Summary

TYMLOS is not indicated for use in females of reproductive potential. There are no human data with TYMLOS use in pregnant women to inform any drug associated risks. Animal reproduction studies with abaloparatide have not been conducted.

Risk Summary

TYMLOS is not indicated for use in females of reproductive potential. There is no information on the presence of abaloparatide in human milk, the effects on the breastfed infant, or the effects on milk production.

Effects on Markers of Bone Turnover

A dose-finding study of abaloparatide administered once daily for 24 weeks in postmenopausal women with osteoporosis demonstrated a dose-response relationship for BMD and bone formation markers.

Daily administration of TYMLOS to postmenopausal women with osteoporosis for 18 months increased the bone formation marker serum procollagen type I N-propeptide (sPINP) and the bone resorption marker serum collagen type I cross-linked C-telopeptide (sCTX). The increase in geometric mean sPINP levels peaked at Month 1 at 93% above baseline in postmenopausal women then decreased slowly over time to 45% above baseline at Month 18. The increase in geometric mean sCTX levels in postmenopausal women peaked at Month 3 at 26% above baseline then decreased to baseline levels by Month 18.

Daily administration of TYMLOS to men with osteoporosis for 12 months increased the bone formation marker sPINP and the bone resorption marker sCTX. The increase in geometric mean sPINP levels peaked at Month 1 at 133% above baseline in men then decreased slowly over time to 84% above baseline at Month 12. The increase in geometric mean sCTX levels in men peaked at Month 6 at 46% above baseline and was 35% above baseline by Month 12.

Cardiac Electrophysiology

A 4-way cross-over thorough QT/QTc study was conducted in 55 healthy subjects who received single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac electrophysiology.

Absorption

The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%.

Distribution

The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L.

Elimination

Specific Populations

Drug Interactions

In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Abaloparatide is not a substrate of the renal transporters OAT1, OAT3, OCT2, MATE1, or MATE2K.

Postmenopausal Women with Osteoporosis

Of the patients receiving TYMLOS for 18 months, 41% (318/773) developed anti-abaloparatide antibodies, and 26% (204/773) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.4% (7/297) developed cross-reactivity to PTHrP, of which 3 of the 7 patients developed neutralizing antibodies to PTHrP. Only 0.3% (1/297) developed cross-reactive antibodies to PTH, which were not neutralizing to PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response, fracture reduction, or adverse events.

Most of the patients with anti-abaloparatide antibodies during treatment with TYMLOS, 86% (275/318), had follow-up antibody measurements every six months after completion of TYMLOS therapy until seroconverting to antibody negative or lost to follow-up. Among these patients, 127 remained antibody positive at 1 year after discontinuing treatment, 55 remained antibody positive at 2 years, and 6 remained antibody positive at 3 years.

Men with Osteoporosis

Of the male patients receiving TYMLOS for 12 months, 25% (36/142) developed anti-abaloparatide antibodies and 1.4% (2/142) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, none developed cross-reactivity to PTHrP or PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response or adverse events.

Carcinogenesis

In a 2-year carcinogenicity study, abaloparatide was administered once daily to male and female Fischer rats by subcutaneous injection at doses of 10, 25, and 50 mcg/kg. These doses resulted in systemic exposures to abaloparatide that were 4, 16, and 28 times, respectively, the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons). Neoplastic changes related to treatment with abaloparatide consisted of marked dose-dependent increases in osteosarcoma and osteoblastoma incidence in all male and female dose groups. The incidence of osteosarcoma was 0-2% in untreated controls and reached 87% and 62% in male and female high-dose groups, respectively. The bone neoplasms were accompanied by marked increases in bone mass.

The relevance of the rat findings to humans is uncertain. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma [see Warnings and Precautions (5.1)].

Mutagenesis

Abaloparatide was not genotoxic or mutagenic in a standard battery of tests including the Ames test for bacterial mutagenesis, the chromosome aberration test using human peripheral lymphocytes, and the mouse micronucleus test.

Impairment of Fertility

Abaloparatide effects on female fertility have not been assessed nonclinically. No adverse effects of abaloparatide on male fertility were observed in male rats. In a male rat fertility study, abaloparatide was administered via subcutaneous injection 2 weeks prior to mating, through the mating period and for approximately 2 weeks after the mating period (for total of 6 weeks) at doses of 10, 25 and 70 µg/kg/day. Abaloparatide did not cause adverse effect on mating, fertility indices, conception rate, reproductive organ weights or sperm parameters up to 70 µg/kg/day (28-fold the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons).

Effect on New Vertebral Fractures

The primary endpoint was the incidence of new vertebral fractures in patients treated with TYMLOS compared to placebo. TYMLOS resulted in a significant reduction in the incidence of new vertebral fractures compared to placebo at 18 months (0.6% TYMLOS compared to 4.2% placebo, p <0.0001). The absolute risk reduction in new vertebral fractures was 3.6% at 18 months and the relative risk reduction was 86% for TYMLOS compared to placebo (Table 3). The incidence of new vertebral fractures at 25 months was 0.6% in patients treated with TYMLOS then alendronate, compared to 4.4% in patients treated with placebo then alendronate (p <0.0001). The relative risk reduction in new vertebral fractures at 25 months was 87% for patients treated with TYMLOS then alendronate, compared to patients treated with placebo then alendronate, and the absolute risk reduction was 3.9% (Table 3). After 24 months of open-label alendronate therapy, the vertebral fracture risk reduction achieved with TYMLOS therapy was maintained.

Effect on Nonvertebral Fractures

TYMLOS resulted in a significant reduction in the incidence of nonvertebral fractures at the end of the 18 months of treatment plus 1 month follow-up where no drug was administered (2.7% for TYMLOS-treated patients compared to 4.7% for placebo-treated patients). The relative risk reduction in nonvertebral fractures for TYMLOS compared to placebo was 43% (logrank test p = 0.049) and the absolute risk reduction was 2.0%.

Following 6 months of alendronate treatment in Study 005, the cumulative incidence of nonvertebral fractures at 25 months was 2.7% for women in the prior TYMLOS group compared to 5.6% for women in the prior placebo group (Figure 1). At 25 months, the relative risk reduction in nonvertebral fractures was 52% (logrank test p = 0.017) and the absolute risk reduction was 2.9%.

Figure 1: Cumulative Incidence of Nonvertebral FracturesExcludes fractures of the sternum, patella, toes, fingers, skull and face and those associated with high trauma. over 25 Months (Intent to Treat Population)Includes patients randomized in Study 003

Figure 1

TYMLOS demonstrated consistent reductions in the risk of vertebral and nonvertebral fractures regardless of age, years since menopause, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.

Effect on Bone Mineral Density (BMD)

Treatment with TYMLOS for 18 months in Study 003 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip, and femoral neck, each with p<0.0001 (Table 4). Similar findings were seen following 6 months of alendronate treatment in Study 005 (Table 4).

There was no evidence of differences in the effects of TYMLOS on BMD across subgroups defined by age, years since menopause, race, ethnicity, geographic region, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.

Effect on Bone Histology

Bone biopsy specimens were obtained from 71 patients with osteoporosis after 12 – 18 months of treatment (36 in the TYMLOS group and 35 in the placebo group). Of the biopsies obtained, 55 were adequate for quantitative histomorphometry assessment (27 in the TYMLOS group and 28 in the placebo group). Qualitative and quantitative histology assessment showed normal bone architecture and no evidence of woven bone, marrow fibrosis, or mineralization defects.

Effect on Bone Mineral Density (BMD)

The primary endpoint was the percent change from baseline in lumbar spine BMD at 12 months in patients treated with TYMLOS compared to placebo. Treatment with TYMLOS for 12 months in Study 019 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip, and femoral neck, each with p<0.0001 (Table 5).

There was no evidence of differences in the effects of TYMLOS on BMD at Month 12 across subgroups defined by age, race, ethnicity, geographic region, presence or absence of prior fracture, and BMD at baseline.