Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Theramex Ireland Limited, 3rd Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1, D01 YE64, Ireland
Pharmacotherapeutic group: Calcium homeostasis, parathyroid hormones and analogues
ATC code: H05AA04
Abaloparatide is a 34 amino acid peptide that shares 41% homology to parathyroid hormone [PTH] and 76% homology to parathyroid hormone related peptide [PTHrP(1-34)], and is an activator of the PTH1 receptor signalling pathway. Abaloparatide stimulates new bone formation on trabecular and cortical bone surfaces by stimulation of osteoblastic activity.
Abaloparatide causes transient and limited increases in bone resorption and increases bone density.
The efficacy and safety of once daily abaloparatide was evaluated in a randomised, multicentre, doubleblind, placebo- and open-label active comparator-controlled (teriparatide) clinical study (ACTIVE study) for 18 months of treatment with 1 month follow-up in 2 070 postmenopausal women aged 50 to 86 years (mean age of 69; 15% were <65 years of age, 65% were 65 to ˂75 years of age, and 20% were ≥75 years of age) who were enrolled and randomised to receive abaloparatide 80 micrograms (N=696), placebo (N=688), or 20 micrograms teriparatide (N=686). Approximately 76% of patients were Caucasian, 19% were Asian, and 4% were Black. Of the total study population, 28% were Hispanic. Women took daily supplemental calcium (500 to 1 000 mg) and vitamin D (400 to 800 IU) per day. The primary endpoint in ACTIVE was the incidence of new vertebral fractures in abaloparatide-treated patients versus placebo.
At baseline, the mean T-scores were -2.9 at the lumbar spine, -2.2 at the femoral neck, and -1.9 at the total hip. At baseline, 42% of patients had no prior fracture, 23% of patients had at least one prevalent vertebral fracture, and 43% had at least one prior non-vertebral fracture.
In the ACTIVE study at 18 months, abaloparatide and teriparatide significantly reduced the absolute risk of new vertebral fractures versus placebo in postmenopausal patients with osteoporosis (p<0.0001; see Table 2).
Table 2. ACTIVE Trial: the effect* of abaloparatide on the risk of new vertebral fracture at 18 months:
| Parameter | PBO (N=600) | ABL (N=583) | TER (N=600) |
|---|---|---|---|
| Number of women with vertebral fracture, n (%) | 25 (4.2) | 3 (0.5) | 4 (0.7) |
| Absolute risk difference vs placebo† (%) (95% CI) | n/a | 3.7 (2.0, 5.6) | 3.5 (1.8, 5.5) |
* Based on Modified Intent to Treat Population (patients with baseline and post-baseline spine radiographs).
† Absolute risk difference was calculated as (PBO – ABL) and (PBO – TER).
PBO = placebo, ABL = abaloparatide, TER = teriparatide, CI = confidence interval
In the ACTIVE study at 19 months, the incidence of non-vertebral fractures was similar between the abaloparatide (2.7%) and teriparatide (2.0%) groups, and not statistically different compared to placebo (3.6%) (see Table 3).
Table 3. ACTIVE Trial: time-to-event of non-vertebral fracture at 19 months:
| Parameter | PBO (N=688) | ABL (N=696) | TER (N=686) |
|---|---|---|---|
| K-M estimated event rate (%) (95% CI) | 3.6 (2.3, 5.4) | 2.7 (1.6, 4.4) | 2.0 (1.1, 3.4) |
| Number of patients with event n (%) | 21 (3.1) | 15 (2.2) | 12 (1.7) |
| Absolute risk difference vs placebo* (%) (95% CI) | n/a | 0.9 (-1.1, 2.9) | 1.6 (-0.3, 3.5) |
* Absolute risk difference was calculated as (PBO – ABL) and (PBO – TER).
PBO = placebo, ABL = abaloparatide, TER = teriparatide, K-M = Kaplan Meier, CI = confidence interval
In the ACTIVE study, abaloparatide significantly increased BMD at all anatomical sites measured, versus placebo at 6, 12 and 18 months. The mean percent change in BMD at 18 months was 9.1% vs 0.5% at the lumbar spine, 3.3% vs 0% at the total hip, and 2.7% vs -0.4% at the femoral neck for abaloparatide versus placebo groups, respectively (all p<0.0001). At the ultra-distal radius, the mean percent change in BMD at 18 months was 1.2% vs -1.0% for abaloparatide versus placebo groups.
Abaloparatide demonstrated consistent increases in BMD measurements regardless of age, years since menopause, race, geographic region, presence or absence of prior fracture (vertebral, non-vertebral), severity of disease, and BMD at baseline.
In postmenopausal women with osteoporosis, the bone anabolic marker (s-PINP) showed a 90% increase above baseline at 1 month, and this effect was sustained throughout the abaloparatide treatment period. The bone resorption marker (s-CTX) showed no increase at 1 month, and a transient 22% increase above baseline at 3 months that returned to baseline at the end of treatment.
Upon completion of the ACTIVE trial, 963 patients, enrolled in the ACTIVExtend trial, an open-label extension study, where all patients received up to 24 months of treatment with 70 mg alendronate (ALN) weekly and calcium and vitamin D supplements. This included 494 patients who had previously received placebo and 469 patients who had previously received abaloparatide. Patients who received teriparatide during the ACTIVE trial were not eligible to participate in the ACTIVExtend trial. Results for vertebral fracture risk reduction at 43 months since randomisation are presented in Table 4.
In the ACTIVExtend study at 43 months, abaloparatide/ALN significantly reduced the absolute risk of new vertebral fractures vs placebo/ALN (p<0.0001; see Table 4). Teriparatide followed by alendronate has not been studied.
Table 4. ACTIVExtend trial: the effect* of abaloparatide/ALN on the risk of new vertebral fracture at 43 months†:
| Parameter | PBO/ALN (N=489) | ABL/ALN (N=457) |
|---|---|---|
| Number of women with vertebral fracture, n (%) | 26 (5.3) | 4 (0.9) |
| Absolute risk difference vs placebo/ALN‡ (%) (95% CI) | n/a | 4.4 (2.3, 6.9) |
* Based on Modified Intent to Treat Population (patients with baseline and post-baseline spine radiographs).
† Alendronate started at 19 months
‡ Absolute risk difference was calculated as (PBO/ALN – ABL/ALN).
PBO = placebo, ABL = abaloparatide, ALN = alendronate, CI = confidence interval
In the ACTIVExtend study at 43 months, abaloparatide/ALN numerically reduced the risk of nonvertebral fractures versus placebo/ALN. The incidence of non-vertebral fractures with abaloparatide/ALN (4.2%) was not statistically different compared to placebo (6.7%) (see Table 5).
Table 5. ACTIVExtend trial: time-to-event of non-vertebral fracture at 43 months*:
| Parameter | PBO/ALN (N=494) | ABL/ALN (N=469) |
|---|---|---|
| K-M estimated event rate (%) (95% CI) | 6.7 (4.8, 9.3) | 4.2 (2.7, 6.4) |
| Number of patients with event n (%) | 32 (6.5) | 19 (4.1) |
| Absolute risk difference vs placebo/ALN† (%) (95% CI) | n/a | 2.5 (-0.4, 5.4) |
* Alendronate started at 19 months
† Absolute risk difference was calculated as (PBO/ALN – ABL/ALN).
PBO = placebo, ABL = abaloparatide, ALN = alendronate, K-M = Kaplan Meier, CI = confidence interval
The mean percent change in BMD through 43 months was 14.7% vs 6.8% at the lumbar spine, 6.3% vs 2.9% at the total hip, 5.0% vs 1.6% at the femoral neck, and 1.1% vs 1.1% at the ultra-distal radius for abaloparatide/ALN versus placebo/ALN groups, respectively.
The European Medicines Agency has waived the obligation to submit the results of studies with abaloparatide in all subsets of the paediatric population in the treatment of osteoporosis (see section 4.2 for information on paediatric use).
The median (range) time to peak concentration of abaloparatide 80 micrograms was 0.5 h (0.25 to 0.52 h) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy subjects after subcutaneous administration of 80 micrograms dose was about 39%.
The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 45 L.
No specific metabolism or excretion studies have been performed with abaloparatide. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance. In vitro studies showed that abaloparatide, at clinically relevant concentrations, does not inhibit or induce Cytochrome P450 enzymes.
The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects, and the mean half-life of abaloparatide is about 1 h. The peptide fragments are primarily eliminated through renal excretion. Active secretion of abaloparatide in the kidneys cannot be ruled out.
Abaloparatide is not a substrate of the renal transporters P-gp, OAT1, OAT3, OCT2, MATE1 or MATE2K. Furthermore, abaloparatide does not inhibit P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3 transporters in vitro at its clinically relevant concentrations.
Abaloparatide systemic exposure was generally increasing with the increase of its subcutaneous doses from 5 micrograms up to 240 micrograms. There was a general tendency towards less than doseproportional increases, and no further increase in abaloparatide systemic exposure was observed as its dose increased to 280 micrograms and 320 micrograms.
Abaloparatide exposure increased with decreasing CrCl. Subjects with mild, moderate and severe renal impairment had Cmax increases of 3%, 28% and 44%, respectively, and AUC increases of 17%, 68% and 113%, respectively, compared to subjects with normal renal function (see sections 4.2 and 4.3).
No studies have been performed in patients undergoing dialysis for chronic renal failure.
No studies have been performed in patients with hepatic impairment. Abaloparatide is a peptide and not an inhibitor or an inducer of hepatic drug metabolising enzymes. The elimination is through proteolytic degradation and renal excretion, and it is unlikely that hepatic impairment will have any significant effect on abaloparatide exposure. No dose adjustment is needed for these patients (see section 4.2).
No age related differences in abaloparatide pharmacokinetics were detected during clinical studies, including postmenopausal women ranging from 49 to 86 years of age.
In a 2-year rat carcinogenicity study, abaloparatide displayed an increase in the overall incidence of osteosarcomas at doses that were 4 times higher than the systemic exposure observed in humans following a subcutaneous dose of 80 micrograms based on AUC comparisons. Neoplastic changes related to the treatment with abaloparatide consisted of dose-dependent increased incidence of osteosarcomas and osteoblastomas. The incidence and earliest occurrence of tumours was similar in both male and female rats. The relevance of these rat findings to humans is uncertain, thus the use of abaloparatide should be avoided for patients at increased risk of osteosarcoma.
In toxicology studies in rats and monkeys, findings included soft tissue mineralization at doses that were approximately 2 and 3 times, respectively, the exposure in humans at daily subcutaneous doses of 80 micrograms.
Subcutaneous administration of abaloparatide at doses that were approximately 0.3, 2.4 and 3.8 times the exposure in humans at daily subcutaneous doses of 80 micrograms to the conscious dog produced a dosedependent transient increase in heart rate lasting approximately 3 hours, had marginal effects on mean arterial blood pressure. Additionally, abaloparatide had marginal effects on the QTc interval, with a nonsignificant tendency towards a decrease in QTc with increasing dose, which is consistent with its minimal effects on hERG potassium currents and Purkinje fibres at clinically relevent concentrations.
Abaloparatide was not genotoxic or mutagenic in a standard battery of tests.
No embryofoetal development or pre/postnatal development studies have been conducted in female animals because the intended population for abaloparatide is postmenopausal women. Effects on male fertility were evaluated in rats, and no impact on male fertility was observed at doses 27 times the exposure in humans at daily subcutaneous doses of 80 micrograms.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
