Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study

Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide‐sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:1 to open‐label abaloparatide administered daily via abaloparatide‐sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide‐sMTS and 10.86% (SE: 0.48%) for abaloparatide‐SC (treatment difference: −3.72% [95% confidence interval: −5.01%, −2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide‐sMTS and 3.70% for abaloparatide‐SC. Median changes from baseline at 12 months in serum procollagen type I N‐terminal propeptide (s‐PINP) were 52.6% for abaloparatide‐sMTS and 74.5% for abaloparatide‐SC. Administration site reactions were the most frequently reported adverse events (abaloparatide‐sMTS, 94.4%; abaloparatide‐SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide‐sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide‐sMTS to abaloparatide‐SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Introduction
O steoporosis-related fractures and associated morbidity and mortality are important public health concerns.(3)(4) For example, in a prospective cohort study, the relative risk of subsequent fracture increased for all sentinel fracture types (except ankle for females and rib for men), ranging from 1.4 to 2.8 in women and 2.9 to 6.2 in men. (4)edications that increase bone mineral density (BMD) and reduce fracture risk include antiresorptive drugs (bisphosphonates, denosumab, estrogens, and selective estrogen receptor modulators) and bone-forming agents (teriparatide, abaloparatide, and romosozumab). (5,6)Despite the availability of these medications, most patients who could benefit from treatment do not receive it. (7)A recent real-world study found only 16.8% of patients designated as very high risk for fracture received osteoporosis treatment, and of those who received treatment, only 21.2% received treatment recommended for patients at very high risk (teriparatide, zoledronic acid, denosumab, abaloparatide, or romosozumab). (8)(11)(12) However, available anabolic therapies are administered by subcutaneous (SC) injection, an impediment to many patients.Alternative forms of administration to accommodate individual patient preferences are important and may reduce the osteoporosis treatment gap. (13)baloparatide is a synthetic analog of human parathyroid hormone-related peptide [hPTHrP (1-34)] currently approved in the United States as a single-subject-use prefilled pen that delivers 80 μg for a daily SC injection (abaloparatide-SC) into the periumbilical region. (14)In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE), 18 months of treatment with abaloparatide-SC increased BMD in women with postmenopausal osteoporosis, decreased the risk of vertebral, nonvertebral, and clinical fractures compared with placebo, and decreased the risk of major osteoporotic fracture compared with teriparatide and placebo. (15)adius Health, Inc., in collaboration with Kindeva Drug Delivery L. P. (previously 3M Drug Delivery), developed a short-weartime transdermal method of administration for abaloparatide.This is referred to as the abaloparatide-solid microstructured transdermal system (abaloparatide-sMTS).Abaloparatide-sMTS consists of a polymeric microneedle array coated with abaloparatide formulated with ZnCl 2 , which extends systemic exposure, and includes an adhesive patch and a spring-actuated applicator. (16)In a phase 1b study, once-daily administration of abaloparatide-sMTS for 28 days provided a consistent pharmacokinetic (PK) profile and produced increases in serum procollagen type I N-terminal propeptide (s-PINP) from baseline similar to those observed with abaloparatide-SC. (16)he objective of this trial was to evaluate the efficacy and safety of abaloparatide delivered daily via sMTS compared with SC administration over 12 months in the treatment of postmenopausal women with osteoporosis at high risk for fracture.

Methods
This was a phase 3, randomized, open-label, multicenter, noninferiority study to evaluate daily abaloparatide-sMTS 300 μg compared with abaloparatide-SC 80 μg for the treatment of postmenopausal women with osteoporosis.A 300-μg abaloparatide-sMTS dose applied to the thigh for 5 min was utilized because it was previously shown to have a PK profile similar to that of abaloparatide-SC 80 μg. (16)It was conducted between August 5, 2019 and November 9, 2021 at 83 sites in Denmark, Hungary, Poland, and the United States.The study consisted of a screening period of up to 2 months, a 1-week pretreatment period, a 12-month treatment period, and a 1-month follow-up period (Fig. 1).The study was approved by the ethics committee at every participating institution and was conducted according to the recommendations of Good Clinical Practice and the Declaration of Helsinki.All participants provided written informed consent to participate in the study.

Participants
Study eligibility criteria were similar to those used for the ACTIVE study.Postmenopausal women aged 50-85 years were eligible for study if they had a BMD T-score ≤À2.5 and >À5.0 at the lumbar spine, total hip, or femoral neck, radiologic evidence, confirmed at screening, of two or more mild or one or more moderate lumbar or thoracic vertebral fractures, or a history of fragility fracture of the forearm, humerus, sacrum, pelvis, hip, femur, or tibia in the past 5 years.Women >65 years of age who met fracture criteria but who had a T-score ≤À2.0 and >À5.0, or did not meet fracture criteria but who had T-scores ≤À3.0 and >À5.0, were also eligible.Other inclusion criteria were good general health, a body mass index of 18.5-33 kg/ m 2 , and normal serum levels of calcium (albumin corrected), parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), phosphorus, and alkaline phosphatase.A 25-hydroxyvitamin D level of ≥20 ng/mL was also required.
Women with a history of more than four mild or moderate vertebral fractures or any severe fractures, based on the Genant Semi-Quantitative Scoring method, were excluded. (17)Women with less than two radiologically evaluable lumbar vertebrae within L1-L4 were ineligible.Other exclusion criteria were prior treatment with PTH-or PTHrP-derived drugs; intravenous bisphosphonates at any time, oral bisphosphonates within the past 3 years, or denosumab within the past 18 months; selective estrogen receptor modulators (e.g., raloxifene or tamoxifen), calcitonin, or tibolone within the past 6 months; or daily treatment with glucocorticoids within the past 12 months.Women with skeletal disorders other than osteoporosis (e.g., Paget disease of bone), any cancer in the past 5 years (other than basal cell or squamous cell cancer of the skin), osteosarcoma at any time, or a history of prior external beam or implant radiotherapy to the bone were also ineligible.

Study drug administration
Participants were randomized 1:1 through interactive response technology to either abaloparatide-sMTS 300 μg or abaloparatide-SC 80 μg in a permuted block randomization scheme.
On day 1, participants received written instructions, were trained by study staff to self-administer the study drug using either the abaloparatide-sMTS applicator (Fig. 2) or the abaloparatide-SC prefilled syringe, and administered their first dose at the study site under the observation of study staff.Thereafter, the study drug was self-administered daily for 12 months (morning was suggested).One to 2 hours before dosing, participants were encouraged to drink 0.25 L (8 oz) of water.
One hour before application, abaloparatide-sMTS was removed from refrigeration.The abaloparatide-sMTS product consists of a microneedle array (316 individual microstructures, 500 μm in height) that is coated with drug formulation (abaloparatide, zinc) and utilizes a separately provided reusable applicator to affix the microneedle array patch to the skin.Abaloparatide-sMTS 300 μg was applied to the thigh at the same time each day using the applicator for 5 min.Adhesion of the sMTS product was assessed immediately before removal each day.Participants were instructed to remain sitting or lying for approximately 5 min after removal of the patch and to alternate thighs with each administration.Using the prefilled pen, abaloparatide-SC 80 μg was administered in the periumbilical region, varying the injection site daily.All participants were provided calcium and vitamin D to ensure that their daily intake was at least 1200 mg/day and 800 IU/day, respectively.

Endpoints and assessments
The primary efficacy endpoint was the percentage change from baseline in lumbar spine BMD by dual-energy X-ray absorptiometry (DXA) at 12 months.Key secondary endpoints were the percentage change from baseline in total hip and femoral neck BMD at 12 months.Additional secondary endpoints included the percentage change from baseline in BMD at 3 and 6 months for lumbar spine, total hip, and femoral neck.During the COVID-19 pandemic, if BMD assessments could not be made on the ideal prespecified day, make-up visits were allowed within a specified number of days from the ideal visit day (up to 30 days after the ideal visit for month 3, up to 120 days after for month 6, and AE 4 days for month 12).DXA scans were centrally adjudicated.Approximately 65% of participants were scanned on Hologic instruments and 35% on Lunar Instruments.The proportion of participants scanned by each type of instrument was similar between treatment groups.The study imaging center performed longitudinal quality control of the DXA instruments and adjusted results for inter-and intrascanner variance.A clinical assessment for new fractures was performed on day 1 and months 1, 3, 6, 9,  PK endpoints included the plasma concentration of abaloparatide from sparse PK sampling.Blood sampling for each participant was at one of the following times: 1-2 hours after dose on day 1, 30 minutes to 1 hour after dose on day 14, 3-4 hours after dose at month 1, 2-3 hours after dose at month 3, 10-30 minutes after dose at month 6, or predose at month 9.
Safety data were collected throughout the study, including adverse events (AEs) and changes in vital signs (including orthostatic blood pressure, pulse rate, body temperature, and respiratory rate).Laboratory tests (hematology, serum chemistry, and urinalysis) were done at screening, day 1, and months 1, 6, and 12. Sample collections for antidrug antibody immunogenicity testing were done at days 1 and 14 and months 1, 3, 6, 9, 12, and 13 (the safety follow-up visit).Electrocardiograms were performed before dose and 1 hour after dose on day 1 and at month 12.
Signs and symptoms associated with administration of study medication were assessed by AE reporting, by investigator and participant scoring, and by review of skin reactions by the study dermatology consultant (Rio Pharmaceutical Services, LLC).

Statistical analysis
Based on the US Food and Drug Administration's recommendation, a clinically meaningful difference of 2.0% between treatment groups in the change from baseline in lumbar spine BMD at 12 months was selected as the noninferiority margin. (18)oninferiority of abaloparatide-sMTS to abaloparatide-SC would be established if the lower bound of the two-sided 95% confidence interval (CI) for the estimated treatment difference in the percentage change from baseline in lumbar spine BMD at 12 months was >À2.0%.A sample size of 474 participants (237 per group) would provide at least 90% power to conclude the noninferiority of abaloparatide-sMTS to abaloparatide-SC, assuming a true mean difference of 0% and a SD of 6.35%, anticipating that approximately 10% of treated participants would not have both a baseline lumbar spine BMD measurement and at least one postbaseline lumbar spine BMD measurement.
The modified intention-to-treat population (mITT), including all randomized participants who received at least one dose of study drug and had a baseline and at least one postbaseline lumbar spine BMD measurement, was the primary population used for all efficacy endpoints.A mixed-effects model for repeated measures (MMRM) with fixed effects for treatment, DXA manufacturer, visit, and treatment-by-visit interaction, and with the appropriate baseline parameter as covariate, was used for all efficacy endpoints.Log-transformed values were used in the analyses of bone turnover markers.Least-squares mean (LSM) for the treatment groups and corresponding 95% CIs for the treatment differences were obtained.Analyses were also performed using MMRM for subgroups defined by participant age, geographic region, fracture history, baseline T-score, and baseline s-PINP.
To understand the underlying relationship between the abaloparatide PK profile and the observed changes in s-PINP, s-CTX, and lumbar spine BMD in this study, a population PK analysis was performed on the abaloparatide plasma concentration data pooled across several phase 1, 2, and 3 studies with dense or sparse PK sampling, including the plasma concentration data from this study.Kaplan-Meier estimates of the incidence rate and the hazard ratio (HR) (and 95% CI) based on a Cox proportional hazards model were used to compare clinical fractures between treatment groups.

Results
A total of 511 participants were randomized (abaloparatide-SC, n = 255; abaloparatide-sMTS, n = 256) (Fig. 3), with 78.5% of participants in the abaloparatide-sMTS group and 74.9% in the abaloparatide-SC group completing the study.Withdrawal by participant and AEs were the most common reasons for withdrawal in both treatment groups.
Participant demographic and baseline characteristics were similar across treatment groups (Table 1).Mean age was 69.1 years, and 96.1% of participants were white.At baseline, the mean T-score was À2.56 at the lumbar spine, À2.16 at the total hip, and À2.49 at the femoral neck.The majority (80.0%) of participants had at least one prior fracture.Calcium and vitamin D exposure was similar between groups.

Bone turnover markers
s-PINP increased in both treatment groups with a similar pattern over time, but the increases were greater in the abaloparatide-SC group than in the abaloparatide-sMTS group.The median s-PINP level increased from 63.40 ng/mL at baseline to 116.20 ng/mL (74.5% change) at month 12 for abaloparatide-SC and increased from 63.25 ng/mL at baseline to 94.40 ng/mL (52.6% change) at month 12 for abaloparatide-sMTS.The geometric mean ratio relative to baseline was greater in the abaloparatide-SC group than in the abaloparatide-sMTS group at all time points (Fig. 6A).At month 1, s-CTX initially declined from baseline in the abaloparatide-sMTS group but increased in the abaloparatide-SC group.At months 3, 6, and 12, s-CTX increased compared to baseline in both groups.The median s-CTX level  increased from 0.384 ng/mL at baseline to 0.492 ng/mL at 12 months for abaloparatide-SC, and increased from 0.387 ng/mL at baseline to 0.474 ng/mL at month 12 for abaloparatide-sMTS.Geometric mean ratio relative to baseline was greater in the abaloparatide-SC group than in the abaloparatide-sMTS group at months 1, 3, 6, and 12 (Fig. 6B).

Safety
The incidence of AEs was greater in the abaloparatide-sMTS group (96.8%) than the abaloparatide-SC group (88.2%) (Table 3); the majority were of mild or moderate severity.The most frequently reported AEs in both groups involved events with preferred terms pertaining to administration site reactions, which occurred more frequently in the abaloparatide-sMTS group (94.4%) than the abaloparatide-SC group (70.5%).However, there was no indication of skin site infection AEs in the abaloparatide-sMTS group.
Several AEs, including palpitations, nausea, headache, dizziness, and back pain, were reported more frequently in the abaloparatide-SC group compared with the abaloparatide-sMTS group.
Hypersensitivity reactions (based on AEs in the Hypersensitivity Standardized MedDRA Query [SMQ]) occurred in 4.8% of participants in the abaloparatide-sMTS group and 5.1% in the abaloparatide-SC group.Hypersensitivity involving the application site (including preferred terms for application/injection site dermatitis, hypersensitivity, rash, and urticaria) was very low: 0.8% in each group.There were no cases of anaphylaxis in either treatment group, and all hypersensitivity AEs were mild to moderate in severity.
Investigators determined that the application of the abaloparatide-sMTS was associated with few dermal signs, and most were mild in severity.The severity of erythema and bleeding tended to decrease from 5 minutes to 1 hour following the application whereas the severity of edema was similar at 5 minutes and 1 hour following the abaloparatide-sMTS application.
Participants reported that abaloparatide-sMTS applications were generally symptom-free or associated with symptoms of mild severity.For participants who reported pain, itching, burning, or tenderness, the severity of the symptom tended to decrease from 5 minutes to 1 hour after application, whereas the severity of localized swelling, which was the most prominent symptom, was similar at 5 minutes and 1 hour after application.Severe symptoms were reported infrequently, and the nature and intensity of participant-assessed symptoms tended to remain similar or decreased during the year of treatment.Thirty-four participants in the abaloparatide-sMTS group had administration site AEs that were adjudicated by the study dermatologist.None were assessed as severe by the investigator.Generally, there was agreement between the investigator's and dermatology consultant's assessment.There was no evidence of determinants of skin sensitization, and none of the predefined dermatologic AEs of special interest (eschar, ulcer, nonhealing wound) were observed.Vital signs, electrocardiograms, and clinical laboratory evaluations were similar in both treatment groups and consistent with those reported previously for abaloparatide-SC. (15,19)ntidrug antibody results were available for 249/252 (98.8%) participants in the abaloparatide-sMTS group and 248/254 (97.6%) participants in the abaloparatide-SC group through month 12. Seventeen of 249 (6.8%) participants treated with abaloparatide-sMTS and 3/248 (1.2%) participants treated with abaloparatide-SC were positive for antidrug antibodies at any postbaseline immunogenicity assessment.Upon subsequent testing, 11/17 who received abaloparatide-sMTS and no participants who received abaloparatide-SC had neutralizing antibodies.There were no apparent differences in clinical efficacy or TEAEs between participants with antidrug antibodies and those without.

Pharmacokinetics
The population PK analysis indicated that there was a lower geometric mean area under the curve (AUC) for the abaloparatide-sMTS group in this study (843 pgÁh/mL) (Fig. 7) than the exposure results from the population PK analysis including abaloparatide-SC treatments in this study (1756 pgÁh/mL) and the ACTIVE study (1171 pgÁh/mL [data unpublished]).

Discussion
This study was conducted to evaluate the noninferiority of abaloparatide-sMTS compared with abaloparatide-SC based on lumbar spine BMD at 12 months in the treatment of postmenopausal women with osteoporosis at high risk for fracture.The safety and tolerability of abaloparatide-sMTS compared with abaloparatide-SC were also evaluated.Clinically meaningful increases in BMD from baseline were observed for both treatment groups; however, the primary objective of evaluating the noninferiority of abaloparatide-sMTS to abaloparatide-SC on the percentage change in lumbar spine BMD at 12 months was not met based on a noninferiority margin of 2.0%.The increases in BMD from baseline for both treatment groups were consistent in the lumbar spine, total hip, and femoral neck at all time points and regardless of age, geographic region, prior fracture, T-score at baseline, and s-PINP levels at baseline.
The exposure based on AUC for the abaloparatide-SC in this study was approximately 50% greater than that for the same treatment in ACTIVE, which is consistent with the larger increase in s-PINP, s-CTX, and lumbar spine BMD through 12 months of treatment in this study compared with ACTIVE. (15)Similarly, the smaller estimated exposure for abaloparatide-sMTS in this study is consistent with the smaller increases in s-PINP, s-CTX (including initial decline at month 1), and lumbar spine BMD for abaloparatide-sMTS compared with abaloparatide-SC within this study.
There were no differences in the prefilled syringe to administer abaloparatide-SC between studies, and although the geographic distribution of patients in the current study included more patients from North America than the ACTIVE study, the demographics of the study populations were otherwise similar.Thus, the reason for differences in exposure for abaloparatide-SC across studies is not clear.There were no indications in patients' assessments that adhesion of the sMTS product may have affected exposure.It is possible that a different dose level  or modification of the sMTS delivery device could improve drug exposure and favorably influence study outcomes.
Although noninferiority between abaloparatide-sMTS and abaloparatide-SC was not established in this study, increases in BMD with abaloparatide-sMTS may exceed surrogate threshold estimates of BMD increases for predicting the clinical effectiveness for fracture reduction. (20)As an example, in a study to validate BMD surrogate endpoints in the FNIH-ASBMR SABRE Project, a total hip BMD increase of 1.83% at 2 years was associated with reduced risk of all fractures, and an increase of 1.42% at 2 years was associated with reduced risk of vertebral fractures.Although values reported in the current study are not adjusted for placebo, we report a total hip BMD increase of 1.97% at 1 year, suggesting that abaloparatide-sMTS may indeed be effective at reducing fracture risk.23) Abaloparatide-sMTS was generally well tolerated in the treatment of postmenopausal women with osteoporosis.Additionally, the safety profile for abaloparatide-sMTS was comparable to that observed for abaloparatide-SC.However, AEs of reactions Abbreviations: SC = subcutaneous; sMTS = solid microstructured transdermal system; TEAE = treatment-emergent adverse event.at the administration site were more frequently reported in the abaloparatide-sMTS group than with abaloparatide-SC, while symptoms previously associated with abaloparatide-SC, such as dizziness, palpitations, and nausea, were more frequently reported in the abaloparatide-SC group.The reasons for increased administration site AEs with abaloparatide-sMTS compared to abaloparatide-SC are not clear; however, there were more withdrawals associated with AEs for the abaloparatide-SC group than for the abaloparatide-sMTS group.A limitation of this study was its reliance on patient ability to apply the study drug throughout the treatment period.However, patients were trained and received written instructions at their first visit on how to self-administer study treatment.Additionally, patients' assessments of adherence suggest that this was unlikely to have affected results.An additional limitation was the unexpected 50% increase in abaloparatide exposure (AUC) with abaloparatide-SC in this study compared to the ACTIVE study, the reasons for which are not clear.Most patients were randomized near or after the onset of the COVID-19 pandemic; however, completion rates and reasons for study drug discontinuation were similar regardless of the timing of randomization relative to pandemic onset.As such, the pandemic did not appear to impact study results.

Conclusions
Noninferiority of abaloparatide-sMTS to abaloparatide-SC for the percentage change in lumbar spine BMD at 12 months was not demonstrated in this study based on a noninferiority margin of 2.0%; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed for both treatment groups.Other than mostly mild skin reactions at the administration site, abaloparatide-sMTS was well tolerated, and there was no identifiable risk for a sensitization reaction.
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Fig. 2 .
Fig. 2. Solid coated microneedle drug delivery system. A. Single-use array patch in holder next to reusable applicator during priming.Applicator cap shown to side.B. Single-use array patch held by hand, as it would be postuse.

and 12 .
Participants reporting that a fracture occurred were to bring radiographs and any medical reports so that all new fractures sustained during the study were documented.Spinal radiographs were collected at screening and as clinically indicated; routine radiographs for subclinical vertebral fractures during treatment were not performed.s-PINPand serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) were measured within 1 hour prior to dosing at day 1 and months 1, 3, 6, and 12.Samples were batched and analyzed by Centre Académique de Recherche et d'Expérimentation en Santé (CARES) (University of Liège, Liège, Belgium).The log ratio of postbaseline value over baseline at each time point was calculated.
Abbreviations: BMD = bone mineral density; CRF = case report form; DXA = dual energy X-ray absorptiometry; ITT = intention to treat; s-CTX = serum carboxy-terminal cross-linking telopeptide of type I collagen; s-PINP = serum procollagen type I N-terminal propeptide; SC = subcutaneous; SD = standard deviation; sMTS = solid microstructured transdermal system.a Participants with any vertebra semiquantitative (SQ) score >0, assessed by locally read X-ray.b Participants with prevalent vertebral fracture and/or prior clinical fracture.c DXA was centrally adjudicated.

Fig. 4 .
Abbreviations: BMD = bone mineral density; mITT = modified intent to treat; SC = subcutaneous; SD = standard deviation; SE = standard error; sMTS = solid microstructured transdermal system.a Results were based on mixed-effects model for repeated measures (MMRM) including fixed effects of treatment, DXA instrument manufacturer, visit and treatment-by-visit interaction, and relevant baseline BMD.

Table 2 .
Percentage Change in BMD at 12 Months (mITT Population)