TRANSDERMAL SYSTEM FOR THE DELIVERY OF ABALOPARATIDE AND METHOD OF USE FOR TREATING OSTEOPOROSIS

Abstract

Provided herein are methods for treating osteoporosis and increasing bone mass density, that includes administering once a day, for about 5 minutes, a transdermal patch loaded with about 300 μg of abaloparatide, and ZnCl.sub.2 at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide. Also provided are the single-use transdermal patches loaded with about 300 μg of abaloparatide, and ZnCl.sub.2 at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide.

Claims

1. A method for treating osteoporosis in a subject in need thereof comprising: administering daily a trans dermal patch applied to the subject's thigh for about 5 minutes, the patch comprising: 300 μg of abaloparatide, and ZnCl.sub.2, at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide, wherein the subject is treated for osteoporosis.

2. A method of increasing bone mass density (BMD) in a subject in need thereof comprising: administering daily a trans dermal patch applied to the subject's thigh for about 5 minutes, the patch comprising: 300 μg of abaloparatide, and ZnCl.sub.2, at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide, wherein the subject achieves at least a 5% increase in BMD by 6 months.

3. A method for transdermally delivering abaloparatide to a subject in an amount bioequivalent to subcutaneous injection of 80 mcg abaloparatide, the method comprising: administering daily a trans dermal patch applied to the subject's thigh for about 5 minutes, the patch comprising: 300 μg of abaloparatide, and ZnCl.sub.2, at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide, wherein an amount of abaloparatide is transdermally delivered to the subject that is bioequivalent to subcutaneous injection of 80 mcg abaloparatide.

4. A once-daily trans dermal system for the delivery of abaloparatide comprising: a plurality of single-use trans dermal patches, each loaded with about 300 μg of abaloparatide, and ZnCl.sub.2 at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide; and instructions to administer one of said trans dermal patches once daily to the thigh for about 5 minutes.

5. An aqueous formulation suitable for coating a trans dermal patch wherein the aqueous formulation comprises 300 μg of abaloparatide, zinc at a molar ratio of 2.2:1 of Zn:abaloparatide.

6. The method, system or formulation according to any of the preceding claims, wherein the patch or formulation further comprises hydrochloric acid.

7. The method, system or formulation according to claim 6, wherein the mole ratio of hydrochloric acid to zinc chloride is at least 0.025.

8. The method, system or formulation according to any of the preceding claims, wherein the pH of the patch or formulation is about 4.5.

9. The method, system or formulation according to any of the preceding claims, wherein the pH of the patch or formulation is between about 4 and 4.75.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1A and FIG. 1B are a graph of plasma concentrations over time and a table of pharmacokinetic parameters, respectively, for Cohort 1, Formula A at 100 mcg, 150 mcg and 200 mcg doses.

[0019] FIG. 2A and FIG. 2B are a graph of plasma concentrations over time and a table of pharmacokinetic parameters, respectively, for Cohort 2, Formula B at 100 mcg, 150 mcg and 200 mcg doses.

[0020] FIG. 3A and FIG. 3B are a graph of plasma concentrations over time and a table of pharmacokinetic parameters, respectively, for Cohort 3, Formula C at 100 mcg, 150 mcg and 200 mcg doses.

[0021] FIG. 4A and FIG. 4B are a graph of plasma concentrations over time and a table of pharmacokinetic parameters, respectively, for Cohort 4.

[0022] FIG. 5A and FIG. 5B are a graph of plasma concentrations over time and a table of pharmacokinetic parameters, respectively, for Cohort 5.

[0023] FIG. 6A-6E are graphs of plasma concentrations for Cohort 6 in linear scale (FIG. 6A) and semi-log scale (FIG. 6B); and tables of pharmacokinetic parameters for Cohort 6 (FIG. 6C), a within cohort comparison (FIG. 6D), and relative bioavailability parameters between doses, application sites, and wear times (FIG. 6E).

[0024] FIG. 7A and FIG. 7B are graphs of plasma concentrations over time for Cohort 7 in linear and semi-log scale, respectively.

DETAILED DESCRIPTION

[0025] Provided herein is a safe, effective, and pain-free alternative to daily self-injection of abaloparatide in the form of a trans dermal device. Application time is only about 5 minutes, yet surprisingly provides a bioequivalent amount of abaloparatide to that achieved with self-injection. The device is a once-daily trans dermal patch that includes 300 μg of abaloparatide disposed on the patch with a release modulating agent, ZnCl.sub.2. This release modulating agent is present on the trans dermal device at a molar ratio of 2.2:1 of ZnCl.sub.2:abaloparatide. That delivery of an effective and safe amount can be achieved with a residence time of about 5 minutes for the patch is unexpected and surprising as demonstrated in the exemplification.

Definition and Abbreviations

[0026] The terms “ZnCl.sub.2” and “zinc chloride” are used interchangeably, and refer to the molecule of zinc chloride including all hydrates and solvates.

[0027] The term “pharmaceutically acceptable zinc salts” refers to pharmaceutically acceptable zinc salts, including solvates and hydrates that are generally recognized, by qualified experts, to be safe under the intended conditions of use (e.g., GRAS as recognized by the FDA). Zinc salts include zinc acetate, zinc carbonate, zinc chloride, zinc gluconate, zinc oxide and zinc sulfate. While the zinc in the zinc salts may (or may not) disassociate from the chloride in water and be dried to include forms that are different from the original compound, it is still referred to as zinc salt for ease of reference and clarity.

[0028] In this application, the amount of pharmaceutically acceptable zinc salt to abaloparatide is described as a mole ratio which is represented herein as “M” unless stated otherwise. For example, a coating solution described as 2.2 M ZnCl.sub.2 indicates a mole ratio of ZnCl.sub.2 to abaloparatide of 2.2:1. The molar ratio is determined, e.g., by calculation of the ratio of ZnCl.sub.2 to abaloparatide added to the coating solution on a molar basis. While the zinc in ZnCl.sub.2 may disassociate from the chloride in water and be dried to include various hydrates, solvates and other forms, the amount of zinc on a molar basis will not substantially differ from that added, and as a result, is still referred to as ZnCl.sub.2 in the transdermal patch.

[0029] The terms “transdermal device” and “patch” are used interchangeably in this application. Suitable trans dermal devices include devices having an array of microstructures that pierce the stratum corneum when pressed against the skin to deliver an agent to the tissues below. Microneedles in the form of micro-blades or microstructures (e.g., as disclosed in WO2017/184355 published 26 Oct. 2017 and filed as PCT/US2017/026462 on 6 Apr. 2017), pierce the stratum corneum upon application of force, making a plurality of tiny openings or slits which serve as passageways through which abaloparatide can be delivered to the body. Alternatively, the microneedles can be hollow to provide a liquid flow path from a reservoir to the microneedles. These trans dermal devices can be deployed with a single-use applicator or an application capable of being used multiple times. The trans dermal patch or device can be any of the patches described herein, or described in International Application Nos. PCT/US2016/056196, filed on Oct. 8, 2016 and published as WO2017/062922, PCT/2017/026462, filed Apr. 6, 2017 and published as WO 2017/184355, or PCT/US2016/055924, filed Oct. 7, 2016 and published as WO2017/062727. The entire content of which as expressly incorporated herein by this reference.

[0030] The term “applicator” refers to a device for applying a trans dermal device or patch to the skin with sufficient force for the microneedle array to pierce the stratum corneum and deliver abaloparatide to the subject.

[0031] The abbreviations employed in this application are provided in Table 1: List of Abbreviations.

TABLE-US-00002 TABLE 1 List of Abbreviations ABL Abaloparatide %AUCextrap Extrapolated portion of AUC0-inf from Tlast to infinity AUC Area under the curve AUC0-inf Area under the curve to infinity AUC0-t Area under the plasma concentration-time curve BLQ Below the limit of quantification BMD Bone mineral density CI Confidence interval CL/F Apparent clearance Clast Last quantifiable concentration Cmax Maximal plasma concentration CV% Coefficient of variation Frel Relative bioavailability in % h Hour hPTH Human parathyroid hormone hPTHrP Human parathyroid-related peptide Kel Apparent terminal elimination rate constant ln natural-log LS Least-square Max Maximum Mean Arithmetic mean Min Minimum min Minute N Sample size, number of observation PK Pharmacokinetic (s) PTH Parathyroid hormone PTHrP Parathyroid hormone-related peptide SC Subcutaneous injection SD Standard deviation t1/2 Apparent terminal elimination half-life TD Trans dermal delivery system Tlast Time of the last quantifiable concentration Tmax Time to maximal concentration μg or mcg micrograms (used interchangeably) Vz/F Apparent volume of distribution

EXEMPLIFICATION

[0032] An open-label, partially randomized, single-dose crossover, pilot PK, safety and tolerability study was conducted in healthy postmenopausal women to select the formulation, dose, application site, and wear time for trans dermal abaloparatide (abaloparatide-TD) with a PK profile comparable to TYMLOS abaloparatide subcutaneous injection (abaloparatide-SC).

[0033] Formulations used in the Cohorts are shown in Table 2: Study Formulations.

TABLE-US-00003 TABLE 2 Study Formulations Study Formulation Doses Formulation Components Cohorts A 100, 150, 200, 260 μg Abaloparatide:ZnCl.sub.2 1:0.7 molar ratio 1, 4, 5 2 × 150 μg B 100, 150, 200 μg Abaloparatide polyethylene glycol (PEG) 2 C 100, 150, 200 μg Abaloparatide:ZnCl.sub.2 1:0.7 molar ratio plus PEG 3, 4 W 200, 300, 400 μg Abaloparatide:ZnCl.sub.2 1:0.71:2.2 molar ratio 5, 6 2 × 200 μg X 200 μg Abaloparatide:ZnAc 1:0.7 molar ratio 5 W-1 300 μg Abaloparatide:ZnCl.sub.2 1:2.2 molar ratio, HCl 7 Reference:  80 μg Abaloparatide 1, 2, 3, 6, 7 SC

[0034] The formulated patch is made by coating with the coating solution in one or multiple coating iterations and then drying the patch or allowing the patch to dry to a fairly constant weight.

[0035] Formulation A 0.7 M ZnCl.sub.2 abaloparatide coating solution (Table 3.1).

TABLE-US-00004 TABLE 3.1 Formulation A: 0.7 M ZnCl.sub.2 abaloparatide coating solution Component Weight (about) % Abaloparatide 45.11 Zinc Chloride, USP (ZnCl.sub.2) 0.89 (approx. 0.7 mole ratio to abaloparatide) Sterile Water for Injection, USP 54.00 Total 100

[0036] Formulation A 0.7 M ZnCl.sub.2 abaloparatide formulation on patch ready to use (after drying) (Table 3.2).

TABLE-US-00005 TABLE 3.2 Formulation A: 0.7 M ZnCl.sub.2 abaloparatide formulation on patch ready to use (after drying) Component Weight (about) % Abaloparatide 98.07 Zinc Chloride, USP (ZnCl.sub.2) 1.93 Total 100

[0037] Formulation B: abaloparatide PEG coating solution (Table 3.3).

TABLE-US-00006 TABLE 3.3 Formulation B: abaloparatide PEG coating solution Component Weight (about) % Abaloparatide 40.5 Polyethylene Glycol 3350NF 14.5 Sterile Water for Injection, USP 45.00 Total 100

[0038] Formulation B: abaloparatide PEG formulation on patch ready to use (after drying) (Table 3.4).

TABLE-US-00007 TABLE 3.4 Formulation B: abaloparatide PEG formulation on patch ready to use (after drying) Component Weight (about) % Abaloparatide 73.64 Polyethylene Glycol 3350NF 26.36 Total 100

[0039] Formulation C: Abaloparatide: ZnCl.sub.2 1:0.7 molar ratio plus PEG coating solution (Table 3.5).

TABLE-US-00008 TABLE 3.5 Formulation C: Abaloparatide:ZnCl.sub.2 1:0.7 molar ratio plus PEG coating solution Component Weight (about) % Abaloparatide 34.84 Polyethylene Glycol 3350NF 12.47 Zinc Chloride, USP 0.69 Sterile Water for Injection, USP 52 Total 100

[0040] Formulation C: Abaloparatide:ZnCl.sub.2 1:0.7 molar ratio plus PEG formulation on patch ready to use (after drying) (Table 3.6).

TABLE-US-00009 TABLE 3.6 Formulation C: Abaloparatide:ZnCl.sub.2 1:0.7 molar ratio plus PEG coating solution Component Weight (about) % Abaloparatide 72.58 Polyethylene Glycol 3350NF 25.98 Zinc Chloride, USP 1.44 Total 100

[0041] Formulation W: 2.2M ZnCl.sub.2 abaloparatide coating solution (Table 3.7).

TABLE-US-00010 TABLE 3.7 Formulation W: 2.2 M ZnCl.sub.2 abaloparatide coating solution Component Weight (about) % Abaloparatide 35.78 Zinc Chloride, USP (ZnCl.sub.2) 2.22 (approx. 2.2 mole ratio Zn to abaloparatide) Sterile Water for Injection, USP 62.00 Total 100

[0042] Formulation W: 2.2M ZnCl.sub.2 abaloparatide formulation on patch ready to use (after drying) (Table 3.8).

TABLE-US-00011 TABLE 3.8 Formulation W: 2.2 M ZnCl abaloparatide formulation on patch ready to use (after drying) Component Weight (about) % Abaloparatide 94.16 Zinc Chloride, USP (ZnCl.sub.2) 5.84 Total 100

[0043] Formulation W-1: 2.2M ZnCl.sub.2 abaloparatide formulation with HCl on patch ready to use (after drying) (Table 3.8.1).

TABLE-US-00012 TABLE 3.8.1 Formulation W: 2.2 M ZnCl.sub.2 abaloparatide formulation on patch ready to use (after drying) Component Weight (about) % Abaloparatide 93.85 Zinc Chloride, USP (ZnCl.sub.2) 6.11 HC1 0.04 Total 100.00

[0044] Formulation X: ZnAc abaloparatide coating solution (Table 3.9).

TABLE-US-00013 TABLE 3.9 Formulation X: ZnAc abaloparatide coating solution Component Weight (about) % Abaloparatide 40.62 Zinc Acetate, USP 1.38 (about 0.7 mole ratio to abaloparatide) Sterile Water for Injection, USP 58.00 Total 100

[0045] Formulation X: ZnAc abaloparatide formulation on patch ready for use (after drying) (Table 3.10).

TABLE-US-00014 TABLE 3.10 Formulation X: ZnAc abaloparatide formulation on patch ready for use (after drying) Component Weight (about) % Abaloparatide 96.7 Zinc Acetate, USP 3.3 Total 100

Transdermal System

[0046] Subjects received a single application of a trans dermal patch (500×550 patch; needles had a length of 500 μm and needle tips were spaced 550 μm from each other). Microneedle trans dermal patches coated with the formulations of abaloparatide were stored refrigerated at 2-8° C. At least one hour prior to use, the trans dermal patches in individual pouches were placed at room temperature. The area of a single patch with microneedles was typically about 1.26 cm.sup.2. If two patches were used, they had a combined area of about 2.52 cm.sup.2. The patch was applied by pushing the delivery device containing the patch to the skin at a force of, e.g., 15-25 newtons. The energy at impact to the patch upon delivery is delivered very quickly to the stratum corneum with a penetration time of less than, for example 50 milliseconds or even less than 10 milliseconds and energy sufficient to penetrate the stratum corneum.

Pharmacokinetic Assessments

[0047] In Cohorts 1-5, a total of 10 venous blood samples were drawn from each subject in each treatment period to measure abaloparatide plasma concentrations at the following time points (clock starts from time of application/injection): 0 (pre-dose), 5, 10, 20, 30, and 60 minutes and 1.5, 2, 3, and 24 hours post-dose.

[0048] Beginning in Cohort 6, a total of 11 venous blood samples were drawn from each subject in each treatment period to measure abaloparatide plasma concentrations at the following time points: 0 (pre-dose), 5, 10, 20, 30, and 60 minutes and 1.5, 2, 3, 4, and 24 hours post-dose.

[0049] In Cohort 7, a total of 12 venous blood samples were drawn from each subject in each treatment period to measure abaloparatide plasma concentrations at the following time points( ) (pre-dose), 5, 10, 20, 30, and 60 minutes and 1.5, 2, 3, 4, 8, and 24 hours post-dose.

[0050] PK parameters of plasma abaloparatide were calculated using a validated Phoenix™ WinNonlin® 7. Summary tables and figures of abaloparatide in plasma were generated using a validated version of Phoenix™ WinNonlin® 7 or R Version 3.4.4. Inferential statistical analyses were performed using validated version of Phoenix™ WinNonlin® 7 (Average Bioequivalence Module).

[0051] The total dose of abaloparatide released from the patch was used for PK parameter calculation following abaloparatide-TD. The total released dose was calculated in the source dataset as: Total Released Dose (μg)=Initial Patch Content (μg)−Patch Residual Drug (μg)−Skin Swab Residual Drug (μg). The nominal dose of abaloparatide (i.e., 80 μg) was used for PK parameter calculations following abaloparatide-SC.

Cohorts 1-3: Study Design

[0052] The study design of Cohorts 1 through 3 followed a 4 period Williams Latin Square Design in which an equal number of subjects in each cohort were randomized to 1 of the 4 treatment sequences. In this design, each subject received each of the 4 treatments in the cohort over the course of the 4 treatment periods (Table 4). All abaloparatide-TD formulations were applied to the periumbilical region of the abdomen for 15 minutes.

TABLE-US-00015 TABLE 4 Cohorts 1 to 3 Treatment Design (All TD treatments used Applicator 1, Site-Abdomen, 15 minutes) Cohort 1 (Formulation A) Cohort 2 (Formulation B) Cohort 3 (Formulation C) Treatment Period Sequence 1 2 3 4 1  SC 80 μg TD 200 μg TD 100 μg TD 150 μg 2 TD 100 μg  SC 80 μg TD 150 μg TD 200 μg 3 TD 150 μg TD 100 μg TD 200 μg  SC 80 μg 4 TD 200 μg TD 150 μg  SC 80 μg TD 100 μg

[0053] Subjects were randomized to receive 1 of the 4 possible dosing sequences shown using equal allocation ratio in each cohort. This design was used for Cohorts 1, 2, and 3 with an evaluation period after each cohort. A different TD patch formulation was used for each cohort. Subjects were enrolled into 1 of 3 cohorts, with each cohort receiving a different TD formulated patch. Each treatment period was separated by a washout period of at least 7 days.

Cohort 1 Results

[0054] Referring to FIG. 1A and FIG. 1B, following a single dose of abaloparatide-TD Formulation A at 3 dose levels, geometric mean plasma abaloparatide AUC and C.sub.max increased from the 100 to 150 μg dose levels and remained stable from the 150 to 200 μg dose levels. Systemic exposure parameters following abaloparatide-TD Formulation A achieved 25 to 44% of abaloparatide-SC AUC and 41 to 56% of abaloparatide-SC C.sub.max.

[0055] Assuming a dose proportional increase in systemic exposure, the observed CL/F suggested that a patch of 350 μg would be required to achieve similar systemic exposure to the SC 80 μg treatment. Given that the systemic exposure (C.sub.max and AUC.sub.0-t) appeared to plateau between 150 and 200 μg TD, the likelihood of successfully matching the target 80 μg SC results with Formulation A appeared low.

[0056] Based on AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max values, the relative bioavailability of abaloparatide following a single administration of abaloparatide-TD Formulation A at dose levels of 100, 150 and 200 μg was 44.1 to 73.6% lower than that of abaloparatide-SC and the 90% CI were outside the 80 to 125% acceptance criteria for similarity for all comparisons.

Cohort 2 Results

[0057] Referring to FIG. 2A and FIG. 2B, following abaloparatide-TD Formulation B, mean plasma abaloparatide concentrations were similar across the 100 to 200 μg dose levels. Mean plasma abaloparatide concentrations were lower following abaloparatide-TD Formulation B for all dose levels compared to abaloparatide-SC.

[0058] Systemic exposure parameters following abaloparatide-TD Formulation B achieved 19 to 29% of abaloparatide-SC AUC and 52 to 56% of abaloparatide-SC C.sub.max. Based on AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max values, the relative bioavailability of abaloparatide following a single administration of abaloparatide-TD Formulation B at dose levels of 100, 150 and 200 μg was 46.6 to 83.0% lower than that of abaloparatide-SC and the 90% CI were outside the 80 to 125% acceptance criteria for similarity for all comparisons.

Cohort 3 Results

[0059] Referring to FIG. 3A and FIG. 3B, following abaloparatide-TD Formulation C, mean plasma abaloparatide concentrations were similar across the 100 to 200 μg dose levels. Mean plasma abaloparatide concentrations were lower following abaloparatide-TD Formulation C for all dose levels compared to abaloparatide-SC.

[0060] Systemic exposure parameters following abaloparatide-TD Formulation C achieved 14 to 33% of abaloparatide-SC AUC and 30 to 43% of abaloparatide-SC C.sub.max. And based on AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max values, the relative bioavailability of abaloparatide following a single administration of abaloparatide-TD Formulation C at dose levels of 100, 150 and 200 μg was 59.1 to 86.9% lower than that of abaloparatide-SC and the 90% CI were outside the 80 to 125% acceptance criteria for similarity for all comparisons.

Summary of Cohorts 1 to 3

[0061] Overall, for Cohorts 1 to 3, the AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max of abaloparatide following a single administration of abaloparatide-TD Formulations A, B or C at dose levels of 100, 150 or 200 μg were lower than those observed for 80 μg abaloparatide-SC.sub.max The systemic exposure (C.sub.max and AUC.sub.0-t) of abaloparatide-TD Formulation A increased from the 100 to 150 μg dose levels and appeared to plateau between 150 and 200 μg. As for Formulations B and C (Cohort 2 and 3), the systemic exposure did not increase with increasing dose and appeared to have already plateaued at 100 μg. Assuming a dose-proportional increase in systemic exposure, a dose of 350 μg of Formulation A would be required to match the systemic exposure of 80 μg abaloparatide-SC.

Cohorts 4 and 5

[0062] In Cohort 4, subjects received abaloparatide-TD Formulation A and Formulation C at 200 μg dose applied to the ventral midline of the thigh with a wear time of 15 minutes. In Cohort 4, treatment period 3, each subject was given study medication through simultaneous application of two abaloparatide-TD 150 μg patches in separate quadrants of the abdomen (Applicator 1). The abaloparatide-TD microneedle patches were applied for 15 minutes, and each treatment period was separated by a washout period of at least 3 days.

[0063] Cohort 5 evaluated four formulations of abaloparatide-TD. Each patch contained a dose of either 200 μg or 260 μg of abaloparatide, applied as a single patch administration to the thigh, or a simultaneous double patch application of 200 μg applied to the ventral midline of thigh with a different patch applicator (Applicator 2). All abaloparatide-TD formulations were applied for 15 minutes. A summary of the design for Cohorts 4 and 5 is shown in Table 5.

TABLE-US-00016 TABLE 5 Treatments for Cohorts 4 and 5 Cohort 4, all TD treatments used Applicator 1, 15 Minutes Cohort 5, all TD treatments used Applicator 2, 15 Minutes Sequence Period 1 Period 2 Period 3 Period 4 4 Form A, Form C, Form A, 200 μg, 200 μg, 2 × 150 μg, Thigh Thigh Abdomen 5 Form W, Form X, Form A, Form W, 200 μg, 200 μg, 260 μg, 2 × 200 μg, Thigh Thigh Thigh Thigh

[0064] Referring to FIG. 4A and FIG. 4B, mean plasma abaloparatide concentrations were higher following abaloparatide-TD Formulation A 200 μg applied to the thigh and 2×150 μg applied to the abdomen treatments compared to abaloparatide-TD Formulation C 200 μg. Mean plasma abaloparatide concentrations were higher with the double patch Formulation A2×150 μg applied to the abdomen compared with the 200 μg single patch applied to the thigh. Based on AUC.sub.0-t, AUC.sub.0-inf and C.sub.max values, the relative bioavailability of abaloparatide following a single administration of abaloparatide-TD Formulations A and Cat dose levels of 200 μg and 2×150 μg was 20.6 to 65.5% lower than that of abaloparatide-SC, except for similar C.sub.max (geometric ratio of 108%) achieved with Formulation A 2×150 μg.

[0065] Referring to FIG. 5A and FIG. 5B, the abaloparatide-TD Formulation W 2×200 μg double patches achieved the highest mean plasma abaloparatide concentrations followed by Formulation W 200 μg and then Formulation A 260 μg and Formulation X 200 μg with similar concentration levels. Based on AUC.sub.0-t, AUC.sub.0-inf and C.sub.max values, the relative bioavailability of abaloparatide following a single administration of abaloparatide-TD Formulations A, W and X at dose levels of 200 and 260 μg was 26.3 to 63.3% lower than that of abaloparatide-SC, except for similar C.sub.max (geometric ratio of 83.2%) achieved with Formulation A 260 μg.

[0066] Formulation W 2×200 μg applied 15 minutes to the thigh (Cohort 5) was the most similar to 80 μg abaloparatide SC with AUC.sub.0-t and C.sub.max values achieving 96.2 and 103% of those of abaloparatide SC, respectively. The double patch application Formulation A 2×150 μg (300 μg total) (Cohort 4) and Formulation W 2×200 μg (400 μg total) (Cohort 5) increased the systemic exposure in a dose-proportional manner compared to a single patch application of 200 μg. Although the application site was different, the AUC.sub.0-t was increased by ˜33% and C.sub.max by ˜42% with Formulation A after increasing the dose by 50% using double patches (i.e., 2×150 μg vs. 200 μg), by increasing the dose released from the patches, which could not be achieved via a greater patch loading dose.

[0067] The best performing abaloparatide formulation in Cohorts 1-5 was Formulation W 2×200 μg applied to the thigh for 15 minutes. And dose proportional systemic exposure for Formulation W was achieved by increasing the number of patches. Doses, application sites and wear times for Formulation W were evaluated further in Cohort 6.

Cohort 6

[0068] Cohort 6 evaluated 3 wear times and 3 doses of abaloparatide-TD, each applied as a single patch administration to the thigh or abdomen using applicator 2. Subjects were randomized for Treatment Periods 1 and 2 to receive abaloparatide-TD 400 μg and abaloparatide-TD 300 μg in a crossover design, applied to the thigh for a 15 minute wear time. For Treatment Periods 3 and 4, subjects received abaloparatide-TD 400 μg applied to the thigh, either for a 5 minute or a 30 minute wear time, respectively. Based on previous cohorts, additional Treatment Periods (5A and/or 5B) were considered, but only Period 5B was evaluated. Subjects in Treatment Period 5B received the reference SC dose (abaloparatide-subcutaneous [SC] 80 μg). For Treatment Period 6, subjects received abaloparatide-TD 300 μg applied to one of the upper quadrants the abdomen for a 15 minute wear time. A summary of the design for Cohort 6 is shown in Table 6.

TABLE-US-00017 TABLE 6 Treatments for Cohort 6 All TD treatments used Formulation W, Applicator 2 Se- Period quence Period 1 Period 2 Period 3 Period 4 5B Period 6 1 400 μg, 300 μg, 400 μg, 400 μg, SC 300 μg, Thigh, Thigh, Thigh, Thigh, 80 μg Abdomen, 15 Minutes 15 Minutes 5 30 15 2 300 μg, 400 μg, Minutes Minutes minutes Thigh, Thigh, 15 Minutes 15 Minutes

[0069] Referring to FIG. 6A-6C, abaloparatide was absorbed with mean tmax ranging from 20 to 60 minutes for TD treatments, compared to 30 minutes for SC.sub.max Formulation W 300 μg produced 25% to 40% higher abaloparatide C.sub.max and AUC than the Formulation W 400 μg (Thigh, 15 minutes). Similar to assessments in previous cohorts, Formulation W 300 μg application to the thigh produced 60% to 80% higher abaloparatide C.sub.max and AUC than application to the abdomen.

[0070] As shown in FIG. 6C, formulation W 400 μg applied for 5 minutes to the thigh provided similar AUC and C.sub.max compared to the SC 80 μg within the same cohort of subjects (4 to 20% higher AUC and 21.1% lower C.sub.max).

[0071] However, compared to the SC 80 μg data pooled across 4 studies, FIG. 6E shows Formulation W 400 μg applied for 5 minutes to the thigh provided 45 to 59% higher AUC and 3.7% lower C.sub.max). When the Formulation W 300 μg patch was applied to the abdomen, the systemic exposure achieved was 34.6 to 46.8% lower than that of achieved for same patch applied to the thigh. For the Formulation W 400 μg patch, the highest systemic exposure levels were reached when the patch was applied for the shortest tested wear time with AUC.sub.0-t, AUC.sub.0-inf and C.sub.max values 52 to 74% higher after 5 minutes than after 15 minutes. Increasing the wear time to 30 minutes did not seem to have any impact on systemic exposure, with similar AUC.sub.0-t, AUC.sub.0-inf and C.sub.max values (13% to 23% higher geometric means) after 15 and 30 minutes.

[0072] Referring to FIG. 6D, for Formulation W 400 μg applied to the thigh, AUC.sub.5 min>AUC.sub.30 min>AUC.sub.15 min (relative bioavailability compared to within-cohort SC was 104%-121%, 55%-70%, and 41%-52%, respectively). Formulation W 300 μg (Thigh, 15 minutes) had a 73% relative bioavailability compared to within-cohort SC, better than 400 μg (Thigh, 15 minutes). Formulation W 300 μg (Thigh, 5 minutes) also had a 96%-99% relative bioavailability compared to pooled SC treatments.

[0073] These results suggested that wear time has a significant factor in the availability of abaloparatide, although the relationship between wear time and systemic exposures was unexpected. For example, at a common dose of 400 μg, the shortest wear time of 5 minutes produced higher systemic exposure than the wear time of 30 minutes, which was slightly greater than the systemic exposure for a wear time of 15 minutes. The reason for this unusual rank order based on wear time is not clear. Decreasing the wear time from 15 to 5 minutes essentially doubled the systemic exposure. However, increasing the wear time to 30 minutes had only a small impact on systemic exposure. The thigh appeared to be a better application site compared to the abdomen, as there was a ˜50 to 60% increase in systemic exposure following administration at that site. Overall, administering a 400 μg patch of Formulation W for 5 minutes to the thigh produced systemic exposures comparable to an 80 μg SC administration. Although for the same 15-minute wear time and application to the thigh, the systemic exposure for Formulation W 300 μg was higher than the systemic exposure for Formulation W 400 μg.

[0074] Based on these results, Cohort 7 was designed to explore four different wear times (5 min, 15 min, 30 min, and 24 hours) for Formulation W-1 300 μg patch applied to the thigh.

Cohort 7

[0075] Cohort 7 evaluated 4 wear times for the 300 μg patch of abaloparatide-TD Formulation W-1 each applied as a single patch administration to the thigh or abdomen using Applicator 3. There were 6 treatment periods for subjects in Cohort 7. Subjects were randomized to 1 of 4 treatment sequences in Treatment Period 1 to 4. Subjects in the randomization treatment stage were treated with 300 μg of abaloparatide-TD with different wear times to the thigh (5, 15, 30 minutes, or 24 hours). Subsequently, all subjects entered the sequential treatment stage starting in Treatment Period 5 and were treated with 300 μg of abaloparatide-TD in the periumbilical region of the abdomen for 15 minutes wear time. In the sixth and final treatment period, subjects were injected with 80 μg of abaloparatide-SC in the periumbilical region of the abdomen. Each treatment period was separated by a washout period of at least 3 days. The design is summarized in Table 7: Treatments for Cohort 7.

TABLE-US-00018 TABLE 7 Treatments for Cohort 7 All TD treatments used Formulation W-1, Applicator 2 Se- Period Period quence Period 1 Period 2 Period 3 Period 4 5B 6 1 300 μg, 300 μg, 300 μg, 300 μg, 300 μg, SC Thigh, Thigh, Thigh, Thigh, Ab- 80 μg 5 min 15 min 30 min 24 Hours domen, 2 300 μg, 300 μg, 300 μg, 300 μg, 15 min Thigh, Thigh, Thigh, Thigh, 15 min 24 Hours 5 min 30 min 3 300 μg, 300 μg, 300 μg, 300 μg, Thigh, Thigh, Thigh, Thigh, 30 min 5 min 24 Hours 15 min 4 300 μg, 300 μg, 300 μg, 300 μg, Thigh, Thigh, Thigh, Thigh, 24 Hours 30 min 15 min 5 min

[0076] As shown in FIGS. 7A, 7B and 7C, abaloparatide was absorbed slowly, with mean tmax ranging from 27 to 35 minutes for TD treatments, compared to 24 minutes for SC.sub.max Similar to assessments in previous cohorts, Formulation W-1 300 μg application to the thigh produced 10% to 25% higher abaloparatide C.sub.max and AUC than application to the abdomen.

[0077] For Formulation W-1 300 μg applied to the thigh, AUC.sub.5 min=AUC.sub.24 h>AUC.sub.30 min>AUC.sub.15 min (relative bioavailability compared to within-cohort SC was 83%-93%, 81-96%, 73%-77%, and 70%-82%, respectively).

[0078] The relative bioavailability for Formulation W-1 compared to SC was similar to that for Formulation W (73-77% vs. 73%, respectively, Thigh, 15 minutes).

[0079] Formulation W-1 300 μg applied 5 minutes and 24 hours to the thigh were the most similar to 80 μg abaloparatide-SC with AUC.sub.0-t and AUC.sub.0-inf values achieving 81.1 to 95.8% of those of abaloparatide-SC, respectively. Additionally, compared to the SC 80 μg data pooled across 4 studies, Formulation W-1 300 μg applied for 5 minutes to the thigh provided 12.2% lower to 1% higher AUC and 31.0% lower C.sub.max). The Formulation W-1 300 μg 5 minutes and 24 hours wear time C.sub.max were lower achieving 62.2 and 45.0% of abaloparatide-SC C.sub.max, respectively, for the within-cohort comparisons.

[0080] For the Formulation W-1 300 μg patch, the highest systemic exposure levels were reached when the patch was applied for the shortest tested wear time with AUC0-t, AUC0-inf and Cmax values 15 to 21% higher after 5 minutes than after 15 minutes. Increasing the wear time to 30 minutes did not seem to have any impact on systemic exposure, with similar AUC.sub.0-t, AUC.sub.0-inf and C.sub.max values (geometric mean ratios 90 to 106%) after 15 and 30 minutes. As for increasing the wear time to 24 hours, AUC0-inf was increased by 28%, while AUC.sub.0-t and the C.sub.max were more or less similar with geometric mean ratios of 117 and 88.4%, respectively.

[0081] For the Formulation W 400 μg patch (Cohort 6) and for Formulation W-1 300 μg (Cohort 7), higher abaloparatide systemic exposure levels were reached when the patch was applied 5 minutes compared to 15 and 30 minutes. However, when the Formulation W-1 patch was applied for 24 hours, total released dose, and therefore total systemic exposure was increased compared to 15 minutes.

Model Prediction for BMD

[0082] Table 8: Model Prediction for the % Change in BMD in Typical Subject, depicts the model prediction for the percent change in BMD in a typical subject. This assumes a baseline T-score of −2.7, and draws upon dose response studies and population PK/PD modeling. Without wishing to be bound to any particular theory, it is believed that AUC is the key driver of BMD increases.

TABLE-US-00019 TABLE 8 Model Prediction for the % Change in BMD in Typical Subject % Change in % Change % Change in % Change in AUC BMD in BMD BMD BMD Treatment (pg .Math. h/mL) 3 Months 6 Months 9 Months 12 Months Placebo 0 0.29 0.42 0.52 0.60 SC 80 μg 1018 4.39 6.28 7.74 8.98 Formulation 942 4.33 6.20 7.64 8.86 W-1 300 μg (Thigh, 5 min)

[0083] Overall, abaloparatide application to the thigh consistently provided greater abaloparatide AUC than application to the abdomen, although the difference was less dramatic for Formulation W-1. And the wear-time of 5 minutes provided greater abaloparatide AUC than the wear times for 15 minutes and 30 minutes for both Formulation W 400 μg and Formulation W-1 300 μg. Formulation W-1 300 μg applied to the thigh for 5 minutes provided 83-93% relative bioavailability compared to SC 80 μg, with only slightly lower expected BMD response.