CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional patent Application. No. 62/293,606, filed on February 10, 2016 and U.S. provisional patent Application. No. 62/359,502, filed on July 7, 2016, both of which are incorporated herein by reference in their entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the sequence listing submitted electronically with this application (ASQII text file 86867.0004.PCT_ST25.txt, created July, 2016) is incorporated herein in its entirety by reference for all purposes.

FIELD

[0003] The present disclosure relates to a pharmaceutical formulation comprising tralokinumab, wherein the formulation is suitable for injection within a drug delivery device configured to deliver to a human subject from about 1 mL to about 3.0 mL of the formulation at a flow rate of up to about 12 mL per minute. An aspect of the disclosure provides for subcutaneous injection of a relatively large volume dose (e.g., 2 mL to 3 mL) of the tralokinumab pharmaceutical formulation, with a tolerable level of pain to a subject.

BACKGROUND

[0004] Interleukin-13 (IL- 13) is a member of the interleukin family of cytokines and a central mediator of inflammatory diseases. There are several IL-13-mediated diseases or disorders in which pathology is associated with (e.g. , caused, exacerbated, or prolonged) by abnormal levels of IL- 13. Examples of IL- 13 -mediated diseases or disorders include asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), ulcerative colitis (UC), allergic rhinitis, chronic rhinosinusitis, fibrosis, Hodgkin' s lymphoma, and atopic dermatitis. Accordingly, IL-13 antagonists offer valuable active agents for the amelioration or treatment of inflammatory conditions associated with IL-13.

[0005] As an IL- 13 antagonist, tralokinumab (also referred to as CAT-354) is a therapeutic biologic of particular interest. More specifically, tralokinumab is a human monoclonal antibody that targets and neutralizes IL- 13, and is therefore useful for the treatment of inflammatory diseases such as asthma or atopic dermatitis. As typical with prefilled syringes currently employed for subcutaneous (SQ) administration of biologies, syringes for delivery of IL-13 antagonists such as tralokinumab deliver about 1 mL of a fairly viscous fluid. Indeed, injection of 1 mL in a single, self-administered dose has been historically regarded as the upper threshold of acceptability, particularly regarding SQ delivery. Therefore, if a larger dose of tralokinumab is prescribed, then the patient must administer, or be administered, at least two injections instead of one. Alternatively, an increased dose volume of up to 3 mL or more may be needed to administer a required dose of active agent(s); but this may cause greater pain intensity during SQ injection. In addition to pain or discomfort experienced when administering a large volume viscous dosage form, subjects generally do not want, or are unable, to hold a syringe or auto-injector in place for more than about 15 seconds as required for the actual injection process. Finally, in the case of SQ administration, a high flow rate of injection can exceed the tissue's physical allowance to accept a large volume dosage form, leading to back-pressure leakage from the subject's injection site. These issues can impact patient compliance, adding to the burdens of the healthcare system. Hence, there remains a need for a delivery device that can be used for less painful subcutaneous injection of a single large-volume dosage form (e.g. , 2 mL) comprising an IL-13 antagonist such as tralokinumab.

SUMMARY

[0006] The present embodiments provide a pharmaceutical formulation for injection comprising tralokinumab, wherein the formulation is disposed within a drug delivery device (as disclosed herein) configured to deliver to a human subject from about 1 mL to about 3 mL of the formulation at a flow rate of up to about 12 mL per minute. An additional aspect relates to drug delivery devices prefilled with the pharmaceutical formulation comprising tralokinumab, which devices are capable of delivering a large-volume dosage form (for example, a 2 mL to 3 mL dosage form rather than a 1 mL dosage form). In some embodiments, the tralokinumab delivery device is capable of delivering a large- volume dosage form (for example, 2 mL to 3 mL rather than 1 mL) of a tralokinumab pharmaceutical formulation, with a level of pain intensity that is tolerable to a subject. These prefilled devices are advantageous, for example, in administering the large-volume viscous dosage form of a tralokinumab pharmaceutical formulation at a rate such that pain does not negatively impact compliance with a prescribed dosing regimen while also ensuring that the dosing regimen does not negatively impact tralokinumab

pharmacokinetics.

[0007] At least one embodiment provides a pharmaceutical formulation for injection comprising tralokinumab, wherein the formulation is disposed within a delivery device (as disclosed herein, see, e.g. , FIGS. 5-13) comprising an insertion mechanism, a drive mechanism, and a sterile fluid pathway, and a container comprising a tralokinumab dosage form, wherein said tralokinumab delivery device is configured to deliver, to a human patient, a volume from about 1 mL to about 3 mL, inclusive, such as 2 mL, at flow rate of up to about 12 mL per minute. In some aspects, the tralokinumab is a monoclonal antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical formulation may include tralokinumab with at least one additional active agent. In some embodiments, the

pharmaceutical formulation may include tralokinumab with 50 mM sodium acetate/acetic acid and 85 mM sodium chloride having a pH of about 5.2 to about 5.7. In some embodiments, the dosage form may include from about lOmg/mL to about 600 mg/mL tralokinumab, inclusive, in an excipient formulation of 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of about 5.5+0.5. In some embodiments, the pharmaceutical formulation may include tralokinumab with 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of 5.5+1. In some embodiments, the pharmaceutical formulation may include tralokinumab where tralokinumab is an antibody or antigen-binding fragment thereof comprising (a) a variable heavy chain comprising the amino acid sequence depicted in SEQ ID NO: l and/or a variable light chain comprising the amino acid sequence depicted in SEQ ID NO:2; or (b) a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:3, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:4, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:5, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:6, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:7, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:8.

[0008] In some embodiments, the dosage form comprises about 300 mg tralokinumab. In specific aspects, tralokinumab is administered at a fixed dose selected from about 50 mg to about 600 mg tralokinumab, inclusive; such as a fixed dose of about 50 mg, about 100 mg, about 150 mg, aboutl75 mg, about 200 mg, about 300 mg, about 325 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg tralokinumab/dose. In some aspects, the tralokinumab is administered in two or more doses. In other aspects, the

tralokinumab is administered daily, twice a week (semi weekly), four- times weekly, once- weekly, once every two weeks, once every four weeks, biweekly (fortnightly), once monthly, twice monthly (semimonthly), every two months (bimonthly), or at a frequency determined by a health care professional. In some embodiments, the tralokinumab is administered once every two weeks. In some embodiments, the device is configured for SQ delivery of about 2 mL of a dosage form comprising about 300 mg tralokinumab. In some embodiments, the tralokinumab delivery device delivers a volume of nominal 2 mL of a pharmaceutical formulation comprising tralokinumab, with the device retaining about 0.2 mL. In some embodiments, the formulation dosage form is administered during a nominal infusion duration of about 4 minutes. In a particular aspect, the pharmaceutical formulation is useful in the treatment of IL-13-mediated diseases or disorders including, e.g., asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, chronic rhinosinusitis, fibrosis, Hodgkin's lymphoma, or atopic dermatitis.

[0009] In at least one embodiment, the pharmaceutical formulation comprising tralokinumab is disposed in a tralokinumab delivery device that is a wearable, on-body device. In at least one embodiment, the tralokinumab delivery device is configured to deliver the tralokinumab dosage form to the patient via an auto-inserted cannula. In some embodiments, the tralokinumab delivery device is disposable. In some embodiments, the tralokinumab is disposed in a container that is removable from the device, and the container may be disposable. In at least one embodiment, the tralokinumab delivery device comprises a removable power source, such as a battery, which may be reusable (i.e., rechargeable) or disposable. In at least one embodiment, the tralokinumab delivery device comprises electronics. In at least one embodiment, the tralokinumab delivery device is capable of providing at least one alert, such as a visual or audible alert. In some embodiments, the tralokinumab delivery device is configured for delivery of the tralokinumab dosage form once-daily, twice a week (semiweekly), four-times weekly, once-weekly, once every two weeks, once every four weeks, biweekly (fortnightly), once monthly, twice monthly (semimonthly), every two months (bimonthly), or at a frequency determined by a health care professional. In some embodiments, the insertion mechanism of the tralokinumab delivery device comprises a cannula. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a variable flow rate. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a preselected flow rate, the flow rate selected from a range of about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of between about 0.8 mL per minute and 5 mL per minute or a flow rate of between about 1 mL per minute and 5 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 1 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute. In other embodiments, the duration of a nominal 2 mL volume of tralokinumab dosage form is no faster than 2 minutes at 18°C to 28°C. In other embodiments, the duration of a nominal 2 mL volume of tralokinumab dosage form is no faster than 1 minute at 18°C to 28°C. In some other embodiments, the dosage form delivery duration of a nominal 2 mL volume is no slower than 15 minutes at 18°C to 28°C. In some embodiments, the dosage form is delivered during a 4-minute nominal infusion duration. In some embodiments, the dosage form is delivered during a 2-minute nominal infusion duration. In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity of about 12 cP at 150mg/mL at 23 °C. In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity range of about 6 cP (135 mg/mL at 28°C) to 32 cP (165 mg/mL at 18°C). In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity range of about 23 cP (162 mg/mL at 28°C). In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity between 1 cP and 100 cP at a temperature between about 5°C and 40°C or about 2°C and 42°C.

[0010] At least one embodiment provides a pharmaceutical formulation comprising tralokinumab disposed in a drug delivery device comprising means for delivering to a human subject a volume of about 1 mL to about 3 mL, inclusive, of a viscous tralokinumab dosage form at a flow rate of up to about 12 mL per minute. In certain embodiments, the delivery is by SQ injection. In some embodiments, the tralokinumab is a monoclonal antibody or an antigen- binding fragment thereof. In some embodiments, the dosage form comprises about 50 mg to about 600 mg, inclusive, of tralokinumab. In some embodiments, the dosage form comprises about 300 mg tralokinumab. In some embodiments, the device is configured for SQ delivery of about 2 mL of a dosage form comprising tralokinumab. In some embodiments, the tralokinumab delivery device is configured for delivery of the dosage form on a daily, twice a week

(semiweekly), four-times weekly, once-weekly, once every two weeks, once every four weeks, biweekly (fortnightly), once monthly, twice monthly (semimonthly), every two months

(bimonthly) basis. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form on a once every two weeks basis. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate ranging from about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of between about 0.8 mL per minute and 5 mL per minute or a flow rate of between about 1 mL per minute and 5 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 1 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute. In other embodiments, the delivery duration of a nominal 2 mL volume of tralokinumab dosage form is no faster than 2 minutes at 18°C to 28°C. In other embodiments, the delivery duration of a nominal 2 mL volume of tralokinumab dosage form is no faster than 1 minute at 18°C to 28°C. In some other embodiments, the delivery duration of a nominal 2 mL volume is no slower than 15 minutes at 18°C to 28°C. In some embodiments, the dosage form is delivered with 4-minute nominal infusion duration. In some embodiments, the dosage form is delivered with 2-minute nominal infusion duration. In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity of about 12 cP at 150mg/mL at 23 °C. In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity range of about 6 cP (135 mg/mL at 28°C) to about 32 cP (165 mg/mL at 18°C). In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity range of about 23 cP (162 mg/mL at 28°C). In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity between about 1 cP and about 100 cP at a temperature between about 5°C and about 40°C or about 2°C and about 42°C, inclusive. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a variable flow rate.

[0011] At least one embodiment provides for a method for administering to a human subject in need thereof a viscous pharmaceutical formulation dosage form comprising tralokinumab, comprising contacting a human subject with a tralokinumab delivery device in which the formulation is disposed, which tralokinumab delivery device is configured to deliver from about 1 mL to about 3 mL, inclusive, of a viscous liquid dosage form at a flow rate of up to about 12 mL per minute, and actuating said device to deliver said dosage form. In certain embodiments, the tralokinumab delivery is by SQ injection. In some embodiments, the tralokinumab is an antibody or an antigen-binding fragment thereof. In some embodiments, the dose is about 300 mg tralokinumab. In some embodiments, the tralokinumab delivery device is configured for SQ delivery of about 2 mL of a dosage form comprising tralokinumab. In some embodiments, the tralokinumab delivery device is actuated once daily. In some embodiments, the delivery flow rate is from a range of about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the delivery flow rate is from a range of about 0.8 mL per minute and 5 mL per minute or about 1 mL per minute and 5 mL per minute. In some embodiments, the flow rate is about 12 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the flow rate is about 1 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute. In some embodiments, the delivery device of the method is configured to deliver the dosage form at duration of about 4-minute nominal infusion duration. In some aspects, the method is useful in the treatment of IL- 13 -mediated diseases or disorders including, e.g. , asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), ulcerative colitis (UC), allergic rhinitis, chronic rhinosinusitis, fibrosis, Hodgkin's lymphoma or atopic dermatitis.

[0012] At least one embodiment provides a drug delivery device comprising a means for delivering to a human patient about 2 mL to about 3 mL of a dosage form comprising tralokinumab, at a flow rate of up to about 12 mL per minute. In certain embodiments, the delivery is SQ injection. In some embodiments, the dosage form comprises about 300 mg tralokinumab. In some embodiments, the device is configured for delivery of the dosage form comprising tralokinumab on a daily, twice a week (semi weekly), four- times weekly, once- weekly, once every two weeks, once every four weeks, biweekly (fortnightly), once monthly, twice monthly (semimonthly), every two months (bimonthly) basis. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form on a once every two weeks basis. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate ranging from about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of between about 0.8 mL per minute and 5 mL per minute or a flow rate of between about 1 mL per minute and 5 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 12 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 2 mL per minute. In some embodiments, the

tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 1 mL per minute. In some embodiments, the tralokinumab delivery device is configured to deliver the dosage form at a flow rate of about 0.167 mL per minute. In some embodiments, the delivery device is configured to deliver the dosage form at duration of about 4- or about 2-minute nominal infusion duration. In some aspects, the drug delivery device comprises one or more components described in FIGS. 5-13. In some embodiments, the drug delivery device comprises one or more components selected from the group consisting of (a) a pump as described in FIG. 9; (b) an insertion mechanism as described in FIGS. 6 or 7; (c) a fluid pathway connection as described in FIGS. 8, 9, 10 or 11; (d) a drive mechanism as described in FIGS. 12 or 13; and (e) an activation mechanism as described in FIGS. 5, 8, or 12.

[0013] At least one embodiment provides for a method for administering to a human patient in need thereof a dosage form comprising tralokinumab, comprising contacting a human patient with a drug delivery device (as described herein, see, e.g. , FIGS. 5-13) prefilled with a tralokinumab pharmaceutical formulation, wherein the device is configured to deliver about 2 mL to about 3 mL of the dosage form at a flow rate of up to about 12 mL per minute, and actuating said device to deliver said dosage form. In some embodiments, the dosage form is about 2 mL pharmaceutical formulation comprising about 300 mg tralokinumab. In certain embodiments, the delivery is SQ injection. In some embodiments, the tralokinumab delivery device is actuated once daily. In some embodiments, the delivery flow rate is preselected from the range of about 0.167 mL per minute to about 12 mL per minute, inclusive. In some embodiments, the flow rate is about 12 mL per minute. In some embodiments, the flow rate is about 2 mL per minute. In some embodiments, the flow rate is about 0.167 mL per minute. In some embodiments, the delivery device of the method is configured to deliver the dosage form at duration of about 4-minute or about 2-minute nominal infusion duration. In some

embodiments, the method of administration includes the delivery of the dosage form comprising tralokinumab on a daily, twice a week (semiweekly), four-times weekly, once-weekly, once every two weeks, once every four weeks, biweekly (fortnightly), once monthly, twice monthly (semimonthly), every two months (bimonthly) basis. In some embodiments, the method of administration is repeated every two weeks. In at least one embodiment, the method is useful in the treatment of IL- 13 -mediated diseases or disorders including, e.g., asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), ulcerative colitis (UC), allergic rhinitis, chronic rhinosinusitis, fibrosis, Hodgkin's lymphoma, or atopic dermatitis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is a bar graph showing delivery times, in seconds (y-axis), for various types of administration (y-axis). tsubQ = Delivery Time, Subcutaneous (SQ) Delivery, With Viscosity Tolerance (Case 1); tsubQvc = Delivery Time, Subcutaneous Delivery, Constant Viscosity (Case 2); tamb = Delivery Time, Ambient Delivery, With Viscosity Tolerance (Case 3); and tambvc = Delivery Time, Ambient Delivery, Constant Viscosity (Case 4). Error bars show min/max error.

[0015] FIG. 2 is a graph presenting spring force profiles as a function of drive assembly force (N) (x-axis) over travel distance (mm) (y-axis).■ indicates minimum;▲ indicates maximum;♦ indicates nominal.

[0016] FIG. 3 is a bar graph conveying the contribution (%) to delivery time variation of components (x-axis) in Case 4, ambient delivery and viscosity constant, by variable groups. Relative contribution, in seconds, is shown as percent on the y-axis.

[0017] FIG. 4 is a bar graph conveying the contribution (%) to delivery time variation of components (x-axis) in SubQ delivery. Total variation from model is 354S and from linearized contribution 26 IS. % Variation Captured in Linearized Form is 74%. The min, nom, and max viscosity inputs are 6.89, 12.12, and 22.7, respectively.

[0018] FIG. 5A is an isometric view of a drug delivery pump, according to one embodiment with integrated safety insertion mechanism; FIG. 5B is an isometric view of the bottom of the same embodiment; FIG. 5C shows an isometric view of the interior components of the same embodiment of a drug delivery pump.

[0019] FIG. 6 shows an isometric view of an insertion mechanism that may be included in a drug delivery device, according to one embodiment.

[0020] FIG. 7A to FIG. 7C show cross-sectional views of an insertion mechanism, according to an embodiment of the present invention, in a locked and ready to use stage (FIG. 7A); in an unlocked and inserted stage (FIG. 7B); and in a retracted stage for drug delivery (FIG. 7C).

[0021] FIG. 8A and FIG. 8B are cross-sectional views of another embodiment of a fluid pathway connection attached to a drug container before then after, respectively, activation. FIG. 8C and FIG. 8D are cross-sectional views of yet another embodiment of a fluid pathway connection attached to a drug container before then after, respectively, activation.

[0022] FIG. 9A shows isometric view, from the distal perspective, of a connection hub, according to one embodiment; FIG. 9B shows an isometric view, from the proximal perspective, of the same connection hub; and FIG. 9C shows a transparent view of that connection hub.

[0023] FIG. 10A and FIG. 10B are isometric views from the distal perspective and the proximal perspective, respectively, of a connection hub, according to another embodiment of the present invention; and FIG. IOC shows a transparent view of the same connection hub.

FIG. 10D and FIG. 10E are isometric views from the distal perspective and the proximal perspective, respectively, of a connection hub, according to another embodiment.

[0024] FIG. 11 A shows an exploded view of the fluid pathway connection, exploded along a longitudinal axis "A," according to at least one embodiment of the present invention; and FIG. 1 IB shows a cross-sectional exploded view of the same fluid pathway connection.

[0025] FIG. 12A shows an isometric view of an example drive mechanism in an embodiment of a drug delivery pump having safety integrated insertion; and FIG. 12B is an exploded view of along an axis "A" of that device.

[0026] FIG. 13A to FIG. 13C present cross-sectional views of an example drive mechanism in the initial inactive state (FIG. 13A); in an actuated state (FIG. 13B); and at the completion of the delivery of the drug dosage form (FIG. 13C).

[0027] FIG. 14 is a scheme of the study design employed to determine suitability of dosage form volume and delivery rate. N = number of subjects. [0028] FIG. 15 is a graph depicting mean (SD) serum concentration time profiles of tralokinumab by cohort (PK population).

[0029] FIG. 16A-16D is a graph showing individual serum concentration time profiles of tralokinumab by cohort (PK population). In Cohort 4 (FIG. 16D), data for a subject with extensive leakage is represented by the line near the x-axis.

[0030] FIG. 17 is a graph showing mean profile plot of injection site pain by cohort (as -treated population).

[0031] FIG. 18 is a graph of mean profile plots of injection site pruritus by cohort (as -treated population).

[0032] FIG. 19 is a graph showing incidence of injection site erythema over time for each cohort following injection of a dosage form comprising 300 mg tralokinumab

(as -treated population).

[0033] FIG. 20 is a graph showing incidence of injection site hematoma or bleeding over time for each cohort following injection of a dosage form comprising 300 mg tralokinumab (as -treated population).

DETAILED DESCRIPTION OF THE INVENTION

[0034] All patents and other publications identified are incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention, but are not to provide definitions of terms inconsistent with those presented herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.

[0035] As used herein and in the claims, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises" and "comprising" are used inclusively rather than exclusively, so that a stated integer or group of integers may include one or more other non-stated integers or groups of integers. The term "or" is inclusive unless modified, for example, by "either." Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about." [0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood to one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. The terms male and female may be used interchangeably to describe corresponding components or complementary aspects thereof and are not a limitation to either particular structure unless context clearly indicates otherwise.

[0037] Headings are provided for convenience only and are not to be construed to limit the invention in any way. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood to one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. In order that the present disclosure can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0038] References to "pharmaceutical agent," "pharmaceutically active,"

"pharmaceutical," "drug," "medicament," "active agent," "active drug" "active pharmaceutical ingredient," "API," and the like, refer in a general sense to substances useful in the medical and scientific arts as suitable for delivery via a syringe, including, for example, drugs, biologies, diagnostic agents (e.g., dyes or contrast agents) or other substances used for therapeutic, diagnostic, or preventative (e.g., vaccines), or research purposes, example pharmaceutical agents include biologies, vaccines, chemotherapeutic agents, contrast agents, small molecules, immunogens, antigens, interferons, polyclonal antibody preparations, monoclonal antibodies, anesthetics, interfering RNAs, gene vectors, insulins, or combinations of any of these. As noted, a dosage form may comprise one or more active therapeutic agents, or a combination of active and diagnostic agents, etc.

[0039] "Inactive" substances refer to carriers, excipients, diluents, and the like, which are well-known in the art, although such substances may have beneficial function in the mixed injectable, such as, for example, surfactant, inorganic or organic salt, stabilizer, diluent, solubilizer, reducing agent, antioxidant, chelating agent, preservative, adjuvants, isotonic or buffering agents, or any excipient conventionally used in pharmaceutical compositions (i.e., "pharmaceutically acceptable excipient") and the like. These active or inactive substances may also include substances having immediate, delayed, controlled, or sustained release characteristics.

[0040] A "dosage form," "pharmaceutical formulation," "formulation," or

"pharmaceutical composition" refers to a drug product that includes at least one active agent and may further include pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art. For example, a typical injectable pharmaceutical formulation includes a parenterally acceptable aqueous solution which is pyrogen- free and has suitable pH, isotonicity, and stability. The dosage forms delivered by the devices disclosed herein can have diagnostic, therapeutic, cosmetic, or research utility in various species, such as for example in human patients or subjects.

[0041] The term "therapeutic agent" as used herein refers to any therapeutically active substance that is administered to a subject to produce a desired, usually beneficial, effect. The term therapeutic agent includes, e.g., classical low molecular weight therapeutic agents commonly referred to as small molecule drugs; and biologies including, but not limited to, antibodies or functionally active portions or fragments thereof, peptides, lipids, protein drugs, protein conjugate drugs, fusion proteins, enzymes, nucleic acids, ribozymes, genetic material, viruses, bacteria, eukaryotic cells, and vaccines. A therapeutic agent can also be a pro-drug, which is metabolized into the desired therapeutically active substance at or after administration to a subject. In some aspects, the therapeutic agent is a prophylactic agent. In addition, the therapeutic agent can be pharmaceutically formulated. A therapeutic agent can also be a radioactive isotope. A therapeutic agent can be an agent activated by a form of energy such as light or ultrasonic energy, or activated by other circulating molecules that can be administered systemically or locally.

[0042] A pharmaceutical formulation can include a therapeutically effective amount of at least one active agent. Such effective amounts can be readily determined by one of ordinary skill in the art based, in part, on the effect of the administered dosage form, or the combinatorial effect of an agent and one or more additional active agents, if more than one agent is used. A therapeutically effective amount of an active agent can also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent (and one or more additional active agents) to elicit a desired response in the individual, e.g., amelioration of at least one condition parameter. For example, a therapeutically effective amount of a dosage form can inhibit (lessen the severity of or eliminate the occurrence of), prevent a particular disorder, or lessen any one of the symptoms of a particular disorder known in the art or described herein. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the active agent or dosage form are outweighed by the therapeutically beneficial effects.

[0043] Accordingly, an active agent can be administered to a subject as a monotherapy. Alternatively, an active agent can be administered to a subject as a combination therapy with another active agent in a combination dosage form, or as an additional treatment, e.g., another treatment for an associated or additional disorder. For example, combination therapy can include administering to the subject (e.g., a human patient) one or more agents (e.g., antibiotics, anticoagulants, anti-hypertensives, or anti-inflammatory drugs) that provide a therapeutic benefit to a subject. In another example, the combination therapy can include administering to the subject an IL-13 antagonist and one or more additional agents (e.g., an anti-IgE antibody, an anti-IL-4 antibody, an anti-IL-5 antibody, an anti-complement agent, or an anti -histamine) that provide therapeutic benefit to a subject who has developed, is at risk of developing, or is suspected of having a pulmonary disorder such as asthma. In some embodiments, an active agent and one or more additional active agents are administered in a single dosage form. In other embodiments, an active agent is administered first in time and an additional active agent(s) is administered second in time. In some embodiments, one or more additional active agents are administered at the same time, but using different drug delivery devices or delivery modes.

[0044] A dosage form delivered according to the devices described herein may replace or augment a previously or currently administered therapy. For example, upon treating with one pharmaceutical formulation, administration of an additional active agent(s) can cease or be diminished, e.g., be administered at lower concentrations or with longer intervals between administrations. In some embodiments, administration of a previous therapy can be maintained. In some embodiments, a previous therapy is maintained until the level of an active agent reaches a level sufficient to provide a therapeutic effect. Accordingly, two therapies can be administered in combination, sequentially, or simultaneously.

[0045] The term "antibody" includes a full antibody; a derivative, portion, or fragment thereof, such as a fragment derived from enzymatic or chemical cleavage or a portion obtained recombinantly; or a mimic of the binding region of an antibody produced either by way of protein expression techniques or through chemical synthesis, which retains functionality as a specific binding member, such as the specific binding activity of at least one antibody antigen- binding domain site. Accordingly, the term antibody includes monoclonal antibodies and all the various forms derived from antibodies, including but not limited to full-length antibodies (e.g., having an intact Fc region), bifunctional antibodies, trifunctional antibodies, antigen-binding fragments (e.g., produced via enzymatic cleavage) or portions (e.g., polypeptides produced using recombinant methods) including, for example, scFv, di-scFv, sdAb, BiTE (bi-specific T-cell engager), Fab, Fab' and F(ab')2 fragments, diabodies, single chain antibodies, and other specific binding members comprising an antibody antigen-binding domain site. The terms "antibody" and "antibodies" as used herein also refer to human antibodies produced for example in transgenic animals or through phage display, as well as chimeric antibodies, humanized antibodies, and fully humanized antibodies or portions thereof that function as a specific binding member. [0046] As used herein, the term "IL-13 antagonist" generally refers to a molecule or agent that can affect the expression, activity, or half-life of IL-13 either in vitro or in vivo; or modulate symptoms, pathology, or sequelae caused by or exacerbated by IL-13 in a subject with an IL-13-mediated disease or disorder, e.g., asthma or atopic dermatitis. Tralokinumab is an IL-13 antagonist "therapeutic agent" as defined herein, which either directly or indirectly can inhibit, lessen, or neutralize IL-13 activity, or can prevent exacerbation of symptoms due to IL-13 dysfunction. In addition to tralokinumab, however, a pharmaceutical formulation as described herein may contain another IL-13 antagonist. In general, tralokinumab is an anti-IL-13 monoclonal antibody having the amino acid sequences shown in SEQ ID NO: l and SEQ ID NO:2, an antigen-binding portion thereof, or an IL-13 antagonizing portion thereof.

Tralokinumab and other anti-IL-13 antibodies, and portions thereof, are described in

WO 2005007699, for example.

[0047] The term "therapeutic agent" as used herein refers to any therapeutically active substance that is administered to a subject to produce a desired, usually beneficial, effect. The term therapeutic agent includes, e.g., classical low molecular weight therapeutic agents commonly referred to as small molecule drugs; and biologies including, but not limited to, antibodies or functionally active portions or fragments thereof, peptides, lipids, protein drugs, protein conjugate drugs, fusion proteins, enzymes, nucleic acids, ribozymes, genetic material, viruses, bacteria, eukaryotic cells, and vaccines. A therapeutic agent can also be a pro-drug, which is metabolized into the desired therapeutically active substance at or after administration to a subject. In some aspects, the therapeutic agent is a prophylactic agent. In addition, the therapeutic agent can be pharmaceutically formulated. A therapeutic agent can also be a radioactive isotope. A therapeutic agent can be an agent activated by a form of energy such as light or ultrasonic energy, or activated by other circulating molecules that can be administered systemically or locally.

[0048] As used herein the terms "treat," "treatment," or "treatment of (e.g., in the phrase "treating a patient having an IL-13-mediated disease or disorder") refers to reducing the potential for an IL-13-mediated disease or disorder, reducing the occurrence of the IL-13- mediated disease or disorder, or a reduction in the severity of the IL-13-mediated disease or disorder, preferably, to an extent that the subject no longer suffers discomfort or altered function due to it (for example, a relative reduction in asthma exacerbations when compared to untreated patients). For example, treating can refer to the ability of a therapy when administered to a subject, to prevent an IL-13 -mediated disease or disorder from occurring or to cure or to alleviate IL-13 -mediated disease symptoms, signs, or causes. Treating also refers to mitigating or decreasing at least one clinical symptom or inhibition or delay in the progression of the condition or prevention or delay of the onset of a disease or illness. Thus, the terms "treat," "treating." or "treatment of (or grammatically equivalent terms) refer to both prophylactic and therapeutic treatment regimes.

[0049] The present disclosure provides methods and systems that provide therapeutic benefit in the treatment of an IL-13-mediated disease or disorder. A therapeutic benefit is not necessarily a cure for a particular IL-13-mediated disease or disorder, but rather encompasses a result that most typically includes alleviation of the IL- 13 -mediated disease or disorder or increased survival, elimination of the IL-13-mediated disease or disorder, reduction of a symptom associate with the IL- 13 -mediated disease or disorder, prevention or alleviation of a secondary disease, disorder or condition resulting from the occurrence of a primary IL-13- mediated disease or disorder, or prevention of the IL-13-mediated disease or disorder.

[0050] As used herein, the term "IL-13-mediated disease or disorder" refers to any pathology caused by (alone or in association with other mediators), exacerbated by, associated with, or prolonged by abnormal levels of IL-13 in the subject having the disorder. Non- limiting examples of IL-13 -mediated diseases or disorders include asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), ulcerative colitis (UC), allergic rhinitis, chronic rhinosinusitis, fibrosis, Hodgkin's lymphoma, and atopic dermatitis.

[0051] As used herein, the term "pulmonary disease or disorder" refers to any pathology affecting at least in part the lungs or respiratory system. Non-limiting examples include asthma, IPF, COPD, allergic rhinitis, or chronic rhinosinusitis. In certain aspects, the pulmonary disease or disorder is IL-13-mediated.

[0052] As used herein, the term "chronic inflammatory skin disease or disorder" refers to any pathology affecting at least in part the skin. Non- limiting examples include atopic dermatitis, skin fibrosis, allergic contact dermatitis, eczema or psoriasis. In certain aspects, the chronic inflammatory skin disease or disorder is IL-13 -mediated.

[0053] The term "asthma" refers to diseases that present as reversible airflow obstruction or bronchial hyper-responsiveness that may or may not be associated with underlying inflammation. Examples of asthma include allergic asthma, atopic asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, asthma due to smoking, asthma uncontrolled on corticosteroids and other asthmas as mentioned, e.g., in the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, National Asthma Education and Prevention Program (2007) ("NAEPP Guidelines").

[0054] The term "COPD" refers to chronic obstructive pulmonary disease. COPD includes two main conditions: emphysema and chronic obstructive bronchitis. Thus, in the broadest sense, COPD refers to COPD itself and also its sub-conditions: chronic bronchitis and emphysema. In some aspects, COPD is stable COPD. In other aspects, COPD refers to a COPD exacerbation. As used herein, the term "exacerbation" refers to a worsening of symptoms of COPD, relative to a patient's baseline condition. In certain embodiments, a COPD exacerbation may be defined as an event in the natural course of the disease characterized by a change in the patient' s baseline lung function, dyspnea, cough, or sputum that is beyond normal day-to-day variations, is acute in onset and may warrant a change in medication in a patient with underlying COPD. In certain embodiments, exacerbation of COPD may be an abrupt increase in symptoms of shortness of breath or wheezing, or increase in production of purulent sputum.

[0055] The term "IPF" refers to idiopathic pulmonary fibrosis, a disease characterized by progressive scarring or fibrosis of the lungs. IPF is a specific type of interstitial lung disease in which the alveoli gradually become replaced by fibrotic tissue. With IPF, progressive scarring causes the normally thin and pliable tissue to thicken and become stiff, making it more difficult for the lungs to expand and preventing oxygen from readily getting into the bloodstream. See, e.g., Idiopathic Pulmonary Fibrosis: Diagnosis & Treatment - International Consensus Statement, Am. J. Respir. Crit. Care Med. 161:646 (2000).

[0056] As used herein, the term "atopic dermatitis" refers to a chronic inflammatory, relapsing, non-contagious and itchy skin disorder that is often associated with other atopic disorders such as allergic rhinitis and asthma. Bieber, New Engl. J. Med. 358: 1483 (2008). Atopic dermatitis is equivalent to neurodermatitis, atopic eczema, or endogenous eczema.

References to atopic dermatitis also include particular forms of atopic dermatitis, which may be named according to the place where they occur, their appearance, or the stress factors that provoke them. These include, but are not limited to, eczema flexurarum, eczema mulluscatum, eczema verrucatum, eczema vaccinatum, eczema dyskoides, dyshydrotic eczema, microbial eczema, nummular eczema, seborrhobic eczema and other forms of eczema; perioral dermatitis and periorbital dermatitis. As used herein, the term atopic dermatitis also comprises the frequently occurring bacterial secondary infections such as those due to, e.g., Staphylococcus aureus infections, pyodermas such as impetigo contagiosa and its derivatives, as well as the follicularis barbae or viral secondary infections. IL-13 is involved in the pathogenesis of the disease and is an important in vivo inducer. See, e.g., Oh et al., J. Immunol. 186:7232 (2011); Tazawa et al., Arch. Dermatol. Res. 295:459 (2004); Metwally et al., Egypt J.

Immunol. 11: 171 (2004).

[0057] The term "IBD" refers to inflammatory bowel disease or disorder. IBD, sometimes termed Crohn's Disease, ileitis, or enteritis, is generally a chronic disorder. IBD frequently causes inflammation in the small intestine, e.g., the ileum, but it can affect any part of the digestive tract from the mouth to the anus. The inflammation can cause pain and can make the intestines empty frequently, resulting in diarrhea. Additional symptoms of IBD include abdominal pain, constipation or alternating diarrhea and constipation, gas, bloating, nausea, weight loss, rectal bleeding, fatigue, and decreased appetite. IBD inflammation can extend deep into the lining of the affected organ, and severe ulceration of the intestinal lumen is often observed. Subjects suffering from IBD have symptoms similar to subjects suffering from Irritable Bowel Disease (also known as Irritable Bowel Syndrome) or ulcerative colitis.

[0058] The terms "subject" or "patient" as used herein refer to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy of an IL-13 -mediated disease or disorder is desired. The terms "subject" or "patient" include any human or nonhuman animal. The term "nonhuman animal" includes all vertebrates, e.g., mammals and non- mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, bears, chickens, amphibians, reptiles, etc. As used herein, phrases such as "a patient having an IL-13-mediated disease or disorder" includes subjects, such as mammalian subjects, that would benefit from the administration of a therapy, imaging or other diagnostic procedure, or preventive treatment for that IL-13 -mediated disease or disorder. In some aspects of the present disclosure, a subject is a naive subject. A naive subject is a subject that has not been administered a therapy, for example a therapeutic agent. In some aspects, a naive subject has not been treated with a therapeutic agent prior to being diagnosed as having an IL-13-mediated disease or disorder, for example, asthma, IFP, COPD, UC, or atopic dermatitis. In another aspect, a subject has received therapy or one or more doses of a therapeutic agent (e.g., a therapeutic agent capable of modulating an inflammatory response associated with an IL-13 -mediated disease or disorder, a pulmonary disease or disorder, an inflammatory bowel disease or disorder or a chronic inflammatory skin disease or disorder) prior to being diagnosed as having an IL-13 -mediated disease or disorder. In one aspect, the therapeutic agent is a small molecule drug. In a specific aspect, the agent is a corticosteroid. In another aspect, the agent can be a leukotriene modifier such as montelukast, zafirlukast or zileuton. In a further aspect, the therapeutic agent can be a methylxanthine (e.g., theophylline) or a cromone (e.g., sodium cromolyn and nedocromil). In another aspect, the therapeutic agent can be a long-acting beta-2 agonist such as salmeterol, fomoterol, or indacaterol. In a further aspect, the agent can be methotrexate or cyclosporin.

[0059] The cytokine interleukin 13 (IL-13) is a central mediator of inflammatory diseases, particularly the physiologic changes induced by allergic inflammation in many tissues. For example, IL-13 is implicated in asthma because it induces many features of allergic lung disease, including airway hyper-responsiveness, goblet cell metaplasia, and mucus

hypersecretion; all of which contribute to airway obstruction. IL-13 also induces secretion of other chemokines that recruit further allergic effector cells to the lung. Hence, IL-13 antagonists offer valuable active agents for the amelioration or treatment of inflammatory conditions associated with IL-13. Tralokinumab (also referred to as CAT-354) is a human monoclonal antibody that targets and neutralizes IL-13; therefore, it is useful for the treatment of pulmonary diseases or chronic inflammatory diseases that may include, e.g., asthma or atopic dermatitis.

[0060] More specifically, IL-13 is a member of the interleukin family of cytokines and is secreted predominantly by CD4+ T-helper-2 (Th2) cells. IL-13 receptors are expressed on a number of cell types including key cells involved in asthma. Hershey, J. Allergy Clin. Immunol. 111:677 (2003). There is considerable evidence that IL-13 is a key mediator in the pathogenesis of established asthmatic disease and may have a number of effects including inflammation, airway hyper-responsiveness (AHR), fibrosis, and increased mucous production. Elevated IL-13 levels have been identified in the sputum of a proportion of patients with asthma including those with severe disease treated with systemic corticosteroids. Saha et al., J. Allergy Clin. Immunol. 121:685 (2008). Indeed, IL-13 is one of the key mediators in the pathogenesis of asthma.

Woodruff et al., Am. J. Respir. Crit. Care Med. 180:388 (2009). Therefore, a significant role for IL-13 in asthma can be expected.

[0061] Tralokinumab is a human monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) subclass that potently and specifically neutralizes interleukin 13 (IL-13) by preventing its interaction with the receptors, IL-13Ral and IL-13Ra2. May et al., British J. Pharmacol. 166: 177 (2012). Further disclosures regarding tralokinumab are found, for example, in WO 2005007699, U.S. Patents No. 7,829,090, No. 7,935,343, and No. 7,947,273; in which particular disclosures for tralokinumab refer to "BAK502G9." Tralokinumab is a human IgG4/Lambda antibody having the following variable heavy chain (VH), variable light chain (VL), and complementarity determining regions (CDR) (underlined in VH and VL) in the heavy chain (HC) and light chain (LC):

Table 1. Amino acid sequences of tralokinumab variable regions and CDRs

BAK502G9 LC CDR1 GGNIIGSKLVH (SEQ ID NO:6)

BAK502G9 LC CDR2 DDGDRPS (SEQ ID NO:7)

BAK502G9 LC CDR3 QVWDTGSDPVV (SEQ ID NO: 8)

[0062] Coupled with the evidence of a relationship between IL-13 expression and disease severity in patients, neutralization of IL-13 by tralokinumab is a credible approach to the treatment of asthma. Hence, inhibition of IL-13 by tralokinumab offers a rational approach to the treatment of the disease (May et al., 2012). Results from Phase 2 studies in adult patients with uncontrolled severe asthma suggest that the addition of tralokinumab at a target dose of 300 mg per day, administered as two 1 mL (150 mg/mL) SQ injections alongside the patient's current asthma therapy may provide clinical improvements in this patient population. This was demonstrated by an improvement in lung function, as well as an acceptable safety and tolerability profile. Piper et al., Eur. Respir. J. 41:330 (2013); Brightling et al., Lancet Respir. Med. 3(9): 692-701 (2015). Several clinical studies have been completed with tralokinumab in asthma. See also WO 200507699; U.S. Patents No. 7,947,273, No. 7,935,343, and

No. 7,829,090.

[0063] For example, a recently completed tralokinumab study was a Phase 2a study in which tralokinumab (150 mg, 300 mg, or 600 mg) or placebo was administered as a SQ injection every 2 weeks (Q2W) for 3 months to 194 adult patients with uncontrolled, moderate- to-severe, persistent asthma requiring treatment with appropriate asthma controller medication. The results of this study demonstrated a clinical effect with the addition of SQ tralokinumab to standard asthma controller medications. Piper et al., 2013. An increase in pre-bronchodilator forced expiratory volume in one second (FEV1) was observed at the first scheduled visit (two weeks) after first dose of tralokinumab. At Day 92 (Week 13), the mean increase from baseline FEV1 was 0.063 L (4.3%) in the placebo group versus 0.210 L (12.5%) in the combined tralokinumab group (150, 300, and 600 mg; p = 0.072).

[0064] Across the majority of study time points, the magnitude of the increase in FEV1 was similar in the 300 and 600 mg tralokinumab groups, and smaller improvements were observed in the 150 mg tralokinumab group. Additionally, there were increases from baseline in office peak expiratory flow (PEF) and forced vital capacity, and a reduction in the requirement for the use of additional short-acting 2-agonist (SABA). Nearly 95% of the patients completed as-planned treatment. The majority of treatment-emergent adverse events (TEAEs) were mild or moderate in severity, and there was a higher frequency of severe and serious TEAEs in the placebo group compared to the combined tralokinumab group. In addition, there were no confirmed anti-drug antibodies (ADA) to tralokinumab in any patient. See also WO 2012/049278. Results from a Phase 2b study investigating tralokinumab in asthma were recently reported. See Brightling et al., 2015. In addition to asthma, tralokinumab is also being studied for other indications, including atopic dermatitis.

[0065] Standard syringes typically employed for the administration of subcutaneous (SQ) dosage forms comprising an IL-13 antagonist, such as tralokinumab, deliver about 1 mL. Therefore, given current dosage forms, if a larger amount of an IL-13 antagonist is prescribed then the patient must administer, or be administered, two injections instead of one. Additionally, current dosage forms comprising the IL-13 antagonist tralokinumab are fairly viscous, such that patients may experience greater pain intensity during SQ injection of a 2 mL dosage form, or if the dosage form were concentrated further (therefore more viscous). Each of these

circumstances increases the risk of patient noncompliance. Hence, there remains a need for a delivery device that can be used for less painful subcutaneous injection of a single 2 mL dosage form comprising an IL-13 antagonist such as tralokinumab.

[0066] Tralokinumab, at a target dose of 300 mg, has been shown to improve lung function in patients with asthma; but this dose has typically been administered as two 1 mL SQ injections. Tralokinumab is currently supplied as a sterile liquid formulation at a concentration of 150 mg tralokinumab per vial (nominal in 1.0 mL) intended for parenteral administration. No incompatibilities between tralokinumab and dosage administration components (i.e., syringe, extension set, or SQ insertion set) have been observed. At least one embodiment, as described herein, provides for a tralokinumab delivery device in which a dosage form comprising 300 mg tralokinumab can be delivered subcutaneously via single large volume (2 mL) injection; this dosage form can be delivered at a flow rate selected from, for example, about 0.167 mL/minute to about 12 mL/minute, inclusive. In at least one embodiment, the drug delivery device is prefilled with a pharmaceutical formulation comprising tralokinumab in suitable pharmaceutical excipient(s). See, e.g. , WO 2007036745, U.S. Patent No. 9,107,945, or U.S. Patent Pub.

No. 20160002327, hereby incorporated by reference. For example, the dosage form may include 10 mg/mL to 600 mg/mL tralokinumab, inclusive, in an excipient formulation of 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% w/v polysorbate 80, pH 5.5. The dosage form may also include 10 mg/mL to 600 mg/mL tralokinumab, inclusive, in an excipient formulation of 50 mM sodium acetate/acetic acid and 85 mM sodium chloride having a pH of 5.2 to 5.7. In some embodiments, the dosage form may include 10 mg/mL to 600 mg/mL tralokinumab, inclusive, in an excipient formulation of 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of 5.5 + 0.5. In addition, the dosage form may include 10 mg/mL to 600 mg/mL tralokinumab, inclusive, in an excipient formulation of 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of 5.5 + 1. Accordingly, a drug delivery device may be prefilled with a pharmaceutical dosage form comprising about 10 mg/mL, 50 mg/mL, 100 mg/mL, 150 mg/mL, 175 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL, 500 mg/mL, 550 mg/mL or 600 mg/mL tralokinumab, etc., as appropriate for treatment of a particular indication. The volume of the dosage form delivered by the device may be 1 mL to 3 mL, inclusive, for example, 2 mL. The device may retain a volume of dosage form such that 2 mL is delivered to the subject and not more than about 2 mL retained in the device (e.g., residual in the fluid conduit).

[0067] Accordingly, a pharmaceutical formulation can include a therapeutically effective amount of tralokinumab. Such effective amounts can be readily determined by one of ordinary skill in the art based, in part, on the effect of the administered dosage form, or the combinatorial effect of an agent and one or more additional active agents, if more than one agent is used. A therapeutically effective amount of tralokinumab, and optionally an additional active agent can also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent (and one or more additional active agents) to elicit a desired response in the individual, e.g., amelioration of at least one condition parameter. For example, a therapeutically effective amount of a tralokinumab dosage form can inhibit (lessen the severity of or eliminate the occurrence of), prevent an IL- 13 -associated disorder, or lessen any one of the symptoms of an IL-13-associated disorder, as is known in the art or described herein. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the tralokinumab or additional active agent or dosage forms are outweighed by the therapeutically beneficial effects.

[0068] Tralokinumab can be administered to a subject as a monotherapy. Alternatively, tralokinumab can be administered to a subject as a combination therapy with another active agent in a combination dosage form, or as an additional treatment, e.g., another treatment for an associated or additional disorder. For example, combination therapy can include administering to the subject (e.g., a human patient) tralokinumab and one or more agents (e.g., antibiotics, anticoagulants, anti-hypertensives, or anti-inflammatory drugs) that provide a therapeutic benefit to a subject. In another example, the combination therapy can include administering to the subject a pharmaceutical formulation comprising tralokinumab, and administering to the subject one or more additional agents (e.g., an anti-IgE antibody, an anti-IL-4 antibody, an anti-IL-5 antibody, an anti-complement agent, or an anti-histamine) that provide therapeutic benefit to a subject who has developed, is at risk of developing, or is suspected of having an IL-13 mediated condition, for example a pulmonary disorder such as asthma. Other active agents with IL-13 antagonist activity include, without limitation: (a) an anti-human-IL-13 antibody, for example,

lebrikizumab (TNX-650, MILR1444A/RG3637, Roche/Genentech) (SEQ ID NO: l and SEQ ID NO:2) or an antigen-binding fragment thereof, ABT-308 (Abbott), GSK679586

(GlaxoSmithKline) or QAX576 (Novartis); (b) an anti-human-IL-13Ral antibody, for example, Merck MK6105; (c) an IL-13-toxin conjugate such as IL-13-PE38QQR (NeoPharm, Inc.); (d) an IL-4 mutein such as Aerovant™ (Aerovance, Inc.); (e) an anti-IL-4Ra antibody such as dupilumab/REGN668 (Regeneron); (f) a nucleic acid (e.g., a double-stranded oligonucleotide directed against IL-4Ra); or (g) an IL-4/IL-13 bispecific antibody such as GSK2434735 (Glaxo SmithKline).

[0069] In some embodiments, tralokinumab and one or more additional active agents are administered in a single dosage form. In other embodiments, tralokinumab is administered first in time and an additional active agent(s) is administered second in time, or vice versa. In some embodiments, tralokinumab and one or more additional active agents are administered at the same time, but using a tralokinumab delivery device and an additional different drug delivery device or delivery mode.

[0070] A dosage form comprising a tralokinumab pharmaceutical formulation, delivered according to the devices described herein, may replace or augment a previously or currently administered therapy. For example, upon treating with one pharmaceutical formulation comprising tralokinumab, administration of an additional active agent(s) can cease or be diminished, e.g., be administered at lower concentrations or with longer intervals between administrations. In some embodiments, administration of a previous therapy can be maintained. In some embodiments, a previous therapy is maintained until the level of an active agent reaches a level sufficient to provide a therapeutic effect. Accordingly, two therapies can be administered in combination, sequentially, or simultaneously.

[0071] A pharmaceutical formulation comprising tralokinumab, particularly when prepared for administration in a tralokinumab delivery device as described herein, may also be referred to as a dosage form comprising tralokinumab. A typical injectable pharmaceutical formulation includes a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity, and stability. The present embodiments provide for tralokinumab delivery devices that are capable of delivering a relatively large dosage form comprising tralokinumab (for example, a 2 mL to 3 mL dosage form rather than a 1 mL dosage form), with a level of pain intensity that is generally tolerable. These devices are advantageous, for example, in administering tralokinumab such that pain does not negatively impact compliance with the dosing regimen. [0072] As used herein, "fluid" refers primarily to liquids, but can also include suspensions of solids dispersed in liquids (dispersions, suspensions, colloidal mixtures), emulsions, liposomal compositions, and gasses dissolved in or otherwise present together within liquids inside the fluid-containing portions of syringes.

[0073] "Glass" should be understood to include other similarly non-reactive materials suitable for use in a pharmaceutical grade application that would normally require glass (e.g., Type I borosilicate glass), including but not limited to certain non-reactive polymers such as cyclic olefin copolymers (COC) and cyclic olefin polymers (COP).

[0074] "Plastic" may include both thermoplastic and thermosetting polymers.

Thermoplastic polymers can be re-softened to their original condition by heat; thermosetting polymers cannot. As used herein, the term "plastic" refers primarily to moldable thermoplastic polymers such as, for example, polyethylene and polypropylene, or an acrylic resin, that also typically contain other ingredients such as curatives, fillers, reinforcing agents, colorants, or plasticizers, etc., and that can be formed or molded under heat and pressure. As used herein, the term "plastic" can include pharmaceutical grade non-reactive polymers or elastomers that are approved for use in applications where they are in direct contact with therapeutic substances, such that the plastics do not interact with the substances contacting the plastic and are not readily susceptible to leaching or gas migration under ambient temperature and pressure.

[0075] The terms "elastomer," "elastomeric material," or "elastomeric" refer primarily to cross-linked thermosetting rubbery polymers that are more easily deformable than resilient plastics, are approved for use with pharmaceutical grade substances, and are not readily susceptible to leaching or gas migration under ambient temperature and pressure. It is appreciated in the art that particular elastomeric polymers are better suited for contact with pharmaceuticals than are some particular plastics; hence the elastomeric material can be a biocompatible material. As used herein, the term "elastomer," "elastomeric," or "elastomeric material" may also include other biocompatible materials, such as styrenic block copolymers (TPE-s), polyolefin blends (TPE-o), elastomeric alloys (TPE-v or TPV), thermoplastic polyurethanes (TPU), thermoplastic copolyesters, or thermoplastic polyamides, among other biocompatible materials which are approved for use with pharmaceutical grade substances, and are not readily susceptible to leaching or gas migration under ambient temperature and pressure.

[0076] References to "prefillable" generally refer to syringes comprising components for filling with a substance prior to dispensing the substance (e.g., dosage form) for its intended use. More specifically, in the context of the delivery device embodiments, the term "prefillable" refers to a configuration or state in which a substance may be introduced into the device any time prior to the delivery (dispense) by the device of the substance(s) for their intended use (such as delivery into a subject or patient). A prefillable syringe thus includes syringes described herein as prefilled, fill-at-time-of-use, fill-on-demand, ready-to-use, and the like.

[0077] A "dosage form" or "formulation" refers to a drug or drug product which includes the active agent and may further include inactive substances such as excipients or diluents as are known in the art. The active agent may be a biologic, such as an antibody, protein, peptide or nucleic acid. A container used in conjunction with the drug delivery devices described herein, configured to deliver a selected dose, may include an additional volume of dosage form to account for "loss" in the delivery device.

[0078] As used herein, the term "pump" is intended to include any number of drug delivery systems which are capable of dispensing a fluid to a user upon activation. Such drug delivery systems include, for example, injection systems, infusion pumps, bolus injectors, spring delivered mechanisms, on-body injectors, and the like. FIG. 5A to FIG. 5C show an exemplary drug delivery device according to at least one embodiment of the present invention.

[0079] As used herein, "needle" can to refer to a variety of needles including but not limited to conventional hollow needles, such as a rigid hollow steel needles, and solid core needles more commonly referred to as a "trocars." For example, a needle can be a 27-gauge solid core trocar. In other embodiments, the piercing member may be any size needle suitable to insert a cannula for subcutaneous delivery of a dosage form comprising a drug. Various embodiments include a piercing member, which may be the same or a different component from the needle, as describe further herein. As used herein, "cannula" can to refer a tube configure for insertion into the body, e.g., for the delivery or removal of fluid or for the gathering of data. A cannula may also surround the inner or outer surfaces of a trocar needle, which thereby allows puncturing of the body to access the intended internal anatomical target and/or cavity.

[0080] With reference to a "biasing member," such as in the context of one or more biasing members for insertion or retraction of the needle, trocar, or cannula, it will be appreciated that a biasing member may be any member that is capable of storing and releasing energy. Non- limiting examples include a spring, such as for example a coiled spring, a compression or extension spring, a torsional spring, and a leaf spring, a resiliently compressible or elastic band, or any other member with similar functions. In at least one embodiment of the present invention, the biasing member is a compression spring. In the context of biasing members, the terms "series," "in series," or "disposed in series" is to be interpreted as springs disposed and operating as they would when connected end-to-end; and the terms "parallel," "in parallel," or "disposed in parallel" is to be interpreted as springs disposed and operating as they would in a side-by-side relationship. [0081] A container may be used in conjunction with the drug delivery devices described herein, such as a prefilled container configured to deliver a selected dose; which container may include an additional volume of dosage form to account for "loss" in the delivery device and still deliver the required dose to the subject.

[0082] As used herein, "fluid" refers primarily to liquids, but can also include suspensions of solids dispersed in liquids (dispersions, suspensions, colloidal mixtures), emulsions, liposomal compositions, and gasses dissolved in or otherwise present together within liquids inside the fluid-containing portions of syringes.

[0083] "Viscosity" refers in general to the state of being thick, sticky, and semifluid in consistency, corresponding to the informal concept of "thickness." In particular, however, "viscosity" of a fluid is a measure of its resistance to gradual deformation by shear stress or tensile stress. Viscosity can be expressed as the magnitude of force needed to overcome internal friction, for example, as measured by the force per unit area resisting a flow, in which parallel layers a unit distance apart have a unit speed relative to one another. The viscosity of a

Newtonian fluid is dependent only on temperature, and not on shear rate and time. The viscosity of non-Newtonian fluids (time dependent) depends on temperature, shear rate and time;

depending on how viscosity changes with time the fluid behavior can be characterized as thixotropic (time thinning, i.e., viscosity decreases with time), rheopetic (time thickening, i.e., viscosity increases with time), or rheomaiaxis (time thinning correlates with breakdown of structure). The viscosity of Non-Newtonian fluids (time independent) depends not only on temperature but also on shear rate. Viscosity may be measured as centipoise (cps), in which water is the standard at 1 cps. Blood has an approximate viscosity of 10 cps; maple syrup 150 cps to 200 cps; motor oil SAE60 1000 cps to 2000 cps; and ketchup 50,000 cps to 70,000 cps.

[0084] As noted, temperature can be a factor in viscosity fluid mechanics, but for the purposes of the analytical modeling discussed herein, temperature is assumed to be ambient and remain substantially so for the course of drug delivery. Those of skill in the art armed with this specification can adjust configuration of a drug delivery device to control, manage, or harness changes in viscosity attributed to temperature. The viscous liquid as envisioned herein may be in liquid form or reconstituted from lyophilized form. Non- limiting examples of viscous fluids include those with at least about 10 cps or about 100 cps at a shear rate of 0.1/second. An example viscosity can in the range of from about 80,000 cps to about 300,000 cps, inclusive, or the viscosity be in the range of from about 140,000 cps to about 280,000 cps, inclusive, at a shear rate of 0.1/second at 25°C, or a viscosity range from about 100 cps to about 1,000 cps, inclusive, at a shear rate 0.1/second at 25 °C. Viscosity can be measured by a rheometer. [0085] The embodiments described herein provide a pharmaceutical formulation comprising tralokinumab disposed in a tralokinumab delivery device capable of delivering a large-volume viscous fluid dosage forms, for example, a 2 mL to 3 mL, inclusive, at a flow rate (which in the context of in vivo use may refer to an administration rate) such that pain is tolerable. Tolerability factors generally include local injection site pain and injection site pruritus post-injection; local injection site reactions (e.g., erythema, bleeding, rash, etc.) post- injection; presence of fluid leakage immediately post-injection; and incidence of treatment- emergent adverse events including clinically significant changes in vital signs, physical examinations, and laboratory parameters. In some embodiments, the tralokinumab delivery devices are capable of delivering, for example, a SQ administration of a 2 mL dosage form comprising about 50 mg/mL to about 400 mg/mL of tralokinumab with acceptable

pharmacokinetics and tolerability. For example, these delivery devices are capable of delivering a SQ administration of a 2 mL dosage form comprising about 150 mg/mL of tralokinumab with acceptable pharmacokinetics and tolerability. The tolerability of such 2 mL SQ injection is generally comparable with two 1 mL SQ injections, the latter being the typical standard practice at this time. Thus, the present embodiments provide for tralokinumab delivery devices that allow for a reduction in the number of injections by the administration of a larger dose volume of a rather viscous dosage form of tralokinumab, over longer injection times, still satisfying patient tolerance of pain.

[0086] In at least one embodiment, the tralokinumab delivery device is a drug delivery pump. As used herein, the term "pump" is intended to include any number of delivery systems that are capable of automatically dispensing a fluid dosage form to a subject upon activation, including spring delivered mechanisms. The tralokinumab delivery device is capable of delivering a range of dosage forms, such as those of different viscosities and volumes. For example, the tralokinumab dosage form may have a volume of 1 mL to 3 mL, inclusive, and a viscosity from about 1 cp to about 100 cps, inclusive. In some embodiments, the device described herein is configured to deliver a tralokinumab dosage form having a viscosity of about 12 cP at 150mg mL at 23°C, inclusive. In some embodiments, the device is configured to deliver a tralokinumab dosage form having a viscosity range of about 6 cP (135 mg/mL at 28 °C) to 32 cP (165 mg/mL at 18°C), inclusive. In some embodiments, the tralokinumab delivery device is configured to deliver a dosage form having a viscosity range of about 23 cP (162 mg/mL at 28°C). In some embodiments, the device is configured to deliver a tralokinumab dosage form having a viscosity between about 1 cP and about 100 cP, inclusive, at a temperature between about 5°C and about 40°C, inclusive. The delivery device is capable of delivering a

tralokinumab dosage form at a controlled flow rate (speed) or of a specified volume. For example, the tralokinumab delivery duration may be no faster than about 2 minutes or about 1 minute at 18°C to 28°C, or no slower than about 15 minutes at 18°C to 28°C. In one

embodiment, the tralokinumab dosage form delivery process is controlled by one or more flow restrictors within the fluid pathway connection or the sterile fluid conduit. Such flow restrictors can be used to control the flow rate of the pharmaceutical formulation from the device, as described herein. In other embodiments, different flow rates may be provided by varying the geometry of the drug container, fluid flow path, or delivery conduit; or by varying the speed at which a component of the drive mechanism advances into the drug container to dispense the formulation therein, or combinations thereof, as described herein.

[0087] The tralokinumab delivery device described herein is generally a wearable, on- body subcutaneous (SQ) bolus injector. The body of the device can therefore include an adhesive component, comprising an adhesive, to temporarily adhere the device to the skin of subject during drug delivery. Typically, the tralokinumab delivery device is configured such that the adhesive component is placed on the portion of the device designed to contact the subject during drug delivery (i.e., the "base" of the device), and covered, e.g., with a removable film layer. The film layer may also serve as a barrier that protects sterility or cleanliness of a portion of the device.

[0088] In at least one embodiment, the tralokinumab delivery device includes an activation mechanism, a drive mechanism, a fluid pathway connection, and an insertion mechanism. The tralokinumab delivery device is further configured to accept a container prefilled with a pharmaceutical formulation comprising tralokinumab, and establish fluid communication with device components as described herein. The insertion mechanism may include an insertion mechanism housing, a manifold guide, at least one insertion biasing member held initially in an energized state, a retraction biasing member, and a hub connected to a proximal end of a needle. See, e.g. , FIGS. 7 A, 7B, and 7C. The retraction biasing member can be held in the initial energized state between the hub and the manifold guide. The manifold can have a septum and a cannula, wherein the annular space between the septum and the cannula defines a manifold header. In some embodiments, the needle and cannula are inserted into the body by an insertion biasing member(s), then the needle is retracted but the cannula remains inserted for administration of the required dose. In a specific embodiment, the needle can be a 27 gauge or smaller solid trocar, configured to insert a 0.026" outer diameter cannula into the subject. The insertion mechanism can be configured to provide an insertion depth of 6 mm + 1.5 mm at a 90-degree angle. Retraction of the needle may open a fluid pathway from the manifold header to the body through the cannula. The fluid pathway is sterile, and is typically empty prior to activation of the device. See U.S. Patent Pub. No. 20130060233. In other embodiments, the needle may be a hollow needle that opens a fluid pathway from the manifold header to the body, is inserted into the body of the subject, and remains inserted for

administration of the dosage form.

[0089] In at least one embodiment, the tralokinumab delivery device includes a drive mechanism having at least one integrated status indication. A tralokinumab delivery pump with integrated status indication can include a housing and an assembly platform, upon which can be mounted an activation mechanism, an insertion mechanism, a fluid pathway connection, a power and control system, and a drive mechanism comprising a drug container. In a particular embodiment, the drive mechanism having integrated status indication includes a drive housing; a status switch interconnect; a drive biasing member; a piston; and a drug container having a cap, a pierceable seal, a barrel, and a plunger seal; in which the drive biasing member is configured to bear upon an interface surface of the piston. The drive mechanism may include an incremental status stem having a stem interconnect, wherein the stem resides within the drive housing and the piston, and wherein the stem has an interconnect that engages one or more contacts on the piston to provide incremental feedback. See U.S. Patent Pub. No. 20130060196. The status indication may comprise a visual alert or an audible alert. For example, a visual alert may comprise a mechanical indication, a lighted indication with, for example, one to three colors, or a liquid crystal display indication. A lighted indication may have or be visible through a viewing window, for example a viewing window provided in the housing of the device, such as a 180 degree viewing window. Similarly, a mechanical indication may be visible through a viewing window in the housing. An audible alert may comprise a mechanical click, or comprise from one to four electronically generated tones; such as an audible indication at "end-of-dose." The housing of the device can include suitable openings that allow sound to escape from the device if such sound is not otherwise audible through the device housing. In some embodiments, the tralokinumab delivery device includes a communication module configured to send and receive wireless, including radio frequency, infrared, and Bluetooth®, data to and from a smart device, including mobile phone, tablet, and laptop, or watch, wristband, glasses or other wearable personal device, as well as Cloud-based data storage and server applications, including healthcare databases.

[0090] The drive mechanism may include a drive housing, a piston adapted to impart movement to a plunger seal within a drug container, at least one biasing member, and a retainer. The container may be a cartridge that is fillable or prefilled, configured to be inserted aseptically into the drug delivery device. The container is generally configured to include a portion capable of containing the dosage form, such as a barrel, vial, or other hollow portion configured to hold a fluid, and is typically pharmaceutical grade glass. For example, the container may be configured to hold a volume of about 3 mL of a pharmaceutical formulation comprising tralokinumab. The container typically comprises pharmaceutical grade glass, such as a 3 mL cartridge of Type 1 borosilicate glass cane. A portion of the container may include an adhesive to affix the container/cartridge within the drug delivery device or secure its connection to the fluid path as described elsewhere herein. Components or a portion of the container can be siliconized, such as with baked silicone oil or by sprayed siliconization. The container may also include one or more seals, at least one of which is movable by the drive (e.g., a plunger), which cooperates with the barrel to hold the fluid dosage form. The plunger may comprise an elastomer, such as a pharmaceutical grade elastomer. The seals may include a coating, such as Omniflex coating (Datwyler) or FluroTec® barrier coating (West Pharmaceutical Services, Inc.). Typically, a drive mechanism includes at least one biasing member, such as, for example, two biasing members disposed in parallel (e.g., concentric inner and outer springs). The biasing members are generally disposed initially to release energy, which release causes the piston to move from a retracted position to an extended position, the piston bearing against the plunger seal to dispense a liquid (i.e., pharmaceutical formulation comprising tralokinumab) from the container. The retainer component(s) may be configured to maintain the biasing member(s) in the energized position and then release the biasing members to permit the piston to dispense the drug. The drive mechanism may also include an end-of-dose indicator. See U.S. Patent Pub. No. 20130060196.

[0091] An example tralokinumab pump drive mechanism, for use in cooperation with a drug container having a plunger seal, includes a drive housing defined as having an axis, and a piston disposed for movement from at least a retracted first position to an extended second position along the axis, the piston adapted to impart movement to the plunger seal within the drug container. The drive mechanism may further comprise a plurality of biasing members disposed in parallel and adapted to move from an energized position to a deenergized position; and a retainer, the retainer being moveable between a retaining position and a releasing position, the retainer disposed to maintain the biasing members in the energized position when the retainer is in the retaining position, and to release the biasing members from the energized position when the retainer moves to the releasing position, the biasing members disposed to cause translocation of the piston from a retracted position to an extended position as the biasing members move from the energized position to the deenergized position. See, e.g. , U.S. Patent Pub. No. 20130066274; see also, e.g., FIGS. 12A, 12B, 13A, 13B, and 13C.

[0092] In at least one embodiment, the tralokinumab delivery device includes an operator-initiated fluid pathway connection that comprises a connection hub, a piercing member, a sterile sleeve, and a drug container having a cap, a pierceable seal, a barrel, and a plunger seal. See, e.g. , FIGS. 6A-6D. The fluid pathway comprises medical grade components, and is sterile and empty until use. See, e.g. , FIGS. 13A and 13B.The piercing member can be retained initially within the sterile sleeve which is located between the connection hub and the pierceable seal of the drug container. The connection hub may surround an internal aperture that functions as a flow restrictor, and the internal aperture can have a piercing member connected to one end and a fluid conduit connected to the other end. See, e.g. , FIGS. 7A-7C and 8A-8E. The drug delivery pump can include integrated sterility maintenance features, such as a housing upon which are mounted an activation mechanism, an insertion mechanism, a fluid pathway connection, a power and control system, and a drive mechanism connected to a drug container. See U.S. Patent Pub. No. 20130066274.

[0093] An exemplary tralokinumab delivery device is shown in FIG. 5A to FIG. 5C. This delivery device 10 includes device housing 12, which contains all of the device components and provides a means of removably attaching the device 10 to the skin of the subject receiving the dosage form. Housing 12 also provides protection against environmental influences to the interior components of the device. Device housing 12 is ergonomically and aesthetically designed in size, shape, and related features to facilitate easy packaging, storage, handling, and use by operators (e.g., patients and health care professionals) who may be untrained or physically impaired. Furthermore, the external surface of the housing 12 may be utilized to provide product labeling, safety instructions, and the like. Housing 12 may include one or more housing subcomponents that are fixedly engageable to facilitate easier manufacturing, assembly, and operation of the drug pump. For example, tralokinumab delivery device 10 includes housing 12 that includes upper housing 12A and lower housing 12B. Tralokinumab delivery device 10 also includes activation mechanism 14, status indicator 16, and window 18. Window 18 may be any translucent or transmissive surface through which the operation of the drug pump may be viewed. Status indicator 16 and window 18 may provide operation feedback to the

operator/subject. The device housing may include an additional window through which a drug- containing portion of the device is visible. The device housing may include a "cover" or similar structure that allows the device (or a compartment within the device) to be opened for removal or insertion of, for example, a cartridge, power supply, or electronics, after which the cover can be closed. Without being bound by a size limitation, an example size of tralokinumab delivery device 10 has the dimensions about 83x50x25 mm (LxWxH). Thus, it should be appreciated that the entire tralokinumab delivery device and the components therein are relatively small compared with some prior art infusion sets and bolus injectors.

[0094] As shown in FIG. 5C, this example tralokinumab delivery device further includes assembly platform 20, sterile fluid conduit 30, drive mechanism 100, drug container 50, insertion mechanism 200, fluid pathway connection 300, and power and control system 400. One or more of the components of such tralokinumab delivery device may be modular in that they are, for example, pre-assembled as separate components (e.g., sub-assemblies or cartridges) and disposed during some point in manufacturing into position on/in assembly platform 20 of tralokinumab delivery device 10. In this embodiment, the device 10 is configured such that when an operator (e.g., subject or patient) activates the device by depressing activation mechanism 14, the device is initiated to: insert a fluid pathway into the subject; enable, connect, or open necessary fluid communications between a drug container, a fluid pathway, and a sterile fluid conduit; and deliver the dosage form stored in the drug container through the fluid pathway, fluid conduit, and into the subject.

[0095] One or more optional safety mechanisms may be utilized, for example, to prevent premature activation of the tralokinumab delivery device. For example, on-body sensor 24 (shown in FIG. 5B) provides a safety feature that ensures that activation mechanism 14 or power and control system 400 is not engaged unless tralokinumab delivery device 10 is in contact with the body of the subject. More specifically, on-body sensor 24 is configured to movably project through an opening located in the exterior of lower housing 10B, where, in use it contacts the subject's body and is displaced into a receiving area in the device. Displacement of on-body sensor 24 permits depression of activation mechanism 14 and subsequent function of the device. In this embodiment, on-body sensor 24 is a safety mechanism: a mechanical lock-out that prevents triggering device 10 by depression of activation mechanism 14 unless the device is in position to administer tralokinumab (i.e., affixed to the subject's skin). Alternatively, the on- body sensor may be an electro-mechanical sensor such as a mechanical lock-out that sends a signal to power and control system 400 to permit activation; or the on-body sensor can be electrically based such as, for example, a capacitive- or impedance-based sensor that must detect tissue before permitting activation of power and control system 400. These concepts are not mutually exclusive, and one or more combinations may be utilized within the breadth of the present embodiments to prevent, for example, premature activation of the drug

delivery function.

[0096] In at least one embodiment, power and control system 400 includes a power source (e.g., a battery) which provides the energy for various electrical components within the device, comprising at least one feedback mechanism, a microcontroller, a circuit board, one or more conductive pads, and one or more interconnects. Other components commonly used in such electrical systems may also be included, as would be appreciated by one having ordinary skill in the art. The power source may be chargeable, rechargeable, removable, replaceable, or disposable. The microcontroller may be, for example, a microprocessor. Power and control system 400 controls several device interactions with the operator, and interfaces with drive mechanism 100. In one embodiment, power and control system 400 interfaces with control arm 40 to identify when on-body sensor 24 has been depressed or activation mechanism 14 has been activated. As such, the control interfaces, between the power and control system and the other components of the drug pump device, are not engaged or connected until activation by the operator as described above. This safety feature prevents accidental operation of the drug pump, and may also conserve the energy of the power source during storage, transportation, and the like. In some embodiments, the electronics components are removable or replaceable.

[0097] In at least one embodiment, interfaces of power and control system 400 interface with drive mechanism 100 through one or more interconnects to relay status indication

(feedback mechanism(s)), such as activation, drug delivery, and end-of-dose, to the

operator/subject. See, e.g. , FIG. 5C. Accordingly, such feedback mechanism(s) may include, for example, audible alarms or light indicators. Thus, for example, power and control system 400 may also interface with status indicator 16 of housing 12, which may be a transmissive or translucent material through which light provides visual feedback to the operator/subject. Power and control system 400 may be configured such that after the on-body sensor or trigger mechanism has been pressed, and if device start-up checks provide no errors, then power and control system 400 provides a ready-to- start status signal via status indicator 16. Insertion mechanism 200 and fluid pathway connection 300 may then be activated directly by user operation of activation mechanism 14. After providing the ready-to-start status signal, and if on- body sensor 24 remains in contact with the body of the subject, power and control system 400 powers drive mechanism 100 to begin delivery of the tralokinumab dosage form through fluid pathway connection 300 and sterile fluid conduit 30. Power and control system 400 can be configured to provide a dispensing status signal during the drug delivery process, via status indicator 16. After the dosage form has been administered into the body of the user, and after the end of any additional dwell time to ensure that substantially the entire dose has been delivered to the subject, power and control system 400 may provide an end-of-dose or okay-to-remove status signal via status indicator 16. This may be independently verified by the user by viewing the drive mechanism and drug dose delivery through window 18 of pump housing 12. Additionally, power and control system 400 may be configured to provide one or more alert signals via status indicator 16, such as alerts indicative of fault or operation failure situations.

[0098] Other power and control system configurations may be utilized with the tralokinumab delivery devices described herein. Such features provide desirable safety integration and ease-of-use parameters to the drug delivery devices. For example, certain activation delays may be used during drug delivery. As mentioned above, one such delay is a dwell time which ensures that substantially the entire dose has been delivered before signaling completion to the user. Similarly, activation of the device may require a delayed depression (i.e., pushing) of activation mechanism 14 of tralokinumab delivery device 10 prior to drug pump activation. Additional safety feature(s) may be integrated into the activation mechanism to prevent partial depression and, therefore, partial activation of the device. Additionally, the power and control system may include a feature permitting the operator/subject to respond to the end-of-dose signals and to deactivate or power-down the drug pump. Such features may similarly require a delayed depression of the activation mechanism, to prevent accidental deactivation of the device.

[0099] Charts and bar graphs depicting variables, components, and delivery times per example embodiments are shown in FIG. 1 to FIG. 4. For example, FIG. 3 shows the contribution to delivery time of groups of delivery device component parts. The relationship between spring force and the travel distance of the fluid delivered is shown in FIG. 2. FIG. 1 allows comparison of component contribution in the delivery of fluids with different viscosities. The four models are further analyzed for component contribution to the time of delivery in Table 2 (Case, Case 2, Case 3 and Case 4).

Table 2

Relative Contribution, seconds Case 1 Case2 Case3 Case4

Needle Diameter 1.0% 1.3% 1% 1.8%

Needle Length 0.1% 0.1% 0% 0.2%

Tubing (SAC-FR) Diameter 1.0% 1.3% 1% 1.8%

Tubng (SAC-FR) Length 0.2% 0.2% 0% 0.3%

Flow Restrictor Diameter 9.9% 13.6% 12% 18.3%

Fluid Path

Flow Restrictor Length 0.9% 1.2% 1% 1.7%

Tubing (FR-NM) Diameter 1.8% 2.5% 2% 3.4%

Tubing (FR-NM) Length 0.2% 0.2% 0% 0.3%

Cannula Diameter 0.1% 0.2% 0% 0.3%

Cannula Length 0.0% 0.0% 0% 0.0%

EXAMPLES

[0100] Previously, drug delivery time selection was selected arbitrarily or based generally on pain. This example provides a clinical study that explored dosage form delivery time based on tolerability. In particular, mean intensity of injection site pain intensity, mean intensity of injection site pruritus and injection site reactions were assessed. These experiences can then be considered when designing a delivery device as described herein, in which the flow rate is controlled by design (e.g., component dimensions) of a tralokinumab delivery device. More specifically, the data generated and the viscosity of the formulation is used to select a nominal delivery time (e.g., 1 niL/min), deliverable using an embodiment of the present drug delivery device. Standard syringes typically employed for the administration of subcutaneous (SQ) dosage forms comprising an IL-13 antagonist, such as tralokinumab, deliver about 1 mL. Therefore, given current dosage forms, if a larger amount of an IL-13 antagonist is prescribed then the patient must administer, or be administered, two injections instead of one. Additionally, current dosage forms comprising the IL-13 antagonist tralokinumab are fairly viscous, such that patients may experience greater pain intensity during SQ injection of a 2 mL dosage form, or if the dosage form were concentrated further (therefore more viscous). Each of these

circumstances increases the risk of patient noncompliance. The present embodiments provide drug delivery devices that are capable of delivering a relatively large-volume dosage form (for example, a 2 mL to 3 mL dosage form rather than a 1 mL dosage form) comprising

tralokinumab, with a level of pain intensity that is generally tolerable. These devices are advantageous, for example, in administering tralokinumab such that pain does not negatively impact compliance with the dosing regimen. [0101] As noted, tralokinumab, at a target dose of 300 mg every two weeks, has been shown to improve lung function in patients with asthma; but this dose has typically been administered as two 1 mL SQ injections. Piper et al., Eur. Respir. J. 41:330 (2013); Brightling et al., Lancet Respir. Med. 3:692 (2015). Tralokinumab is currently supplied as a sterile liquid formulation at a concentration of 150 mg tralokinumab per vial (nominal in 1.0 mL) intended for parenteral administration. No incompatibilities between tralokinumab and dosage administration components (i.e., syringe, extension set, or SQ insertion set) have been observed. At least one embodiment described herein provides a tralokinumab delivery device capable of delivering a dosage form comprising 300 mg tralokinumab, delivered as a single large- volume (2 mL) SQ injection at a flow rate selected from, for example, about 0.167 niL/minute to about 12 mL/minute, inclusive, such as 2 niL/minute or 6 mL/minute.

[0102] SQ injections allow for at-home patient self-administration, which does not appear to increase incidence of adverse events, while increasing patient satisfaction, convenience, and ease of use, patient confidence, which accordingly increases adherence to medication. Boccon-Gibodi & Bouillet, Clin. Exp. Immunol. 168:303 (2012); Bittner et al., Arzneimittelforschung 62:401 (2012); Aberer et al., Allergy 69:305 (2014); Bernstein et al., Allergy Asthma Proc. 36:92 (2015).

[0103] Currently, most SQ injection volumes are limited to 1 mL because larger volumes have been associated with increased injection pain, high SQ back pressure, site leakage, or injection-site reactions. Jorgensen et al., 30 Ann. Pharmacother. 729 (1996); Heise et al., Diabetes Obes. Metab. 16:971 (2014). Monoclonal antibodies often have to be formulated at concentrations of 100 mg/mL or greater, resulting in highly viscous solutions that complicate delivery by injection. Shire et al., J. Pharm. Sci. 93: 1390 (2004); Liu et al., J. Pharm. Sci.

94: 1928 (2005). Nevertheless, self-administered SQ injections of up to 1 mL are currently acceptable for therapeutic monoclonal antibody products. Bittner et al., 2012; Borras-Blasco et al., Expert Opin. Biol. Ther. 10:301 (2010); Lunven et al., Cardiovasc. Ther. 32:297 (2014). Thus, prior to the present example, delivery of a target dose of 300 mg tralokinumab required two SQ injections of 1 mL dosage form each comprising 150 mg tralokinumab. The need for multiple injections is less convenient for the patient, and may lead to non-compliance with dosing requirements. There is a need for a device and method that delivers a required dose of tralokinumab in a single SQ injection that is well tolerated.

[0104] Importantly, studies investigating SQ rehydration and SQ immunoglobulin replacement therapy have shown that subcutaneous tissue can accommodate volumes larger than 1 mL with good tolerability, depending on the flow rate and method of delivery. Gardulf et al., 26 J. Clin. Immunol. 177 (2006); Gustafson et al., Clin. Exp. Immunol. 152:274 (2008). A previous study reported a favorable safety profile in terms of pain, swelling, and treatment- emergent adverse effects (TEAEs) following administration of a single large-volume (3.5 mL) SQ injection of a highly viscous placebo solution used to mimic an injection of a biotherapeutic agent. Dias et al., AAPS Pharm. Sci. Tech. 16: 101 (2015). Additionally, demonstration of effective PK (i.e. similar PK to that delivered by 2 x 1 mL injections) following administration of a large- volume dosage form comprising tralokinumab further supports the use of the present wearable, on-body drug delivery device. See FDA, Infusion Pumps Total Product Life Cycle: Guidance for Industry & FDA Staff. (2014).

[0105] The tolerability of injecting a viscous dosage form in a larger volume, delivered at different rates, can be investigated in human subjects. Regarding tolerability, study subjects can be queried using the visual analog scale (VAS) of pain intensity, which consists of a line, most often 100 mm long, with two descriptors representing extremes of pain intensity (e.g., no pain and extreme pain) at each end. Subjects rate their pain intensity by making a mark somewhere on the line that represents their pain intensity, and the VAS is scored by measuring the distance from the "no pain" end of the line. Hawker et al., Arthritis Care Res. 63:S240 (2011). There has been discussion in the literature regarding VAS cut-offs for what is considered mild, moderate, or severe pain; and the VAS is somewhat dependent on the type of pain being measured (e.g., chronic or acute). Jensen et al., J. Pain 4:407 (2003). Therefore, VAS descriptors are not attributed with specificity, but the number of subjects who have pain >50mm are noted: this pain level is considered moderate- severe, and hence clinically significant. Also, due to the subjective nature of pain, one may expect some variability associated with pain assessment. Coghill & Eisenach, Anesthesiology 98: 1312 (2003); Nielsen et al., J. Pain 10:231 (2009); Coghill, Headache 50: 1531 (2010). Nevertheless, the VAS can provide valuable information on the pain associated with SQ injection. Dias et al., 2015; Heise et al., Diabetes Obes.

Metab. 16:971 (2014).

[0106] Briefly, a pharmaceutical formulation comprising tralokinumab, target dose 300 mg administered as two 1 mL subcutaneous injections every 2 weeks, has been shown to improve lung function in patients with asthma. This example provides evaluation of

pharmacokinetic (PK) and tolerability profile of tralokinumab 300 mg administered

subcutaneously via one large volume (2 mL) injection at different flow rates, against the current two 1 mL subcutaneous injections method. This study randomized 60 healthy adults to receive 300 mg tralokinumab, as two 1 mL subcutaneous injections, each delivered over 10 seconds, or one 2 mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0.167 mL/min). No clinically meaningful difference in the PK profile of tralokinumab was observed between cohorts. Immediately following injection, mean [SD] injection-site pain intensity was lowest following a 0.167 mL/min injection (5.1 mm [8.0] via visual analogue scale [VAS]) and greatest following a 12 mL/min injection (41 mm [27.7] via VAS); with mean injection-site pruritus intensity low for all subjects. Two types of local injection- site reactions were observed within 72 hours of injection; erythema (58.3%) and hematoma/bleeding (18.3%). All TEAEs were mild. These data support tralokinumab delivery via a single 2 mL subcutaneous injection, particularly when administered at slower flow rates.

[0107] As noted herein, tralokinumab is a human monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) subclass that potently and specifically neutralizes IL-13 by preventing its interaction with the receptors, IL-13Ral and IL-13Ra2. May et al., Br. J.

Pharmacol. 166:177 (2012). IL-13 is one of the key mediators in the pathogenesis of asthma (Woodruff et al., Am. J. Respir. Crit. Care Med. 180:388 (2009)), thus inhibition of IL-13 by tralokinumab offers a rational approach to the treatment of the disease (May et al., 2012).

Results from phase 2 studies in adult patients with uncontrolled severe asthma suggest that the addition of tralokinumab at a dose of 300 mg every two weeks, administered as two 1 mL subcutaneous (SQ) injections, alongside the patient's current asthma therapy may provide clinical improvements in this patient population. Piper et al., Eur. Respir. J. 41:330 (2013); Brightling et al., Lancet Respir. Med. 3:692 (2015). These clinical improvements were demonstrated by an improvement in lung function, as well as an acceptable safety and tolerability profile. Piper et al., 2013; Brightling et al. (2015). Tralokinumab is currently being investigated for the treatment of asthma in multiple Phase 3 studies.

[0108] This example reflects a Phase 1, open-label, parallel- group study undertaken to determine the feasibility of administering a single 2 mL SQ injection to support the delivery of a 300 mg dose of tralokinumab, by investigating the PK and tolerability when delivered at different flow rates. Informed consent was obtained from all study participants prior to the initiation of any study procedure. All study activities complied with Good Clinical Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and all applicable regulatory requirements. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable

ethical standards.

[0109] An objective of this example determined the local tolerability, overall safety, and immunogenicity profile of delivering, to healthy adult volunteers, a 2 mL viscous dosage form comprising 300 mg tralokinumab, injected at different flow rates. Another objective was to evaluate the PK profile of a single SQ dose of 300 mg tralokinumab, delivered as a 2 mL injection at different flow rates. [0110] More specifically, in this Phase 1, open-label, single-blind, parallel-group study (NCT02085473), healthy males and females were enrolled from one site in the United States. Subjects aged 19-65 years with a body mass index of 19.0 kg/m2 to 30.0 kg/m2 were included in the study. Enrolled subjects were randomized to one of four cohorts in a 1: 1 : 1: 1 ratio. See FIG. 18 for study design. Randomization was stratified by gender due to the potential for gender differences in pain perception and sensitivity. Wisenfeld-Hallin, Gend. Med. 2: 137 (2005); Paller et al, Pain Med. 0:289 (2009). A minimum of five males and five females were to be randomized to each cohort; the additional subjects could have been of either sex. Subjects were in the study for up to 79 days, which included a screening / consent period of up to 21 days, a 1-day treatment period, and a 57-day post-treatment follow-up period.

[0111] A screening visit was performed in the 21 days prior to dosing. Subjects were admitted to the study unit on Day -1. Following administration of 300 mg tralokinumab on Day 1 (dosing was considered Day 1), subjects were assessed regarding tolerability and injection site reaction, then discharged and followed up as outpatients for 57 days for safety, tolerability, immunogenicity, and PK sampling.

[0112] For dosing, vials of tralokinumab were equilibrated to room temperature before dose preparation. The nominal dose volume plus was increased with additional 1.5 mL of dose volume to account for losses in administration sets. The fluid path consisted of sterile, 510(k)- cleared components attached together via Luer-Lok™ connections. The fluid path was primed using 1 mL dosing volume at an infusion rate of 2 niL/min before administration for all cohorts. All injections were administered SQ in the abdomen. For all cohorts, tralokinumab was delivered via a 10 mL plastic Luer-Lok™ syringe, B Braun microbore extension set and an insertion set apparatus. A Harvard syringe pump (HA3000W PHD Ultra infuse/withdraw syringe pump; Pennsylvania, USA) was used to deliver tralokinumab at a predetermined volume and flow rate to ensure accuracy of delivery times.

[0113] Each subject in Cohort 1 received two separate injections at sites spaced at least 3 cm apart on the same side of the abdomen. For each subject in Cohorts 2, 3 and 4, a single injection site was identified on the same side of abdomen. Cohorts 1 and 2 were injected via a rigid needle, winged infusion set (Terumo 25 gauge x 0.5" Surflo® needle [Surflo®, New Jersey] with 8" tubing [Terumo, Liverpool, UK]) to mimic standard SQ injection via pre-filled auto-injectors. Cohorts 3 and 4 were injected via a soft cannula insertion set (Animas® Inset infusion system [Animas Corp., Livingstone, UK] with a 6 mm, 25-gauge, soft cannula) to mimic typical wearable, on-body devices (e.g., insulin pump therapy devices).

[0114] Tralokinumab (formulated in a pharmaceutical formulation comprising 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of 5.5 + 1) was delivered at the following delivery times: Cohort 1 at 10 sec for each 1 mL injection (i.e., 6 niL/min) per injection) (reference arm, 2 x 1 mL); Cohort 2 at 10 sec for a single 2 mL injection (i.e., 12 niL/min, or 1 mL/5 sec); Cohort 3 at 1 min for a single 2 mL injection (i.e., 2 niL/min, or 1 mL/30 sec); Cohort 4 at 12 min for a single 2 mL injection (i.e., 0.167 mL/min, 1 mL/360 sec). A summary of the four Cohorts is shown in Table 3:

Table 3. Regimens for delivery of 300 mg tralokinumab per cohort

[0115] Regarding statistical analysis of the populations, the as-treated population included all subjects who received any amount of tralokinumab. Subjects were included according to the injection flow rate received, even if different from that to which they were randomized. Demographics and safety and tolerability endpoints were summarized based on the as-treated population. The PK population included all subjects in the as-treated population with at least one detectable tralokinumab serum concentration and for whom the PK parameters could be adequately estimated. A total of fifteen subjects per treatment arm were included. A previous study, NCT01592396, showed a coefficient of variation (CV) of 37% for area under the serum concentration-time curve from zero to infinity (AUC0-∞) for tralokinumab. Assuming the same CV of 37% for AUC0 across the cohorts, and using a two-sided, two-sample t-test at a significance level of 0.05, the sample size of fifteen subjects per cohort provided 84% power to detect a 1.5 -fold difference in AUC0-∞ between Cohort 1 and any of the other

treatment cohorts.

[0116] PK parameters were analyzed for the PK population using non-compartmental models as implemented in Phoenix WinNonlin® version 6.3 (Princeton, NJ), a component of Phoenix vl.3. Other safety/tolerability endpoints were analyzed for the as-treated population. For injection-site pain and pruritus, descriptive statistics such as mean, median, standard deviation were reported at each assessment time point by cohort. Wilcoxon rank sum tests were used to compare VAS scores between Cohort 1 and each of Cohorts 2, 3, and 4, no multiplicity adjustment was made given the exploratory nature of the study. [0117] Regarding planned analyses, a primary endpoint for the study was to determine the PK profile of tralokinumab. Blood samples were taken for PK analyses immediately prior to tralokinumab administration and then on Days 2, 4, 6, 8, 10, 15, 22, 36, and 57. Tralokinumab serum concentrations were quantified using a previously described, validated sandwich immunoassay. Oh et al., Br. J. Clin. Pharmacol. 69:645 (2010).

[0118] Two key endpoints were local injection site pain intensity and injection site pruritus post-injection, as measured by a 100 mm visual analogue scale (VAS; where 0 mm = no pain/itch, and 100 mm = worst imaginable pain/itch). Local injection- site pain intensity was also recorded at 1 min and 6 min during the injection for Cohort 4 due to the longer delivery time of the injection. For subjects in Cohort 1, the overall assessment of pain intensity and pruritus from both injection- sites was reported for each time point post injection. Local injection-site reactions (including erythema, hematoma or bleeding, local warmth, swelling, and/or rash) were measured and summarized using descriptive statistics by cohort over time. These were based on the presence or absence of signs or symptoms of local injection-site reactions, as assessed by a blinded assessor immediately after administration. Assessment of injection- site reactions was blinded for Cohorts 2, 3 and 4, but was not possible for Cohort 1 which had two injection- sites; due to the variation in administration times, subjects were not blinded in this study.

[0119] Local injection-site reactions were recorded on a dedicated and standardized assessment questionnaire. If there were differences in injection-site reactions between the two sites for subjects in Cohort 1, the most severe reaction was recorded. If it occurred, fluid leakage was measured immediately following administration by blotting the injection- site with a pre- weighed absorbent material and the amount of leakage quantified by gravimetric analysis. To assess the presence of anti-drug antibodies (ADA) against tralokinumab, blood samples were collected both immediately prior to tralokinumab administration on Day 1, and on Day 57.

[0120] Injection- site assessments were made immediately following tralokinumab injection and then at 10 min, 20 min, 30 min, and, 60 min, and 2 hr, 4 hr, 8 hr, 24 hr, and 72 hr post- injection. Local injection-site reactions were recorded as a specific endpoint and only reported as adverse events (AEs) if they met one or more of the following criteria: were a serious adverse event; led to premature termination of the injection during tralokinumab administration; required concomitant medication or other medically important intervention; or had an impact on the general condition of the subject, as judged by the investigator.

[0121] The incidence of TEAEs, including clinically significant changes in vital signs, physical examinations, and laboratory parameters were investigated. The TEAEs and serious TEAEs (SAEs) were described by system organ class (SOC) and preferred term. The severity and relationship of these AEs to tralokinumab was summarized. Injection-related AEs were also summarized.

[0122] Overall, sixty subjects met the eligibility criteria and were randomized into the study, fifteen subjects per cohort. All subjects received study medication and there were no discontinuations; all sixty subjects completed the study of this example; all sixty randomized subjects were included in the as-treated population. Mean (SD) age of the population was 38.3 (12.2) years with an overall equal number of male and female subjects. Demographic characteristics were generally similar between the four cohorts as shown in Table 4:

Table 4. Subject demographics (as-treated population)

BMI, body mass index; min, minute; SQ, subcutaneous; SD, standard deviation.

[0123] Concerning the PK evaluation, fifty-eight subjects were included in the PK population. Three subjects (one from Cohort 3 and two from Cohort 4) had extensive leakage of tralokinumab, attributed to incorrect placement of the insertion set. Extensive leakage was defined as a measured leakage weight >1 g, equivalent to 50% of the injection volume

(calculated based on a known density of 1.046 g/L, tralokinumab solution weighs 2.092 g; thus, 1 g represents 1 mL or 50% of the injection volume). Of the three subjects with extensive leakage, two (one from Cohort 3 and one from Cohort 4) were excluded from the PK population because serum tralokinumab concentrations were below the level of detection at all PK sampling time points after dosing. The subject with extensive leakage who remained in the PK population was included because detectable serum concentrations of tralokinumab were observed;

additional analyses excluding this subject were also performed on all PK parameters. [0124] Mean tralokinumab serum concentration-time profiles were similar across the four cohorts (FIG. 15). Individual PK profiles in each cohort are presented in FIG. 16. A summary of the PK parameters can be found in Table 5, below, in which AUC(0-∞) is the area under the serum concentration-time curve from zero to infinity; AUC(O-t) is the AUC to last observation; CI is the confidence interval; CL/F is the apparent systemic clearance; Cmax is the maximum concentration; CV is the coefficient of variation; Tmax, is time to Cmax; and Vz/F, apparent terminal-phase volume of distribution:

Table 5. Tralokinumab pharmacokinetic parameters (PK population)

a Additional analysis excluding the subject with extensive leakage of tralokinumab.

b Fold difference (95% CI) is the ratio of the geometric mean AUC(o- _∞ ) for cohort 1 to that for each of cohorts 2, 3, and 4.

[0125] There were no significant clinical differences in any of the PK parameters between the cohorts. The area under the serum concentration versus time curve from time 0 to infinity (AU o-oo)) in Cohorts 2 and 3 were similar (<15% difference) compared with Cohort 1 (Table 5). The ratio of AUC ₍ o _∞) for Cohort 1 to that for Cohort 4 (fold difference) was 1.1, when the subject with extensive leakage was excluded from Cohort 4 (Table 5). No subjects had confirmed positive AD As to tralokinumab in the study.

[0126] Regarding local tolerability based on injection-site pain intensity, immediately after injection, the mean (SD) injection- site pain intensity was 21.9 mm (20.9) in diameter in Cohort 1; 41.0 mm (27.7) in Cohort 2 (p = 0.034); 17.7 (15.5) in Cohort 3 (p = 0.675); and 5.1 mm (8.0) in Cohort 4 (p = 0.002). See FIG. 15. By 10-min post injection, mean injection- site pain intensity markedly decreased for all cohorts with similar mean scores for all cohorts observed by 30 min and at subsequent assessments. Injection-site pain intensities of >50 mm in diameter on the VAS (moderate or above pain intensity rating (Jensen et al., J. Pain 4:407 (2003)), immediately following injection occurred in two subjects (13.3%) in Cohort 1, six subjects (40.0%) in Cohort 2, and no subjects in Cohorts 3 or 4. When moderate or higher pain intensity occurred, it decreased to <50 mm on the VAS within 20 min for all subjects. There were no notable differences in injection- site pain intensity between male and female subjects in any of the cohorts at any time point following injection. See FIG. 17.

[0127] Regarding local tolerability based on injection-site pruritus intensity, overall the mean injection- site pruritus intensity was low for all cohorts immediately post- injection (mean [SD] 4.8 mm [7.5] in cohort 1, 15.1 mm [20.2] in cohort 2 [p = 0.147], 4.0 mm [5.6] in cohort 3 [p = 0.841], and 6.9 mm [15.5] in cohort 4 [p = 0.507]. See FIG. 16. Mean [SD] VAS injection- site pruritus intensity at 30 min post injection for subjects in Cohort 1 did reach statistical significance compared to Cohort 4 (0.5 mm [0.7] vs 1.8 mm [1.8], respectively; p = 0.035); the level of intensity was low for both groups, however, and the difference was not considered clinically meaningful. Injection-site pruritus intensities of >50 mm occurred in two subjects in Cohort 2 and one subject in Cohort 4 immediately following injection, but these reduced to <5 mm within 30 min post-injection. See FIG. 18.

[0128] Regarding local tolerability based on local injection-site reactions, a summary of injection-site reactions following injection of tralokinumab is shown in Table 6:

Table 6. Injection-site reactions reported within 72 hr post-injection

300 mg 1 "ralokinumab, SQ Injection

2 x 1 mL 1 x 2 mL

Category Cohort 1 Cohort 2 Cohort 3 Cohort 4

Total 6 mL/min 12 mL/min 2 mL/min 0.167 mL/min

N = 60 N = 15 N = 15 N = 15 N = 15

Erythema 7 (46.7%) 5 (33.3%) 2 (80.0%) 11 (73.3%) 35 (58.3%)

Hematoma or Bleeding 2 (13.3%) 1 (6.7%) 3 (20.0%) 5 (33.3%) 11 (18.3%)

[0129] There were two types of local injection- site reactions observed: erythema and hematoma or bleeding; all events were mild in severity. Overall, seven subjects reported injection-site erythema from Cohort 1, 5 from Cohort 2, 12 from Cohort 3, and 11 from

Cohort 4, within 72 hours of receiving the tralokinumab injection. All were assessed as Grade 1 in severity. Overall, injection-site erythema was resolved by 2 hr post injection for all cohorts. One Grade 1 (mild) injection- site erythema reaction of 5 mm in diameter was reported in Cohort 3 at 24 hr following injection and was resolved by 72 hr post injection. The mean diameter of injection-site erythema was measured, being numerically highest for cohort 2 immediately post-injection (mean [SD] 25.0 mm [15.0] for Cohort 1, 37.5 mm [24.7] for Cohort 2, 29.1 mm [11.1] for Cohort 3, and 27.8 mm [18.6] for Cohort 4). See FIG. 19.

[0130] Injection- site hematoma or bleeding occurred sporadically following

tralokinumab injection, with the highest incidence in Cohort 4. See FIG. 15. Two subjects reported injection- site hematoma or bleeding from Cohort 1, one from Cohort 2, three from Cohort 3, and five from Cohort 4, within 72 hr of receiving the tralokinumab injection. All were Grade 1 in severity. The mean diameter of injection-site hematoma or bleeding was measured, and overall found to be numerically highest for Cohort 4 (mean [SD] 2.8 mm [2.0] immediately post- injection [no patients reported injection- site hematoma or bleeding in cohorts 1, 2 and 3 at this time point]). One subject each of Cohort 1 and Cohort 2 reported a mild injection-site hematoma at 24 hr post-injection; both events were resolved by 72 hr following injection. One mild injection-site hematoma or bleeding reaction of 20 mm in diameter was reported in Cohort 3 at the 72-hr time point. See FIG. 20. This event was not followed up to resolution per protocol follow-up procedures, however, and was recorded as a protocol deviation.

[0131] Concerning tralokinumab leakage, leakage of tralokinumab was observed at the injection-site in one subject in Cohort 3 and three subjects in Cohort 4. Of these four subjects, one subject in Cohort 3 and two subjects in Cohort 4 had extensive leakage (defined as a measured leakage weight >1 g). Extensive tralokinumab leakage in these subjects was not attributed to the injection volume or flow rate, but to the incorrect placement of the insertion sets (Animas Inset™ infusion system) used in Cohorts 3 and 4, which resulted in the soft cannula assembly slipping partially off the needle and bending on insertion.

[0132] Concerning safety and tolerability, there were no deaths, SAEs, or TEAEs that resulted in discontinuation of tralokinumab reported in this study. All reported TEAEs reported were mild in intensity. The proportions of subjects having at least one TEAE were similar across the four cohorts. The overall safety profile of 300 mg tralokinumab SQ was favorable, with all TEAEs being mild in severity, and no SAEs, discontinuations, or deaths being reported. An overall summary of TEAEs reported by >1 subject and reported injection-site reactions (as- treated population) is presented in Table 7:

Table 7. Overall summary of TEAEs

Throat irritation 0 2 (13.3%) 0 0 2 (3.3%)

Vomiting 0 2 (13.3%) 0 0 2 (3.3%)

[0133] The most frequently reported TEAEs in the overall subject population were headache (16.7%), nasal congestion (5.0%), and rhinorrhea (5.0%). An injection-site reaction occurred in one subject (6.7%) from Cohort 2 (injection-site pain). This was recorded as a TEAE due to its impact on the general condition of the subject, as judged by the investigator and was described as mild in severity. No clinically meaningful abnormalities in hematology, serum chemistry, or urinalysis laboratory values were observed. There were no clinically meaningful changes in vital signs from baseline to day-57.

[0134] This study was designed to evaluate tolerability of a single SQ dose of 300 mg tralokinumab, when delivered as a 2 mL injection at different flow rates, compared with that observed with the currently used two 1 mL injections; and to examine the PK profile and safety of the large- volume delivery. These data provide an insight into the PK profile of 300 mg tralokinumab (formulated in a pharmaceutical formulation comprising 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of 5.5 + 0.1) when administered at different delivery rates, and support the design of a large volume delivery device with a delivery time of up to 12 min without affecting the PK of tralokinumab. No clinically meaningful differences were seen between the cohorts of healthy volunteers in any of the measured PK parameters, supporting the feasibility of a single 2 mL injection treatment regimen. The lack of difference in PK is not surprising, however, given that the absorption of tralokinumab after SQ administration occurs over a time scale of days - as evidenced by a Tmax value of 6-8 days in the four cohorts analyzed. Thus, PK is unlikely to be affected by differences in a delivery method that varies by only a few minutes.

[0135] When 300 mg tralokinumab (formulated in a pharmaceutical formulation comprising 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% poly- sorbate-80 having a pH of 5.5 + 0.5) was delivered as a 2 mL injection at a low flow rate (12 min infusion, [0.167 mL/min]; prolonged injection time), the injection-site pain intensity was lower compared with that observed following two 1 mL injections. Conversely, delivery of a large- volume injection over a relatively fast flow rate (10 sec [12 mL/min flow rate or 1 mL/5 sec]) which mimicked flow rates of known large- volume autoinjector devices, resulted in higher pain scores and a higher incidence of pain scores with an intensity of >50 mm on the VAS immediately post injection compared with the other assessed delivery methods. It is important that, in addition to delivery of 2 mL of tralokinumab at a slower flow rate (1 min or 12 min) resulting in a similar PK profile as that seen when delivering two 1 mL injections, there were no adverse consequences that impacted the favorable tolerability profile. These data support the feasibility of using large volume injections at intermediary flow rates that can be controlled by design and configuration of the tralokinumab delivery device. This study was not powered to detect detailed differences in pain intensity, however, and confirmation in larger, blinded, controlled clinical studies may further support the suitability of a 2 mL dose volume delivered with an injection time over a faster period (i.e., a matter of seconds). See SHL Group, White Paper - Auto Injectors: From Planning to Launch (2013). Additionally, there is variability associated with pain assessments due to the subjective nature of this parameter. See Coghill et al., PNAS 100:8538 (2003); Nielsen et al., J. Pain 20:231 (2009); Coghill et al.,

Headache 50: 1531 (2010).

[0136] In addition to the positive PK and pain intensity findings observed in this example, the mean intensity of injection-site pruritus was low at all time-points post-injection, and was generally similar between all cohorts. Compared with Cohort 1, injection- site pruritus scores were numerically higher in Cohort 2 immediately following tralokinumab injection, with pruritus intensity at its highest in subjects who received a single 2 mL injection at a 12 mL/min flow rate (Cohort 2). This flow rate, equivalent to 1 mL/5 sec, simulates a large volume autoinjector (LVAI) and suggests that the slower flow rates that can be controlled in the wearable, on-body drug delivery devices described herein will be better tolerated with less pruritus and less pain. When taken together with the PK and injection- site pain intensity data, these results further highlight the feasibility of using large volume injections at intermediary volume flow rates (2 mL/min to 0.167 mL/min) that can be selected and delivered by the devices designed accordingly as described herein. Furthermore, erythema and hematoma or bleeding were the only types of local injection-site reactions reported, and all were mild in severity. Both erythema and hematoma or bleeding were reported at a higher incidence in Cohorts 3 and 4 compared with Cohorts 1 and 2. These injection-site reactions may have been related to the soft cannula insertion set, however, rather than the delivery method. The adhesive required to apply the soft cannula to the skin may also have caused an increase in the reddening and itching of the skin around the injection-site, and the longer residence time of the cannula in the skin could have been the cause of the increase in hematoma or bleeding seen at the injection-site in Cohort 3 and, particularly, Cohort 4, rather than the volume or flow rate of the injection. As shown by the various embodiments described herein, the devices are easily adaptable to incorporate suitable components that avoid leakage. [0137] The open-label exploratory design of the study may limit the statistical weight of some of these analyses. In particular, the assessors who evaluated local reactions could not be blinded to the treatment allocation of subjects in Cohort 1. The large variations in delivery flow rate and the difference in number of injections received also prevented blinding of the subjects to the treatment received. Because different delivery apparatus was used for Cohorts 1 and 2 (rigid needle) and for Cohorts 3 and 4 (soft cannula), caution is required when directly comparing the tolerability data from these groups. The obvious differences between the delivery devices were demonstrated by the three subjects who experienced significant leakage of the tralokinumab dosage form after drug delivery via a soft cannula. The observed leakage was likely due to incorrect application of the insertion set. This example did not investigate the higher flow rates that may also be achieved with lower viscosity preparations. Finally, the small sample size prevented any meaningful statistical comparisons across cohorts with respect to the secondary endpoints and no correction for multiple testing was applied due to the exploratory nature of the study.

[0138] The exploratory study of this example showed no significant differences in the PK profile of tralokinumab when compared across a range of injection flow rates. The overall tolerability of a single, large- volume 2 mL injection comprising 300 mg tralokinumab was generally consistent with that of two 1 mL injections when delivered at a slow rate (between 1 min - 12 min, or 1 mL/30sec - 360 sec, or 360 mL/hr) of the large-volume tralokinumab dosage form, and may have the potential to lower the perceived pain compared with the currently approved injection regimen. Data from this example relating to PK and tolerability support the use of a single large- volume injection. These data can be used as a source of design input to generate an operating range of delivery times for a large- volume injection that result in acceptable PK and tolerability. The use of large- volume injection could reduce the need for multiple injections with biotherapeutic drugs, and may improve patient adherence and persistence with treatment.

[0139] In conclusion, the results presented in this example suggest delivery of 300 mg tralokinumab (formulated in a pharmaceutical formulation comprising 50 mM sodium acetate/acetic acid, 85 mM sodium chloride, and 0.01% polysorbate 80 having a pH of 5.5 + 0.5) via a single 2 mL SQ injection at the range of flow rates studied was associated with acceptable tolerability profiles. These data support the feasibility of the single 2 mL injection treatment regimen, particularly at slower delivery rates. Thus, it may be possible to reduce the number of injections through the administration of larger dose volumes by using the on-body drug delivery devices described herein, with provide viscous dosage form delivery over longer injection times. These results support the large- volume injection devices described herein, which enable delivery of a target dose of tralokinumab as a single injection.

[0140] Although the exemplified devices may be used for SQ delivery, it should be noted that they are also suitable for adaptation to intravenous, intramuscular, or intradermal delivery. For example, toxicology studies were conducted in cynomolgus monkeys following single and repeated intravenous (IV) and subcutaneous (SQ) doses of tralokinumab. Following multiple IV doses of up to 100 mg/kg/week tralokinumab (longest administration schedule was weekly for 26 weeks), there were no local or systemic dose-limiting toxicities and a no- observed-adverse-effect-level of 100 mg/kg/week was identified. Repeated SQ dose studies in cynomolgus monkeys showed no local or systemic effects when administered as 4-weekly SQ doses up to 225 mg/injection or as 13-weekly doses up to 300 mg/injection. No adverse effects were noted in a pilot embryo-fetal development toxicity study and in a pre- and post-natal development study following the highest dose tested (100 mg/kg IV).

[0141] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.