Bispecific GLP-1ra / GLP-2ra fusion protein dosage forms and methods

Abstract

The present disclosure relates generally to ingestible devices containing a bispecific GLP-1RA / GLP-2RA fusion protein, wherein the devices are structured and formulated to deliver therapeutically effective amounts of the fusion protein into a gastrointestinal (GI) lumen wall or into and through a GI lumen wall into a peritoneum or peritoneal cavity after ingestion of the device, and achieve desired pharmacokinetic and pharmacodynamic effects.

Description

Attorney Docket No. 130257-0765 (770.601)BISPECIFIC GLP-1RA / GLP-2RA FUSION PROTEIN DOSAGE FORMS AND METHODS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application 63 / 776,720, filed March 24, 2025, the entire contents of which are incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on March 18, 2026, is named 130257-0765_SL.xml, and is 129,535 bytes in size.FIELD

[0003] The present disclosure relates generally to dosage forms, devices, and methods for delivery of a bispecific GLP-1RA / GLP-2RA fusion protein by ingestion. More specifically, the present disclosure relates to ingestible dosage forms (e.g., ingestible devices) that contain a composition comprising a bispecific GLP-1RA / GLP-2RA fusion protein that are structured and formulated to deliver therapeutically effective amounts of the bispecific GLP-1RA / GLP-2RA fusion protein into a gastrointestinal (GI) lumen wall (e.g., stomach wall, intestinal wall, colon, etc.) of the subject or into and through a GI lumen wall into a peritoneum or peritoneal cavity of the subject to achieve desired pharmacokinetic and pharmacodynamic results. The devices and methods may be useful, for example, for the treatment of obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and other conditions in which treatment with a bispecific GLP-1RA / GLP-2RA fusion protein may be indicated.BACKGROUND

[0004] The following discussion is merely provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto.

[0005] GLP-1 receptor agonists (RAs) work by mimicking the naturally occurring hormone called glucagon-like peptide 1 (GLP-1), which stimulates the pancreas to release insulin when blood sugar levels rise, effectively lowering blood sugar levels in patients. GLP-lRAs also promote satiety by signaling to the brain that the stomach is full, leading to reduced appetite and potential weight loss.

[0006] GLP-2RAs, on the other hand, work by binding to the glucagon-like peptide-2 (GLP-2) receptor on the surface of intestinal cells, which may help to improve nutrient absorption, reduce inflammation, and promote intestinal growth.14905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0007] It has been proposed to combine a GLP-1RA with a GLP-2RA in a single molecule as a potential treatment for diabetes and obesity. This combination may help, for example, with weight loss, inflammation, and gut barrier function in humans. For example, U.S. Patent Application No.17 / 910,348 (published as US PG-PUB 2024 / 0368239) titled “NOVEL BISPECIFIC PROTEIN AND USE THEREOF” discusses bispecific fusion proteins having a GLP-1 analogue and a GLP-2 analogue fused to each other. For example, the fusion protein may include a first fusion protein in which a GLP-1 analogue is linked to an antibody Fc region and a second fusion protein in which a GLP-2 analogue is linked to an antibody Fc region.

[0008] Bispecific fusion proteins are typically administered parenterally (e.g., subcutaneously) instead of by ingestion due to the presence of digestive enzymes in the stomach and intestines that readily cleave the protein chains and break them down before they can be absorbed into the bloodstream, essentially destroying their biological activity. However, parenteral administration can be painful and inconvenient for patients, which can impact patient compliance and quality of life.

[0009] There remains a need for dosage forms, devices, and methods for delivery of bispecific GLP-1RA / GLP-2RA fusion proteins by ingestion.SUMMARY

[0010] In one embodiment, a method of administering a bispecific GLP-1 RA / GLP-2RA fusion protein to a subject in need thereof is provided. The method includes administering to the subject by ingestion an ingestible device containing a composition comprising a therapeutically effective dose of the bispecific GLP-1 RA / GLP-2RA fusion protein. In another embodiment, an ingestible device for use in delivering a bispecific GLP-1 RA / GLP-2RA fusion protein to a subject in need thereof is provided. The device contains a composition comprising a therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein. In any embodiments, the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or into and through a GI lumen wall into a peritoneum or peritoneal cavity of the subject following ingestion.

[0011] In one or more embodiments, the bispecific GLP-1 RA / GLP-2RA fusion protein exhibits a bioavailability that is greater than a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein. In one or more embodiments, the bispecific GLP-1 RA / GLP-2RA fusion protein exhibits a bioavailability that is substantially the same as a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

[0012] In one or more embodiments, the bispecific GLP-1 RA / GLP-2RA fusion protein exhibits a Cmax that is less than a Cmax of subcutaneously administered bispecific GLP-1 RA / GLP-2RA fusion 24905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)protein. In one or more embodiments, the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Cmax that is substantially the same as a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

[0013] In one or more embodiments, the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Tmax that is greater than a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein. In one or more embodiments, the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Tmax that is substantially the same as a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

[0014] In one or more embodiments, the subject is suffering from one or more conditions selected from obesity, diabetes, NAFLD, and NASH.

[0015] In one or more embodiments, the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is from about 4 mg to about 30 mg, e.g., from about 4 mg to about 30 mg of a bispecific GLP-1RA / GLP-2RA fusion protein as described herein, such as PG-102-8. In one or more embodiments, the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is about 12 mg (e.g., about 12 mg of PG-102-8). In one or more embodiments, the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is about 30 mg (e.g., about 30 mg of PG-102-8).

[0016] In one or more embodiments, the device is administered twice weekly. In one or more embodiments, the device is administered twice weekly with about 24 hours between each dose. In one or more embodiments, the device is administered twice weekly with about 12 hours between each dose on the same day. In one or more embodiments, the device is administered thrice weekly. In one or more embodiments, the device is administered thrice weekly with about 24 hours between each dose. In one or more embodiments, the device is administered thrice weekly with about 12 hours between each dose.

[0017] In one or more embodiments, the composition is a liquid composition. In one or more embodiments, the composition is a liquid composition that includes the bispecific GLP-1RA / GLP-2RA fusion protein, a buffering agent, a solubilizing agent, a binder, and an antioxidant. In one or more embodiments, the liquid composition further includes a surfactant selected from polysorbate 80 or poloxamer 188.

[0018] In one or more embodiments, the composition is injected into a GI lumen wall of the subject and / or into a peritoneum or peritoneal cavity of the subject following ingestion. In one or more embodiments, the composition is injected via a hollow needle.34905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0019] In one or more embodiments, the GI lumen wall is a wall of the stomach. In one or more embodiments, the GI lumen wall is a wall of the intestine. In one or more embodiments, the wall of the intestine is a wall of the small intestine.

[0020] In one or more embodiments, the ingestible device is comprised within a swallowable capsule.

[0021] In one or more embodiments, the method or use comprises a titration dosing period followed by a maintenance dosing period. In some embodiments, the titration dosing period comprises administering a first dose of the bispecific GLP-1RA / GLP-2RA fusion protein once weekly (QW) for two weeks, followed by administration of a second dose twice weekly (Q2W) for two weeks, followed by administration of a third dose three times weekly (TIW) as a maintenance dose. In some embodiments, the first, second, and third doses are the same amount of the bi specific GLP-1RA / GLP-2RA fusion protein, optionally wherein the first, second, and third doses are about 30 mg of a bispecific GLP-1RA / GLP-2RA fusion protein as described herein (e.g., about 30 mg of PG-102-8).

[0022] In any embodiments, the bispecific GLP-1RA / GLP-2RA fusion protein:comprises a GLP-1RA moiety comprising the amino acid sequence of one of SEQ ID NOs.1-11, optionally comprising the amino acid sequence of one of SEQ ID NOs.1, 4, 5, or 11;comprises a GLP-2RA moiety comprising the amino acid sequence of one of SEQ ID NOs.17-22, optionally comprising the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 19;comprises a GLP-1RA moiety comprising the amino acid sequence of one of SEQ ID NOs.1-11, optionally comprising the amino acid sequence of one of SEQ ID NOs.1, 4, 5, or 11, and comprises a GLP-2RA moiety comprising the amino acid sequence of one of SEQ ID NOs. 17-22, optionally comprising the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 19;comprises a GLP-1RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 23 to 30;comprises a GLP-2RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs. 31 to 36;comprises a GLP-1RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 23 to 30 and a GLP-2RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs. 31 to 36; oris selected from PG-102-1, PG-102-2, PG-102-3, PG-102-4, PG-102-5, PG-102-6, PG-102-7, PG-102-8, or PG-102-9.44905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 (FIG. 1) is a schematic view illustrating an example of an ingestible device.

[0024] Figure 2 (FIG. 2) is a partial cutaway view illustrating an example of the ingestible device of FIG. 1 in a folded state disposed in a swallowable capsule.

[0025] Figure 3 (FIG. 3) is a cross-sectional view of a delivery structure of an embodiment of the ingestible device of FIG. 1.

[0026] Figures 4-7 (FIGS. 4-7) illustrate an actuation sequence of the device of FIG. 3 in a small intestine of a subject.

[0027] Figures 8-9 (FIGS. 8-9) illustrate a partial cross-sectional view of another example of the ingestible device of FIG. 1.

[0028] Figure 10 (FIG. 10) shows the serum concentration vs. time curve obtained after oral administration of a single dose of an ingestible dosage form of abispecific GLP-1RA / GLP-2RA fusion protein (RT-114) or single subcutaneous (SC) injection of the bispecific GLP-1RA / GLP-2RA fusion protein as described herein in the canine study of Example 1.

[0029] Figure 11 (FIG. 11) shows the peak decreases in body weight in the canine study of Example 1.

[0030] Figures 12-13 (FIGS. 12-13) show the serum drug levels v. food consumption in the canine study of Example 1.DETAILED DESCRIPTION

[0031] The present disclosure provides dosage forms, devices, and methods for delivery of a bispecific GLP-1RA / GLP-2RA fusion protein using an ingestible dosage form (an ingestible device), where the device is structured to deliver the bispecific GLP-1RA / GLP-2RA fusion protein into a GI lumen wall (e.g., stomach wall, intestinal wall, etc.) of the subject or into and through a GI lumen wall into a peritoneum or peritoneal cavity of the subject (and thereafter systemically via the bloodstream and / or lymphatics). The bispecific GLP-1RA / GLP-2RA fusion protein may be delivered via a hollow tissue penetrating member structured to penetrate a GI lumen wall of the subject and / or into a peritoneum or peritoneal cavity of the subject after ingestion of the device. The ingestible device may be disposed within a capsule, such as a swallowable capsule.I. Definitions

[0032] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.54905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0033] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Unless otherwise specified, materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein, based on the guidance provided herein.

[0034] As used herein, the singular terms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Reference to an object in the singular is not intended to mean “one and only one” unless explicitly so stated, but rather “one or more”.

[0035] As used herein, the terms “e.g.,” “such as”, “for example”, “for an example”, “for another example”, “examples of’, “by way of example”, and “etc.” indicate that a list of one or more nonlimiting example(s) precedes or follows; it is to be understood that other examples not listed are also within the scope of the present disclosure.

[0036] As used herein, the terms “substantially” and “about” when used with a numerical value mean the numerical value stated as well as up to and including plus or minus 10% of the numerical value. For example, “about 10” should be understood as both “10” and “in a range between and including 9 and 11”.

[0037] As used herein, a phrase in the form “A / B” or in the form “A and / or B” means (A), (B), or (A and B); a phrase in the form “at least one of A, B, and C” means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0038] As used herein, the terms “comprising”, “comprise”, “comprises”, “includes”, and “including” are intended to mean that the compositions and methods include the recited elements, but do not exclude others.

[0039] As used herein, the phrase “therapeutically effective amount” with reference to a bispecific GLP-1RA / GLP-2RA fusion protein means a dose that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. It is emphasized that a therapeutically effective amount of bispecific GLP-1RA / GLP-2RA fusion protein will not always be effective in treating the condition for which it is administered in every individual subject, even though such dose is deemed to be a therapeutically effective amount by those of skill in the art. Those skilled in the art can adjust what is deemed to be a therapeutically effective amount in accordance with standard practices as needed to treat a specific subject. A therapeutically effective amount may vary based on, for example, the age and weight of the subject, and / or the subject’s overall health, the condition being treated, and / or the severity of the condition of the subject being treated.64905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0040] A “therapeutic level” of circulating bispecific GLP-1RA / GLP-2RA fusion protein in a human subject means a plasma level associated with the specific pharmacological effect for which the drug is administered in a subject in need of such treatment.

[0041] The term “ingest” or a grammatical variation thereof (e.g., “ingesting”, “ingestion,” “ingested” or “ingestible”) refers herein to taking into the stomach, whether by swallowing or by other means of depositing into the stomach (e.g., by depositing into the stomach by endoscope or depositing into the stomach via a port).

[0042] The term “lumen” refers herein to the inside space of a tubular structure. Examples of lumens in a body include arteries, veins, and tubular cavities within organs. The term “gastrointestinal lumen” or “GI lumen” refers generally to any lumen of the GI tract (e.g., a lumen of the esophagus, stomach, small intestine, large intestine, or colon); the term “GI lumen wall” refers to a lumen wall of a GI lumen.

[0043] The term “lumen wall” refers to a wall of a lumen, where the wall includes all layers from an inner perimeter to an outer perimeter of the lumen, such as, with respect to lumens in a body, the mucosa, submucosa, muscularis, serosa, and an outer wall of the lumen, with the constituent blood vessels and tissues.

[0044] The term “gastrointestinal tract” or “GI tract” as used herein refers herein to the intake / expulsion system of a body including, for example, the mouth, pharynx, esophagus, stomach, pylorus, small intestine, cecum, large intestine, colon, rectum, anus, and valves or sphincters therebetween.

[0045] The terms “individual,” “subject,” and “patient” are used interchangeably herein, and include any individual mammalian subject (e.g., bovine, canine, feline, equine, or human). In specific embodiments, the subject, individual, or patient is a human.

[0046] The term “component” refers herein to one item of a set of one or more items that together make up a device, a composition, or a system under discussion. A component may be in a solid, powder, gel, plasma, fluid, gas, or other constitution. For example, a device may include multiple solid components which are assembled together to structure the device and may further include a fluid component that is disposed in the device. For another example, a composition may include a single component, or two or more components which are mixed together to make the composition. A composition may be in the form of a fluid (e.g., a liquid), a slurry, a powder, or a solid (e.g., in a condensed or a consolidated form such as a tablet or microtablet). A device or system can include one or more compositions and / or one or more other components.74905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0047] The term “design” or a grammatical variation thereof (e.g., “designing” or “designed”) refers herein to characteristics intentionally incorporated based on, for example, estimates of tolerances (e.g., component tolerances and / or manufacturing tolerances) and estimates of environmental conditions expected to be encountered (e.g., temperature, humidity, external or internal ambient pressure, external or internal mechanical pressure, stress from external or internal mechanical pressure, age of product, or shelflife, or, if introduced into a body, physiology, body chemistry, biological composition of fluids or tissue, chemical composition of fluids or tissue, pH, species, diet, health, gender, age, ancestry, disease, or tissue damage); it is to be understood that actual tolerances and environmental conditions before and / or after delivery can affect characteristics so that different components, devices, compositions, or systems with a same design can have different actual values with respect to those characteristics. Design encompasses also variations or modifications before or after manufacture.

[0048] The term “manufacture” or a grammatical variation thereof (e.g., “manufacturing” or “manufactured”) as related to a component, device, composition, medicament, or system refers herein to making or assembling the component, device, composition, or system. Manufacture may be wholly or in part by hand and / or wholly or in part in an automated fashion.

[0049] The term “structured” or a grammatical variation thereof (e.g., “structure” or “structuring”) refers herein to a component, device, composition, or system that is manufactured according to a concept or design or variations thereof or modifications thereto (whether such variations or modifications occur before, during, or after manufacture) whether or not such concept or design is captured in a writing.

[0050] The term “degrade” or a grammatical variation thereof (e.g., “degrading”, “degraded”, “degradable”, and “degradation”) refers herein to weakening, partially degrading, or fully degrading, such as by dissolution, chemical degradation (including biodegradation), decomposition, chemical modification, mechanical degradation, or disintegration, which encompasses also, without limitation, dissolving, crumbling, deforming, shriveling, or shrinking.

[0051] The term “non-degradable” refers to an expectation that degradation will be minimal, or within a certain acceptable design percentage, for at least an expected duration in an expected environment.

[0052] The term “GLP-1 analogue” refers to a protein that biologically performs the function of GLP-1 and can mediate downstream signaling by binding to the GLP-1 / Exendin-4 receptor and is also referred to as “GLP-1 receptor agonists” or “GLP-lRAs”.84905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0053] The term “GLP-2 analogue” refers to a protein that biologically performs the function of GLP-2 and can mediate downstream signaling by binding to the GLP-2 receptor and is also referred to as “GLP-2 receptor agonists” or “GLP-2RAs”.

[0054] The term “fusion protein” refers to a recombinant protein in which two or more proteins or domains responsible for a specific function in the protein are linked so that each protein or domain is responsible for its inherent function.

[0055] The term “bispecific GLP-1 RA / GLP-2RA fusion protein” refers to a recombinant protein including a GLP-1 analogue and a GLP-2 analogue that are fused to each other. For example, the fusion protein may include a first fusion protein in which a GLP-1 analog is linked to an antibody Fc region and a second fusion protein in which a GLP-2 analog is linked to an antibody Fc region. The bispecific fusion protein may be produced by dimerization of the first and second fusion proteins.

[0056] The terms “bispecific GLP-1 RA / GLP-2RA fusion protein” and “composition of bispecific GLP-1RA / GLP-2RA fusion protein” may be used interchangeably herein and refer to a composition including one or more components where at least one of the components is a bispecific GLP-1RA / GLP-2RA fusion protein. The composition can include, for example, a GLP-1 RA / GLP-2RA fusion protein either as the sole active agent or including one or more additional active agents.

[0057] Various abbreviations may be used herein for standard units, such as deciliter (dl), milliliter (ml), microliter (pl), international unit (IU), centimeter (cm), millimeter (mm), nanometer (nm), inch (in), kilogram (kg), gram (gm), milligram (mg), microgram (pg), nanogram (ng), millimole (mM), degrees Celsius (°C), degrees Fahrenheit (°F), millitorr (mTorr), hour (hr), minute (min), second (s or sec), millisecond (ms), microsecond (ps), or nanosecond (ns).II. Ingestible Dosage Forms (Ingestible Devices)

[0058] As noted above, the ingestible dosage forms described herein are ingestible devices that contain a composition including a dosage of bispecific GLP-1RA / GLP-2RA fusion protein. The composition may be in a liquid form and be delivered via a hollow needle that is structured to penetrate a GI lumen wall of the subject and be inserted into the GI lumen wall or surrounding bodily environment (e.g., peritoneum or peritoneal cavity) of the subject after ingestion of the device (e.g., after swallowing the device or after ingestion of the device by another mode, such as via an endoscope or stomach port), thereby delivering the bispecific GLP-1 RA / GLP-2RA fusion protein systemically to the subject. Specific embodiments of such devices are described in more detail below. Typically, the materials used to form the components of the devices are classified as food grade, food additive, active or94905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)inactive food ingredient or GRAS (Generally Recognized As Safe by the FDA). The devices (including any capsule shell) may be biodegradable or include biodegradable material(s).

[0059] FIG. 1 illustrates an example of an ingestible device 100 according to one or more embodiments of the present disclosure. Device 100 is shown to include an expandable member in the form of a balloon 102, a delivery structure 104, and an actuator in the form of a gas generating mechanism 105. Delivery structure 104 contains a composition 130 including a dosage of bispecific GLP-1RA / GLP-2RA fusion protein.

[0060] In other examples, composition 130 may be disposed separately from delivery structure 104, such as in a separate container (e.g., reservoir) that is coupled to or in fluid communication with delivery structure 104. In addition, device 100 may include an expandable member in the form of an accordion shaped structure, foldable wings, a patch, or other expandable structure instead of balloon 102.

[0061] As shown in FIG. 1, device 100 is in an unfolded state, but device 100 may be folded (e.g., rolled, flattened, twisted) in such a manner to fit inside an ingestible enclosure to facilitate ingestion of device 100. For example, FIG. 2 illustrates device 100 in a folded state and disposed in an ingestible enclosure shown as a swallowable capsule 200 according to one example. Capsule 200 includes an optional outer coating 202 disposed over at least an outer portion of capsule 200. Enclosure 200 and outer coating 202, if present, are structured to allow for ingestion of device 100, and to temporarily protect the contents of device 100 from degradation within one or more portions of the GI tract of a subject. As shown in FIG. 2, capsule 200 includes a first section 200a at least partially overlapping a second section 200b in a press-fit arrangement to define capsule 200.

[0062] In one or more embodiments, capsule 200 can degrade under certain conditions. Further, different portions of capsule 200 may be structured to degrade under different conditions or at different degradation rates depending on a target site within the GI tract for delivering composition 130. For example, a portion of, or all of, capsule 200 may be constructed of a material that degrades in water (e.g., in the presence of water in the form of humidity or moisture in an ambient environment, such as within the body) and / or degrades when exposed to a pH level above a particular threshold or within a particular range (e.g., a pH level associated with a desired location or portion of the GI tract, such as a pH level associated with a target site within the GI tract (e.g., stomach, small intestine) for delivering composition 130).

[0063] Optional outer coating 202 optionally covers a portion of, or all of, capsule 200. Outer coating 202 may include a single layer or multiple layers. The various layers may be formed of the same 104905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)material or different materials. In one or more embodiments, outer coating 202 can degrade under certain conditions, as described above with reference to capsule 200. An example of outer coating 202 is an enteric coating, such as an enteric coating that degrades in water at a given rate and / or degrades when exposed to solutions with a pH level above a particular threshold or within a particular range. Another example of outer coating 202 is a protective coating (e.g., wax), such as a coating which protects a portion of an outer surface of capsule 200 from coming into contact with fluids or tissues (e.g., bodily tissue or fluids).

[0064] In one or more embodiments, degradation of capsule 200 and / or outer coating 202, if present, can allow fluid (e.g., bodily fluid in the stomach or in the intestine) to enter an interior of capsule 200 to cause balloon 102 to expand, as described in further detail herein.

[0065] Referring again to FIG. 1, balloon 102 is a flexible structure that can expand from a collapsed state (e.g., folded) to an expanded state within a desired location of a GI tract of a subject for delivery of composition 130. Balloon 102 includes an inflator section 102a, a deflator section 102b, a lower section 102c, and an elongated section 102d extending between inflator section 102a and deflator section 102b. The various sections of balloon 102 cooperatively define an enclosed interior 102e for containing various components of device 100. Balloon 102 may further include a deflation valve 103 to help facilitate excretion of device 100 after delivering composition 130. As discussed below, balloon 102 is structured to inflate at a desired location within a lumen of the GI tract (e.g., stomach, small intestine, large intestine) in response to a gas pressure generated within interior 102e via gas generating mechanism 105 coupled to balloon interior 102e.

[0066] Gas generating mechanism 105 is shown to include a reactant reservoir 105a that is disposed within, or otherwise coupled to, balloon interior 102e. Reactant reservoir 105a is structured to hold a first reactant 105b therein and to temporarily prevent first reactant 105b from contacting a second reactant 105e, which is separately disposed within balloon interior 102e. First reactant 105b may be, for example, citric acid. Second reactant 105e may be, for example, a carbonate, such as potassium bicarbonate. In other examples, first reactant 105b and second reactant 105e may be other types of reactants (e.g., an acid and a base) which when mixed result in the formation of a gas sufficient to inflate balloon 102. Second reactant 105e is shown disposed within balloon interior 102e at inflator section 102a near first reactant 105b. In other examples, first reactant 105b and second reactant 105e may be contained in other areas of balloon 102 so long as they are temporarily separated from each other.114905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0067] Reactant reservoir 105a is in selective fluid communication with balloon interior 102e via a reactant conduit 105d and a release 105c. Release 105c is coupled to reactant conduit 105d on an outer portion of balloon 102 such that upon activation (e.g., degradation) of release 105c, first reactant 105b can exit from reactant reservoir 105a into balloon interior 102e via reactant conduit 105d. For example, reactant reservoir 105a may be pressurized by a volume of first reactant 105b disposed therein. Release 105c may be in the form of a degradable plug or clip which blocks an interior portion of reactant conduit 105d to temporarily prevent first reactant 105b from entering interior 102e from reservoir 105a. When fluid in the GI tract contacts release 105c (e.g., upon degradation of capsule 200 and / or outer coating 202), release 105c can subsequently degrade to allow reactant reservoir 105a to discharge first reactant 105b via reactant conduit 105d into balloon interior 102e.

[0068] Combining first reactant 105b with second reactant 105e within interior 102e causes a chemical reaction resulting in the formation of a gas (e.g., carbon dioxide (CO2)). The gas causes balloon 102 to expand to an inflated state within a GI lumen resulting in substantial alignment of elongated section 102d with a surface of the GI lumen wall, which thereby results in substantially perpendicular alignment of a longitudinal axis of delivery structure 104 with the lumen wall surface. Further, expansion of balloon 102 within a GI lumen can position delivery structure 104 relative to (e.g., proximate to or in contact with) a surface of the GI lumen wall. Substantial alignment of elongated section 102d and positioning / orienting of delivery structure 104 relative to the GI lumen wall can, advantageously, help to facilitate delivery of composition 130 from delivery structure 104 into the GI lumen wall without exposing composition 130 to the GI lumen environment. In this manner, device 100 can substantially preserve composition 130 within a portion of the GI tract before delivery into a GI lumen wall, or into and through the GI lumen wall into a peritoneum or peritoneal cavity for systemic uptake of one or more therapeutic agents contained therein.

[0069] In other examples, balloon 102 may include a different type of gas generating mechanism, such as a pressurized gas container (e.g., carbon dioxide (CO2) cartridge), or other type of gas generating mechanism that can be disposed in, or otherwise coupled to (e.g., fluidly coupled), balloon 102 or other expandable member.

[0070] In still other examples, balloon 102 may be self-expanding without a gas generating mechanism. For example, balloon 102 or other expandable member, may include a shape memory material (e.g., a wireframe structure) that is structured to bias the balloon or other expandable member to an expanded shape upon reaching a desired location of the GI tract of a subject.124905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0071] Still referring to FIG. 1, delivery structure 104 is shown coupled to balloon 102 and at least partially disposed within balloon interior 102e. In other examples, delivery structure 104 can be positioned entirely outside of balloon interior 102e but be in fluid communication with balloon interior 102e. Delivery structure 104 is shown to contain composition 130, but in other examples, composition 130 may be contained separately from delivery structure 104, such as in a separate reservoir or container. As described herein, delivery structure 104 is structured to actively deliver (e.g., inject) composition 130 into the GI lumen wall via the generated gas within balloon interior 102e. For example, composition 130 may be in a fluid form (e.g., liquid) and may be expelled through a hollow needle coupled to or disposed in delivery structure 104. The hollow needle can be structured to penetrate into the GI lumen wall, or into and through the GI lumen wall into the peritoneum or peritoneal cavity of a subject by way of the gas acting on delivery structure 104 to eject composition 130 through the needle and into the GI lumen wall.

[0072] In other examples, composition 130 may be expelled as a fluid jet by way of a spring mechanism or gas acting on a piston or plunger to eject composition 130 from a reservoir through an opening or nozzle in device 100. The fluid jet of composition 130 can have sufficient force to actively penetrate the GI lumen wall and enter the blood stream.

[0073] Referring to FIG. 3, a detail view of an ingestible device 300 (an embodiment of device 100) with a delivery structure 304 (an embodiment of delivery structure 104) is shown according to an example embodiment, where like reference numerals refer to like components between embodiments but are increased by an order of 200 (e.g., balloon 102 is equivalent to balloon 302, etc.). In this example, delivery structure 304 is shown to include a housing 306, a piston 308, a needle 312, and a valve 314.

[0074] Housing 306 is coupled to, and partially disposed in, balloon 302. Housing contains piston 308, needle 312, valve 314, and composition 330 therein. Housing 306 is structured to receive a gas pressure from balloon interior 302e through a first opening 306a of housing 306 to cause needle 312 to penetrate through a needle seal 320 at a second opening 306b of housing 306 into a GI lumen wall and to discharge composition 330 through needle 312 into the tissue.

[0075] Piston 308 is releasably coupled to housing 306 and is shown to include a flexible membrane 310 coupled thereto to define a reservoir 310a for containing a volume of composition 330 therein. Reservoir 310a may contain a volume of fluid of from about 50 pL to about 250 pL, including about 50 pL, 100 pL, 150 pL, 200 pL, 250 pL, or any value therebetween.134905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)

[0076] In other examples, a second piston or plunger may be movably coupled to piston 308 instead of membrane 310 to contain composition 330 and to eject composition 330 in response to a gas pressure generated within balloon interior 302e.

[0077] Valve 314 is structured to control a flow of composition 330 from piston 308 to needle 312 and includes a puncture member 316 and a pierceable valve seal 318 coupled to piston 308. Valve seal 318 is structured to contain composition 330 within reservoir 310a until puncture member 316 pierces valve seal 318.

[0078] Needle 312 is coupled to piston 308 and is structured to penetrate the GI lumen wall to deliver composition 330 into the GI lumen wall, or into and through the GI lumen wall into a peritoneum or peritoneal cavity of a subject. Needle 312 may have a shape sufficient to penetrate GI wall tissue and may be structured as a hook, a conical structure, a shaft, or other tissue penetrating shape. Needle 312 may include a biodegradable material to allow needle 312 to degrade in whole or in part in the GI tract of a subject upon delivering composition 330. In other examples, needle 312 may be substantially non-degradable or include substantially non-degradable portions.

[0079] Referring to FIGS. 4-7, an example actuation sequence of ingestible device 300 in a GI tract of a subject is shown after ingestion of device 300. FIG. 4 illustrates device 300 in a second state after device 300 has reached a desired location in the GI tract (e.g., the stomach, small intestine, large intestine) of the subject for delivering composition 330. In this example, device 300 is shown in the small intestine. As shown in FIG. 4, and as discussed above with reference to balloon 102 in FIGS. 1-2, balloon 302 has been inflated by a gas (represented by directional arrows 350) generated within balloon interior 302e such that elongated section 302d is substantially aligned with a surface of the intestinal wall and housing distal end 306b is oriented and positioned relative to (e.g., proximate to or in contact with) the surface of the intestinal wall with longitudinal axis 306e being substantially perpendicular to the intestinal wall.

[0080] As shown in FIG. 4, upon reaching the small intestine, gas pressure 350 generated within balloon interior 302e can pass through first opening 306a to apply a pressure against membrane 310 on piston 308. As shown in FIG. 5, when gas pressure 350 reaches or exceeds a threshold value (e.g., a pressure associated with full or partial inflation of balloon 302), the pressure causes piston 308 (including composition 330 contained therein) to release from housing 306 to move axially along longitudinal axis 306e relative to housing 306 such that needle 312 penetrates the GI lumen wall. As shown in FIG. 6, upon sufficient axial movement of piston 308 relative to housing 306, valve 314 is structured to open (e.g., by puncture member 316 contacting housing 306 to cause puncture member144905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)316 to deflect and pierce valve seal 318) to thereby allow composition 330 to flow from reservoir 310a to needle 312. As shown in FIGS. 6-7, gas pressure 350 applied against membrane 310 then causes membrane 310 to deform (e.g., constrict, invert) relative to piston 308 (since piston 308 is at the end of its axial stroke within housing 306) and thereby discharge composition 330 through needle 312 into the GI lumen wall, or into and through the GI lumen wall into a peritoneum or peritoneal cavity of the subject.

[0081] Referring now to FIGS. 8-9, an ingestible device 400 (another embodiment of ingestible device 100) is shown including another version of delivery structure 104 (shown as delivery structure 404). More specifically, delivery structure 404 is shown to include a housing 406 with a different vent configuration and tissue interface to help reduce needle penetration force and optimize delivery success rate. The actuation sequence and actuation mechanics are otherwise the same as device 300 discussed above, where like reference numerals refer to like components between embodiments but are increased by an order of one hundred (e.g., membrane 410 is equivalent to membrane 310, etc.). Accordingly, for the sake of efficiency, the following description focuses only on the vent configuration and tissue interface of housing 406.

[0082] As shown in FIGS. 8-9, housing 406 includes a plurality of vent openings 406d disposed in an upper surface of housing 406. In this example, housing 406 includes four vent openings 406d disposed circumferentially about longitudinal axis 406c, however, it should be appreciated that housing 406 may include more or fewer than four vent openings, where one or more vary in diameter and are optimized for gas flow. Vent openings 406d extend through housing 406 into an interior of housing 406 where piston 408 is disposed to allow for venting of air back pressure generated by piston 408 during actuation, and for venting of gas generated within balloon interior 402e after discharge of composition 430.

[0083] A housing valve member 422 is coupled (e.g., press fit, sealed / adhered) to housing 406 adjacent to vent openings 406d at an upper surface of housing 406. Housing valve member 422 is positioned over each vent opening 406d and is structured to prevent ingress of contaminants (e.g., fluid, particulates) to help maintain a substantially sterile environment within housing 406. Housing valve member 422 further functions as a pressure relief valve for selectively venting housing 406 and balloon interior 402e. For example, housing valve member 422 may be movably coupled (e.g., adhered) to a portion of housing 406, such as along an inner circumferential edge closest to longitudinal axis 406c. During actuation when piston 408 moves axially toward second opening 406b, the air back pressure generated within housing 406 can cause housing valve member 422 to deform and / or pivot (e.g., bend, deflect, etc.) away from vent openings 406d, so as to expose one or more of vent openings 406d and 154905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)allow the generated back pressure to pass through openings 406d past housing valve member 422 and outwardly away from device 400. Housing valve member 422 may deflect upward away from housing 406 in such a manner to direct the vented gas laterally away from housing 406 to thereby help to maintain relative positioning between housing 406 and the GI lumen wall surface. Housing valve member 422 works in conjunction with vent openings 406d to maximize the speed at which the back pressure is applied to valve member 422. For example, the surface area of valve member 422 may be maximized to receive the highest possible pressure through vent openings 406d based on the size of vent openings 406d.

[0084] In this manner, housing valve member 422 may help to reduce back pressure generated within housing 406 to thereby maximize the velocity of piston 408 during actuation, which in turn may help to ensure more consistent penetration of needle 412 into the GI lumen wall.

[0085] Still referring to FIGS. 8-9, housing 406 further includes an extension 406e extending longitudinally from housing 406 along longitudinal axis 406c. Extension 406e has a hollow cylindrical shape with an outer diameter DI and may include a frusto-conical base, which may help provide sufficient rigidity for extension 406e. A needle seal 420 is coupled to extension 406e at a distal end of extension 406e.

[0086] As shown in FIG. 9, extension 406e is structured to create a local stretch zone LSZ in the GI lumen wall upon expansion of balloon 402 within a GI lumen to help reduce the force required for needle 412 to penetrate the GI lumen wall surface. For example, by minimizing outer diameter DI of extension 406e, the contact surface area between housing 406 and the GI lumen wall surface is minimized, which can allow extension 406e to locally stretch the GI lumen wall surface and create sufficient tissue separation to reduce the required force for needle 412 to penetrate the tissue. Outer diameter DI may vary in size depending on the thickness or diameter of needle 412.

[0087] While the prior examples illustrate embodiments of delivery structure 104 coupled to an expandable balloon, it should be appreciated that embodiments of delivery structure 104 described herein may be used with, or otherwise incorporated into, a variety of other device configurations. For example, embodiments of delivery structure 104 described herein may be incorporated directly into a swallowable capsule, endoscope, or other ingestible enclosure, which enclosure may include an actuator operatively coupled to delivery structure 104. The actuator may include one or more of a spring, a gas generating mechanism, or other mechanism for generating a force within the ingestible enclosure. The generated force may be used to actuate delivery structure 104 to deliver composition 130 through one or more openings in the enclosure into a GI lumen wall, or into and through the GI164905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)lumen wall into a peritoneum or peritoneal cavity of the subject. The openings may be temporarily covered by a coating, plug, shell, or other structure that can degrade in response to a condition in the GI tract to reveal the opening(s), such as in the presence of GI fluid or in response to a particular pH in the GI tract (e.g., a pH in the small intestine).III. Bispecific GLP-1RA / GLP-2RA Fusion Protein Composition

[0088] A bispecific GLP-1RA / GLP-2RA fusion protein useful in accordance with the present disclosure is not particularly limited, and can be any functional bispecific GLP-1 RA / GLP-2RA fusion protein. As noted above, the term “bispecific GLP-1RA / GLP-2RA fusion protein” as used herein refers to a recombinant protein including a GLP-1 moiety (e.g., a GLP-1 analogue as described herein) and a GLP-2 moiety (e.g., a GLP-2 analogue as described herein) that are fused to each other, e.g., directly or via a linker, typically via a peptide linker as discussed in more detail below.

[0089] In specific embodiments, the bispecific fusion protein comprises a GLP-1 moiety (e.g., a GLP-1 analogue as described herein), a GLP-2 moiety (e.g., a GLP-2 analogue as described herein), and a half-life extending moiety, such as an antibody Fc region, PEG, XTEN, PAS, ELP, glycine-rich HAP, GLP, or serum albumin. The half-life extending moiety may be located between the GLP-1 moiety and the GLP-2 moiety (e.g., as a linking moiety) or at the N-terminus or C-terminus of one or both of the GLP-1 moiety and the GLP-2 moiety.

[0090] As used herein, the term “GLP-1” is an abbreviation of “glucagon-like peptide-1,” which is a peptide hormone consisting of 30 or 31 amino acids (GLP-1 (7-36) amide and GLP-1 (7-37)). Active GLP-1 contains two alpha-helical regions at amino acid positions 13-20 and 24-35 and a linker region connecting the two alpha-helical regions.

[0091] As used herein, the term “GLP-2” is an abbreviation of “glucagon-like peptide-2,” which is a peptide hormone consisting of 33 amino acids.

[0092] As used herein, the term “GLP-1 analogue” refers to a protein that biologically performs the function of GLP-1 and can mediate downstream signaling by binding to the GLP-l / Exendin-4 receptor, and is also referred to as a “GLP-1 receptor agonist” or “GLP-l-RA.” As used herein, the term “GLP-1 analogue” includes constructs comprising the amino acid sequence of GLP-1 (e.g., SEQ ID NO:2, a wildtype sequence). Other non-limiting examples of suitable GLP-1 analogues include Exendin 3 (e.g., SEQ ID NO: 3), Exendin 4 (e.g., SEQ ID NO: 4), GLP-l / Exendin 4 hybrid peptides (e g., SEQ ID NO: 5), Lixisenatide (e g., SEQ ID NO: 6), Exendin-4-XTEN (e g., SEQ ID NO: 7), Albiglutide (e.g., SEQ ID NO: 8), Liraglutide (e.g., SEQ ID NO: 9), and Taspoglutide (e.g., SEQ ID NO: 10), in which the 8th and 35th amino acids are methylated and the terminal amino acid is amidated 174905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)(when prepared in the form of a fusion protein with other peptides, the C-terminus can be a normal carboxyl group without amidation). In some embodiments, a GLP-1 analogue comprises an A2G substitution relative to GLP-1 (e.g., SEQ ID NO:1). Additionally, a GLP-1 analogue may comprise a tandem repeat of two or more GLP-1 peptides (or analogues) optionally connected in each instance via a linker peptide (e.g., SEQ ID NO: 11).

[0093] As used herein, the term “GLP-2 analogue” refers to a protein that biologically performs the function of GLP-2 and can mediate downstream signaling by binding to the GLP-2 receptor, and is also referred to as a “GLP-2 receptor agonist” or “GLP-2-RA.” As used herein, the term “GLP-2 analogue” includes constructs comprising the amino acid sequence of GLP-2 (e.g., SEQ ID NO: 18, a wild-type sequence). Other non-limiting examples of suitable GLP-2 analogues include Teduglutide (Gattex, Revestive) (SEQ ID NO: 17, comprising an A2G substitution relative to GLP-2), SEQ ID NO: 19 (comprising substitutions A2G, N16G, and L17Q relative to GLP-2, which may suppress dimerization of GLP-2 or subsequent formation of aggregates during recombinant production, while maintaining the function of GLP-2), and SEQ ID NO:20 (comprising substitutions A2G, L17Q, SEQ ID NO: 20) relative to GLP-2. Another non-limiting example of a suitable GLP-2 analogue is Glepaglutide (SEQ ID NO: 21) (see, e.g., Jeppesen et al. Gastroenterology. 2025 Apr;168(4):701-713. e6. doi: 10.1053 / j.gastro.2024.11.023). Another non-limiting example of a suitable GLP-2 analogue is GLP-2 analogue 10 (SEQ ID NO: 22), in which the 11th and 18th amino acids are substituted with cysteine and in which there is an intramolecular crosslink with a lapidated crosslinker between thiol groups of the two substituted cysteines, and in which nine C-terminal amino acids of Exendin 4 are added at the C-terminus of the GLP-2 amino acid sequence (see, e.g., Yang et al., J. Med. Chem. 61:3218-3223, 2018). In some embodiments, a GLP-2 analogue comprises an A17E (alanine to glutamine) substitution relative to GLP-2. Additionally, a GLP-2 analogue may comprise a tandem repeat of two or more GLP-2 peptides (or analogues) optionally connected in each instance via a linker peptide. In specific embodiments, the GLP-2 analogue is GLP-2, glepaglutide, or GLP-2 analogue 10.

[0094] As used herein, the term “half-life extending moiety” refers to a functional group that may extend in vivo half-life, such as an antibody Fc region (see, e.g., Capon et al., Nature 337:525-531, 1989), polyethylene glycol (PEG) (see, e.g., Caliceti and Veronese, Adv. Drug Delivery Rev. 55: 1261-1277, 2003), XTEN (see, e.g., Schellenberger et al., Nat. Biotechnol. 27:1186-1190, 2009; US PG PUB 2010 / 0239554), Pro-Ala-Ser (PAS) (see, e.g., Schlapschy et al., Protein Eng. Des. Sei.26:489-501, 2013), elastine-like peptide (ELP) (see, e.g., Floss et al., Trends Biotechnol. 28:37-45, 2010), glycine-rich homo-amino-acid polymer (HAP) (see, e.g., Schlapschy et al., Protein Eng. Des.184905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)Sei. 20:273-284, 2007), gelatine-like protein (GLK) ((see, e.g., Huang et al., Eur. J. Pharm. Biopharm.74 (3): 435-441, 2010), and serum albumin ((see, e.g., Sheffield et al., Cell Physiol. Biochem., 45 (2): 772-782, 2018), and the like.

[0095] In specific embodiments, the bispecific fusion protein is a heterodimer comprising a GLP-1 -RA fusion protein comprising a GLP-1 moiety (e.g., a GLP-1 analogue as described above) and a halflife extending moiety such as an antibody Fc region, and a GLP-2-RA fusion protein comprising a GLP-2 moiety (e.g., a GLP-2 analogue as described above), and a half-life extending moiety, As noted above, the bispecific fusion protein may include a GLP-l-RA fusion protein in which a GLP-1 analogue is linked to an antibody Fc region and a GLP-2-RA fusion protein in which a GLP-2 analogue is linked to an antibody Fc region, wherein the bispecific fusion protein is produced by homodimerization of the GLP-l-RA and GLP-2-RA fusion proteins.

[0096] As used herein, the term “antibody Fc region” is used in accordance with its ordinary meaning in the art, and refers to a fragment of an antibody that interacts with the Fc receptor, for example. An antibody Fc region typically has a homodimer structure in which fragments containing the second and third constant regions (CH2 and CH3) of an antibody heavy chain are linked by an intermolecular disulfide bond at the hinge region.

[0097] In specific embodiments, Knobs-into-Holes (KiH) designs are used to promote formation of heterodimers between the GLP-l-RA and GLP-2-RA fusion proteins (e.g., between first and second fusion proteins) to form the bispecific fusion protein (heterodimer). For example, one of the fusion proteins (containing a GLP-1 analogue or GLP-2 analogue) may comprise a Knob structure provided by a modified Fc region, and the other fusion protein (containing the other of a GLP-1 analogue or GLP-2 analogue) may comprises a Hole structure provided by a modified Fc region (see, e.g., Wei et al., Oncotarget 2017, 8 (31): 51037-51049; Ridgway et al., Protein Eng. 1996, 9 (7): 617-621; Carter, P., J. Immunol. Methods 2001, 48 (1-2): 7-15; Merchant et al., Nat. Biotechnol. 1998, 16 (7): 677-681). For example, one fusion protein may comprise a modified hybrid Fc region in which the 10th amino acid, serine (S), is substituted with cysteine (C), and the 23rd amino acid, threonine (T), is substituted with tryptophan (W) in the CH3 domain (Knob structure), and the other fusion protein may comprise a modified hybrid Fc region in which the 5th amino acid, tyrosine (Y), is substituted with cysteine (C), the 23rd amino acid, threonine (T), is substituted with serine (S), the 24th amino acid, leucine (L), is substituted with alanine (A), and the 63rd amino acid, tyrosine (Y), is substituted with valine (V) in the CH3 domain (Hole structure). Alternatively, one fusion protein may comprise a modified hybrid Fc region in which the 5th amino acid, tyrosine (Y), is substituted with cysteine (C), the 23rd amino acid, threonine (T), is substituted with serine (S), the 24th amino acid, leucine (L), is substituted with 194905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)alanine (A), and the 63rd amino acid, tyrosine (Y), is substituted with valine (V) in the CH3 domain (Hole structure), and the other fusion protein may comprise a modified hybrid Fc region in which the 10th amino acid, serine (S), is substituted with cysteine (C), and the 23rd amino acid, threonine (T), is substituted with tryptophan (W) in the CH3 domain (Knob structure). Optionally, one fusion protein may comprise a modified hybrid Fc region in which the 22nd amino acid, threonine (T), is substituted with tyrosine (Y) in the CH3 domain, and the second fusion protein may comprise a modified hybrid Fc region in which the 63rd amino acid, tyrosine (Y), is substituted with threonine (T) in the CH3 domain. Alternatively, the other protein may comprise a modified hybrid Fc region in which the 63rd amino acid, tyrosine (Y), is substituted with threonine (T) in the CH3 domain, and the first fusion protein may comprise a modified hybrid Fc region in which the 63rd amino acid, tyrosine (Y), is substituted with threonine (T) in the CH3 domain. (The variation of the 63rd amino acid may be expressed as Y86T, etc., if following the IMGT (International ImMunoGeneTics Information System) numbering rules (Lefranc et al., Dev. Comp. Immunol., 27:55-77, 2003), rather than numbering based on the amino acid sequence of the CH3 domain of human IgGl having the amino acid sequence represented by SEQ ID NO: 69).

[0098] Thus, the antibody Fc region may be a hybrid antibody Fc region, such as a hybrid antibody Fc region of any of SEQ ID NOs: 12 to 16, which include hybrid antibody Fc regions with “knob” and “hole” designs. The hybrid antibody Fc region may be further modified to reduce the risks of adverse side effects, such as ADCC (antibody-dependent cell cytotoxicity) and CDC (complement-dependent cytotoxicity), when administered in vivo. Such a hybrid antibody Fc region may be one disclosed in Korean Patent No. 897938, or may be a hybrid Fc region variant consisting of the amino acid sequence of SEQ ID NO: 14 (in which, relative to the hybrid Fc region of SEQ ID NO: 13, the 18th amino acid (threonine) is substituted with glutamine and the 196th amino acid (methionine) is substituted with leucine), or may be a hybrid Fc region variant consisting of the amino acid sequence of SEQ ID NO: 15 (in which, relative to the hybrid Fc region of SEQ ID NO: 12, the 18th amino acid (threonine) is substituted with glutamine and the 196th amino acid (methionine) is substituted with leucine).

[0099] It will be understood that the GLP-l-RA and GLP-2-RA fusions proteins may include one or more linkers (e.g., one or more amino acid or peptide linkers, such as a flexible peptide linker) between different moi eties, e.g., between any GLP-1 analogue / GLP-2 analogue repeating unts and / or between a GLP-1 analogue / GLP-2 analogue and a half-life extending moiety, etc. It also will be understood that the bispecific fusion protein may include a linker (e.g., one or more amino acid or peptide linkers, such as a flexible peptide linker) linking the GLP-l-RA and GLP-2-RA fusions proteins, e.g., linking the GLP-l / GLP-2 moi eties or linking other portions of the fusion proteins, such as the half-life 204905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)extending moi eties (if present). In specific embodiments, one of the linkers (e.g., present in one of fusion proteins or linking the fusion proteins) may comprise a glycan-binding domain.

[0100] Thus, in the bispecific fusion protein, one or more linker peptides may be inserted between fusion partners of the fusion proteins, that is, between peptides or domains. In the case of a bispecific fusion protein having the GLP-1 analogue and the GLP-2 analogue fused to each other, a linker peptide may be inserted between the GLP-1 analogue and the GLP-2 analogue. In the case of a bispecific fusion protein created by dimerization of the first fusion protein and the second fusion protein, a linker peptide may be inserted between an antibody Fc region and the GLP-1 analogue in the first fusion protein and likewise, a linker peptide may be inserted between an antibody Fc region and the GLP-2 analogue in the second fusion protein. The linker peptide may or may not include an N-glycosylated site. In some embodiments, a first fusion protein may not include an N-glycosylated site in the linker peptide and the second fusion protein may include an N-glycosylated site in the linker peptide. Optionally, both the first fusion protein and the second fusion protein may not include an N-glycosylated site, or the first fusion protein may not include an N-glycosylated site in the linker peptide and the second fusion protein may include an N-glycosylated site in the linker peptide.

[0101] The linker peptide may be any suitable linker peptide. Non limiting examples of suitable linker peptides include EPKSSDKTHTCPPCP (SEQ ID NO: 37), EPKSCDKTHTCPPCP (SEQ ID NO: 38), GGGGSGGGGSGGGGSEPKSSDKTHTCPPCP (SEQ ID NO: 39), GGGGSGGGGSGGGGSEPKSCDKTHTCPPCP (SEQ ID NO: 40), AKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECP (SEQ ID NO: 41), GGGGSGGGGSGGGGSEKEKEEQEERTHTCPPCP (SEQ ID NO: 42), GGGGSGGGGGGGGSAKNTTAPATTRNTTRGGEEKKKEKEKEEQEERTHTCPPCP (SEQ ID NO: 43), AAGSGGGGGSGGGGSGGGGS (SEQ ID NO: 44), GGGGSGGGGSGGGGS (SEQ ID NO: 45), GGSGG (SEQ ID NO: 46), GGSGGSGGS (SEQ ID NO: 47), GGGSGG (SEQ ID NO: 48), (G4S)n(subunit: SEQ ID NO: 49, n is an integer of 1 to 10), (GGS)n(n is an integer of 1 to 10, SEQ ID NOs: 70-78), (GS)n(n is an integer of 1 to 10, SEQ ID NOs: 79-87), (GSSGGS)n(subunit: SEQ ID NO: 50, n is an integer of 1 to 10), KESGSVSSEQLAQFRSLD (SEQ ID NO: 51), EGKSSGSGSESKST (SEQ ID NO: 52), GSAGSAAGSGEF (SEQ ID NO: 53), (EAAAK)n(subunit: SEQ ID NO: 54, n is an integer of 1 to 10), CRRRRRREAEAC (SEQ ID NO: 55), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO: 56), GGGGGGGG (SEQ ID NO: 57), GGGGGG (SEQ ID NO: 58), AEAAAKEAAAAKA (SEQ ID NO: 59), PAPAP (SEQ ID NO: 60), (Ala-Pro)n(n is an integer of 1 to 10, SEQ ID NOs: 88-96), VSQTSKLTRAETVFPDV (SEQ ID NO: 61), PLGLWA (SEQ ID NO: 62), TRHRQPRGWE (SEQ ID NO: 63), AGNRVRRSVG (SEQ ID NO: 64),214905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)RRRRRRRR (SEQ ID NO: 65), GFLG (SEQ ID NO: 66), GSSGGSGSSGGSGGGDEADGSRGSQKAGVDE (SEQ ID NO: 67), or GSTSGSGKPGSGEGS (SEQ ID NO: 68).

[0102] In specific embodiments the bispecific GLP-1RA / GLP-2RA fusion protein is any one or more disclosed in US PG-PUB 2024 / 0368239, which is incorporated herein by reference in its entirety. In specific embodiments the bispecific fusion protein comprises a GLP-1RA moiety comprising the amino acid sequence of one of SEQ ID NOs. 1-11, such as one of SEQ ID NOs. 1, 4, 5, and 11. In specific embodiments the bispecific fusion protein comprises a GLP-2RA moiety comprising the amino acid sequence of one of SEQ ID NOs. 17-22, such as SEQ ID NO. 17 of SEQ ID NO. 19. . 1, 4, 5, and 11. In specific embodiments the bispecific fusion protein comprises a GLP-1RA moiety comprising the amino acid sequence of one of SEQ ID NOs. 1-11, such as one of SEQ ID NOs. 1, 4, 5, and 11, and a GLP-2RA moiety comprising the amino acid sequence of one of SEQ ID NOs. 17-22, such as SEQ ID NO. 17 of SEQ ID NO. 19.

[0103] In further specific embodiments, the bispecific fusion protein comprises a GLP-1RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 23 to 30. In specific embodiments the bispecific fusion protein comprises a GLP-2RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 31 to 36. In further specific embodiments the bispecific fusion protein comprises a GLP-1RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 23 to 30 and a GLP-2RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 31 to 36. In specific embodiments the bispecific GLP-1RA / GLP-2RA fusion protein is any one or more of PG-102-1 (previously named MG12-1), PG-102-2 (previously named MG12-2), PG-102-3 (previously named MG12-3), PG-102-4 (previously named MG12-4), PG-102-5 (previously named MG12-5), PG-102-6 (previously named MG12-6), PG-102-7 (previously named MG12-7), PG-102-8 (previously named MG12-8), or PG-102-9 (previously named MG12-9) disclosed in US PG-PUB 2024 / 0368239 and described in Table 1 below.

[0104] TABLE 1.Example Example Overall GLP-1 / 2 Analogue Linker Fc Configuration / Region No. Name (SEQ ID NO) (SEQ ID NO)(SEQ ID NO)1 PG-102-1 1. GLP-1 (1) Glycan linker Knob first fusion hole (43)2. GLP-2 (17) protein (24)Unmodified(42) Second fusion protein (32)224905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)2 PG-102-2 1. GLP-2 (17) Glycan linker Knob second fusion hole (43)2. GLP-1 (1) protein (33)Unmodified(42) First fusion protein (25) 3 PG-102-3 1. Exendin-4 (4) Glycan linker Knob first fusion hole (43)2. GLP-2 (17) protein (26)Unmodified(42) Second fusion protein (32) 4 PG-102-4 1. GLP-l / Exendin-4 hybrid Glycan linker Knob first fusion hole (43)(5) protein (27)Unmodified2. GLP-2 (17) (42) Second fusion protein (34) 5 PG-102-5 1. GLP-l / Exendin-4 hybrid Unmodified Knob first fusion hole (42)(5) protein (28)Modified (42)2. GLP-2 (17) Second fusion protein (34) 6 PG-102-6 1. GLP-2 (17) Glycan linker Knob second fusion hole (43)2. GLP-l / Exendin-4 hybrid protein (35)Unmodified(5) (42) First fusion protein (28) 7 PG-102-7 1. GLP-l / Exendin-4 hybrid Glycan linker Knob first fusion hole (43)(5) protein (29)Unmodified2. GLP-2 (19) (39) Second fusion protein (36) 8 PG-102-8 1. GLP- 1 tandem repeat (11) Unmodified Knob first fusion hole (39)2. GLP-2 (19) protein (30)Unmodified(39) Second fusion protein (36) 9 PG-102-9 1. GLP- 1 tandem repeat (11) Unmodified Knob first fusion hole (39)2. GLP-2 (17) protein (30)Unmodified(42) Second fusion protein (34)

[0105] As described herein, the bispecific GLP-1RA / GLP-2RA fusion protein may be present in a liquid composition that is contained in a reservoir of an ingestible device for delivery into a GI lumen wall, or into and through the GI lumen wall into a peritoneum or peritoneal cavity of a subject following ingestion of the device. The bispecific GLP-1RA / GLP-2RA fusion protein may be present in the composition in any amount suitable for providing the target dose in the ingestible device, and in one or more embodiments, may be present in an amount of from about 1% to about 99% w / v of the234905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)composition, including from about 25% to about 85% w / v, including from about 50% to about 75% w / v, including about 53.3% w / v or about 74.1% w / v.

[0106] The liquid composition may further include one or more excipients including one or more of a buffering agent, a solubilizing agent, a surfactant, an antioxidant, a binder, or other excipient. The buffering agent may include L-histidine, and in one or more embodiments, may be present in the composition in an amount of from about 3% to about 7% w / v, including about 3.8% w / v or about 6.8% w / v. The buffering agent may further include sodium dihydrogen phosphate dehydrate, and in one or more embodiments, may be present in the composition in an amount of from about 1% to about 3% w / v, including about 1.2% w / v or about 2.2% w / v. The buffering agent may further include disodium phosphate dihydrate, and in one or more embodiments, may be present in the composition in an amount of from about 0.4% to about 1% w / v, including about 0.48% w / v or about 0.87% w / v. The solubilizing agent may include glycine, and in one or more embodiments, may be present in the composition in an amount of from about 1% to about 4% w / v, including about 1.9% w / v or about 3.3% w / v. The surfactant may include one or more of polysorbate 80 or pol oxamer 188, and in one or more embodiments, may be present in the composition in an amount of from about 0% to about 0.5% w / v, including about 0% w / v, about 0.25% w / v, or about 0.44% w / v. The antioxidant may include L-methionine, and in one or more embodiments, may be present in the composition in an amount of from about 3% to about 7% w / v, including about 3.7% w / v or about 6.6% w / v. The binder may include sucrose, and in one or more embodiments, may be present in the composition in an amount of from about 14% to about 27% w / v, including about 14.8% w / v or about 26.7% w / v.

[0107] Other excipients may be added, such as one or more other buffers, solubilizers, surfactants, antioxidants, binders, or other excipients. The selection and proportions of the different ingredients may be taken into consideration during the formulation process so as to achieve a desired therapeutic dose of the drug.IV. Methods of Treatment and Pharmaceutical Uses

[0108] Also provided herein are treatments (methods of treatment and pharmaceutical uses) comprising administering an ingestible device according to any embodiments described herein by ingestion to a subject in need thereof, e.g., by the subject swallowing the device (orally administering) or by ingesting the device by another mode, such as via an endoscope or stomach port. In some embodiments, the treatments (methods of treatment and pharmaceutical uses) comprise once weekly, twice weekly, or more frequent administration of an ingestible device as described herein. In some244905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)embodiments, the treatments (methods of treatment and pharmaceutical uses) comprise alternative dosing regimens as described in more detail below.

[0109] In general, the disclosed methods of treatment and pharmaceutical uses are contemplated for treating conditions such as obesity, diabetes, NAFLD, NASH, and other conditions in which treatment with a bispecific GLP-1RA / GLP-2RA fusion protein may be indicated. In specific embodiments, the disclosed methods of treatment and pharmaceutical uses are for treating obesity.

[0110] The disclosed methods of treatment and pharmaceutical uses may be used for any subject in need of administration of a bispecific GLP-1RA / GLP-2RA fusion protein including human and nonhuman mammals. In human subjects, the age and size of the human is not limited, and may include pediatric, adult, and geriatric subjects, as well as subjects at, above, or below a normal range of body weight or height.[OHl] In some embodiments, the ingestible device contains a dose of bi specific GLP-1RA / GLP-2RA fusion protein effective to achieve a therapeutic plasma level for the condition being treated. In some embodiments, the ingestible device contains a dose of the bispecific GLP-1RA / GLP-2RA fusion protein effective for the treatment of obesity.

[0112] In one or more embodiments, the dose (e.g., the therapeutically effective dose) of the bispecific GLP-1RA / GLP-2RA fusion protein is from about 4 mg to about 30 mg, e.g., from about 4 mg to about 30 mg of a bispecific GLP-1RA / GLP-2RA fusion protein as described herein. In one or more embodiments, the dose (e.g., the therapeutically effective dose) of the bispecific GLP-1RA / GLP-2RA fusion protein is about 12 mg. In one or more embodiments, the dose (e.g., the therapeutically effective dose) of the bispecific GLP-1RA / GLP-2RA fusion protein is about 30 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 4 mg, or more. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 4 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 8.5 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 10 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 12 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 15 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 20 mg. In some embodiments, the ingestible device contains a dose of bispecific GLP-1RA / GLP-2RA fusion protein of about 30 mg. In any embodiments, the bispecific GLP-1RA / GLP-2RA fusion protein may be the bispecific GLP-254905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)1RA / GLP-2RA fusion protein as described herein, such as any of PG-102-1, PG-102-2, PG-102-3, PG-102-4, PG-102-5, PG-102-6, PG-102-7, PG-102-8, or PG-102-9, including PG-102-8.

[0113] In some embodiments, the ingestible device is used to provide different doses of bispecific GLP-1RA / GLP-2RA fusion protein over a course of a treatment. For example, in some embodiments, the dose of the bispecific GLP-1RA / GLP-2RA fusion protein is titrated up from an initial dose to a maintenance dose, e.g., in a titration dosing phase. In some embodiments, the initial dose may be below a therapeutically effective dose and / or the dosing frequency of the initial dosing regimen may be less than a therapeutically effective frequency. In some embodiments, the initial dose may be followed by an intermediate dose. In some embodiments, the intermediate dose may be below a therapeutically effective dose and / or the dosing frequency of the intermediate dosing regimen may be less than a therapeutically effective frequency. In some embodiments, the initial dose or, optionally, intermediate dose, may be followed by a maintenance dosing phase, which typically is a therapeutically effective dosing regimen. Titration of the bispecific GLP-1RA / GLP-2RA fusion protein from an initial dose to the maintenance dose may improve patient tolerance, and be associated with reduced gastrointestinal side effects and / or other side-effects associated with GLP-1RA / GLP-2RA therapies. In some embodiments, the titration dosing period comprises administering a first dose of the bispecific GLP-1RA / GLP-2RA fusion protein once weekly (QW) for two weeks, followed by administration of a second dose of the bi specific GLP-1RA / GLP-2RA fusion protein twice weekly (Q2W) for two weeks, followed by administration of a third dose of the bispecific GLP-1RA / GLP-2RA fusion protein three times weekly (TIW) as a maintenance dose. In some embodiments, the first, second, and third doses are the same amount of the bispecific GLP-1RA / GLP-2RA fusion protein. For example, the first, second, and third doses may each be 30 mg of a bispecific GLP-1RA / GLP-2RA fusion protein as described herein, such as any of PG-102-1, PG-102-2, PG-102-3, PG-102-4, PG-102-5, PG-102-6, PG-102-7, PG-102-8, or PG-102-9, including PG-102-8. In other embodiments, two or more of the first, second, and third doses are different amounts of the bispecific GLP-1RA / GLP-2RA fusion protein, e.g., with the second and / or third dose being a greater amount than that of the first dose.

[0114] In some embodiments, twice weekly dosing of a bispecific GLP-1RA / GLP-2RA fusion protein as described herein of 30 mg (e.g., given on days 1 and 2, or given within about 12 hours of each other on the same day) will achieve therapeutically effective plasma concentrations for the treatment of obesity. Twice weekly dosing at a dose of about 30 mg, or more frequent dosing at a lower dose, may also provide additional benefits relating to tolerability of bispecific GLP-1RA / GLP-2RA fusion protein compared to, for example, once weekly dosing at a higher dose (e.g., about 60 mg) or less frequent dosing. For example, twice weekly dosing at a dose of about 30 mg each (given within about 264905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)24 hours of each other) may exhibit a Cmax that is less than a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein at a higher, less frequent dose (e.g., once weekly SC administration of about 60 mg). Likewise, twice weekly dosing at a dose of about 30 mg each may exhibit a Tmax that is greater than a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein at a higher, less frequent dose (e.g., once weekly SC administration of about 60 mg).

[0115] In some embodiments, thrice weekly dosing of a bi specific GLP-1RA / GLP-2RA fusion protein as described herein of 30 mg (e.g., given on days 1, 2, and 3, or given within about 12 hours of each other) will achieve therapeutically effective plasma concentrations for the treatment of obesity. Thrice weekly dosing at a dose of about 30 mg may provide additional benefits relating to tolerability of bispecific GLP-1RA / GLP-2RA fusion protein compared to, for example, once weekly dosing at a higher dose (e.g., about 90 mg) or less frequent dosing. For example, thrice weekly dosing at a dose of about 30 mg each (given within about 24 hours of each other) may exhibit a Cmax that is less than a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein at a higher, less frequent dose (e.g., once weekly SC administration of about 90 mg). Likewise, thrice weekly dosing at a dose of about 30 mg each may exhibit a Tmax that is greater than a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein at a higher, less frequent dose (e.g., once weekly SC administration of about 90 mg).

[0116] In some embodiments, the ingestible device contains a liquid therapeutic composition comprising bispecific GLP-1RA / GLP-2RA fusion protein and one or more excipients, as described herein above.

[0117] For treatment of obesity in adult patients weighing 80 kg or more, the dosing regimen can include twice weekly oral administration (e.g., oral ingestion) of a device as described herein containing a dose of 30 mg, each given within about 24 hours of each other (e.g., on days 1 and 2 of a given week), or given within about 12 hours of each other on the same day. Alternatively, the dosing regimen can include thrice weekly oral administration (e.g., oral ingestion) of a device as described herein containing a dose of 30 mg each, given within about 24 hours of each other (e.g., on days 1 and 2 and 3 of a given week), or given within about 12 hours of each other. In one or more embodiments, the dosing regimen can include a titration dosing phase followed by a maintenance dosing phase, e.g., as outlined above. Example titration and maintenance dosing regimens are described in the paragraphs that follow.

[0118] Sample titration dosing regimens for treating an adult patient suffering from obesity:274905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)• Once weekly (QW) administration of 30 mg for one month;• Once weekly (QW) administration of 30 mg for two weeks followed by administration of 30 mg twice weekly (Q2W) for two weeks;• Twice weekly (Q2W) administration of 15 mg for one month;• Three times weekly (TIW) administration of 10 mg for one month;• Daily (QD) administration of about 4 mg for one month.

[0119] Sample maintenance dosing regimens for treating an adult patient suffering from obesity:• Twice weekly (Q2W) administration of 30 mg (given within about 24 hours of each other);• Twice weekly (Q2W) administration of 30 mg (given within about 12 hours of each other on the same day);• Three times weekly (TIW) administration of 20 mg;• Three times weekly (TIW) administration of 30 mg;• Daily (QD) administration of about 8.5 mg.• Daily (QD) administration of about 12.8 mg.

[0120] In some embodiments, an ingestible device as described herein comprising a liquid composition of bispecific GLP-1RA / GLP-2RA fusion protein is used to provide a dose of up to about 30 mg per device, such as for devices having a 200 pL capacity, depending on the formulation of the composition and its concentration.

[0121] In accordance with any embodiments using an ingestible device as described herein, a given dose can be provided by one ingestible device as described herein containing one or more payloads that collectively contain(s) the stated dose of bispecific GLP-1RA / GLP-2RA fusion protein, or by administering two or more ingestible devices as described herein, wherein the payload(s) of each device collectively contain(s) a portion of the stated dose of bispecific GLP-1RA / GLP-2RA fusion protein, e.g., by administration of one, two, three, 4, 5, 6, 7, 8, 9, 10, or more ingestible devices as described herein each comprising a bispecific GLP-1RA / GLP-2RA fusion protein composition as described herein.

[0122] Currently, bispecific GLP-1RA / GLP-2RA fusion proteins require administration by parenteral (e.g., subcutaneous) injection, which may be inconvenient and uncomfortable for some patients. The present disclosure addresses this limitation by providing a route of administration that effectively delivers bispecific GLP-1RA / GLP-2RA fusion protein into the system of a subject being treated 284905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)without requiring injection, such as oral administration or ingestion by another mode, such as via an endoscope or stomach port. The disclosed treatments may provide a more convenient and less invasive approach than those that are currently available.

[0123] In addition to improved ease of administration, patient comfort, and patient compliance, administration of bispecific GLP-1RA / GLP-2RA fusion protein via an ingestible device as described herein may offer one or more other advantages, such as one or more of enhanced bioavailability, tolerability (e.g., due to dosing flexibility), uptake efficiency, and reduced immunogenicity as compared to another route of administration, such as subcutaneous injection. In some embodiments, delivery of bispecific GLP-1RA / GLP-2RA fusion protein via an ingestible device as described herein exhibits a bioavailability that is greater than a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein. In some embodiments, bispecific GLP-1RA / GLP-2RA fusion protein administered via an ingestible device as described herein exhibits a bioavailability that is substantially the same as a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

[0124] Thus, in accordance with some aspects, the present disclosure provides methods of administering bispecific GLP-1RA / GLP-2RA fusion protein to a subject in need thereof, comprising administering to the subject by ingestion an ingestible device containing a composition comprising bispecific GLP-1RA / GLP-2RA fusion protein, wherein the device is structured to deliver the composition into an intestinal wall of the subject or into and through an intestinal wall into a peritoneum or peritoneal cavity of the subject, after ingestion. As noted above, the administration may comprise oral administration (e.g., swallowing the device) or ingestion of the device by another mode, such as via an endoscope or stomach port. The composition may be delivered via a hollow needle structured to penetrate an intestinal wall of the subject and be inserted into the intestinal wall or into and through the intestinal wall into a peritoneum or peritoneal cavity of the subject after ingestion of the device. The administration of such ingestible devices may be repeated, for example, at a frequency of twice weekly or more / less frequently, such as in accordance with any of the dosing regimens described above. The composition may be in a liquid form contained within a reservoir of the ingestible device. The composition is protected from the gastrointestinal (GI) tract environment (e.g., protected against degradation due to ingress of fluid reaching the composition) until the composition is injected into the wall of the small intestine, which is insensitive to sharp stimuli so that the subject does not register pain from the injection.

[0125] The present disclosure also provides methods of treating one or more conditions such as obesity, diabetes, NAFLD, NASH, and other conditions in which treatment with a bispecific GLP- 294905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)1RA / GLP-2RA fusion protein may be indicated, comprising administering by ingestion to a subject in need thereof an ingestible device as described herein, such as in accordance with any of the dosing regimens described above.

[0126] While specific embodiments have been described and illustrated, it should be understood that components or characteristics of one embodiment can be combined or substituted with one or more components or characteristics from other embodiments. Further, for any positive recitation of a component, characteristic, constituent, feature, step or the like, the present disclosure specifically contemplates the exclusion of that component, value, characteristic, constituent, feature, step or the like. It also should be understood that illustrations may not necessarily be drawn to scale. There can be distinctions between the artistic renditions in the present disclosure and the actual apparatus, due to variables in manufacturing processes and such. There can be other embodiments of the present disclosure which are not specifically illustrated. Thus, the specification and drawings are to be regarded as illustrative rather than restrictive.

[0127] The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples.EXAMPLESExample 1 - Orally Delivered Bispecific GLP-1RA / GLP-2RA Fusion Protein in Canines

[0128] The ability to deliver bispecific GLP-1RA / GLP-2RA fusion protein by an ingestible device as described herein was assessed in canines. The pharmacokinetic (PK) profile of a single dose of bispecific GLP-1RA / GLP-2RA fusion protein (PG-102-8) administered via an ingestible device as described herein was compared to the PK profile obtained through a single subcutaneous (SC) injection. Canines weighing between 15-31 lbs. were divided into 2 groups as follows:• Group 1 (SC group; n=6): 12 mg (60 mg / mL; equivalent to ~60 mg human dose) liquid composition of bispecific GLP-1RA / GLP-2RA fusion protein delivered parenterally by subcutaneous injection (“SC”);• Group 2 (ingestible device group; n=10): one ingestible device containing 12 mg (60 mg / mL) liquid composition of bispecific GLP-1RA / GLP-2RA fusion protein delivered orally by swallowing the device (“RT-114”).

[0129] After fasting for at least 12 hours, bispecific GLP-1RA / GLP-2RA fusion protein was administered to canines as described herein according to the study groups described above. Abdominal 304905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)radiographic imaging was done to monitor capsule transit and confirm deployment within the small intestine. Blood levels of bispecific GLP-1RA / GLP-2RA fusion protein were assessed pre-dose, and at 6 hours, 12 hours, 18 hours, 24 hours, and on days 2-5, 7, 10, 14 post administration. PK results are shown in FIG. 10 and in the table below (mean ± SEM).Administration Route Pharmacokinetic Parameters(Mean ± SEM)Cmax Tmax AUClast(pg / mL) / kg (days) ((day pg / mL) / kg) Ingestible Device (“RT-114”) 1.51 ± 0.19 0.7 ± 0.1 5.48 ± 0.3312.0 mg (n = 9*)SC 1.06 ± 0.13 1.3 ± 0.3 4.92 ± 0.5212.0 mg (n = 6)*One animal was excluded from the data set after it was determined that the device deployed in the stomach.

[0130] The results show that bispecific GLP-1RA / GLP-2RA fusion protein can be successfully delivered by an ingestible device as described herein, with a PK success rate of 100% (for all animals in which the device successfully deployed in the small intestine). The ingestible devices showed a 111% relative bioavailability compared to the SC route of administration. The ingestible devices also showed a higher and faster (but not statistically significant) Cmax and Tmax, respectively, relative to the SC route of administration.

[0131] Referring to FIG. 11, from a pharmacodynamic (PD) perspective, the ingestible device group showed substantially the same average peak weight loss compared to the SC group, but with relatively less variability. More specifically, the ingestible devices showed an average peak weight loss of 6.7% ± 0.5% (± SEM) and the SC group showed an average peak weight loss of 6.7% ± 2.2% (± SEM).

[0132] In addition, as shown in FIGS. 12-13, both the ingestible device group and SC group showed substantially the same decreases in food consumption concomitant with rises in plasma drug concentrations, further demonstrating the comparable PD effects between both routes of administration. More specifically, the ingestible devices group showed an average of 4.6 ± 0.6 days (± SEM) of decreased food intake and the SC group showed an average of 4.7 ± 1.3 days (± SEM) of decreased food intake.

[0133] These data underscore the surprising advantages of the compositions, medicaments, dosage forms, devices, and methods disclosed herein.314905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)Example 2 - Phase I Clinical Trial

[0134] A two-part Phase 1 clinical study will be conducted in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of an ingestible device as described herein containing a liquid composition as described herein containing 12 mg or 30 mg of a bispecific GLP-1RA / GLP-2RA fusion protein as described herein (e.g., PG-102-8). The study will enroll healthy male and female participants aged 18 to 65, inclusive, at the time of consent, subject to screening for inclusion and exclusion criteria.

[0135] Part 1 of the study will enroll up to 30 healthy volunteers in the following dose groups:• Group 1A: 12 mg bispecific GLP-1RA / GLP-2RA fusion protein administered via SC injection (N = up to 10)• Group IB: 12 mg bispecific GLP-1RA / GLP-2RA fusion protein administered via an ingestible device as described herein (N = up to 20)

[0136] Part 2 of the study will enroll up to 30 obese but otherwise healthy participants in the following randomized (1:2) 8-week repeat administration dose groups:• Group 2A: Placebo administered weekly (QW) (N = up to 10):o Dose 1 : Placeboo Doses 2-8: Placebo (two placebos given 24 hours apart)• Group 2B: Bispecific GLP-1RA / GLP-2RA fusion protein administered weekly (QW) via an ingestible device as described herein (N = up to 20):o Dose 1: 30 mg bispecific GLP-1RA / GLP-2RA fusion protein administered via an ingestible device as described hereino Doses 2-8: 60 mg bispecific GLP-1RA / GLP-2RA fusion protein administered via two ingestible devices (30 mg each) as described herein 24 hours apart.

[0137] For Part 2 of the study, bispecific GLP-1RA / GLP-2RA fusion protein will be administered weekly to participants according to the randomization assignment. For Dose 1, one capsule (placebo or ingestible device) will be administered on Day 1. For doses 2-8, two capsules (placebo or ingestible device) will be administered 24 hours apart on Days 8 / 9, 15 / 16, 22 / 23, 29 / 30, 36 / 37, 43 / 44, and 50 / 51. Participants will stay in the clinic during dosing days.

[0138] Safety and PK assessments will be made periodically throughout the study. The primary endpoints will include evaluating safety and tolerability of bispecific GLP-1RA / GLP-2RA fusion 324905-2572-8915.3Attorney Docket No. 130257-0765 (770.601)protein when administered via an ingestible device as single and multiple doses by assessing treatment emergent adverse events (TEAEs) in healthy volunteers. The secondary endpoints will include determining serum PK parameters (including Cmax, Tmax, ti / 2, and area under the serum concentration curve (AUC)) and PD effects when administered as multiple doses. The exploratory endpoints will include determining the effects of bispecific GLP-1RA / GLP-2RA fusion protein on inflammatory biomarker (plasma hsCRP), lipids, glucose, and glycated hemoglobin (HBAlc) when administered as multiple doses.334905-2572-8915.3

Claims

Attorney Docket No. 130257-0765 (770.601)What is claimed is:

1. A method of administering a bispecific GLP-1RA / GLP-2RA fusion protein to a subject in need thereof comprising: administering to the subject by ingestion an ingestible device containing a composition comprising a therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or into and through a GI lumen wall into a peritoneum or peritoneal cavity of the subject following ingestion.

2. The method of claim 1, wherein the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a bioavailability that is greater than a bioavailability of a subcutaneously administered dose of bispecific GLP-1RA / GLP-2RA fusion protein.

3. The method of claim 1, wherein the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a bioavailability that is substantially the same as a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

4. The method of any one of claims 1-3, wherein the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Cmax that is less than a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

5. The method of any one of claims 1-3, wherein the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Cmax that is substantially the same as a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

6. The method of any one of claims 1-5, wherein the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Tmax that is greater than a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

7. The method of any one of claims 1-5, wherein the bispecific GLP-1RA / GLP-2RA fusion protein exhibits a Tmax that is substantially the same as a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

8. The method of any one of claims 1-7, wherein the subject is suffering from one or more conditions selected from obesity, diabetes, NAFLD, and NASH.

9. The method of any one of claims 1-8, wherein the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is from about 4 mg to about 30 mg.Attorney Docket No. 130257-0765 (770.601)10. The method of any one of claims 1-9, wherein the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is about 12 mg.

11. The method of any one of claims 1-9, wherein the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is about 30 mg.

12. The method of any one of claims 1-11, comprising twice weekly administration of the device, optionally on consecutive days with about 24 hours between each dose or on the same day with about 12 hours between each dose.

13. The method of any one of claims 1-11, comprising thrice weekly administration of the device, optionally with about 12 hours between each dose or on consecutive days with about 24 hours between each dose.

14. The method of any one of claims 1-13, wherein the composition is a liquid composition.

15. The method of any one of claims 1-14, wherein the composition is delivered into the GI lumen wall or into and through the GI lumen wall into a peritoneum or peritoneal cavity by injection via a hollow needle.

16. The method of any one of claims 1-15, wherein the composition is a liquid composition that comprises the bispecific GLP-1RA / GLP-2RA fusion protein, a buffering agent, a solubilizing agent, a binder, and an antioxidant.

17. The method of claim 16, wherein the liquid composition further comprises a surfactant selected from polysorbate 80 or poloxamer 188.

18. The method of any one of claims 1-17, wherein the ingestible device is comprised within a swallowable capsule.

19. The method of any one of claims 1-18, wherein the device is administered by oral ingestion.

20. The method of any one of claims 1-19, wherein the GI lumen wall is a wall of the stomach.

21. The method of any one of claims 1-19, wherein the GI lumen wall is a wall of the intestine.

22. The method of claim 21, wherein the wall of the intestine is a wall of the small intestine.Attorney Docket No. 130257-0765 (770.601)23. The method of any one of claims 1-22, wherein the method comprises a titration dosing period followed by a maintenance dosing period.

24. The method of claim 23, wherein the titration dosing period comprises administering a first dose of the bispecific GLP-1RA / GLP-2RA fusion protein once weekly (QW) for two weeks followed by administering a second dose of the bi specific twice weekly (Q2W) for two weeks, optionally wherein the first dose is the same as the second dose.

25. The method of claim 23 or 24, wherein the maintenance dosing period comprises administering the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein three times weekly (TIW).

26. The method of claim 23 or 24, wherein the maintenance dosing period comprises administering the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein twice weekly (Q2W).

27. An ingestible device for use in delivering a bispecific GLP-1RA / GLP-2RA fusion protein to a subject in need thereof, the device comprising: a composition comprising a therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or into and through a GI lumen wall into a peritoneum or peritoneal cavity of the subject following ingestion, optionally wherein the device is for administration twice or three times weekly.

28. The device for use of claim 27, wherein the bispecific GLP-1RA / GLP-2RA fusion protein delivered from the device exhibits a bioavailability that is greater than a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

29. The device for use of claim 27, wherein the bispecific GLP-1RA / GLP-2RA fusion protein delivered from the device exhibits a bioavailability that is substantially the same as a bioavailability of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

30. The device for use of any one of claims 27-29, wherein the bispecific GLP-1RA / GLP-2RA fusion protein delivered from the device exhibits a Cmax that is less than a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.Attorney Docket No. 130257-0765 (770.601)31. The device for use of any one of claims 27-29, wherein the bispecific GLP- 1RA / GLP-2RA fusion protein delivered from the device exhibits a Cmax that is substantially the same as a Cmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

32. The device for use of any one of claims 27-31, wherein the bispecific GLP-1RA / GLP-2RA fusion protein delivered from the device exhibits a Tmax that is greater than a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

33. The device for use of any one of claims 27-31, wherein the bispecific GLP-1RA / GLP-2RA fusion protein delivered from the device exhibits a Tmax that is substantially the same as a Tmax of subcutaneously administered bispecific GLP-1RA / GLP-2RA fusion protein.

34. The device for use of any one of claims 27-33, wherein the subject is suffering from one or more conditions selected from obesity, diabetes, NAFLD, and NASH.

35. An ingestible device containing a bispecific GLP-1RA / GLP-2RA fusion protein, the device comprising: a composition comprising a therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or into and through a GI lumen wall into a peritoneum or peritoneal cavity of the subject following ingestion.

36. The device for use of any one of claims 27-34 or the device of claim 35, wherein the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is from about 4 mg to about 30 mg.

37. The device for use of any one of claims 27-34 or the device of claim 35, wherein the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is about 12 mg.

38. The device for use of any one of claims 27-34 or the device of claim 35, wherein the therapeutically effective dose of the bispecific GLP-1RA / GLP-2RA fusion protein is about 30 mg.

39. The device for use of any one of claims 27-38 or the device of any one of claims 35-38, wherein the composition is a liquid composition.

40. The device for use of any one of claims 27-39 or the device of any one of claims 35-39, further comprising a hollow needle structured to inject the composition into the GI lumen wall or through the GI lumen wall and into the peritoneum or peritoneal cavity of the subject.Attorney Docket No. 130257-0765 (770.601)41. The device for use of any one of claims 27-40 or the device of any one of claims 35-40, further comprising a swallowable capsule, wherein the ingestible device is comprised within the swallowable capsule.

42. The device for use of any one of claims 27-41 or the device of any one of claims 35-41 wherein the GI lumen wall is a wall of the stomach.

43. The device for use of any one of claims 27-41 or the device of any one of claims 35-41, wherein the GI lumen wall is a wall of the intestine.

44. The device for use or device of claim 43, wherein the wall of the intestine is a wall of the small intestine.

45. Use of an ingestible device according to any one of claims 35-44 in a method for delivering bispecific GLP-1RA / GLP-2RA fusion protein to a subject in need thereof or in the manufacture of a medicament for treating one or more conditions selected from obesity, diabetes, NAFLD, or NASH in a subject in need thereof.

46. The method, device, device for use, or use of any one of the preceding claims, wherein the bispecific GLP-1RA / GLP-2RA fusion protein:comprises a GLP-1RA moiety comprising the amino acid sequence of one of SEQ ID NOs.1-11, optionally comprising the amino acid sequence of one of SEQ ID NOs.1, 4, 5, or 11;comprises a GLP-2RA moiety comprising the amino acid sequence of one of SEQ ID NOs.17-22, optionally comprising the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 19;comprises a GLP-1RA moiety comprising the amino acid sequence of one of SEQ ID NOs.1-11, optionally comprising the amino acid sequence of one of SEQ ID NOs.1, 4, 5, or 11, and comprises a GLP-2RA moiety comprising the amino acid sequence of one of SEQ ID NOs. 17-22, optionally comprising the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 19;comprises a GLP-1RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 23 to 30;comprises a GLP-2RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs. 31 to 36;comprises a GLP-1RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs: 23 to 30 and a GLP-2RA fusion protein comprising the amino acid sequence of one of SEQ ID NOs. 31 to 36; orAttorney Docket No. 130257-0765 (770.601)is selected from PG-102-1, PG-102-2, PG-102-3, PG-102-4, PG-102-5, PG-102-6, PG-102-7, PG--8, or PG-102-9.

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