TREATMENT OF POST-BARIATRIC HYPOGLYCEMIA USING MINI-DOSE STABLE GLUCAGON

Abstract

Post-bariatric hypoglycemia (PBH) is an increasingly-recognized complication of gastric bypass surgery. Current therapeutic options have suboptimal efficacy. Small doses of stable liquid glucagon can be used to treat or prevent post-bariatric hypoglycemia.

Claims

1-35. (canceled)

36. A method of preventing or treating hypoglycemia in a post-bariatric surgery subject comprising: (a) determining whether or not the post-bariatric surgery subject is at risk of developing post-bariatric hypoglycemia (PBH); and (b) administering a therapeutic formulation comprising a glucagon peptide, a glucagon analog, or salts thereof to the subject if the subject is determined to be at risk of developing PBH.

37. The method of claim 36, further comprising monitoring the subject's blood glucose levels.

38. The method of claim 36, wherein the hypoglycemia is a post-prandial hypoglycemia episode.

39. The method of claim 36, wherein the hypoglycemia is a severe hypoglycemia episode.

40. The method of claim 38, wherein the subject's post-prandial blood glucose levels are decreasing and are below 100, 90, 80, 70, 60, or 50 mg/dL.

41. The method of claim 40, wherein the subject's blood glucose falls below 100, 90, 80, 70, 60, or 50 mg/dL within 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes after a meal.

42. The method of claim 36, wherein the therapeutic formulation is administered 10 to 90 minutes after a meal.

43. The method of claim 37, wherein the therapeutic formulation is administered when the subject's blood glucose decreases by 0.5 to 10 mg/dL/min 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes after a meal.

44. The method of claim 36, wherein the therapeutic formulation comprises 50 to 300 g of a glucagon peptide, a glucagon analog, or salts thereof.

45. The method of claim 36, wherein the therapeutic formulation comprises 150 g of a glucagon peptide, a glucagon analog, or salts thereof.

46. The method of claim 36, wherein the therapeutic formulation is administered as a bolus.

47. The method of claim 36, wherein the therapeutic formulation is administered as an infusion over 90 seconds to 45 minutes.

48. The method of claim 36, wherein the therapeutic formulation is administered from a delivery apparatus.

49. The method of claim 48, wherein the delivery apparatus comprises: (i) a reservoir containing the therapeutic formulation; and (ii) an electronic pump configured to intradermally, subcutaneously, or intramuscularly deliver at least a portion of the therapeutic formulation to the subject.

50. The method of claim 48, wherein the apparatus is a closed-loop system, an open-loop system, or a no-loop system for delivering the therapeutic formulation to the subject.

51. The method of claim 36, wherein the therapeutic formulation is a single-phase solution comprising the glucagon peptide, glucagon analog, or salts thereof, dissolved in a non-aqueous solvent.

52. The method of claim 51, wherein the non-aqueous solvent is an aprotic polar solvent.

53. The method of claim 52, wherein the aprotic polar solvent is dimethylsulfoxide (DMSO).

54. The method of claim 52, wherein the aprotic polar solvent is a deoxygenated aprotic solvent.

55. The method of claim 52, wherein the therapeutic formulation further comprises an ionization stabilizing excipient, wherein (i) the glucagon peptide, glucagon analog, or salts thereof is dissolved in the aprotic polar solvent in an amount from about 0.1 mg/mL up to the solubility limit of the glucagon peptide, glucagon analog, or salts thereof, and (ii) the ionization stabilizing excipient is dissolved in the aprotic solvent in an amount to stabilize the ionization of the glucagon peptide, glucagon analog, or salts thereof.

56. The method of claim 55, wherein the ionization stabilizing excipient is at a concentration of 0.1 mM to less than 100 mM.

57. The method of claim 55, wherein the ionization stabilizing excipient is a mineral acid.

58. The method of claim 57, wherein the mineral acid is sulfuric acid or hydrochloric acid.

59. The method of claim 57, wherein the mineral acid is sulfuric acid.

60. The method of claim 55, wherein the ionization stabilizing excipient is sulfuric acid and the aprotic polar solvent is DMSO.

61. The method of claim 55, wherein the therapeutic formulation has a moisture content of less than 10, 5, or 3%.

62. The method of claim 55, wherein the therapeutic formulation further comprises a preservative at less than 10, 5, or 3% w/v.

63. The method of claim 62, wherein the preservative is benzyl alcohol.

64. The method of claim 55, wherein the therapeutic formulation further comprises a sugar alcohol at less than 10, 5, or 3% w/v.

65. The method of claim 64, wherein the sugar alcohol is mannitol.

66. The method of claim 55, wherein the therapeutic formulation further comprises at least one carbohydrate.

67. The method of claim 66, wherein the carbohydrate is trehalose and/or mannitol.

68. The method of claim 55, wherein the therapeutic formulation comprises at least 80 wt. % of the aprotic polar solvent, 3 to 7 wt. % of the carbohydrate, 0.001 to 0.1 wt. % of an amphoteric molecule, and 0 wt. % to less than 0.1 wt. % of the acid.

69. The method of claim 36, wherein the therapeutic formulation has a water content of 0 to less than 15 wt. %, 0 to less than 3 wt. %, 3 to 10 wt. %, or 5 to 8 wt. %.

70. The method of claim 36, wherein the glucagon peptide, glucagon analog, or salts thereof, has been previously dried from a buffer, wherein the dried glucagon peptide, glucagon analog, or salts thereof, has a first ionization profile that corresponds to an optimal stability and solubility for the glucagon, glucagon analog, or salt form thereof, wherein the dried glucagon peptide, glucagon analog, or salts thereof, is reconstituted into an aprotic polar solvent and has a second ionization profile in the aprotic polar solvent, and wherein the first and second ionization profiles are within 1 pH unit of one another.

71. The method of claim 49, wherein the therapeutic formulation has been stored in the reservoir for at least 1, 2, 3, 4, 5, 6, 7, 14, 21, 30, 45, or 60 days.

Description

DETAILED DESCRIPTION

[0048] It is well known that obesity, both in adults and children, is increasing in the United States and is becoming a substantial concern to medical professionals. In some extreme cases various types of surgery are used to reduce and control weight. The number of such surgeries has increased significantly over the past few years, to the point where approximately 200,000 surgeries are performed each year, with the number expected to continue to increase.

[0049] Gastric bypass surgery, however, is not without its complications, risks and negative consequences. One such complication is hyperinsulinemic hypoglycemia, which generally refers to after meal spikes in insulin with resulting extreme drops in blood sugar, where the patient experiences significant negative effects, including extreme sleepiness and fatigue, anxiety, in some cases a confusional state and passing out, or even seizures in extreme cases.

I. Treatment of Post-Bariatric Hypoglycemia (PBH)

[0050] In another aspect, the present invention provides methods of treating diseases, conditions, or disorders by administering to a subject glucagon, a glucagon analog or salt thereof for treating such disease, condition, or disorder. In certain aspects the glucagon or glucagon analog can be in a stable formulation and in an amount effective to treat, alleviate, or prevent the disease, condition, or disorder. In particular embodiments the disorder is post bariatric hypoglycemia (PBH).

[0051] In some embodiments, a therapeutic method of the present invention comprises treating, ameliorating, or preventing hypoglycemia by administering to a subject having or at risk of developing PBH an effective amount of a glucagon or a glucagon analog or salt thereof. The subject can be identified as having or at risk of developing PBH by glucose monitoring.

[0052] Administered dosages of glucagon, glucagon analog, or salts thereof for treating PBH are in accordance with dosages and scheduling regimens described herein. General guidance for appropriate dosages of all pharmacological agents used in the present methods is provided in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, 2006, supra, and in a Physicians' Desk Reference (PDR), for example, in the 65th (2011) or 66th (2012) Eds., PDR Network, LLC, each of which is hereby incorporated herein by reference. The appropriate dosage for treating PBH will vary according to several factors, including the formulation of the composition, patient response, the severity of the condition, the subject's weight, and the judgment of the prescribing physician. Effective doses of the described formulations deliver a medically effective amount of glucagon, glucagon analog, or a salt thereof. The dosage can be increased or decreased over time, as required by an individual patient or determined by medical personnel.

[0053] Nonetheless, an alert value can be defined that draws the attention of both patients and caregivers to the potential harm associated with hypoglycemia. In certain aspects an alert value can be a falling blood glucose levels below 90, 80, 70, 60, or 50 mg/dL. In a further aspect the alert value can be a falling blood glucose levels below 100, 90, 80, 70, 60, or 50 mg/dL that decreases by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/dL or more over a period of time (e.g., within 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute(s)) after a meal. Patients at risk for hypoglycemia (i.e., those that have had bariatric surgery and previous episodes of hypoglycemia) should be alert to the possibility of developing hypoglycemia at a self-monitored plasma glucoseor continuous glucose monitored subcutaneous glucoseconcentration of70 mg/dL. (3.9 mmol/L).

[0054] The condition of severe hypoglycemia is an event requiring assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Typically, these events begin occurring at plasma glucose concentrations of 50 mg/dL (2.8 mmol/L). Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration70 mg/dL (3.9 mmol/L). Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration70 mg/dL (3.9 mmol/L). Probable symptomatic hypoglycemia is an event during which symptoms typical of hypoglycemia are not accompanied by a plasma glucose determination but that was presumably caused by a plasma glucose concentration70 mg/dL (3.9 mmol/L). Pseudo-hypoglycemia is an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia with a measured plasma glucose concentration>70 mg/dL (>3.9 mmol/L) but approaching that level.

[0055] In light of the current specification a determination of an effective amount or dose is well within the capability of those skilled in the art. Generally, the formulations to deliver these doses may contain glucagon, glucagon analog, or salt thereof present at a concentration from about 0.1 mg/mL up to the solubility limit of the therapeutic agent in the formulation. This concentration is preferably from about 1 mg/mL to about 100 mg/mL. In certain aspects the concentration is about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, or about 100 mg/mL.

[0056] The formulations of the present invention may be for subcutaneous, intradermnal, or intramuscular administration (e.g., by injection or by infusion). In some embodiments, the formulation is administered subcutaneously. The formulations can also be delivered transdermally, such as by topically applying the composition to skin (e.g., spreading the composition on skin or loading the composition onto a dermal patch and attaching the dermal patch to the skin).

[0057] Glucagon or glucagon analog formulations can be administered by infusion or by injection using any suitable device. For example, a formulation may be placed into a syringe (e.g., a pre-filled syringe), a pen injection device, an auto-injector device, or a pump device. In some embodiments, the injection device is a multi-dose injector pump device or a multi-dose pen device. The formulation is presented in the device in such a fashion that the formulation is readily able to flow out of the needle upon actuation of an injection device, such as an auto-injector, in order to deliver the therapeutic agent. Suitable pen/auto injector devices include, but are not limited to, those pen/auto injection devices manufactured by Becton-Dickenson, Swedish Healthcare Limited (SHL Group), YpsoMed Ag, and the like. Suitable pump devices include, but are not limited to, those pump devices manufactured by Tandem Diabetes Care, Inc., Delsys Pharmaceuticals, Insulet Corp. and the like.

[0058] In some embodiments, the glucagon or glucagon analog formulations are provided as ready for administration in a vial, a cartridge, or a pre-filled syringe.

[0059] Certain aspects of the methods described herein can be implemented using a pump-based system. Pump-based systems used to administer the glucagon compositions can include closed-loop, open-loop, or no-loop systems. In certain aspects glucagon or glucagon analog formulations can be used with such systems that are designed to be carried or stored in a pump container without having to be reconstituted (i.e., they are readily available to be administered to the patient/subject from the pump container). Further, the formulations can be stable at non-refrigerated temperatures (20-35 C.) for extended periods (>2 months) (i.e., the formulations can be safely stored in the pump container without risking substantial loss in activity of the glucagon in the formulation or risking the formation of insoluble aggregates than will inhibit delivery and clog the infusion apparatus).

[0060] The pump-based system can include: (1) a glucose sensor that is or can be inserted in a patient and that is capable of measuring blood glucose levels (e.g., either directly via contact with the patient's blood or indirectly via contact with the patient's interstitial fluid); (2) a transmitter that sends the glucose information from the sensor to a monitor (e.g., via radio frequency transmission); (3) a pump that is designed to store and deliver the glucose formulation to the patient; and/or (4) a monitor (e.g., one that can be built into the pump device or a stand-alone monitor) that displays or records glucose levels. For a closed-loop system, the glucose monitor can be capable of modifying the delivery of the glucagon formulation to the patient via the pump based upon an algorithm. Such a closed-loop system requires little to no input from the patient and instead actively monitors blood glucose levels and administers the needed amount of the glucagon formulation to the patient to maintain an appropriate glucose level and prevent the occurrence of hypoglycemia. For an open-loop system, the patient would actively participate by reading their glucose monitor and adjusting the delivery rate/dose based on information provided by the monitor. For a no-loop system, the pump would deliver the glucagon formulation at a fixed (or basal) dose. The no-loop system can be used without a glucose monitor and without a glucose sensor if so desired.

[0061] Certain aspects include a glucagon delivery apparatus comprising a reservoir containing a composition comprising glucagon, a glucagon analog, or a salt form thereof, a sensor configured to measure a patient's blood glucose level, and an electronic pump configured to intradermally, subcutaneously or intramuscularly deliver at least a portion of the composition to a patient based on the patient's measured blood glucose level. The sensor can be positioned on the patient such that it contacts the patient's blood or contacts the patient's interstitial fluid or both. The sensor can be configured to transmit data (for example, wirelessly, via radio frequency or bluetooth low energy (BLE), or via a wired connection) to a processor configured to control operation of the electronic pump. The processor can be configured to control operation of the pump based, at least in part, on the data obtained by the sensor. In one instance, the processor can be configured to control operation of the pump to intradermally, subcutaneously or intramuscularly inject at least a portion of the composition if the data obtained by the sensor indicates a glucose level below a defined threshold or indication that a defined threshold will be breached in a particular period of time (e.g., an indication of impending hypoglycemia or an indication that the blood glucose levels will fall to below 70, 60, or 50 mg/dL within a certain period of time (e.g., within 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute(s)). Such an indication can be determined by identifying a downward trend of blood glucose levels (e.g., by the blood glucose monitoring device) as well as the speed or trajectory of this downward trend. The glucagon delivery apparatus can also include a monitor configured to communicate information indicative of the patient's glucose level. The monitor can include a speaker or a display device, or both. The monitor can be configured to communicate an alert when a glucose level of the patient is estimated to be at a defined threshold. Still further, the apparatus can be configured to allow manual adjustment of at least one of a delivery rate and a dose of the composition intradermally, subcutaneously or intramuscularly delivered by the pump.

[0062] In some embodiments, the stable formulation is used for formulating a medicament for the treatment of hypoglycemia. In some embodiments, the stable formulation comprises glucagon, glucagon analog, or a salt thereof (e.g., glucagon acetate).

II. Glucagon and Glucagon Analog Formulations

[0063] Therapeutic agents, such as glucagon and glucagon analogs, in the context of the present invention encompass peptide or protein compounds and pharmaceutically acceptable salts thereof. In certain aspects, when the therapeutic agent is present in the deoxygenated aprotic polar solvent, the stability of the therapeutic agent may be further enhanced when compared with the same therapeutic agent present in an untreated aprotic polar solvent. The increased stability can be attributed due, at least in part, to a reduction in the oxidative degradation of the therapeutic agent or the oxidative degradation of the aprotic polar solvent, or both. One of skill is aware of which therapeutic agent is suitable for treating certain diseases or conditions and would be capable of administering effective amounts of a therapeutic agent in a formulation as described herein for the treatment of a disease or condition.

[0064] Non-limiting examples of peptides and proteins and salts thereof) that can be used in the context of the present invention include, but are not limited to glucagon or analogs thereof.

[0065] The therapeutic agent of the invention can be administered intracutaneously in the prevention, diagnosis, alleviation, treatment, or cure of disease. Examples of proteins and proteinaceous compounds which may be formulated and employed in the delivery system according to the present invention include those proteins which have biological activity, or which may be used to treat a disease or other pathological conditions.

[0066] Any suitable dosage of peptide or peptides can be formulated, Generally, the peptide (or, in embodiments comprising two or more peptides, each of the peptides) is present in the formulation in an amount ranging from about 0.1 mg/mL to about 100 mg/mL. In some embodiments, the peptide is present in the formulation in an amount ranging from about 5 mg/mL, to about 60 mg/mL. In other embodiments, the peptide is present in the formulation in an amount ranging from about 10 mg/mL to about 50 mg/mL. In still other embodiments, the peptide is present in the formulation in an amount ranging from about 1 mg/mL to about 15 mg/mL. In yet other embodiments, the peptide is present in the formulation in an amount ranging from about 0.5 mg/mL to about 5 mg/mL. In yet other embodiments, the peptide is present in the formulation in an amount ranging from about 1 mg/mL, to about 50 mg/mL.

[0067] In some embodiments, the formulations can further comprise an antioxidant. In other embodiments, the formulations can further comprise a chelator. In still other embodiments, the formulations can further comprise a preservative.

[0068] Formulations used in the described therapies and methods include a glucagon or a glucagon analog or salt thereof present in an aprotic polar solvent system. In particular aspects aprotic polar solvent system includes at least one ionization stabilizing excipient. The glucagon or a glucagon analog or salt thereof can be dissolved (e.g., fully or partially solubilized) or suspended (fully or partially) in the aprotic polar solvent system. Further, the formulation can be structured as a single phase solution, a paste or slurry, a gel, an emulsion, or a suspension.

[0069] In some embodiments, the glucagon, glucagon analog or salt thereof is present in an aprotic polar solvent that is neat, i.e., it does not contain a co-solvent. In other embodiments the glucagon, glucagon analog or salt thereof is present in a solvent system that is a mixture of two or more aprotic polar solvents (i.e., an aprotic polar solvent system). An example would be a 75/25 (% v/v) mixture of DMSO and NMP. In some embodiments, a co-solvent can be used, where in one or more aprotic polar solvents are mixed with a co-solvent. Non-limiting examples of co-solvents include water, ethanol, propylene glycol (PG), glycerol, and mixtures thereof. In certain aspects water can be specifically excluded or limited as a co-solvent, i.e., the co-solvent can be a non-aqueous co-solvent. The co-solvent may be present in the formulation in an amount ranging from about 0.5% (w/v) to about 50% (w/v), e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% (w/v). In some embodiments, the co-solvent is present in the formulation in an amount ranging from about 10% (w/v) to about 50% (w/v), from about 10% (w/v) to about 40% (w/v), from about 10% (w/v) to about 30% (w/v), from about 10% (w/v) to about 25% (w/v), from about 15% (w/v) to about 50% (w/v), from about 15% (w/v) to about 40% (w/v), from about 15% (w/v) to about 30% (w/v), or from about 15% (w/v) to about 25% (w/v).

[0070] Still further, a glucagon or glucagon analog formulation can include one or more excipients. In some embodiments, the excipient is selected from sugars, starches, sugar alcohols, antioxidants, chelators, and preservatives. Examples of suitable sugars excipients include, but are not limited to trehalose, glucose, sucrose, etc. Examples of suitable starches for stabilizing excipients include, but are not limited to, hydroxyethyl starch (HES). Examples of suitable sugar alcohols (also referred to as polyols) for stabilizing excipients include, but are not limited to, mannitol and sorbitol. Examples of suitable antioxidants include, but are not limited to, ascorbic acid, cysteine, methionine, monothioglycerol, sodium thiosulphate, sulfites, BHT, BHA, ascorbyl palmitate, propyl gallate, N-acetyl-L-cysteine (NAC), and Vitamin E. Examples of suitable chelators include, but are not limited to, EDTA, EDTA disodium salt (edetate disodium), tartaric acid and salts thereof, glycerin, and citric acid and salts thereof. Examples of suitable inorganic salts include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, calcium sulfate, and magnesium sulfate. Examples of suitable preservatives include, but are not limited to, benzyl alcohols, methyl parabens, propyl parabens, and mixtures thereof. Additional formulation components include local anesthetics, such lidocaine or procaine. In some embodiments, an additional stabilizing excipient is present in the formulation in an amount ranging from about 0.05% (w/v) to about 60% (w/v), from about 1% (w/v) to about 50% (w/v), from about 1% (w/v) to about 40% (w/v), from about 1% (w/v) to about 30% (w/v), from about 1% (w/v) to about 20% (w/v), from about 5% (w/v) to about 60% (w/v), from about 5% (w/v) to about 50% (w/v), from about 5% (w/v) to about 40% (w/v), from about 5% (w/v) to about 30% (w/v), from about 5% (w/v) to about 20% (w/v), from about 10% (w/v) to about 60% (w/v), from about 10% (w/v) to about 50% (w/v), from about 10% (w/v) to about 40% (w/v), from about 10% (w/v) to about 30% (w/v), or from about 10% (w/v) to about 20% (w/v). In some embodiments, the additional stabilizing excipient is present in the formulation in an amount that is about, at most, or at least 0.1, 0.5, 1, 2, 3, 4, 5, 6, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% (w/v).

III. Kits/Containers

[0071] Kits are also contemplated as being used in certain aspects of the present invention. For instance, a formulation of the present invention can be included within a kit. A kit can include a container. In one aspect, for instance, the formulation can be comprised within a container that is ready to administer to a subject without having to reconstitute or dilute the formulation. That is, the formulation to be administered can be stored in the container and be readily used as needed. The container can be a device. The device can be a syringe (e.g. pre-filled syringe), a pen injection device, an auto-injector device, a device that can pump or administer the formulation (e.g., automatic or non-automatic external pumps, implantable pumps, etc.) or a perfusion bag. Suitable pen/auto-injector devices include, but are not limited to, those pen/auto-injection devices manufactured by Becton-Dickenson, Swedish Healthcare Limited (SHL Group), YpsoMed Ag, and the like. Suitable pump devices include, but are not limited to, those pump devices manufactured by Tandem Diabetes Care, Inc., Delsys Pharmaceuticals, Insulet Corp., and the like.

EXAMPLES

[0072] The following examples are provided to better illustrate the claimed invention and are not intended to be interpreted as limiting the scope of the invention. To the extent that specific materials or steps are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.

Example 1

Randomized, Placebo-Controlled, Double Blind, 2-Way Crossover Study Followed by an Open-Label Crossover Extension With Standard of Care, to Evaluate The Incidence and Duration of Post-Prandial Hypoglycemia in Post-Bariatric Surgery Patients

[0073] The study described has a primary objective of evaluating the incidence and duration of hypoglycemia after having meals (PG less than 70 mg/dL). And as a secondary objective assessing the (i) prevention of post prandial hypoglycemia episodes (defined as glucose levels below 70 mg/dl); (ii) prevention of severe hypoglycemia episodes (defined as glucose levels below 54 mg/dl); and prevention of rebound hyperglycemia after administration of study drug (defined as glucose levels above 180 mg/dl). Also the time in goal range will be evaluated (defined as glucose levels within 70-180 mg/dl), reported in minutes; as wells the neurogenic symptoms of hypoglycemia (if present) as documented using the Edinburgh Hypoglycemia Symptoms Score.

[0074] Other objective include: Assessing (i) the ability of a patient to self-administer glucagon using vial and syringe after CGM alert, in the open-label arm; (ii) patient satisfaction with vial and syringe format, at the end of the open-label arm; (iii) patient quality-of-life comparison measured by [EQ-5D/SF-36/etc.] between glucagon and standard-of-care in the open-label period; and (iv) fear of hypoglycemia at baseline and at the end of open-label study. Oral carbohydrate utilization in the out-patient setting.

[0075] Subjects will be adult male or female patients with post-bariatric surgery hypoglycemia syndrome defined as minimum of at least one hypoglycemic episode per week requiring intervention. Approximately 35 subjects are anticipated to be screened for this study to achieve the goal of 24 subjects completing the study with evaluable results for all treatment periods. To allow for possible drop-outs, approximately 28 subjects may be randomized.

[0076] This is an inpatient, randomized, placebo-controlled, blinded, two-way crossover study, followed by an open-label two-way crossover study in an outpatient setting, to evaluate efficacy and safety of administering a glucagon formulation in subjects with PBHS.

[0077] Subject should stop their current off-label medication for PBH for 24 hours before the treatment visit. If the subject is on LAR depot octreotide, they should be converted to an immediate acting octreotide which is stopped 24 hours before the treatment visit.

[0078] The study will involve two daytime clinical research center (CRC, or comparable setting) mixed meal tolerance test (MMTT) sessions 7-28 days apart, with random assignment to receive glucagon 300 mcg during one session and placebo during the other.

[0079] In-patient blinded visits will be followed by a 6-week open-label outpatient treatment. Subjects in this outpatient two-arm crossover study will be randomized to receive both 3 weeks of self-administered glucagon 300 mcg as needed using a vial and syringe, and 3 weeks of standard of care.

[0080] The estimated duration of study participation for individual subjects is approximately 4 weeks in clinical research center and 6 weeks in open label. The estimated duration of the entire study is 6 months.

[0081] Inclusion Criteria. Males or females diagnosed with ongoing post-bariatric surgery hypoglycemia with prior episodes of hypoglycemia, unresponsive to dietary intervention (low glycemic index, controlled carbohydrate portions) and oral acarbose. History of bariatric surgery 6 months prior to enrollment. Minimum one episode of hypoglycemia per week requiring intake of oral carbohydrates. Age 18-65 years of age, inclusive, at screening. Willingness to follow all study procedures, including attending all clinic visits.

[0082] Exclusion Criteria. Documented hypoglycemia occurring in the fasting state (>12 hours fast); Chronic kidney disease stage 4 or 5; Hepatic disease, including serum ALT or AST greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin<3.0 g/dL; or serum bilirubin>2.0; Congestive heart failure, NYHA class, III or IV; History of myocardial infarction, unstable angina or revascularization within the past 6 months; History of a cerebrovascular accident in past 6 months or with major neurological deficits; Seizure disorder (other than with suspect or documented hypoglycemia); Active treatment with any diabetes medications except for acarbose; Active malignancy, except basal cell or squamous cell skin cancers; Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease); Known insulinoma; Major surgical operation within 30 days prior to screening; Hematocrit below 33%; Bleeding disorder, treatment with warfarin, or platelet count<50,000; Blood donation (1 pint of whole blood) within the past 2 months; Active alcohol abuse or substance abuse; Current administration of oral or parenteral corticosteroids; Pregnancy and/or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception and to refrain from breast-feeding during the study and for at least 1 month after participating in the study. Acceptable contraception includes birth control pill/patch/vaginal ring, Depo-Provera, Norplant, an IUD, the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence; Use of an investigational drug within 30 days prior to screening.

[0083] There will be no involvement of special vulnerable populations such as pregnant women, prisoners, institutionalized or incarcerated individuals, or others who may be considered vulnerable populations.

[0084] Summary of Protocol. Visit 1Screening. Adult male or female patients with PBHS will be recruited from multiple clinical research centers. Patients will undergo a history and physical examination, with emphasis on inclusion and exclusion criteria. Blood and urine samples will be obtained for screening laboratory testing including hemoglobin A1c, CBC, comprehensive chemistry, urinalysis, and pregnancy test (if applicable). Fear of hypoglycemia score will be recorded. Consent forms will be reviewed in detail with potential participants. Subjects will be screened within 30 days of visit 2.

[0085] Washout period. Subject should stop their current off label medication for PBHS for 24 hours before the treatment visit. If subject is on LAR depot octreotide, they should be converted to an immediate acting octreotide which is stopped 24 hours before the treatment visit.

[0086] Visit 2CGM Sensor Placement: Two continuous glucose monitor sensors (Dexcom G4) will be placed on the anterior abdominal wall (to ensure sensor availability and calibration for visit day. Participants will be provided a glucometer and instructed in both sensor insertion and calibration techniques. If patient has prior experience with sensor insertion and calibration, then this visit may occur concurrent with visit 1.

[0087] Visit 3Mixed Meal TestingTreatment 1 ((</=3 days following Visit 2). Subjects will arrive in the morning after an overnight fast. An intravenous line will be inserted in a vein in ant-cubital fossa for blood sampling. Placement of the Dexcom sensor will be verified, and calibration verified using at least 2 venous blood glucose samples obtained 15 minutes apart. Two blood samples will be obtained for measurement of plasma glucose (via YSI analytical device) immediately and subsequent hormonal assays. Subject will be randomized after blood sample is collected. The subject will then be asked to drink a liquid mixed meal containing at least 60 gm of carbohydrates, e.g. 2 bottles of Ensure compact gm over 10 minutes. Blood samples will be collected for immediate (in room) glucose measurements (YSI) every 10 minutes till blood glucose reaches 110 mg/dl. Once venous glucose levels fall below 110 mg/dl, glucose will be measured at 5-minute intervals (YSI). This blood sampling series will conclude once sensor glucose levels fall to 90 mg/dl and the sensor displays down arrows indicating glucose levels are continuing to decrease. When the plasma glucose fall to 90 mg/dl and the sensor displays down arrows indicating glucose levels are continuing to decrease, the subject will be administered the blinded study drugs from a vial & syringe, via the subcutaneous route in the abdomen by a healthcare provider. Time will be reset to 0 min at the time of drug delivery. After study drug administration, plasma glucose will be measured (YSI) at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes. Hormone profiles should be monitored at 10, 20, 30, 45, 60, 75, 90, and 120 minutes.

[0088] At any time post-dosing, if a subject exhibits signs of neuroglycopenia or glucose level falls at or below 54 mg/dl for greater than 5 minutes, a 25 mL IV bolus dose of 50% dextrose will be given. Signs and symptoms should be monitored and if the subject's condition fails to improve within 15 minutes, additional dextrose or other intervention may be given at the discretion of the investigator. At time of alarm trigger and before each administration of study drug, the Edinburgh Hypoglycemia Symptoms Score will be assessed. This will be repeated at 15, 30 and 60 minutes following study drug administration. Baseline glucose levels should be verified prior to discharge, CGM sensors will be removed. Sensors will be downloaded for subsequent analysis of appropriateness of dose timing. Blood samples collected during this visit will be processed and stored per the analytical laboratory guidelines, until analysis for hormone levels to verify typical patterns in response to meal ingestion and to assess endogenous responses to the study drug

[0089] Visit 4CGM Sensor Placement [After a wash-out period of 7 to 28 days]: Two continuous glucose monitor sensors (Dexcom G4) will be placed on the anterior abdominal wall (to ensure sensor availability and calibration for visit day). Participants will be provided a glucometer and instructed in both sensor insertion and calibration techniques. If patient is already trained on CGM sensor insertion and calibration, this visit is not required.

[0090] Visit 5Mixed Meal TestingTreatment 2 ((</=3 days following Visit 4). After a wash-out period of 7 to 28 days, subjects will return to the clinic and the study procedures will be repeated with each subject crossed over to the other treatment arm. After study-related procedures are performed on each of the treatment days, subjects will be trained on open-label extension study procedures before discharge.

[0091] Open-Label Two-arm Crossover Study Extension. Study staff will discuss open-label procedures with each patient. Patients will be trained to self-administer 300 mcg of glucagon using a vial & syringe via the subcutaneous route in the abdomen to treat hypoglycemia. This typically occurs 60-90 minutes following a post-prandial spike in glucose levels. Glucagon administration should occur when there is an alert from CGM at 90 mg/dl and the sensor displays down arrows indicating glucose levels are continuing to decrease. The patient will be discharged home into the open-label study with 1 new CGM & 6 sensors. Patient should replace every week a calibrate daily using blood glucose meter, per manufacture instructions. Subject should enter all information in e-dairy, and the CRC will follow up every week to ensure sensor replacement & calibration has occurred. Subject will be randomized to either RTU-Glucagon or standard of care (SOC) treatment for 3 weeks, followed by 3 weeks with the other treatment. Two glucagon emergency kits (GEK) will be provided to each subject should severe hypoglycemia persist despite treatment with experimental drug or oral glucose (in SOC arm). If the glucose level falls at or below [54 mg/dl], or if the patient develops neuroglycopenia or discomfort with signs and symptoms of hypoglycemia, patient should self-treat with a provided GEK emergency kit and glucose tablets. Patient will return home with one attached CGM & sensor, with appropriate hypoglycemia alarms set as determined by the clinician. The CGM sensors will be replaced and recalibrated per manufacturer label across the 6-week outpatient study. Patient should record all hypoglycemia events and subsequent treatments (glucagon and/or oral carbohydrate) in an e-diary.

[0092] Visit 6End of Study Safety Follow-up [42 to 49 days following visit 5]: At the end of 6 weeks patients will return to the clinic, CGM, sensors will be removed and data downloaded. E-diary and all data forms will be received and inspected by study staff. Patients will undergo a brief physical examination and any AEs that occurred during the outpatient study will be reviewed. Blood and urine samples will be obtained for screening laboratory testing including hemoglobin A1c, CBC, comprehensive chemistry, urinalysis, and pregnancy test (if applicable). Fear of hypoglycemia score following use of investigation drug will be recorded.

[0093] The primary endpoint will be the treatment effect on glucose levels within the lab study, as measured by YSI 2300 and/or YSI 2900 and the treatment effect on glucose levels within the open-label study, as measured by CGM. Other secondary endpoints can include glucose levels below, within, or above target range after study drug administration in lab measure YSI, measured by CGM during open-label study and defined as area under the curve (AUC) and area over the curve (AOC) in minutes: Below range, as defined by plasma glucose 70 mg/dl. Below range, as defined by plasma glucose between 54-70 mg/dl. Below range, as defined by plasma glucose<54 mg/dl. Within range, as defined by plasma glucose between 70-180 and/dl. Above range, as defined by plasma glucose>180 mg/dl. As well as the treatment effect on symptoms of hypoglycemia, as measured by [Edinburgh Hypoglycemia Symptoms Score] during the inpatient lab study.

[0094] Exploratory endpoints can include: Usability of the vial and syringe, as measured by [XERIS questionnaire?] at end of open-label study. Quality of Life index, measured by [EQ-5D/SF-36/etc.] at baseline and at the end of open-label study. Hormone profile (Insulin and glucagon) during the inpatient portion of the study. Fear of hypoglycemia at baseline and at the end of open-label study. Carbohydrate utilization compared between study drug and SOC.