Search

EP-3978011-B1 - TREATMENT OF POST-BARIATRIC HYPOGLYCEMIA WITH GLP-1 ANTAGONISTS

EP3978011B1EP 3978011 B1EP3978011 B1EP 3978011B1EP-3978011-B1

Inventors

  • MCLAUGHLIN, Tracey L.
  • CRAIG, Colleen M.

Dates

Publication Date
20260506
Application Date
20160523

Claims (14)

  1. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia in a patient by subcutaneous administration of a composition comprising a therapeutically effective amount of exendin(9-39); wherein the therapeutically effective amount is 2-100 mg of exendin(9-39) per dose; and wherein the composition is administered in a volume of 0.25 ml to 2 ml once per day or twice per day.
  2. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia of claim 1, wherein the composition is an isotonic solution that comprises at least one of an antimicrobial preservative, a tonicity adjusting agent, or a buffer.
  3. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia of claim 2, wherein the tonicity adjusting agent comprises mannitol.
  4. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia according to any of claims 1 to 3, wherein the therapeutically effective amount is 10-75 mg of exendin(9-39) per dose.
  5. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia according to any of claims 1 to 4, wherein the exendin(9-39) is administered in a volume of 0.5 ml to 1.5 ml once per day.
  6. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia according to any of claims 1 to 5, wherein the patient has previously had bariatric surgery, in particular wherein said bariatric surgery is Poux-en-Y gastric bypass, vertical sleeve gastrectomy, placement of an endosleeve device, duodenal mucosal resurfacing, partial bypass of the duodenum, vagal nerve blockade, or pyloroplasty.
  7. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia according to any of claims 1 to 5, wherein the patient has previously had gastrointestinal surgery.
  8. Exendin(9-39) for the use in the treatment and prevention of hyperinsulinemic hypoglycemia of claim 7, wherein said gastrointestinal surgery is gastrectomy, Nissen Fundoplication, or esophagectomy.
  9. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia according to any of claims 1 to 8, wherein the composition is an immediate release composition comprising 2.5-40 mg/ml of exendin(9-39) and is obtained by solubilizing lyophilized exendin(9-39) with saline or other pharmacologically acceptable diluent, and wherein the solution is administered by a dual-chamber pen injector or a vial/syringe device.
  10. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia of claim 9, wherein the lyophilized exendin(9-39) is provided in a 1-3 ml or 5 ml dual-chamber cartridge compatible with a disposable dual chamber pen injector.
  11. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia according to any of claims 1 to 8, which comprises an exendin(9-39) is administration twice per day, with a subcutaneous morning administration of a therapeutically effective amount of exendin(9-39), wherein the exendin(9-39) is administered at a first dosage; and a subcutaneous evening administration of a therapeutically effective amount of exendin(9-39), wherein the exendin(9-39) is administered at a second dosage; wherein the therapeutically effective amount of exendin(9-39) for the evening administration is greater than the therapeutically effective amount of exendin(9-39) for the morning administration.
  12. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia of claim 11, wherein the dosage of the evening administration is greater than the dosage of the morning administration.
  13. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia of claim 11 or 12, wherein the dosage of the morning administration is from 10-16 mg/ml of exendin(9-39).
  14. Exendin(9-39) for use in the treatment and prevention of hyperinsulinemic hypoglycemia according to claim 13, wherein the dosage of the evening administration is from 15-20 mg/ml of exendin(9-39).

Description

FIELD OF THE INVENTION The present disclosure provides exendin(9-39) and exendin(9-39)-containing compositions for use in the treatment of hyperinsulinemic hypoglycemia of any origin, and the prevention of associated acute symptoms and chronic outcomes in which an exendin(9-39), a glucagon-like peptide-1 receptor antagonist (GLP1RA), is formulated for subcutaneous administration and administered in a therapeutically effective dose, often by route of subcutaneous injection, either alone or in combination with an amylinomimetic or other anti-gastric emptying agent. In various embodiments, the patient receiving therapy has had bariatric surgery, a metabolic procedure, or a gastrointestinal surgery, and the hyperinsulinemic hypoglycemia ("hyperinsulinemia" or more generally hypoglycemia) suffered by the patient is believed by his or her physician to be due to complications of that surgery or some other procedure or condition likely to result in similar disease pathology. The disclosure therefore relates to the fields of biology, chemistry, medicinal chemistry, medicine, molecular biology, and pharmacology. The invention is as defined in the claims. BACKGROUND OF THE INVENTION Roux-en-Y gastric bypass (RYGB), widely performed for medically complicated obesity, cures type 2 diabetes in 85% of cases. The physiologic mechanisms mediating diabetes resolution is controversial, but the reduction in glucose excursions prior to weight loss has led to postulates that the incretin hormone, glucagon-like peptide-1 (GLP-1), may play an important role. GLP-1 stimulates the secretion of insulin by pancreatic beta cells and is responsible for the "incretin" effect: incretin hormones enhance the glucose-dependent secretion of insulin, such that pancreatic beta cells will secrete more insulin after an oral glucose load than after an isoglycemic IV glucose load. Enhanced secretion of GLP-1 after RYGB, and a resultant elevation in insulin secretion, may play a primary role in the resolution of diabetes after RYGB. Indeed GLP-1 analogs have been developed to treat diabetes. However, as the use of bariatric surgical procedures continues to increase worldwide, a severe complication - hyperinsulinemic hypoglycemia - is increasingly reported. Present in 1-6% of RYGB patients, this disorder leads to severe symptomatic hypoglycemia that plagues patients often multiple times daily, with glucose concentrations low enough (20-40 mg/dl) to cause seizures, altered mental status, loss of consciousness, cognitive dysfunction, disability, and death. Quality of life is severely diminished, and many patients cannot care for themselves or others, work, drive, or be left alone. There is no effective treatment and severe cases have been managed with near-total to total pancreatectomy, which results in insulin-dependent diabetes and is associated with a 6% surgical mortality risk. Given the severity of this chronic disorder with unmet clinical need, an effective therapeutic treatment is urgently needed. It would thus be useful to provide a method for the treatment of hyperinsulinemic hypoglycemia post bariatric surgery and prevention of its acute symptoms and chronic outcomes, and a pharmaceutical composition for such therapeutic. Salehi et al., Gastroenterology, 146:669-680 (2014) describes the treatment of patients with hyperinsulinemic hypoglycemia resulting from gastric bypass surgery by continuous intravenous infusion of the Glucagon-like Peptide-1 (GLP-1) receptor antagonist exendin (9-39). Furthermore, US 2008/269130 A1 describes methods of treating and ameliorating congenital and neonatal hyperinsulinism and post-prandial hypoglycemia, comprising the administering an antagonist of the GLP-1 receptor, such as exendin (9-39). SUMMARY OF THE INVENTION While the present disclosure generally provides for the treatment and prevention of hyperinsulinemic hypoglycemia, in a particular aspect, this invention relates to exendin(9-39), a GLP-1 receptor antagonist ("GLP-1RA"), for use in the treatment and prevention of hyperinsulinemic hypoglycemia in a patient by subcutaneous administration of a composition comprising a therapeutically effective amount of exendin(9-39); wherein the therapeutically effective amount is 2-100 mg of exendin(9-39) per dose; and wherein the composition is administered in a volume of 0.25 ml to 2 ml once per day or twice per day. In particular, the subcutaneous formulations of exendin(9-39) are provided as immediate release preparations or as extended / slow release preparations, and are conveniently packaged, for example, in the form of the dual-chamber pen device provided by the invention, or an alternate vial and syringe combination provided by the invention for patients to self-administer, or their care providers to administer, therapeutically effective amounts of the exendin(9-39). For exendin(9-39) therapeutically effective doses range from 2-100 mg. In some embodiments, exendin(9-39) is formulated and administered in an