Avexitide
Post-Bariatric Hypoglycemia (PBH)

Targeted blockade of GLP-1

PBH is characterized by frequent, symptomatic severe hypoglycemia. While mild cases can be managed with dietary modification, moderate-to-severe cases are refractory, and off-label use of medications (eg, octreotide, diazoxide, acarbose) is often poorly tolerated and/or incompletely efficacious. Consequently, a substantial unmet medical need remains for patients with PBH. The presence of inappropriately high insulin secretion after oral ingestion of nutrients has been well-established, with hyperinsulinemia occurring in response to oral but not intravenous glucose, due to exaggerated incretin effect. Plasma concentrations of glucagon-like peptide-1 (GLP-1), secreted by intestinal L-cells in response to oral nutrients are markedly elevated after meal intake in affected patients. GLP-1 is a gastrointestinal hormone secreted in response to meals that binds to GLP-1 receptors on the beta cells of the pancreas, enhancing the release of insulin and lowering blood glucose levels. In patients with PBH, exaggerated GLP-1 secretion results in dysregulated secretion of insulin and resultant symptomatic hypoglycemia.

Avexitide: Designed to Normalize Insulin Secretion

In PBH, a typical carbohydrate loaded meal results in patients experiencing early nutrient sensing which triggers exaggerated GLP-1 secretion by intestinal L-cells. Post-prandial GLP-1 has been shown to be increased approximately 10-fold in PBH patients. GLP-1 circulates to the beta cells of the pancreas, leading to increased insulin secretion and lower systemic blood glucose levels. In patients suffering from PBH, the glucose lowering is severe, putting them at risk of seizures, altered mental status, loss of consciousness, cognitive dysfunction, disability, and death. Quality of life can be severely diminished, and many PBH patients cannot care for themselves, work, drive, or be left alone. There is no approved treatment for PBH.

Avexitide clinical studies

Five proof of concept clinical studies in >70 patients with severe PBH have been completed with avexitide (below).

Avexitide: Proof of Concept Demonstrated in Phase 2

The Phase 2 PREVENT study was conducted in 18 patients with refractory, severe PBH enrolled across 5 US academic centers and dosed as outpatients in the PREVENT study. All patients received placebo subcutaneous (SC) injections for 14 days in a single-blinded manner followed by avexitide SC 30 mg twice daily (BID) injections for 14 days and 60 mg once daily (QD) injections for 14 days, for a total of 28 days active dosing, in a double-blind, cross-over design.

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The primary efficacy endpoint of improved postprandial glucose nadir during mixed meal tolerance testing (MMTT) was achieved with statistical significance with avexitide 30 mg BID (57.1 vs 47.1 mg/dL; P = 0.001) and 60 mg QD (59.2 vs 47.1 mg/dL; P = 0.0002), with fewer participants requiring glycemic rescue during each of the active dosing regimens than during placebo dosing. The secondary endpoint of reduced postprandial insulin peak during MMTT was also statistically significant with avexitide 30 mg BID (349.5 vs 454.5 IU/mL; P < 0.03) and 60 mg QD (357.2 vs 454.5 IU/mL; P = 0.04). Improvements in metabolic and clinical parameters were also monitored during each patient’s daily routine in the outpatient setting and assessed by self-blood glucose monitoring (SBGM), electronic diary, and continuous glucose monitoring (CGM). Patients experienced fewer episodes of level 1 hypoglycemia (blood glucose concentrations of <70 mg/dL), level 2 hypoglycemia (blood glucose concentrations <54 mg/dL), and level 3 hypoglycemia (a severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery) during avexitide as compared with placebo. Patients also demonstrated reductions in percent time in hypoglycemia and number of episodes of hypoglycemia as measured by CGM. Avexitide was well-tolerated in this study. There were no treatment-related serious adverse events and no participant withdrawals. Adverse events were typically mild to moderate in severity. The most common adverse events were injection site bruising, nausea, and headache, all of which occurred with lower frequency during avexitide dosing periods than during the placebo dosing period.

Reduced Hypoglycemia During Outpatient Assessment

CONSISTENT REDUCTIONS OBSERVED AS MEASURED BY SMBG, E-DIARY, CGM

¹ Rate is defined as number of episodes in each treatment period normalized to 14 days ² Hypoglycemia (Level 1, ADA) is defined as SBGM concentrations <70 mg/dL ³ Clinically Important Hypoglycemia (Level 2, ADA) is defined as SBGM concentrations <54 mg/dL ⁴ Severe Hypoglycemia (Level 3, ADA) is defined as a severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery. This applies regardless of whether a patient receives external assistance. ⁵ Number of events <54 mg/dL is defined as the number of episodes with CGM values <54 mg/dL sustained for at least 15 min during daytime hours (8AM to midnight) during each treatment period normalized to 14 days ⁶ Percent time is expressed as the percentage of CGM values that are <54 mg/dL during daytime hours (8am-12am) during each treatment period normalized to 14 days For more information, visit clinicaltrials.gov.

AVEXITIDE CLINICAL STUDIES IN PBH

• Tan, M. "Efficacy and Safety of Avexitidefor Treatment of Hypoglycemia after Gastrointestinal Surgery; Assessment of Novel Dosing Regimens in an Expanded Indication." ENDO 2022.
• Craig C et al. "PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia." J. Clin. Endocrin. Metab. 2021.
• Lee C et al. "28-Day dosing with avexitide Improves hyperinsulinemic hypoglycemia in patients with severe, refractory post-bariatric hypoglycemia: the PREVENT study." J Endocr Soc. 2019;3(Suppl 1):OR20-5.
• Craig CM et al. "Efficacy and pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric hypoglycaemia." Diabetes Obes Metab. 2018;20(2):352-361.
• Craig C et al. "Critical role for GLP-1 in symptmoatic post-bariatric hypoglycaemia." Diabetologia. 2017;60(3):531-540.
• Tan MJ et al. "Repeat subcutaneous dosing of exendin 9-39 reduces hyperinsulinemic hypoglycemia and neuroglycopenic symptoms in patients with post-bariatric hypoglycemia." Eiger BioPharmaceuticals. American Diabetes Association. June 9-13, 2017.
• Craig C, McLaughlin TL. "Subcutaneous exendin (9-39) effectively treats post-bariatric hypoglycemia." Presented at: American Diabetes Association, 76th Scientific Sessions; June 10-14, 2016; New Orleans, LA.

DISEASE OVERVIEW

• Patti ME, Goldfine AB. "The rollercoaster of post-bariatric hypoglycaemia." Lancet Diabetes Endocrinol. 2016;4(2):94-6.
• Angrisani L et al. "Bariatric Surgery Worldwide 2013." Obes Surg. 2015;25(10):1822-1832.
• Patti ME, Goldfine AB. "Hypoglycemia after gastric bypass: the dark side of GLP-1." Gastroenterology. 2014;146(3):605-8.
• Salehi M et al. "Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass." Gastroenterology. 2014;146(3):669-680.e2.
• Singh E, Vella A. "Hypoglycemia After Gastric Bypass Surgery." Diabetes Spectr. 2012;25(4):217-221.