Obesity currently affects over 40% of US adults and by 2030 a projected 50% of US adults will be obese and 25% severely obese. The use of bariatric surgery to address obesity and related comorbidities has increased by more than 50% over the past decade, with further increases expected due to the addition of bariatric surgery to the treatment algorithm for uncontrolled diabetes.
Post-bariatric hypoglycemia (PBH) is a rare but increasingly prevalent complication of bariatric surgery that affects approximately 10% of patients who undergo Roux-en-Y gastric bypass (RYGB) and 4% of those who undergo vertical sleeve gastrectomy (VSG). This disorder leads to frequent symptomatic hypoglycemia, often resulting in glucose concentrations low enough to cause seizures, altered mental status, loss of consciousness, cognitive dysfunction, disability, and death. Quality of life can be severely diminished, and many patients cannot care for themselves or others, work, drive, or be left alone.
PBH leads to altered mental status, seizures, and coma, which are unresponsive to diet modification.
Avexitide is a well characterized, first-in-class, selective GLP-1 antagonist that reduces post-bariatric hypoglycemia
Avexitide competes with endogenous GLP-1 for the GLP-1 receptor, counteracting the effects of excessive GLP-1 secretion. Avexitide has been shown in clinical studies to effectively prevent postprandial hyperinsulinemia and hypoglycemia and reduce neuroglycopenic symptoms in patients with PBH.
Avexitide is a 31 amino acid peptide fragment of Exenatide, and has never been approved or commercialized for any indication. Avexitide has been dosed in 54 patients across four Phase 2 studies in patients suffering from Post-Bariatric Hypoglycemia. Avexitide has been granted Breakthrough Therapy Designation, as well as Orphan Drug Designation in the European Union by the EMA for the treatment of non-insulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS) and Orphan Drug Designation by the US FDA for the treatment of Hyperinsulinemic Hypoglycemia. Both of these broad designations include PBH. Avexitide is generally well tolerated. Most commonly reported side effects were transient, mild to moderate injection site bruising, nausea, and headache.
Avexitide: A 31 amino acid fragment of Exenatide*
*Exenatide is marketed as Byetta for type 2 diabetes and is well characterized.
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 poorly tolerated and 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 post-bariatric hypoglycemia, a typical carbohydrate loaded meal results in patients experiencing early nutrient sensing which triggers calcium stimulated GLP-1 secretion by intestinal L-cells. Post-prandial GLP-1 is increased 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 is severely diminished, and many PBH patients cannot care for themselves, work, drive, or be left alone. There is no effective treatment for severe hypoglycemia associated with bariatric surgery.
Avexitide clinical studies
Five proof of concept clinical studies in >70 patients with severe post-bariatric hypoglycemia have been completed with avexitide (below).
Avexitide: Proof of Concept Demonstrated in Phase 2
Phase 2, 28-day Study
The most recently completed 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 Hypoglycemia (Hypoglycemia symptoms confirmed by SBGM concentrations of <70 mg/dL), Severe Hypoglycemia (neuroglycopenic symptoms confirmed by SBGM concentrations <55 mg/dL), and a reduced rate of rescue during both dosing regimens of avexitide as compared with placebo. Rescue is defined as self- or third-party administration of oral or g-tube intake to prevent or treat Hypoglycemia. Patients also demonstrated reductions in percent time in Hypoglycemia during diurnal periods (8 am to midnight) 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