Xeris Pharmaceuticals has announced positive findings from the outpatient stage of a Phase 2 proof-of-concept study of its developmental ready-to-use (RTU) glucagon in patients who experience postprandial hypoglycaemic episodes following bariatric surgery.
This was a Phase 2 prospective, randomised, placebo-controlled, double-blind proof-of-concept study that included an in-clinic stage followed by a 12-week outpatient stage. Subjects were randomly assigned to receive RTU glucagon or placebo during two separate meal challenges in an in-clinic stage crossover design, and then enter a parallel design outpatient stage where they were assigned to an investigational product for 12 weeks.
Hypoglycaemia that occurs after bariatric and other forms of upper gastrointestinal surgery is a condition called post-bariatric hypoglycaemia (PBH). It usually occurs six months to eight years after surgery and is an uncommon and rarely reported metabolic complication that can be severe and disabling for some patients. Hypoglycaemia episodes from PBH occur 1-3 hours after meals (postprandial hypoglycaemia), often at a frequency of >10 times per month. Persistent or unrecognized hypoglycaemia from PBH can progress to severe hypoglycaemia (blood glucose <54 mg/dL) with symptoms such as loss of consciousness, seizures, coma, and even death. When postprandial hypoglycaemia episodes in PBH occur, they can be difficult to acutely treat with oral carbohydrates alone, because an overcompensation with oral carbohydrates can frequently trigger a subsequent hypoglycaemia episode (rebound hypoglycaemia).
“Post-bariatric hypoglycaemia (PBH) is a rare complication of bariatric surgery that can significantly diminish the quality of life for those affected. Once diagnosed, the goal of PBH treatment is to reduce the frequency and severity of hypoglycaemic events after meals. However, managing PBH is complex because patients often fail dietary intervention and we do not have effective pharmacotherapy,” said Dr Helen Lawler, endocrinologist, Assistant Professor, Endocrinology, Diabetes and Metabolism at the University of Colorado School of Medicine. “Patients feel frustrated because of the limited therapeutic options, where unfortunately, today there are no approved therapies to treat PBH. This PBH research will help us understand the potential for ready-to-use glucagon to offer real-world benefits such as the avoidance of oral carbohydrates to treat postprandial hypoglycaemia, reduced weight gain, and the reduction of rebound hypoglycaemia.”
For the study, subjects self-administered a mini dose (300 µg) of RTU glucagon or placebo when they experienced hypoglycaemia symptoms (e.g., anxiety, nausea, sweating, tremors, palpitations), and blood glucose response was measured after the study drug is self-administered. In situations where hypoglycaemia (blood glucose ≤70mg/dl) is present at mini-dosing or continues after treatment, oral glucose tabs were recommended in addition to the study drug.
Results from the 12 subject, 12-week outpatient stage recorded more than 200 postprandial hypoglycaemia episodes across both treatment arms. Subjects frequently experienced postprandial episodes within 90-120 minutes after finishing meals and were able to successfully self-administer RTU glucagon during these events. Similar to the in-clinic stage, the sole use of a 300 µg RTU glucagon was adequate to restore or maintain normal blood glucose levels within 15 minutes of administration and maintained up to 120 minutes.
During episodes when blood sugar was >70mg/dL at drug dosing, RTU glucagon and placebo were comparable in maintaining blood sugar within normal levels, and RTU glucagon did not elicit hyperglycaemia. During episodes when blood sugar was <70mg/dL at drug dosing and without the use of glucose tabs, RTU glucagon successfully restored blood glucose levels to normal levels (blood sugar ≥70mg/dL) within 15 minutes, at a higher frequency when compared to placebo (91% versus 73%). When failures were observed, subjects in both treatment arms exhibited near-normal counterregulatory responses to hypoglycaemia, sufficient to avoid severe hypoglycaemia.
Subjects’ use of glucose tablets, both during and after drug dosing as a follow-on rescue, was observed only within the placebo treatment arm. In this placebo arm, glucose tablet use during postprandial hypoglycaemia episodes resulted in rebound hypoglycaemia (29.4%) however, rebound hypoglycaemia was not observed in the RTU glucagon treatment arm.
Treatment emergent adverse events with RTU glucagon were comparable to placebo, including negligible injection site reactions. The most common related AE was nausea (16.7%) and vomiting (8.3%) that was mild in severity and self-limited. RTU glucagon (300μg) appears safe and well tolerated, and no serious adverse events occurred.
“We are encouraged by the results of the completed proof-of-concept PBH study. The first half of this study demonstrated the utility of liquid, stable, ready-to-use glucagon in conditions beyond rescue for severe hypoglycaemia, and demonstrating safety and effectiveness in situations that require self-administration by the patient,” said Paul R Edick, Xeris’ Chairman and CEO. “We believe the completed outpatient stage study further establishes the safety profile and utility for mini dosing RTU glucagon in a real-world setting. Further evaluation of RTU glucagon in PBH is warranted, especially in those who manifest blunted counterregulatory responses to hypoglycaemia, and in refractory disease. We anticipate an end-of-phase 2 meeting with the FDA later this year to discuss a clinical path forward for this programme.”