Avexitide reveals promise for hypoglycemia after weight-loss surgical procedure

Avexitide (Eiger Biopharmaceuticals), a first-in-class GLP receptor blocker, significantly reduced hypoglycemia in patients with refractory post-bariatric hypoglycemia, new research finds.

Postbariatric hypoglycemia is a complication of bariatric surgery estimated to occur in approximately 29% to 34% of people who undergo Roux-en-Y gastric bypass and 11% to 23% of people who undergo vertical gastric sleeve surgery undergo. It typically manifests about 1-3 hours after meals and can lead to severe neuroglycopenic symptoms, including blurred vision, confusion, drowsiness, and incoordination.

In addition, more than a third (37%) of sufferers experience hypoglycemia awareness. This can lead to seizures in about 59%, unconsciousness and hospitalization in 50%, car accidents and even death. More than 90% of those affected consider themselves disabled and 41% say they are unable to work.

There are currently no approved medical treatments for postbariatric hypoglycemia. The standard of care is medical nutrition therapy with a low-carbohydrate restricted diet and small, frequent, mixed meals. When this does not work, stepwise off-label pharmacotherapy has been tried, including acarbose (Precose), octreotide (Sandostatin), and diazoxide (Proglycem).

But “these are limited by efficacy and tolerability,” said Marilyn Tan, MD, who presented the results of the Phase 2 study of Avexitide on June 11 at ENDO 2022, the annual meeting of the Endocrine Society.

In very severe cases, gastrostomy tubes or bypass reversal are options, but these result in weight gain and incomplete efficacy. “There is an urgent need for safe, effective, and targeted therapies for postbariatric hypoglycemia,” said Tan, clinical associate professor of endocrinology at Stanford University School of Medicine, Stanford, California.

The pathophysiology is not fully understood, but there appears to be an exaggerated GLP-1 response leading to abnormal insulin secretion and symptomatic hyperinsulinemic hypoglycemia. Avexitide (formerly Exendin 9-39) blocks the GLP-1 receptor and moderates the excessive GLP-1 response, she explained.

Sought for comment, session moderator Michelle Van Name, MD, told Medscape Medical News, “This is an issue and it is important that we understand more about it and identify different treatment options so these patients can continue to live full, healthy post-bariatric lives.” Surgery.”

And avexitide also has potential for treating congenital hyperinsulinism, “which is a very difficult disease to treat in babies,” noted Van Name, a pediatric endocrinologist at Yale University, New Haven, Connecticut.

The drug reduced all levels of hypoglycemia, across all types of surgery

The study enrolled 14 women and 2 men with severe refractory postbariatric hypoglycemia despite medical nutritional therapy. A majority (9) had undergone Roux-en-Y gastric bypass, 4 had vertical sleeve gastrectomy, 2 had gastrectomy, and 1 had a Nissen fundoplication. Seven patients (43.7%) lost consciousness due to hyperinsulinemic hypoglycaemia. None had diabetes.

They were randomly assigned to either subcutaneous avexitide 45 mg twice daily or 90 mg once daily for 14 days each, with a 2-day washout period, followed by a switch to the other dose.

Both doses resulted in a significant reduction in hypoglycemia as measured by autologous blood glucose testing. The once daily dose reduced stage 1 (glucose <70 mg/dL) hypoglycaemia by 67.5% and stage 2 (<54 mg/dL) by 53.3% (p=0.0043).

In severe hypoglycaemia (ie, altered mental status/unskilled), even greater reductions were observed — 67.5% for twice-daily dosing (p=0.0003) and 66.1% for once-daily dosing (p=0, 0003). .

“This is consistent with what we have seen in previous Avexitide studies,” Tan noted.

Using blinded continuous glucose monitoring (CGM), more hypoglycemic events were recorded because episodes were recorded that the patient was unaware of. There was a significant reduction in the percentage of time spent with stage 1 and 2 hypoglycemia and in the absolute number of hypoglycaemic events over 14 days.

Here, the effect was greater at the 90 mg once-daily dose, with up to a 65% reduction in time spent and the number of events, but the results for the twice-daily dose were also significant, Tan said.

The drug was effective in all surgical subtypes. Patients who underwent vertical sleeve gastrectomy/gastrectomy had higher rates of baseline hypoglycemia and “robust responses to subcutaneous injections of avexitide.” This underscores the crucial role of GLP-1,” Tan said.

No serious adverse events occurred. The most commonly reported side effects were diarrhoea, headache, flatulence and injection site reactions/bruising. All were mild and self-limiting and resolved without treatment. No participant discontinued the study.

Eiger Biopharmaceuticals is currently working with the US Food and Drug Administration and the European Medicines Agency to develop a Phase 3 study.

The study is an investor-initiated study funded by Eiger Biopharmaceuticals. Tan receives research support from Eiger Biopharmaceuticals, Inc. as a site researcher. Van Name is an investigator for a study sponsored by Provention Bio.

Endocrine Society Annual Meeting #ENDO2022.
Presented on June 11, 2022.

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, and other work appears in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.

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