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Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist used to treat type 2 diabetes, may be a potential treatment for idiopathic intracranial hypertension (IIH).

In a small phase 2 trial, subcutaneous injections of exenatide led to a significant reduction in intracranial pressure (ICP), as well as the number of monthly headaches in patients with IIH.

Based on the positive results, exenatide for IIH is now being trialed in two phase 3 studies.

“This is an exciting time as we may see the first licensed treatment option coming through for a patient group in great need,” Alexandra Sinclair, order clavamox canada MBChB, PhD, University of Birmingham, UK, told Medscape Medical News.

Sinclair served as principal investigator for the phase 2 IIH Pressure Trial. The results were published online March 13 in the journal Brain.

First Clinical Proof of Concept

IIH is a chronic condition characterized by unexplained elevated ICP. Weight gain is the major risk factor for IIH, which most commonly occurs in women of reproductive age with obesity.

Chief symptoms of IIH include chronic disabling headaches and loss of vision. Other features of the disease include ringing in the ears, neck and back pain, and impaired cognition.

“Although previously thought to be rare, the number of patients with IIH is increasing each year (the incidence has increased by more than 350% in the last 10 years),” Sinclair told Medscape Medical News.

In earlier work, Sinclair and colleagues observed that GLP-1 receptor agonists act on the choroid plexus in the brain to lower cerebral spinal fluid secretion, and consequently, ICP.

The phase 2 trial was designed to obtain “first clinical proof of concept” for exenatide in IIH and provide a basis to move into pivotal phase 3 testing, said Sinclair.

The randomized, double-blind, placebo-controlled trial recruited 16 women (mean age, 28 years) with active IIH. They received a loading dose of subcutaneous exenatide 20 μg (seven patients) or equivalent volume of subcutaneous 0.9% saline placebo (eight patients) and were then dosed for 12 weeks (self-administered at home) with either subcutaneous exenatide 10 μg or equivalent volume of placebo twice daily.

The primary clinical outcome was the difference in ICP between exenatide and placebo measured by telemetric ICP monitoring at 2.5 hours, 24 hours, and 12 weeks.

Exenatide “significantly and meaningfully” lowered ICP across all three time points, the researchers report. The difference in ICP between groups was −4.2 mmHg (P = .048) at 2.5 hours, −4.7 mmHg (P = .030) at 24 hours, and −4.1 mmHg (P = .058) at 12 weeks.

“No studies that have evaluated other drugs (used off-label) to treat IIH have shown ICP reduction within the first 24 hours of administration. IIH patients can deteriorate rapidly (over days), and hence, a drug with rapid onset of action is clinically advantageous for IIH,” the researchers note in their article.

Exenatide also led to a significant reduction in monthly headache days of 7.7 (secondary endpoint) between baseline and 12 weeks. A reduction in monthly headache days of 1.5 to 2 days is regarded as meaningful in randomized controlled trials for chronic migraine.

Exenatide also led to significant improvement in visual acuity at 12 weeks. The magnitude of change (five letters) was equivalent to one line on the visual acuity chart.

There were serious adverse events related to use of exenatide. Overall, adverse events were relatively low, with nausea (which settled in the first week) being the most common adverse event, seen in over 85% of patients receiving twice-daily injections of exenatide (Byetta).

To reduce the need for frequent injection (and nausea), a once-weekly subcutaneous formulation of exenatide called Presendin will be trialed through the University of Birmingham start-up company Invex Therapeutics.

“This is such exciting progress,” Shelly Williamson, chair of patient charity IIH UK, said in a statement. 

“New drug options are vitally important for IIH, and this trial brings hope to the millions of patients living with the condition. We very much look forward to the next steps and seeing the drug tested in two large phase 3 clinical trials,” Williamson added.

A Life-Altering Treatment?

Commenting on the research for Medscape Medical News, Sweta Sengupta, MD, with Duke University School of Medicine, Durham, North Carolina, noted that medications for IIH are limited.

“Acetazolamide, which is a diuretic that lowers intracranial pressure, is the first-line treatment. In patients with contraindications, side effects, and/or continue to have elevated pressure despite medications, other options are vastly limited. In this population, an effective medication with different properties and mechanism of action, like exenatide, could be life-altering,” Sengupta said.

He noted that there have been past bench-side data that suggested GLP-1R agonists regulate cerebrospinal fluid secretion, but this is the first randomized controlled trial studying the effect of GLP-1 receptor agonists on ICP in patients with IIH in a minimally invasive manner.

“Exenatide-related pressure decrement not only occurred early (2.5 hours after administration) but also was sustained. This decrease in pressure was even present in the absence of significant weight reduction,” Sengupta said.

“While not enough patients were analyzed to assess patient-centered endpoints like headache severity and disability, a decrease in monthly headache days and improved visual acuity was observed,” he noted.

“Phase 3 large-scale studies will help assess more patient-centered endpoints and also further clarify the benefit of exenatide in those with IIH,” Sengupta added.

Funding for the study was provided by the University of Birmingham, UK, and Invex Therapeutics. Sinclair has reported receiving personal fees from Invex Therapeutics in her role as director during the conduct of the study. Sengupta has reported no relevant financial relationships.

Brain. Published online March 13, 2023. Full text

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