Clinical hold lifted for Phase 2 trial of XPro1595 in mild Alzheimer’s

INmune recruiting patients until mid-year; top-line data expected 6 months later

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) has lifted a clinical hold on a Phase 2 trial testing INmune Bio’s investigational treatment XPro1595 in people with Alzheimer’s disease.

Regulators issued the hold in 2022 pending additional manufacturing information from INmune. The company addressed some of the FDA’s concerns, but the regulator maintained its hold, seeking more data on the therapy’s long-term potency.

The FDA was the only regulatory agency to pause the MINDFuL Phase 2 trial (NCT05318976). Enrollment in Australia, Canada, and some European countries continued during the U.S. hold.

INmune is still seeking participants for MINDFuL. The company looks to enroll as many as 201 people, ages 60-85, who have mild Alzheimer’s with certain biomarkers of inflammation. INmune expects to enroll the last trial participant by mid-year, with top-line data available about six months after that.

“We are pleased with the FDA’s response and will continue to work closely with the agency in anticipation of our Phase 3 [Alzheimer’s disease] program,” Raymond J. Tesi, MD, CEO of INmune, said in a company press release.

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Trial to wrap this year, with Phase 3 planned for early 2025

The company plans to complete the Phase 2 trial this year, followed by an end-of-Phase 2 meeting with the FDA early next year “to confirm our planned global Phase 3 trial that will include sites in the U.S., Canada, U.K., [European Union] and Pacific Rim,” Tesi said.

XPro1595, also called pegipanermin or simply XPro, is a protein designed to bind to and inhibit a soluble form of tumor necrosis factor (TNF), a pro-inflammatory molecule found at high levels in the brain of people with Alzheimer’s and is implicated in disease progression.

INmune believes that by blocking this protein, XPro will help ease inflammation and slow Alzheimer’s progression. It is also being developed for treatment-resistant forms of depression.

TNF inhibitors are approved for other diseases. However, these medications block non-harmful forms of TNF in addition to soluble TNF, the version believed to drive inflammation. XPro, by specifically targeting soluble TNF, may eliminate side effects caused by off-target blockage. Preclinical studies have demonstrated its ability to do that, according to INmune.

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XPro designed to cross blood-brain barrier

XPro is also designed to be able to cross the blood-brain barrier, a tight-knit cellular layer that helps prevent harmful substances circulating in the bloodstream from reaching the brain and spinal cord. Many medications, including approved TNF inhibitors, aren’t able to breach this barrier, limiting their usefulness in neurological disease treatment.

Data from a Phase 1b clinical trial (NCT03943264) showed XPro reduced a biomarker of neuroinflammation in adults with mild to moderate Alzheimer’s, in addition to boosting the integrity of nerve cell projections in certain brain regions.

Dosing in MINDFul began in 2022, with participants randomly assigned to receive XPro (1 mg/kg) or a placebo, given as a once-weekly, subcutaneous (under-the-skin) injection for 23 weeks.

The main goal is to evaluate changes in cognition, as assessed by the Early and Mild Alzheimer’s Cognitive Composite. Secondary goals include other cognitive assessments, measures of nerve fiber health and neurodegeneration, and levels of inflammatory biomarkers.

After the main trial, participants will have the option to enter an open-label extension study (NCT05522387) in which they will be treated with XPro1595 for at least a year.