Baseline Analysis of MINDFuL Trial Highlights Screening Success of Enrolling Patients With Immune Dysfunction

C.J. Barnum, PhD

A new analysis of the MINDFuL trial (NCT05318976) testing investigational XPro1595 (INmune Bio) suggest that patients with Alzheimer disease (AD) with biomarkers of immune dysfunction do not represent a uniquely difficult group to enroll, as their screen failure rate was not abnormally high. Since less than 10% of screen failures were attributed to not meeting immune dysfunction criteria, this implies most patients meeting general AD criteria also met the immune dysfunction biomarker criteria.¹

MINDFuL is a phase 2 study aiming to determine whether 1.0 mg/kg of investigational XPro1595 confers a benefit on cognition, function, and biomarkers of white matter in patients with early AD. The trial, expected to have data released in June 2025, is a randomized study that includes a unique inclusion criteria component, enrolling patients with evidence of immune dysfunction, thereby aligning the patients’ biology with the mechanism of action of XPro1595, a brain penetrant neutralizer of soluble tumor necrosis factor (solTNF).

Baseline demographic and disease characteristics were presented in a poster at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, by senior author C.J. Barnum, PhD, vice president of CNS Development at INmune Bio. Enrollment for the study was completed in November 2024, with a total of 757 patients screening and 208 randomized to the trial. The 72% screen rate failure was mainly attributed to patients being out of eligible range for the Mini-Mental State Exam (MMSE) score, followed by other reasons such as MRI lesions, amyloid-ß negativity/undocumented, unable to comply with study, and less than 1 enrichment biomarker available.

Of the 208 included, 92 had mild cognitive impairment (MCI) and 116 had mild AD, both of which had similar age ranges. Using the whole cohort, most patients are White (95.2%), followed by Asian (2.4%), Other, or missing (2.4%). The time since diagnosis was 1.18 years (SD, 1.56), with most patients being carriers of the apolipoprotein (APOE) e4 genotype (69.2%). Among carriers, 118 were heterozygotes and 26 were homozygotes. At screening, the mean MMSE scores were 25.85 for the entire cohort, 26.52 for those with MCI, and 25.31 for those with mild AD. Clinical Dementia Rating-Sum of Boxes mean scores were 3.03 (SD, 1.55) in the overall cohort, 2.41 (SD, 1.19) in the MCI group, and 3.51 (SD, 1.63) in the mild AD group.

In the study patients had to have at least 1 blood biomarker associated with immune dysfunction, which may include high sensitivity C-reactive protein greater than 1.5 mg/L, erythrocyte sedimentation rate above 10 mm/hr, glycated hemoglobin greater than 6.0 DCCT%, or at least 1 APOE e4 allele. Among the 208 patients included, 64.4% had at least 1 enrichment biomarker, 43.8% had 2, 18.8% had 3, and 2.4% had all 4. Enrichment biomarkers of enrolled patients indicated that no single biomarker of immune dysfunction was superior regardless of sex and disease status.

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In 2022, the FDA placed a hold on the MINDFuL phase 2 study, seeking additional manufacturing information from INmune. Nearly 2 years later, in January 2024, the company announced the removal of the clinical hold, with the trial on track to enroll its last patient mid-2024. At the time, RJ Tesi, chief executive officer at INmune Bio, alluded to the potential of a phase 3 study in AD.²

In a statement, he wrote, "We are pleased with the FDA’s response and will continue to work closely with the agency in anticipation of our Phase III AD program. Our primary goal is to complete the Phase II program in 2024 followed by an end-of-Phase II meeting with the FDA in early 2025 to confirm our planned global Phase III trial that will include sites in the U.S., Canada, U.K., E.U. and Pacific Rim."

XPro1595, a next-generation inhibitor of TNF, previously demonstrated the ability to decrease biomarkers of neuroinflammation in a phase 1b study of AD. Announced in January 2021, data from the open-label, dose-escalation study showed that cytokine/chemokine cerebrospinal fluid (CSF) levels after 12 weeks of therapy were decreased, with multiple statistically significant reductions (c-reactive protein & YKL-40; P ≤.0001). Additionally, investigators reported a significant correlation between neuroinflammation, as measured by CSF, and MRI white matter free water (R² = 0.75; P <.01), a validated biomarker of neuroinflammation.³

Proteomic analysis of CSF revealed that targeting neuroinflammation significantly impacted multiple Alzheimer’s disease-related pathways, including immune and inflammatory responses, neuronal function and injury, dendritic spine morphogenesis, and synaptic plasticity. Notably, the analysis showed an approximate two-fold reduction in neurodegeneration markers visinin-like protein 1 and neurofilament light, along with a three-fold change in contactin-2 and a half-fold change in neurogranin—both linked to synaptic plasticity (P <0.0001).

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REFERENCES
1. Staats, K, Pope P, Blomberg T, et al. ALZHEIMER’S DISEASE (AD) AND INFLAMMATION: BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE-2 STUDY OF XPRO1595 IN EARLY AD. Presented at: 2025 AD/PD Annual Meeting; April 1-5. ABSTRACT 3281
2. INmune Bio Announces FDA Removal of Clinical Hold for Alzheimer’s Disease Program. News release. INmune Bio. January 30, 2024. Accessed April 2, 2025. https://www.globenewswire.com/news-release/2024/01/30/2819914/0/en/INmune-Bio-Announces-FDA-Removal-of-Clinical-Hold-for-Alzheimer-s-Disease-Program.html
3. INmune Bio, Inc. Announces XPro1595 Found to Decrease Neuroinflammation and Neurodegeneration Biomarkers in Patients with Alzheimer’s Disease in Phase 1b Trial. News release. INmune Bio. January 21, 2021. Accessed April 2, 2025. https://www.inmunebio.com/index.php/newsroom/2021-news/inmune-bio-inc-announces-xpro1595-found-to-decrease-neuroinflammation-and-neurodegeneration-biomarkers-in-patients-with-alzheimers-disease-in-phase-1b-trial