Soluble TNF Inhibitor XPro Shows Mixed Results in Phase 2 MINDFuL Trial of Alzheimer Disease

RJ Tesi, MD

Recently announced data from the phase 2 MINDFuL trial (NCT05318976) showed that treatment with XPro (INmune Bio), an investigational tumor necrosis factor (TNF) inhibitor, failed to show an effect in the modified intent-to-treat population (mITT); however, the agent led to key changes in clinical measures of cognition, behavior, and an Alzheimer disease (AD)-related biomarker in a predefined analyses. Additional analyses from the study are expected to be presented at the upcoming Alzheimer’s Association International Conference (AAIC), held June 27-31 in Toronto, Canada.¹

The double-blind, placebo-controlled study included 208 participants with early-stage AD with biomarkers of elevated neuroinflammation, 200 of which made up the mITT. Within the mITT group, investigators failed to observe a statistically significant difference vs placebo in the primary end point of Early Mild Alzheimer’s Cognitive Composite (EMACC), an assessment of cognition. The more positive changes came within a subgroup of patients (n = 100) with 2 or more biomarkers of inflammation.

In this prespecified group, investigators recorded an effect size of 0.27 on the primary end point of EMACC as well as an effect size of –0.24 on the secondary end point of Neuropsychiatric Inventory, both favoring XPro. According to the company, a biological effect of the investigational treatment was observed in blood levels of phosphorylated tau 217 (effect size, –0.20), a promising AD biomarker associated with amyloid and tau pathology.

"These results highlight the potential of XPro™," RJ Tesi, MD, chief executive officer at INmune Bio, said in a statement.¹ "Our findings indicate that XPro™ may offer benefits to Alzheimer’s patients across all age groups, regardless of comorbidities, additional medications, or ApoE4 status. This evidence lays the foundation for advancing XPro™ as a promising treatment option for Alzheimer’s disease."

Based on these data, INmune Bio plans to file for breakthrough therapy designation with the FDA, as well as schedule and end-of-phase 2 meeting with the agency to determine the next steps in development. The company also is expected to engage with regulatory authorities outside of the U.S., including the United Kingdom and European Union.

Throughout the phase 2 study, XPro was considered safe and well tolerated, with no reports of amyloid-related imaging abnormalities, as well as no deaths, drug-related hospitalizations or organ system toxicity. Injection site reactions, found to be more common in the XPro group (80% of cases vs 20% of cases on placebo), was the most common reason for patients discontinuing the trial. Of the 14 participants on XPro who left, 10 were because of injection site reactions.

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XPro, which has been in development for a few years, is an advanced TNF inhibitor that targets soluble TNF while preserving trans-membrane TNF and TNF receptors. TNF has been shown to be upregulated in the brains of patients with AD, particularly around amyloid plaques. The idea is that targeting TNF in AD may reduce harmful inflammation, protect synapses, and potentially slow disease progression; however, clinical translation has been limited by delivery challenges and safety considerations.

CJ Barnum, PhD

"By targeting neuroinflammation, a key driver of Alzheimer’s disease progression, XPro™ offers a novel mechanism to potentially slow disease progression and cognitive symptoms for persons living with Alzheimer’s disease and inflammation," CJ Barnum, PhD, vice president of CNS Drug Development at INmune Bio, said in a statement.¹ "The continued development of this therapeutic, whether as a standalone treatment or in combination with other therapies, holds promise in addressing this critical and growing unmet medical need."

Earlier this year, at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, the company presented a baseline analysis of the phase 2 study, highlighting the ease of recruiting patients with AD with biomarkers of immune dysfunction. Overall, the study’s screen failure rate was 72%, which 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.²

Coming into the study, 92 of the 208 patients had mild cognitive impairment (MCI) and 116 had mild AD, both of which had similar age ranges. According to the data presented, 64.4% of patients had at least 1 enrichment biomarker, 43.8% had 2, 18.8% had 3, and 2.4% had all 4. The enrichment biomarkers included 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.

The next-generation TNF inhibitor was previously studied in a phase 1b, open-label, dose-escalation trial of patients with AD. Findings announced in January 2021 revealed that treatment with the therapy led to decreases in cytokine/chemokine cerebrospinal fluid levels after 12 weeks, 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

REFERENCES
1. INmune Bio Reports Key Findings from Phase 2 MINDFuL Trial of XPro™ in Early Alzheimer’s Disease. News release. INmune Bio. June 30, 2025. Accessed July 10, 2025. https://www.inmunebio.com/index.php/newsroom/2025-news/muneioeportseyindingsfromhase2urialo20250630043503
2. 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
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 July 10, 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