Background

This pegylated protein biologic targets and neutralizes the inflammatory cytokine TNFα. A non-receptor binding variant of TNFα, XPro1595 forms heterotrimers with native soluble TNFα and prevents its interaction with the type 1 TNFα receptor (Steed et al., 2003). 

Unlike etanercept and other widely used nonselective TNF inhibitor drugs, this second-generation TNF inhibitor does not block signaling by membrane-bound TNFα through the type 2 receptor. Thus, XPro1595 appears to selectively inhibit neuroinflammation mediated by type 1 receptors, but does not suppress innate immunity or myelination mediated by type 2 receptors (Zalevsky et al., 2007; Brambilla et al., 2011). In adult mice, long-term treatment with etanercept, but not XPro1595, suppressed hippocampal neurogenesis, learning, and memory (Yli-Karjanmaa et al., 2019). 

XPro1595 is administered by subcutaneous injection and enters the brain.

TNFα is a central player in inflammatory responses. Its protein levels are low in healthy brain but chronically elevated in many neuroinflammatory diseases, including AD. In animal models of AD, TNFα promotes microglial activation, synaptic dysfunction, neuronal cell death, accumulation of plaques and tangles, and cognitive decline (Chang et al., 2017). 

Preclinical XPro1595 evaluation has been reported in three mouse models of AD. In 5XFAD mice, twice-weekly subcutaneous dosing for two months reduced brain amyloid deposition and immune cell infiltration, and improved synaptic function (Mar 2015 conference news; MacPherson et al., 2017). One-month-old TgCRND8 mice received a one-month continuous subcutaneous infusion of XPro1595 and, by six months, had less amyloid deposition than untreated littermates, as well as normalized hippocampal neuron synaptic function (Cavanagh et al., 2016). Intracranial administration reduced pre-plaque amyloid pathology in 3xTg mice (McAlpine et al., 2009); up to six weeks of intracranial infusions in old rats reduced microglia activation and improved synaptic function and cognition (Sama et al., 2012). Blocking soluble TNFα with XPro1595 was also reported to ameliorate the AD risk that results from the effects of a high-fat, high-glucose diet on insulin metabolism, immune, and neural function (De Sousa Rodrigues et al., 2019; MacPherson et al., 2023). 

XPro1595 reportedly improved outcomes in rodent models of Parkinson’s and Huntington’s diseases, but no clinical trials are ongoing (Barnum et al., 2014; McCoy et al., 2006; Hsiao et al., 2014). In a company-sponsored study of five rhesus monkeys with toxin-induced progressive parkinsonism, XPro1595 reduced some markers of inflammation, but did not prevent the degeneration of dopaminergic neurons (Joers et al., 2020).

Findings

In November 2019, INmune Bio began a Phase 1b open-label safety and target engagement trial in 20 patients with clinically diagnosed probable Alzheimer’s disease. Participants must have evidence of peripheral inflammation by way of elevated blood C-reactive protein, acetylated hemoglobin, or erythrocyte sedimentation rate, or carry at least one APOE4 allele. Participants received weekly injections of 0.3, 0.6, or 1.0 mg/kg XPro1595 for three months. The primary outcome was safety. Secondary outcomes included change from baseline in biomarkers of neuroinflammation, including blood and CSF C-reactive protein, TNFα, interleukin-1, and interleukin-6; an MRI measure of brain edema; and assessment of breath volatile organic compounds. Investigators also measured CSF Aβ and tau, and cognitive and psychiatric endpoints (Nov 2018 news). 

In October 2020, INmune started a 366-patient trial in the United States to evaluate this drug's ability to treat pulmonary complications of COVID-19. The study was terminated for futility in October 2021, after enrolling 76 patients.

In January 2021, the company announced results on six patients treated with the 1 mg/kg dose. The drug was safe, with injection site reactions being the main adverse event. After three months, white-matter free water, an exploratory imaging marker of neuroinflammation, was decreased by 5 percent. Participants also registered decreases in multiple inflammatory proteins in the CSF, detected by cytokine assays and proteomics analysis. The changes were sustained in three patients who continued on the drug for a year (press release/webinar). The study was completed in September 2021.

IIn February 2022, the company began the Phase 2 MINDFuL trial in people with mild AD and signs of inflammation. As in the Phase 1b, participants must have some combination of elevated C-reactive protein, hemoglobin A1c, or erythrocyte sedimentation rate, and at least one APOE4 allele. The trial plans to randomize 201 participants in a 2:1 ratio to weekly subcutaneous injections of 1 mg/kg XPro1595 or placebo for six months. The sole primary outcome is the six-month change in the Early and Mild Alzheimer’s Cognitive Composite. Secondary outcomes include the Clinical Dementia Rating and other measures of cognition and daily function, MRI measures of axonal and gray matter integrity and brain structure, biomarkers of amyloid, tau, and inflammation, and adverse events. The study is anticipated to run until July 2025 in Australia, Canada, and the United States, and offers an optional open label extension of up to 18 months for all participants.

In April 2022, INmune registered a Phase 2 in 60 participants with mild cognitive impairment who were also positive for amyloid and APOE4. Dosing and primary outcome were the same as the MINDFuL design. The company withdrew this trial before enrollment began, because they plan to enroll MCI patients in MINDFuL.

In May 2022, the FDA placed a clinical hold on XPro1595 trials in the United States, and requested additional information on the manufacturing of the drug (company press release). The trial is active in Australia, where the first patient began treatment in April (press release). As of October 2023, the MINDFul trial is active in Australia and Canada.

INmune is developing XPro1595 for treatment-resistant depression (company pipeline). It is also undergoing trials for cancer, under the name INB03 (see Australian/New Zealand Clinical Trials Registry and Aug 2019 press release). A third indication for hepatitis, under the name of NeuLiv (company press release) or LIVNate, no longer appears in the pipeline.

For trials on XPro1595 in Alzheimer’s disease, see clinicaltrials.gov.