Therapeutics

XPro1595

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Overview

Name: XPro1595
Synonyms: Pegipanermin, INB03, NeuLiv, XENP1595, DN-TNF, XENP345, XPro™ , LIVNate
Therapy Type: Other
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment
U.S. FDA Status: Alzheimer's Disease (Phase 2), Mild Cognitive Impairment (Phase 2)
Company: INmune Bio Inc.

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., 2007Brambilla 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., 2019MacPherson 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.

Last Updated: 16 Oct 2023

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References

News Citations

  1. More Private Funding for Alzheimer’s Research
  2. Systemic Inflammation: A Driver of Neurodegenerative Disease?

Therapeutics Citations

  1. Etanercept

Research Models Citations

  1. 5xFAD (B6SJL)
  2. TgCRND8
  3. 3xTg

Paper Citations

  1. . Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science. 2003 Sep 26;301(5641):1895-8. PubMed.
  2. . Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J Immunol. 2007 Aug 1;179(3):1872-83. PubMed.
  3. . Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain. 2011 Sep;134(Pt 9):2736-54. PubMed.
  4. . TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex. Brain Behav Immun. 2019 Sep 7; PubMed.
  5. . Tumor necrosis factor α Inhibition for Alzheimer's Disease. J Cent Nerv Syst Dis. 2017;9:1179573517709278. Epub 2017 May 15 PubMed.
  6. . Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol Dis. 2017 Jun;102:81-95. Epub 2017 Feb 24 PubMed.
  7. . Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer's disease model. Neurobiol Aging. 2016 Nov;47:41-49. Epub 2016 Jul 25 PubMed.
  8. . Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis. 2009 Apr;34(1):163-77. PubMed.
  9. . Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One. 2012;7(5):e38170. Epub 2012 May 29 PubMed.
  10. . Targeting soluble tumor necrosis factor as a potential intervention to lower risk for late-onset Alzheimer's disease associated with obesity, metabolic syndrome, and type 2 diabetes. Alzheimers Res Ther. 2019 Dec 31;12(1):1. PubMed.
  11. . Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model. Front Cell Neurosci. 2023;17:895017. Epub 2023 Mar 15 PubMed.
  12. . Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. J Parkinsons Dis. 2014;4(3):349-60. PubMed.
  13. . Inhibition of soluble tumor necrosis factor is therapeutic in Huntington's disease. Hum Mol Genet. 2014 Apr 15; PubMed.
  14. . Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. J Neurosci. 2006 Sep 13;26(37):9365-75. PubMed.
  15. . Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series. Neurobiol Dis. 2020 Oct;144:105027. Epub 2020 Jul 24 PubMed.

External Citations

  1. press release/webinar
  2. company press release
  3. press release
  4. company pipeline
  5. Australian/New Zealand Clinical Trials Registry
  6. press release
  7. company press release
  8. clinicaltrials.gov

Further Reading

Papers

  1. . Topical Administration of a Soluble TNF Inhibitor Reduces Infarct Volume After Focal Cerebral Ischemia in Mice. Front Neurosci. 2019;13:781. Epub 2019 Aug 7 PubMed.
  2. . Neurodegenerative disease treatments by direct TNF reduction, SB623 cells, maraviroc and irisin and MCC950, from an inflammatory perspective - a Commentary. Expert Rev Neurother. 2019 Jun;19(6):535-543. Epub 2019 May 24 PubMed.
  3. . Chronic psychological stress during adolescence induces sex-dependent adulthood inflammation, increased adiposity, and abnormal behaviors that are ameliorated by selective inhibition of soluble tumor necrosis factor with XPro1595. Brain Behav Immun. 2019 Oct;81:305-316. Epub 2019 Jun 25 PubMed.
  4. . Systemic Inhibition of Soluble Tumor Necrosis Factor with XPro1595 Exacerbates a Post-Spinal Cord Injury Depressive Phenotype in Female Rats. J Neurotrauma. 2019 Jul 10; PubMed.
  5. . Preventing synaptic deficits in Alzheimer's disease by inhibiting tumor necrosis factor alpha signaling. IBRO Rep. 2018 Jun;4:18-21. Epub 2018 Feb 2 PubMed.
  6. . XPro1595 ameliorates bone cancer pain in rats via inhibiting p38-mediated glial cell activation and neuroinflammation in the spinal dorsal horn. Brain Res Bull. 2019 Jul;149:137-147. Epub 2019 Apr 16 PubMed.
  7. . Selective targeting of Tumor Necrosis Factor Receptor 1 induces stable protection from Crohn's-like ileitis in TNF ΔARE mice. J Crohns Colitis. 2021 Dec 10; PubMed.
  8. . Pharmacological Inhibition of Soluble Tumor Necrosis Factor-Alpha Two Weeks after High Thoracic Spinal Cord Injury Does Not Affect Sympathetic Hyperreflexia. J Neurotrauma. 2021 Aug 1;38(15):2186-2191. Epub 2021 Feb 1 PubMed.
  9. . Selective inhibition of soluble TNF using XPro1595 relieves pain and attenuates cerulein-induced pathology in mice. BMC Gastroenterol. 2021 May 28;21(1):243. PubMed.
  10. . Selective Inhibition of Soluble Tumor Necrosis Factor Alters the Neuroinflammatory Response following Moderate Spinal Cord Injury in Mice. Biology (Basel). 2023 Jun 12;12(6) PubMed.
  11. . Selective inhibition of soluble TNF using XPro1595 improves hippocampal pathology to promote improved neurological recovery following traumatic brain injury in mice. CNS Neurol Disord Drug Targets. 2022 Jun 10; PubMed.
  12. . Selective inhibition of soluble tumor necrosis factor signaling reduces abdominal aortic aneurysm progression. Front Cardiovasc Med. 2022;9:942342. Epub 2022 Sep 16 PubMed.