Therapeutics

XPro1595

Overview

Name: XPro1595
Synonyms: INB03, NeuLiv, XENP1595, DN-TNF, XENP345
Therapy Type: Other
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: INmune Bio Inc.

Background

This 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 (De Sousa Rodrigues et al., 2019). 

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). 

Findings

In November 2019, INmune Bio began a Phase 1b open-label safety and target engagement trial in 18 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 receive weekly injections of 0.03, 1.0, or 3.0 mg/kg XPro1595 for three months. The primary outcome is safety. Secondary outcomes include 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 will also measure CSF Aβ and tau, and cognitive and psychiatric endpoints (Nov 2018 news). 

The study ran through 2020 and 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).

In October 2020, INmune started a 366-patient trial in the U.S. to evaluate this drug's ability to treat pulmonary complications of COVID-19. 

For all trials on XPro1595, see clinicaltrials.gov

INmune is developing the same drug for cancer, under the name INB03 (see Australian/New Zealand Clinical Trials Registry and Aug 2019 press release). It is also developing the compound for a form of hepatitis, under the name of NeuLiv (company press release).

Last Updated: 04 Feb 2021

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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. . 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.
  12. . Inhibition of soluble tumor necrosis factor is therapeutic in Huntington's disease. Hum Mol Genet. 2014 Apr 15; PubMed.
  13. . 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.

External Citations

  1. press release/webinar
  2. clinicaltrials.gov
  3. Australian/New Zealand Clinical Trials Registry
  4. Aug 2019 press release
  5. company press release

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. . 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.