Slide 1: Targeting Innate Immune Dysfunction: XPro1595 Alzheimer's KOL event
I N M B HARNESSING THE POWER OF THE INNATE IMMUNE SYSTEM Targeting Innate Immune Dysfuction XPro1595 Alzheimer’s KOL event Sept 7, 2021
Slide 2: Forward Looking Statements
F O R W A R D L OO K I NG S T A T E M E N T S This presentation contains “forward - looking statements” Forward - looking statements reflect our current view about future events . When used in this presentation, the words “anticipate,” “believe,” “estimate,” “expect,” “future,” “intend,” “plan,” or
Slide 3: Phase 1b Trial in Alzheimer's: Design and Inclusion
Design ▪ Multiple dosing cohorts ▪ Weekly XPro1595 Œ SubQ injections for 3 months ▪ Biomarkers of neuroinflammation at 0 and 12 weeks Inclusion ▪ AD Diagnosis ▪ Biomarkers of inflammation (CRP, ESR, HgbA1c, APOE4) STUDY GOAL • Demonstrate Safety • Reduce biomarkers of inflammation and neurodegenerat
Slide 4: Demographics of patients that have completed 12 weeks
Demographics of patients that have completed 12 weeks 4 0 . 3 m g / k g (N=5) XPro1595 dose 1 . 0 m g / k g (N=6) 0 . 6 m g / k g (N=5) Total ( N = 16 ) Mean Age (SD) Years 7 0 (56 - 86 ) 6 5 (60 - 71 ) 7 1 (61 - 78 ) 6 8 (56 - 86 ) Gender Male 1 3 1 5 Female 4 3 4 11 MMSE (Baseline) Mild (>21) 5 1
Slide 5: Assessing biomarkers of Neurodegeneration
TMTcalibrator Ρ analysis of human CSF with Alzheimer’s Disease brain tissue trigger White Matter Quality MRI CSF Assessing biomarkers of Neurodegeneration 5
Slide 6: Hypothesis of neurodegeneration
Neurodegeneration hypothesis of neurodegeneration – synapse white matter cell body axon m y el i n Cell body ne u r oin f lamm a tion 6
Slide 7: XPro1595 reduction of Neuroinflammation is dose-dependent
XPro1595 reduction of Neuroinflammation is dose - dependent CS F f oll ow ing 12 w ee k s of tre a tment Olink® Target 48 Cytokine 7 CCL8 OLR1 IL27 IL2 CXCL9 TGFA IL6 TNFSF12 CCL11 HGF FLT3LG IL17F IL7 IL18 CCL13 TNFSF10 CXCL10 IFNG IL10 CCL19 IL15 CCL3 CXCL8 MMP12 CSF2 CSF3 VEGFA IL17C CCL2 IL17A O
Slide 8: XPro1595 improves biological processes involved in synaptic formation and function
Mitochondrial function Axon extension and function Dendrite d e velopm e n t X P r o 1 5 9 5 i m p r o v e s b i o l o g i c a l p r o c e ss e s i n v o l v e d i n s y n a p t i c f o r m a t i o n a n d f u n c t i o n CSF f ollow i n g 12 we eks of t reatme n t Neurotransmitter regulation Synaps
Slide 9: Assessing white matter pathology – pTau217/181
A ss e ss i n g w h i t e M a tt e r p a t h o l o g y – p T a u 2 1 7 / 1 8 1 CSF fol l ow i ng 12 w e e ks of t rea t ment 9 p<0.0 0 01 p<0.01
Slide 10: Assessing white matter pathology - pTau
A ss e ss i n g w h i t e M a tt e r p a t h o l o g y - p T a u Neurofibrillary Tangle Disintegration of Microtubles T au 10
Slide 11: pT217 and pT181 detectable prior to symptom onset
Longitudinal analysis show that pT217 and pT181 are detectable prior to symptom onset and correlate with aggregated tau and Braak staging in AD Figure 1: Evolution of tau pathophysiology in mutation carriers (n=152) in the Dominantly Inherited Alzheimer Network (DIAN). 1 1 Barthélemy NR, et al. Nat
Slide 12: Assessing white matter pathology – pTau217 dose response
Assessing white Matter pathology – pTau217 dose response CSF fol l ow i ng 12 w e e ks of t rea t ment 12
Slide 13: Imaging what matters
CREATIVE HEADLINE Imaging what matters Inmune Bio Phase 1B September 7th webinar
Slide 14: Why study white matter in AD?
W HY STUDY WHITE M ATTER IN AD ? CHANGES IN WHITE MATTER MICROSTRUCTURE AXONAL LOSS DEMYELINATION LOSS OF OLIGODENDROCYTES MICROGLIAL ACTIVATION VASCULAR DEGENERATION Brun and Englund 1986; de la Monte 1989; Englund 1998; Englund and Brun 1990; Sjobeck et al. 2003; 2005; Zimmer et al . 201
Slide 15: White matter biomarkers
White Matter (WM) biomarkers + Increased EC space axons, myelin , extra - cellular water HEALTHY WM NEUROINFLAMMATION AXON LOSS & DEMYELINATION
Slide 16: Virtual biopsy: WM biomarkers
Virtual biopsy : WM biomarkers + Increased EC space axons myelin e xt r a - c ellular water HEALTHY WM NEUROINFLAMMATION AXON LOSS & DEMYELINATION
Slide 17: How? Diffusion MRI microstructure WM biomarkers
How? Diffusion MRI microstructure WM biomarkers • Diffusion is sensitive to free, restricted, hindered water • Intra / extra cellular water • Degeneration of the tissue MRI
Slide 18: Neuroinflammation – Free Water
[1] Unterberg, A. W., et al. "Edema and brain trauma." Neuroscience 129.4 (2004): 1019 - 1027. 2 Syková, Eva, and Charles Nicholson. "Diffusion in brain extracellular space." Physiological reviews 88.4 (2008): 1277 - 1340. 3 Pasternak, Ofer, et al. "Excessive extracellular volume reveals a neurodege
Slide 19: Axonal degeneration – Apparent Fiber Density
Axonal d e g e n e ration AXONAL DEGENERATION – APPARENT FIBER DENSITY 1 Adalbert, R., and M. P. Coleman. "Axon pathology in age-related neurodegenerative disorders." Neuropathology and applied neurobiology 39.2 (2013): 90 - 108. 2 Salvadores, Natalia, Mario Sanhueza, and Patricio Manque. "Axonal de
Slide 20: Demyelination – Tissue Radial Diffusivity
Loss of myelin, distorted & granulation of the myelin sheath 1 Tissue radial diffusivity 2 (RDt) is sensible to demyelination 2 M HE A L T H Y W TISSUE 2. Chad, J. A., et al. (2018). Neurobiology of Aging, 71, 161 – 170 DEMYELINATION – TISSUE RADIAL DIFFUSIVITY (RDt) heal t h y c ont r ol white matt
Slide 21: Healthy aging tissue vs AD mouse model fornix
Healthy aging tissue fornix axons myelin f r e e w a t er FW AFD RDt AD mouse model 15 month fornix Confirmed in ADNI databas with N= 36 human patients over 2 years
Slide 22: Macro-connectivity
Macr o - connectivity 160,000 km of white matter (100,000 miles)
Slide 23: Where? & Why?
W HERE ? & W HY ? - Uncinate Fasciculus - Arcuate Fasciculus - Inferior Fronto - Occipital Fasciculus - Inferior Longitudinal Fasciculus - Corpus Callosum (anterior part) - Corpus Callosum (parietal part) - Cingulum Bundles involved in the Alzheimer’s Disease neuropathology (metareview of 20+ years
Slide 24: Tractometry: Virtual dissection & biopsy
Tractometry: Virtual dissection & biospy Imaging what matters t r ac t o g r ap h y W & AFD & myelin biomarkers « T HE H OW & W HERE » I) N EUROINFLAMMATION (FW) II) F IBER DENSITY (AFD) & III ) MYELIN CONTENT (RD T ) MARKERS IN ALZHEIMER ’ S D ISEASE WHITE MATTER BUNDLES
Slide 25: INmune Bio Phase 1b trial XPro1595 longitudinal changes
Imaging what matters INmune Bio Phase1b trial XPro595 longitudinal changes (1 mg/kg dose)
Slide 26: Longitudinal FreeWater
Longitudinal FreeWater 0 3 6 18 21 24 9 12 15 Visit (months) - 60 - 50 - 40 - 30 - 20 - 10 20 10 0 30 Free - water in AD bundles (% change) XPro1595 1 mg/kg ADNI database N = 36 N = 6 N = 5 N = 5 N = 3 AD bundles - 46% X P r o1 5 95
Slide 27: Longitudinal Apparent Fiber Density
Longitudinal Apparent Fiber Density 0 3 6 18 21 24 9 12 15 Visit (months) - 10 0 - 5 5 15 10 20 Fiber Density in AD bundles (% change) XPro1595 1 mg/kg ADNI database N = 36 N = 6 N = 5 N = 5 N = 3 AD bundles +17% X P r o1 5 95
Slide 28: Longitudinal Radial Diffusivity
Longitudinal Radial Diffusivity - 20 - 5 0 5 Radial Diffusivity in AD bundles (% change) XPro1595 1 mg/kg ADNI database N = 36 N = 6 N = 5 0 3 6 N = 5 N = 3 9 12 15 18 21 24 27 30 33 36 Visit (months) AD bundles - 16% - 10 X P r o1 5 95 - 15
Slide 29: Increase in WM volume (macrostructure)
I NCREASE IN WM VOLUME ( MACROSTRUCTURE ) 0 1 2 5 00 0 5 50 0 6 00 0 6 50 0 3 6 9 Visit (months) Left Inferior Temporal volume (mm 3 ) 0.0381 0.1226 0 . 083 9
Slide 30: Summary
Summa r y x White matter microstructure degenerates with Alzheimer’s Disease x Neuroinflammation as well as axon & myelin disruption x Non - invasive advanced MRI & Imeka tools quantify where & how white matter is disrupted and rescued In Alzheimer’s Disease bundles over a 12 - month period: 1) XPro
Slide 31: Thank you! Contact us
Thank you! I N M B CONTACT US INmune Bio Inc. 980 N. Federal Hwy, Suite 110 Boca Raton, FL 33432 (858) 964 - 3720 www.inmunebio.com Questions?