HARNESSING THE POWER OF THE INNATE IMMUNE SYSTEM Modulating an Innate Immune Response Against Diseases INMB CORPORATE PRESENTATION Aug 2020
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INVESTMENT SUMMARY Immunology company, advancing through Phase I and Phase II clinical trials ▪ Catalyst rich programs with multiple readouts in 2020 and 2021 ▪ Two platforms with novel approaches targeting the innate immune system ▪ DOMINANT NEGATIVE TUMOR NECROSIS FACTOR (DN-TNF) PLATFORM First dominant-negative protein to enter clinic selectively targeting inflammation without immunosuppression NK CELL PRIMING PLATFORM INKmune primes patient’s NK cells to eliminate residual disease Over 65 publications from multiple universities worldwide on both platforms with extensive in vivo data ▪ Notable shareholder and director, Xencor ▪ Insiders own ~50% ▪ 3
PIPELINE Focused on Developing Therapies that Target the INNATE IMMUNE System DN-TNF PLATFORM DISEASE FIELD PRE-CLINICAL PHASE I PHASE II (POC) PIVOTAL EST. NEXT MILESTONE 1H-21 Trastuzumab Resistance initiate p2 ONCOLOGY 1H-21 NASH Initiate p2 GI 2H-20 Alzheimer’s Disease Complete p1 CNS 3Q-20 COVID-19 Initiate p2 NK PRIMING DISEASE FIELD PRE-CLINICAL PHASE I PHASE II (POC) PIVOTAL NEXT MILESTONE PLATFORM 1H21 Ovarian initiate p1 CANCER 2H20 Myelodysplastic Syndrome Initiate p1 ONCOLOGY 4
DN-TNF PLATFORM T E C N O L O G Y NEXT GENERATION TNF INHIBITOR -SAFER AND SELECTIVE TO TARGET MARKETS EXISTING TNF INHIBITORS MUST AVOID 5
TUMOR NECROSIS FACTOR (TNF) The “Master” Cytokine LCN2 PRO-INFLAMATORY ANTI-INFLAMATORY IL 6 sTNF promotes translation ▪ of IL6, Lipocalin 2 and other downstream cytokines sTNF Plasma Concentration Block sTNF and ▪ downstream pro- inflammatory cytokines do not occur Time Adapted from Andreasen et al 2008 6
THE BIOLOGY OF CURRENT TNF INHIBITORS X Current Inhibitors Are Not Selective and Block Both Forms of TNF Negative effects of TNF are a result of sTNF WHEREAS tmTNF X X Transmembrane-bound Soluble TNF (‘sTNF’) PROVIDES (‘tmTNF’) GOOD BAD IMMUNOSUPPORTIVE AND NEUROPROTECTIVE FUNCTION IMPORTANT TO HOST SURVIVAL TNFR2 TNFR1 Internalization Adapted from MacEwan et al 2002 7
TNF BIOLOGY. HOW DN-TNF WORKS DIFFERENCES: DN-TNF Neutralizes ONLY Soluble TNF and Leaves Transmembrane TNF Selective vs. and the Receptors Functional Non-Selective TNF Inhibition DN Non- Selective TNF Decreases Y Y “BAD” sTNF with DN-TNF Only “GOOD” tmTNF continues to inflammation does not bind to receptors bind to TNFR1 and TNFR2 Increased risk Y N of infection Increased risk Y N of cancer Causes Y N demyelination TNFR1 TNFR2 TNFR1 Neuroprotective N Y Internalization Enhances N Y neuroplasticity Adapted from MacEwan et al 2002 8
SELECTIVE TARGETING FUNCTIONAL tmTNF PREVENTS PREVENTS DEMYLINATION IMMUNOSUPPRESSION Non-selective TNF Inhibition Causes Demyelination, Non-selective TNF Inhibition Causes Immunosuppression DN-TNF Promotes Remyelination CUPRIZONE Model of Multiple Sclerosis % Survival DN-TNF ETANERCEPT Anti-inflammatory NOT Anti-inflammatory AND immunosuppressive immunosuppressive Days Post-Infection REMYELINATION 9
Clinical Trial to Test Neuroinflammation as the Common Denominator of ALZHEIMER’S DISEASE 10
sTNF A VALIDATED TARGET IN ALZHEIMERS DISEASE RISK OF ALZHEIMER’S DISEASE IN MAN Risk of general population Adapted from Chou et al. 2016 8.5M claims AD risk is not reduced by other anti-inflammatory treatments Despite positive AD activity, non-selective TNF inhibitors increase the risk of cancer, infection, and MS 11
PHASE 1 AD TRIAL IMMUNOLOGIC BIOMARKERS Phase IB trial in Alzheimer’s patients with biomarkers of inflammation BEHAVIORAL BIOMARKERS OF INFLAMMATION SLEEP DISORDERS DEPRESSION PSYCHOSIS APATHY AGGRESSION DESIGN BIOLOGICAL BIOMARKERS OF INFLAMMATION 18 patients in 3 cohorts ▪ Weekly XPro1595™ SubQ injections for 3 months ▪ Biomarkers of inflammation at 0, 6, 12 weeks ▪ MRI INCLUSION Must have 1 inflammatory biomarker (local lab): FreeWater content of white matter ▪ hsCRP>1.5 ▪ ESR>10 CSF ▪ HbA1C >6% BLOOD ▪ APOE4 positive Inflammation & Inflammation & Neurodegeneration Neurodegeneration ( Roche NeuroTool kit ) ( Roche NeuroTool kit ) ENDPOINTS ▪ Safety BREATH ▪ Change in inflammation (blood, CSF , Brain, breath, behavior) Volatile Organic Compounds ▪ Change in neuropsychiatric symptoms, cognition, QOL 12
WHITE MATTER FREE WATER A Biomarker For Neuroinflammation Free water = edema/swelling = inflammation
WHITE MATTER FREE WATER: A Biomarker For Neuroinflammation White Matter Free Water WMFW - sex and age matched NC and AD subjects Normal aging AD From Dumont 2019 14
NEUROINFLAMMATION CONTINUES TO INCREASE OVER TIME AND CORRELATES WITH CHANGES TO AMYLOID Dumont et al Descoteaux Frontiers in Aging Neuroscience 2019
NEUROINFLAMMATION – FREE WATER WHITE MATTER Measure Inflammation in specific white matter tracts Measures Whole brain inflammation Inferior longitudinal fasciculus , Uncinate fasciculus Arcuate fasciculus Uncinate fasciculus , Inferior fronto-occipital fasciculus , Safe White Matter Mask Splenium of the corpus callosum , Inferior longitudinal fasciculus
XPRO1595 REDUCES WHOLE BRAIN NEUROINFLAMMATION
XPro1595 reduces neuroinflammation within the
Arcuate Fasciculus Premotor cortex Broca’s area Wernicke's area The arcuate plays a key role in language processing – the ability to understand or express speech
SUMMARY ▪ Neuroinflammatory biomarkers assessed by free water white matter in 6 AD patients ▪ N=3 at 0.3 mg/kg of XPro1595 ▪ N=3 at 1.0 mg/kg of XPro1595 ▪ Dose- dependent reduction in whole brain neuroinflammation (“safe mask free water”) ▪ A more focused analysis shows a 40.6% reduction neuroinflammation within the Arcuate Fasciculus – dose independent.
Clinical Trial to Determine if Targeting Soluble TNF (sTNF) may Prevent Catastrophic Complications of COVID-19 21
BLUNTING CYTOKINE STORM AND HYPERINFLAMMATION TNF levels elevated in COVID-19 Patients ▪ Cytokine storm caused by increase expression of sTNF , 250 IL1, and IL6 ▪ sTNF significantly elevated in blood of patients 200 ▪ Neutralizing sTNF should decrease expression of IL1 and IL6 150 ▪ Ideal therapy has 5 characteristics: ▪ Safe and well tolerated 100 ▪ Not immunosuppressive 50 ▪ Easy to use Normal TNF level ▪ Rapid onset <10pg/ml 0 *p<0.05 Non-ICU ICU ▪ Targets inflammation Diao2020 22
Endothelial cell inflammation: the real “villain” in C19? • sTNF activates endothelial cells to upregulate Tissue Factor • Tissue Factor causes blood clots • Clots can block blood vessels in: • Lungs • Kidneys • Brain • Heart • more From McGonagle Lancet 2020 23 BTIG FireSide Chat August 10, 2020
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