Focus on CNS Drug Development Treating secondary progressive multiple sclerosis. Simon Wilkinson, CEO

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1 Focus on CNS Drug Development Treating secondary progressive multiple sclerosis Simon Wilkinson, CEO

2 Forward Looking Statements 2 This Presentation (and any financial information that may be provided by Innate Immunotherapeutics Limited - the Company ) may contain forward looking statements that involve risks and uncertainties. Such statements include statements regarding the Company s belief or current expectation and are necessarily based on the Company s current understanding of the markets and industries in which it operates. That understanding could change or could prove to be inconsistent with actual developments. The Company s actual results could differ materially from the results discussed in this Presentation, including those anticipated in or implied by any forward looking statements.

3 What is multiple sclerosis? (Source: MedicineNet, Inc) The myelin sheath protecting the nerve fibers inside the CNS is damaged by a likely combination of both autoimmune and neuro degenerative processes This triggers inflammatory pathology that causes further damage In early disease, myelin is fully or partially repaired Over time, scar-like plaque builds up around damaged axons inhibiting repair 3

4 Is Multiple Sclerosis and CNS disease? 4 Until recently most market discussions about multiple sclerosis have focused on the early stage relapsing-remitting course of the disease. In early MS, relapses are largely mediated by auto-reactive proinflammatory adaptive immune cells crossing the blood brain barrier and attacking the myelin sheath an autoimmune process or disease. In spite of drugs designed to block, or sequester, or divert such autoimmune activity, within 20 years ~70% of RRMS patients transition to a progressive stage of disease where deficits steadily accumulate in the absence of relapses and existing RRMS drugs become ineffective. Progressive MS is now largely viewed as a neurodegenerative disorder. The pathologic role of myeloid derived innate immune cells in neurodegenerative disorders is well understood. However we now know that both macrophages and microglia can also play vital roles limiting inflammation & promoting tissue repair in CNS disorders including progressive MS.

5 Myeloid cells play an important role in CNS disorders 5 This myeloid cell bi-polar behaviour is essential so that an immune response can adapt according to the stage, severity, location, & type of disease. Peripherally derived macrophages, and the CNS equivalent microglia cells, can be activated or polarised towards either a M1 inflammatory phenotype or a M2 anti-inflammatory phenotype. In addition to being anti-inflammatory within the CNS, M2 macrophages and microglia have been shown to: support myelin repair by clearing myelin debris 1. secrete important tropic factors that can directly promote neuronal survival and axon regeneration 2,3,4. 1. Kotter MR et al Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci. 26, Butovsky O et al., Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Molec. Cell. Neurosci. 31, Rolls A et al., 2008.Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 5, e Kuo HS et al., Acid fibroblast growth factor and peripheral nerve grafts regulate Th2 cytokine expression, macrophage activation, polyamine synthesis, and neurotrophin expression in transected rat spinal cords. J. Neurosci. 31,

6 The Journal of Neuroscience, July 8, (27): Significance Statement There is a growing appreciation that macrophages exert diverse functions in the injured and diseased CNS. Indeed, both macrophage-mediated repair and macrophage-mediated injury occur, and often these effector functions are elicited simultaneously. Understanding the mechanisms governing the reparative and pathological properties of activated macrophages is at the forefront of neuroscience research.

7 Introducing MIS416 a MYELOID targeting immune modulator 7 MIS416 is a highly purified microparticle derived from the naturally occurring bacteria P. acnes MIS416 reliably, safely, and uniquely targets myeloid cells MIS416 targeted myeloid cells: Increase in number switch activity from pathogenic to reparative traffic into the CNS (past the blood brain barrier) The targeted cells have an anti-inflammatory effect inside the CNS and have also been shown to: support myelin repair by clearing myelin debris MIS x 0.5 micron rod shaped microparticle secrete important tropic factors that can directly promote neuronal survival and axon regeneration

8 MIS416 effect on cellular and soluble anti-inflammatory pathways 8 Tolerogenic DC Bone marrow-derived monocyte Alternate/non classical/m2 macrophage IL-10 TGFb IL-27 stnfr PDL-1?? Arginase IDO IL-12p70 IL-1b TNFa MHC I/II CD80/86 NO sil-1r Anti-inflammatory/tolerance mechanisms Pro-inflammatory mechanisms Upregulation following MIS416 treatment: in Mouse in Human under investigation?

9 MIS416 effect on tropic factors associated with CNS protection/repair 9 VEGF (pg/ml) Vascular Endothelial Factor Baseline (pre-treatment) 24 hr post dose sample number (arbitary) EPO (pg/ml) Erythropoietin pre-treatment 24 hr post dose sample number (arbitary) A selection of phase 1B and 2A patient plasma samples were analysed to screen for the induction of factors associated with neuroprotection. IGF-1 (pg/ml) Insulin Growth Factor-1 Baseline (pre-treatment) 24 hr post dose HGF (pg/ml) Hepatocyte Growth Factor (Baseline) pre-treatment 24 hr post dose Data are shown from examples that showed a clear response for a given factor Samples are assigned arbitrary sample numbers sample number (arbitary) sample number (arbitary)

10 Phase 2B trial in SPMS a clinical Proof of Platform 10 Double blinded, placebo controlled 12 month trial of MIS416 in 90 patients 2:1 randomisation, once weekly 500 mcg i.v. injection of MIS416 or saline Baseline, quarterly, and end of dosing (EoD) clinical assessments including: Hand/arm function & strength, cognition, visual acuity, fatigue, MSFC and EDSS Patient reported outcomes: SF-36, pain (BPI), and fatigue (NFI-MS) Baseline, month 3 & EoD MRI (whole brain atrophy and magnetization transfer ratio) 45 patients (50% of the target 90 patients) are now enrolled, consented or in washout period (for previous RRMS drugs) enrolment is on going

11 MIS416 - A CNS REPAIR PLATFORM 11 Turning off inflammation, removing tissue debris, supplying repair and protective factors, are all criterial functions of the innate immune system relative to repairing tissue damage inside the CNS, whether the damage is caused by trauma or certain diseases. The presence of inflammation inside the CNS, as a consequence of certain other diseases, can amplify disease damage and/or lessen the effectiveness of disease modifying therapies. Activating the regulatory functions of the innate immune system to switch off inflammation inside the CNS makes sense especially when anti-inflammatory drugs can t cross the blood-brain barrier and access the CNS! If MIS416 works in patients with SPMS, a disease where there is both tissue damage (the myelin) and ongoing inflammation inside the CNS, then MIS416 becomes a platform to be used in other conditions or diseases requiring these critical CNS repair tools Further announcements can be expected within the next 8-12 weeks

12 Post Phase 2B path to market for SPMS 12 There are no effective drugs approved to treat SPMS Approval of a drug for SPMS could be reviewed under FDA s Expedited Programs for Serious Conditions Pharma with existing drugs for early stage MS (RRMS) are actively seeking drugs to treat SPMS Biogen s RRMS drug Tecfidera sold US$3b in 2014 following approval part way through 2013 Upon completion of Phase 2B (2016) Innate s strategy is to license / sell to large Pharma company Potential Target Partners or Acquirers

13 Post Phase 2B path to market for SPMS 13 What does a partnering deal look like in SPMS? December 2014: Servier paid US$47 million option fee to fund Phase 2B trial of GeNeuro s blocking antibody to supposed MS-associated retrovirus Received option to the non-us territorial rights tied to a $408 million package of milestones N.B. The non-us territory accounts for about ~25% of global MS drug revenues Also option buy an equity stake sometime in 2015 See announcement: < LATE BREAKING NEWS Celgene to acquire Phase 3 MS company Receptos for US$7.2 billion cash Deal has ranked Receptos #1 for the most value created by any biotech in the last 10 years.

14 Thank you Two clinical trial patients talk about their ongoing experience with MIS416: Simon Wilkinson, CEO or tel Australian Securities Exchange (ASX) ticker - IIL

Bioshares Investment Summit Presentation

ABN 16 165 160 841 ASX RELEASE 20 JULY 2015 Bioshares Investment Summit Presentation Innate Immunotherapeutics' CEO Mr. Simon Wilkinson gave a presentation (attached) at the 2015 Bioshares Investment Summit