Focus on CNS Drug Development
Treating secondary progressive multiple sclerosis
Simon Wilkinson, CEOForward Looking Statements
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.
• 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
(Source: MedicineNet, Inc)
• 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
pro-inflammatory 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.
Is Multiple Sclerosis and CNS disease?
• Progressive MS is now largely viewed as a neurodegenerative disorder.
• The pathologic role of myeloid derived innate immune cells in
neuro-degenerative 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.
• 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 debris1.
– secrete important tropic factors that can directly promote neuronal survival and axon regeneration2,3,4.
Myeloid cells play an important role in CNS disorders
1. Kotter MR et al. 2006. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci. 26, 328–332
2. Butovsky O et al., 2006. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Molec. Cell. Neurosci. 31, 149–160
3. Rolls A et al., 2008.Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 5, e171.
4. Kuo HS et al., 2011. 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, 4137–4147
The Journal of Neuroscience,
July 8, 2015
– 35(27):9966-9976
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.
• 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)
MIS416 2.0 x 0.5 micron rod shaped microparticle
Introducing MIS416 – a MYELOID targeting immune modulator
• The targeted cells have an anti-inflammatory effect inside the
CNS and have also been shown to:
– support myelin repair by clearing myelin debris
– secrete important tropic factors that can directly promote neuronal
survival and axon regeneration
Tolerogenic DC Alternate/non classical/M2 macrophage Bone marrow-derived monocyte IL-10 TGFb IL-27 sTNFR sIL-1R Pro-inflammatory mechanisms Arginase IDO Anti-inflammatory/tolerance mechanisms IL-12p70 IL-1b TNFa MHC I/II CD80/86 NO
MIS416 effect on cellular and soluble anti-inflammatory pathways
Upregulation following MIS416 treatment: in Mouse in Human under investigation PDL-1 ? ? ? 8
1 2 3 4 5 6 7 8 9 10 0
100 200 300
sample number (arbitary)
V E G F (p g /m L )
Vascular Endothelial Factor
Baseline (pre-treatment) 24 hr post dose 1 2 3 4 5 6 0 100 200 300 400 500
sample number (arbitary)
IG F -1 (p g /m L )
Insulin Growth Factor-1
Baseline (pre-treatment) 24 hr post dose 1 2 3 4 5 6 7 8 9 10 11 12 0 200 400 600
sample number (arbitary)
H G F (p g /m L )
Hepatocyte Growth Factor
(Baseline) pre-treatment 24 hr post dose 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 0 2000 4000 6000 8000 20000 40000
sample number (arbitary)
E P O (p g /m L ) Erythropoietin pre-treatment 24 hr post dose A selection of phase 1B and 2A patient plasma samples were analysed to screen for the induction of factors
associated with neuroprotection.
Data are shown from examples that showed a clear response for a given factor Samples are assigned
arbitrary sample numbers
Phase 2B trial in SPMS – a clinical “Proof of Platform”
• 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
MIS416 - A CNS REPAIR “PLATFORM”
• 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
Post Phase 2B – path to market for SPMS
• 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
Post Phase 2B – path to market for SPMS
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: <http://tinyurl.com/fb141202>
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.
www.innate
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Australian Securities Exchange (ASX) ticker - IIL
