1
HARNESSING THE POWER OF PRECISION MEDICINE TO TREAT ALZHEIMER’S AND OTHER NEURODEGENERATIVE DISEASES
TorontoStockExchange(TSX)ticker:PMN.TOU.S.OTCQBticker:ARFXF
January23,2018
Forward Looking Statement: Safe Harbor
This slide deck may contain certain forward-looking information. Such information involves known and unknown risks, uncertainties and other factors that may cause actual results, performance or achievements to be materially different from those implied by statements herein, and therefore these statements should not be read as guarantees of future performance or results. All forward-looking statements are based on the Company’s current beliefs as well as assumptions made by and information currently available to it as well as other factors. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this slide deck. Due to risks and uncertainties, including the risks and uncertainties identified by the Company in its public securities filings available online at www.sedar.com. Actual events may differ materially from current expectations. The Company disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
2
Investment highlights
• ProMIS is developing a portfolio of disease modifying therapies in neurodegenerative diseases, including Alzheimer’s disease, based on our proprietary discovery platform
- Neurodegenerative diseases a high priority area for large pharma licensing and acquisition
• ProMIS lead programs are following a “best in class” strategy targeting amyloid beta in Alzheimer’s disease, with advantages over ”first in class” therapy from Biogen (aducanumab)
• Listed on the TSX, ticker symbol PMN.TO. Listed on U.S. OTCQB, ticker symbol ARFXF and pursuing U.S. NASDAQ listing in 2018
• Highly experienced management team
3
The potential value of Biogen’s aducanumab is gaining wide recognition…good news in Alzheimer’s…and a rising tide for ProMIS
4
• Goldman Sachs Buy Biogen 08/16/17 “$12B peak sales estimate”
• Morgan Stanley Upgraded to OW Biogen 10/05/17 “Alzheimer’s Disease Remains a Must-Own Catalyst”
• RBC Initiate Biogen SP 09/14/17 “theoretical total market size could be $25B in U.S. alone...65% probability of success for aducanumab”
• Jeffries Initiates Coverage 07/10/17 “estimates odds of aducanumab success at 60%”
• Evaluate Pharma June 2017 “Aducanumab the highest NPV program in all industry” pipelines, Estimates NPV of $10B”
Biogen’s aducanumab is a good bet to be the first disease modifying therapy in Alzheimer’s…
• First ever amyloid beta targeted therapy with positive Phase 2 data, in December 2014
- ProMIS programs inspired by its success
• Biogen presented positive three year follow up data in November 2017 –still slowing disease progression
• Pivotal trials ongoing, data likely available in H1 2020
• ProMIS has generated scientific evidence supporting aducanumab’s superiority over prior failed therapies
5
6
The three largest products in industry history were not first in class, but “best in class” – the inventors identified improvements to existing drugs
ProMISfollowingthe“bestinclass”playbook:
• Tookadvantageof“proofofbiology”developedbyearlierproducts:thescientificrationaleforaducanumab’ssuccess,whenallpriorprogramsfailed
• UsedProMIS proprietaryscienceplatformtodesignanimprovedproduct,whichmayyieldsuperiorclinicalresults
Lipitor Humira Sovaldi/Harvoni (Pharmasset)Cholesterol RA,Crohn’s HepatitisC1996 2003 2014
PeakSales$BB’s
$12BB$16BB
$25BB
7
There is a scientific framework for understanding clinical performance of existing therapies…..and the rationale for ProMIS potential advantages
TherapeuticPotency
Drugdeliveredtothepathogen
Bindingtothepathogen?
Avoidsideeffects,dosehigh
Avoidtargetdistraction
Aducanumab
PMN310
X ++ ++
+++ +++ +++
Sideeffect(ARIA-E)limitsdoselevel
Bindingtoplaqueormonomer“wastes”therapeuticammunition
Betterbindingtotoxicoligomersthanfailedclinicalprogrambapineuzumab
TargetProductProfile
Binding the right form of amyloid beta is critical: the toxic oligomer is the target
8
Aducanumab• Phase2success• ARIA-Esideeffect
Solanezumab• Phase2failure• Phase3failure
Bapineuzumab• Phase2failure• Phase3failure• ARIA-Esideeffect
MONOMERS- bindingwastestherapeuticammunition
FIBRILS(Plaque)- bindingwastestherapeuticammunition- contributestoARIA-Esideeffect
OLIGOMERS- therighttarget
PMN310• Selectivebindingto
oligomers->Expectedimprovementin
efficacy&safety
9
ARIA-E associated with both aducanumab & bapineuzumab; PMN310 lack of binding to Ab plaque deposits suggests a potential safety advantage*
Aducanumab PMN310
Plaquebinding
Vasculardepositbinding
Nobindingtoplaqueorvasculardeposits
*PMN310IgG4isotypealsocorrelatedwithlackofARIA-E
Not all oligomers are created equal… soluble low molecular weight toxic oligomers drive neurotoxicity and disease progression
• Recent findings from leading researchers show AD brain homogenates contain heterogeneous Ab aggregates dominated by high molecular weight species (>70kDa, or ~15+ “monomers”)1,2
• Neurotoxic activity resides primarily in the LMW (low molecular weight) fraction (<70 kDa)1
• This is consistent with reports from many oligomer researchers that a subset of the LMW oligomers are the most toxic oligomers (dimer, tetramer, dodecamer)1,3-7
• Importantly, purified oligomers from human brains are different and more potent than those synthesized in vitro2,4
10
1Yang,Tetal,2017,JNeurosc;2EsparzaTJetal,2016,NatureScientificReports;3Shankar,GMetal,2008,NatMed;4Jin,Metal,2011,PNAS;5Cleary,JPetal,2005,NatureNeurosc;6Lesne,SEetal,2013,Brain;7Ferreira,STetal,2015,FrontiersinCellularNeuroscience
11
HMWFraction
LMWFraction
Thyroglobulin670kDa
GammaGlobulin158kDa
Ovalbumin44kDa
Myoglobin17kDa
Evaluating soluble pooled brain extract from eight AD patients using SEC: the profile supports the existence of three main subsets of toxic oligomers
Abmonomer4.5kDa
Tetramer(4)~18kDa
Dodecamer (12)~56kDa
Dimer(2)~9.0kDa
--- ADSolubleBrainExtract
--- Molecularweightmarkers
Aducanumab is a more effective binder of “the real thing” than bapineuzumab, which may contribute to better clinical outcomes…PMN310 is best of all
12
Humanize
d PMN310
Aducanumab
Bapineu
zumab
huIgG10
10
20
30
40
50B
indi
ng R
espo
nse
(RU
)
• Bindingofantibodiestothetoxicoligomer-enrichedLMWfractionofsolublehumanADbrainextractwasevaluatedbysurfaceplasmonresonance(SPR)
• Resultsrepresentativeof2SPRrunswithextractsfrom8differentADbrains
• huIgG1=Backgroundcontrol
13
Alzheimer’s…the root cause
14
The cause of Alzheimer’s: the progressive death of neurons in the brain
1 ReviewedinBloom2014,JAMANeurol
Healthy BrainBrain with
Mild Cognitive Impairment>15M Patients in US
Brain with AD1
>5M Patients in US
The number of AD patients and associated costs are rising rapidly
• By 2050, one new case of AD is expected to develop every 33 seconds in the U.S.
• $500B Cost in the US, combining direct medical and indirect costs
• Fastest growing cause of death
Alzheimer’s disease: soluble toxic amyloid beta oligomers, not plaque, are the most neuropathogenic amyloid beta species
• SynapseabnormalitiesandmemoryimpairmentcorrelatepoorlywithplaqueburdeninhumanandmouseAD1,2
• Aβ monomersandAβ insolublefibrils(plaque)havelittleornodemonstrabletoxicityinvitroorinvivo3-5
• SolubleAβ oligomersshowthehighestdegreeofneurotoxicity6• Toxicityinprimaryneuronculturesandbrainslices3,5,7-9
• Inductionofcognitiveimpairmentinrodents3,4,10
15
1Jacobsenetal,22006,PNAS;2Brieretal,2016,ScienceTransMed;3Shankaretal,2008,NatureMed;4Clearyetal,2005,NatureNeuroscience;5Hongetal,2016,Science;6Benilovaetal,2012,NatureNeuroscience- Review;7Lacoretal,2007,JNeuroscience;8Jinetal,2011,PNAS;9Laurenetal,2009,Nature;10Balduccietal,2010,PNAS
Synaptotoxicity ofhumanAb oligomersonhippocampalneuronsinvitro75min 6h 24h 24hcontrol
Monomers Oligomers Fibrils
Normal Monomers Oligomers Fibrils
Ab speciesinjected
InvivoimpairmentofrecognitionmemorybyAb oligomers,notmonomersandnotfibrils10
Current insight about Alzheimer’s biology: prion-like toxic oligomers are the disease pathogens
16
AmyloidPlaque
AbMonomer
Ab Prion-likeneurotoxicoligomers
Non-toxicaggregates*
InductionofTauPrionFormation
&Disease
Progression
“Non-Toxic”Pathway
LowMolecularWeightOligomersDimer(2),Tetramer(4)
Dodecamer (12)
APP
Propagationofmisfolding
“Toxic”pathway
*Yangetal,2017,JNeurosc:HMWsolubleaggregatesinbrainhomogenatewithMWof70kDa– 600kDa(15– 140“monomer”equivalents)
17
Dr. Eliezer Masliah, new head of US Nat’l Institute of Aging, stressed the need for therapies targeting the toxic oligomer at the AAN1 meeting in April 2017
• “A common mechanism underlies the top 3 neurodegenerative disorders, including Alzheimer’s: monomers aggregate into oligomers that are toxic to synapses and propagate in a prion-like fashion”
• Need to target oligomers of amyloid beta, tau, alpha-synuclein … [with therapy]
• Biogen’s aducanumab is showing promise, since it targets aggregated amyloid beta [oligomers]
1AmericanAcademyofNeurology
ProMIS used its proprietary technology platform to design antibodies with advantages over prior therapies
18
Greater selectivity for the toxic oligomer (AβO)
• No monomer binding (like aducanumab), better efficacy
• No plaque binding (improvement over aducanumab), lower risk of brain edema side effect
• IgG4 (improvement over aducanumab) – lower risk of brain edema side effect
19
Product Oligomer>MonomerBinding(SPR)
NoPlaqueBinding(IHC,Dotblot)
ADBrainExtract/CSFvsCTL(SPR)
Inhibitionofinvitro
propagation
Inhibitionofinvitroneurotox
Inhibition ofinvivoneurotox
PMN310✔ ✔ ✔ ✔ ✔ ✔
PMN330✔ ✔ ✔ ✔ ✔ ✔
PMN350✔ ✔ ✔ ✔ ✔ ✔
Firstleadproduct
Secondleadproduct
Thirdleadproduct
PMN310, PMN330 and PMN350 have all shown target-selective binding and functional performance
PMN310 blocks oligomer propagation and neurotoxicity in vitro
20
Complete inhibition of oligomer propagation in vitro
0 1 0 2 0
0
2 ´ 1 00 5
4 ´ 1 00 5
6 ´ 1 00 5
I n c u b a t i o n T i m e ( h r s )
Re
la
ti
ve
F
lu
or
es
ce
nc
e
Un
it
s
A ß 4 2 + 3 0 5 - 6 1A ß 4 2
Incubationtime(hrs)
Relativ
eflu
orescenceun
its Ab42 Ab42+PMNMab
Inhibition of Ab oligomer toxicity in vitro
CTL AβO 5:1 1:1 1:2 5:1 1:1 1:240
50
60
70
80
90
100
110
120
Cel
l Via
bilit
y (%
of c
ontr
ol)
AbO + PMN mAb PMN mAb alone
(Thioflavin-based assay) (Primary mouse cortical neurons)
Normalpropagation
InhibitionbyPMNantibody
AbO +/- Mab
Novel Object Recognition Assay• Control mice remember a familiar object when re-exposed
to it and spend more time exploring a new object
• Oligomer-injected mice lose the ability to discriminate between known and novel objects and spend equivalent amounts of time exploring both
7 days
-0.2
0.0
0.2
0.4
0.6
Vehicle AβOPMN310+vehicle
PMN310+AβO
Discrim
inationInde
x
#
* *
Discriminationindex=(Timeexploringnewobject– timeexploringfamiliarobject)/totalexplorationtimeResultspressreleasedJanuary9,2017,www.promisneurosciences.com 21
N=12 per arm, *different from AβO (p < 0.05), #different from vehicle (p <0.05)
Administration of PMN310 to mice: prevents loss of short-term memory formation caused by toxic oligomers
THE RESULTSTHE EXPERIMENT
• Mice are tested for discriminating objects after brain injection of:
• Buffer (vehicle) - normal response • Toxic Aβ Oligomer• PMN310 and buffer (vehicle)• PMN310 and Aβ Oligomer
In vivo improvement of hippocampal synaptic and inflammation markers suggests cognitive benefit came from preventing neuronal death
22
Decrease in hippocampal marker of inflammation
Vehicl
eAβ
O
PMN Mab
+ AβO
PMN Mab
+ Vehicl
e0.0
0.5
1.0
1.5
TNF-α
(pg/
ug to
tal p
rote
in) TNF-a
#
*
#* #*
Vehicl
eAβ
O
PMN Mab
+ Aβ
O
PMN Mab
+ Veh
icle
2
3
4
5
6
7
8
9
PSD
-95
(pg/
ug to
tal p
rote
in)
Vehicl
eAβ
O
PMN Mab
+ Aβ
O
PMN Mab
+ Veh
icle
0
5
10
15
20
25
SNA
P25
(pg/
ug to
tal p
rote
in)PSD-95 SNAP25
#
*
#
*#
#
*
#
#*
Preservation of hippocampal synaptic proteins
*DifferentfromVehicle(p<0.05);#DifferentfromAbO (p<0.05)
Biogen’s aducanumab is the first amyloid beta-targeted therapy with positive clinical efficacy results.. Likely first in class - PMN310 scientifically designed to be best in class
23
Product Company Phase2Result
Phase3Result
MonomerBinding*
OligomerBinding*
Plaquebinding*
AntibodyIsotype
Solanezumab Lilly Failed,n=52 Failed,3trials +++ + None IgG1
Bapineuzumab J&J,Pfizer Failed,n=234 Failed ++ ++ +++ IgG1
Verubecestat Merck Noefficacyreadout,n=200
Failed DepletesMonomer
N/A N/A N/A
Crenezumab Roche Failed, n=450 Ongoing at4xdoseofPh2
+ ++ +++ IgG4
Gantenerumab Roche Failed Stoppedenrolling
+ ++ +++ IgG1
Aducanumab Biogen PositiveEfficacyn=166
Ongoing,expected2020
None +++ +++ IgG1
PMN310,330,350 ProMIS Ontrackfor2021
None +++ None IgG4
*Source:AndreUddin,MackieResearch
24
There is a scientific framework for understanding clinical performance of existing therapies…..and the rationale for ProMIS potential advantages
TherapeuticPotency
Drugdeliveredtothepathogen
Strengthofbindingtothepathogen
Avoidsideeffects,dosehigh
Avoidtargetdistraction
Bapineuzumab
Aducanumab
PMN310
X
X
X
++
+
++
+++ +++ +++
Thisprofileledtofailure….
Thisprofilewilllikelyleadtoapproval….
PMN310profilemayleadtosuperiorityand”BestinClass”
25
Getting more antibody to the target: properties of PMN310 support improved therapeutic potency versus other Ab-directed antibodies
LMW ToxicOligomers
Plaque
Monomers
Aducanumab
HMW AggregatesBapineuzumab
• Greater specificity for toxic oligomers –> No target distraction, greater efficacy
• Reduced risk of ARIA-E –> Ability to dose higher
huPMN310
26
ProMIS Neurosciences pipeline: Output of a highly productive discovery engine
ProductCandidate
Target Protein
Disease Area Focus Discovery Pre-Clinical Phase I
PMN310 Toxic Amyloid βOligomers Alzheimer’s1
PMN350 Toxic Amyloid βOligomers Alzheimer’s1
PMN330 Toxic Amyloid βOligomers Alzheimer’s1
In Process Tau Protein Alzheimer’s2
PMN110PMN120PMN130
Superoxide Dismutase-1 (SOD1)
Amyotrophic Lateral Sclerosis
(ALS)
Under Evaluation
TAR DNA-Binding Protein 43 (TDP43)
Amyotrophic Lateral Sclerosis
(ALS)3
In Process alpha synuclein Parkinson’s Disease4
ProMIS leadprograms:abestinclassstrategyinAlzheimer’s
1 PotentialuseinDownsyndrome2 Potentialuseinotherdementias,eg.chronictraumaticbraininjury3 Potentialuseinfrontotemporaldementia4 PotentialuseinLewybodydementia
27
ProMIS value creation potential – medium term
2018 2019 H12020
Aducanumabpivotaldatapublic
PMN310ScientificDifferentiation;INDenabling PMN310Phase1SAD
Potentialpartnering– othertargets:TDP43,SOD1,alphasynuclein,tau
Diagnosticsdevelopment,collaborations
Aducanumab pivotaltrials
ProMIS Neurosciences: summary
• Developing “best in class” therapies targeting the root cause of Alzheimer’s and other neurodegenerative disease
• ProMIS proprietary technology platform is generating additional differentiated products in dementia, ALS, and Parkinson’s disease; potential partnering opportunities
• Numerous near term catalysts • Lead product PMN310 in Alzheimer’s disease on track to
• Further confirm differentiation from likely “first in class” Biogen’s aducanumab• Initiate clinical trials in 2019 and• Potentially superior clinical data vs aducanumab
ProMIS pursuing NASDAQ listing, likely in 2018
28
Thank You
Eugene Williams, Executive [email protected]+1 (617) 460-0978
Website: www.promisneurosciences.comTwitter: https://twitter.com/ProMISincLinkedIn:https://www.linkedin.com/company/promis-neurosciences
We appreciate your interest in ProMIS Neurosciences and the exciting developments in AD therapeutics. Please feel free to contact us with any additional questions.
Elliot Goldstein, MD, [email protected]+1 (415) 341-5783
29
Investor Relations Contact:Nick Rigopulos, PresidentAlpine Equity [email protected]+1 (617) 901-07856
Name
30
Experienced leadership team
24
Prior ExperienceTitle Years of Experience
Executive Chairman
CEO
Chief Science Officer
Chief Physics Officer
CFO
Chief Development Officer
25+
25+
25+
20
25+
25+
§ Former SVP at Genzyme, with senior roles integrating commercialization, drug development, and deal making
§ Recently the CEO of Dart Therapeutics, an Orphan Disease drug development company
§ Founder and director of Adheris, which became the largest company in the patient adherence/compliance area
§ Held positions as SVP of Strategic Product Development at SmithKline Beecham (now GSK)
§ Chief Operating Officer and Chief Medical Officer of Maxygen§ Chief Operating Officer at DART Therapeutics
§ Holds the Canada Research Chair in Neurodegeneration and Protein Misfolding Diseases,
§ Serves as the Director of the University of British Columbia ALS Centre,
§ Awarded the Jonas Salk Prize for biomedical research in 2000
§ Professor at UBC in the Department of Physics and Astronomy since 2001§ Appointed as the Canada Research Chair in Theoretical Molecular Biophysics§ Associate member of the Genome Sciences and Technology Program, the
Bioinformatics Program, and the Institute for Applied Mathematics at the University of British Columbia
§ Founding Managing Director of Danforth Advisors§ Served as the Chief financial officer of Homology, Inc, GenePeeks,
Inc., Transkaryotic Therapies, Inc., Cidara, Inc., Apellis, Inc. and Stealth BioTherapeutics, Inc.
§ Former VP of Research at Genzyme§ Associate Immunopathologist at SmithKline Beecham where she
established an Immunotoxicology program§ Her work has resulted in over 60 scientific publications and
multiple patents
Gene Williams
Elliot Goldstein
Neil Cashman
Steven Plotkin
Dan Geffken
Johanne Kaplan
NameAnthony Giovinazzo
Richard Gregory
Bill Wyman
Johannes Roth
Pat Kirwin
31
Independent board of directors
25
Prior ExperienceYears of Experience25+
25+
15+
§ President and CEO of Sunovion CNS Development Canada ULC
§ President, CEO and a Director of Cynapsus Therapeutics from 2009 to 2016 and one of the three original inventors and patent holders of the company’s Parkinson’s focused technology
40+
§ Chief Scientific Officer & Executive VP for Research at ImmunoGen
§ Held a variety of roles at Genzyme and Sanofi-Genzyme, including Vice President for Gene Therapy, Head of Corporate Research and Head of R&D
§ Co-founded the management consulting firm, Oliver Wyman & Co
§ Former President of the Management Consulting Group called Booz Allen and Hamilton
§ Founding director and partner at FiveT Capital Holding AG§ A board member of Insilico Biotechnology AG
§ Senior partner at Kirwin LLP§ Advises and represents businesses in a range of industries and
sizes from local to multinational30+
Name
32
Scientific/business advisory board
26
Prior ExperienceYears of Experience
ScientificAdvisoryBoard(SAB)
BusinessAdvisoryBoard
Todd Golde, MD, PhD.
Lary Walker, PhD.
Bill Mobley, MD, PhD.
§ Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida
§ Associate Professor of Neurology and Research Professor at Emory University Yerkes National Primate Research Center
§ Dean for Neurosciences Initiatives, Distinguished Professor of Neurosciences, and Florence Riford Chair for Alzheimer Disease at the University of California, San Diego
Mara Aspinall, MBA § Executive Chairman of GenePeeks§ Former President and CEO of Ventana Medical Systems, a division of
Roche Group, a worldwide leader in the development and commercialization of tissue-based cancer diagnostics
Nigel Burns, PhD. § CEO and Founder of SweetSpot Therapeutics Ltd§ Served as Senior Vice President of Cambridge Antibody Technology
Michael Higgins, MBA § Currently an Entrepreneur-in-residence at Polaris Partners§ Previously at Genzyme, served as Vice President of Corporate Finance
and Vice President of Business Development, and was involved with multiple business units, including Cell Therapy, Gene Therapy and Orphan Diseases
25+
20+
25+
25+
25+
20+
“Restart”July 2015
May 2016
Sep 2016
$25MM
$10MM
$2MM$2.5MM at $2MM Pre
$1MM at
$9MM Pre
$1.5MM at
$24MM Pre
Financial Status
• Cash life into H2 2018
• Common stock – 220,058,533
• Warrants – 24,708,098
33
ProMIS has successfully raised $12.5MM in 5 rounds, at increasing values
23
$2.7MM at
$26MM Pre
Feb 2017
$4.8MM At
$50 MM Pre
$50MM
Sep 2017