Jefferies Healthcare ConferenceNew York, NYJune 7, 2019

Treating Neurodegenerative Disease by Reversing Synaptic

Dysfunction

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Company Overview

Clinical-stage therapeutics company focused on treating neurodegenerative diseases through blocking effects of inflammation on the synapse• Builds on new scientific

understanding around synaptic dysfunction, the pathogenic driver in the early clinical stages of neurodegenerative disease

Developing neflamapimod for Alzheimer’s disease (AD) : potent, highly specific inhibitor of p38α kinase • Most advanced oral drug targeting

synaptic dysfunction in AD

• Positive Phase 2a results published in April 2018 demonstrating potential for improving episodic memory function in patients with AD

• Phase 2b clinical study fully enrolled, with results expected in Q4’19

Phase 2 studies in Huntington’s disease and dementia of Lewy bodies planned for 2019

Raised $31.2M since March 2018

Based in Cambridge, MA; launched in 2014 by experienced R&D executives

NEW NEWNEW

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At the Forefront of a Fundamental Shift in the AD Field

disease understanding• Progression of pathology

in relation to clinical expression of disease

• Amyloid plaque build-up starts years before onset of clinical symptoms

scientific understanding• Target mechanisms

underlying inflammation-induced synaptic dysfunction in the hippocampus that is driver of disease in early clinical stages

regulatory policy• Provides framework for

developing drugs in early-stage AD

• Improvement of cognition is a clinical benefit

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Why Target Synaptic Dysfunction?

• Progressive deterioration of synaptic function and structure constitutes major driver of the early clinical stages of neurodegenerative disease– Neuronal loss occurs in later stages of neurodegenerative process and

represents the end stage of neurodegeneration

• Synaptic dysfunction is a convergence point for initiation and establishment of the neurodegenerative process, regardless of the “cause”

• Synaptic dysfunction is responsive to therapeutic intervention in animal models

+BENEFICIAL

EFFECTS

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Inflammation in the Brain Is Key Driver of Synaptic Dysfunction in AD

Amyloid Plaque Clearance in Alzheimer’s Disease

Synaptic Dysfunction

Neurodegeneration

NEUROINFLAMMATION-

DELETERIOUSEFFECT

Synaptic Dysfunction leading to Episodic Memory Deficits

Over time, synaptic loss and neurodegeneration

• Aging• Amyloid-beta, tau• ApoE4• Mitochondrial dysfunction

Hippocampal Neuron

Recent Mechanistic Understanding of Hippocampal Synaptic Dysfunction

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INFLAMMATORYSTRESS

Stress-activated intracellular

response

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P38α Inhibition Reverses Synaptic Dysfunction and Restores Cognitive Function

• p38α antagonist reverses inflammation (IL-1β) or amyloid-beta (Aβ) induced impairment of hippocampal synaptic plasticity in vitro(Li et al, 2011; Koppensteiner et al, 2016; Prieto et al, 2015)

• In animal models:- Chemical inhibitor reversed Aβ induced synaptic dysfunction and loss (Watterson et al, 2013;

Munoz et al, 2007) - p38α gene knockout in neurons improves synaptic function, memory function and reduced

amyloid-beta production in Alzheimer’s transgenic mice (Colié et al, 2017, Schnoder et al, 2016) - Three different p38α small molecule inhibitors reversed spatial learning deficits in transgenic

Alzheimer’s mice, aged tauopathy mice, and aged rats, respectively (Roy et al, 2015; Maphis et al, 2016; Alam, 2016)

CO

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Drug that both restores cognitive function and slows decline

6 months after start of treatment

Drug that only slows cognitive decline

Placebo or no treatmentStart Treatment

TimeDiagnosis 18 months

Reversing Synaptic Dysfunction Provides Ability to Demonstrate Proof-of-Concept in Six Month Clinical Study

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Neflamapimod: Oral, Potent p38⍺ Kinase Inhibitor

Brain penetrantBrain tissue concentration two-fold higher than in blood

Crystal structure of neflamapimod bound to p38⍺ protein

(2.4 nM binding potency)

Chemical structure of neflamapimod (aka VX-745)

Duffy et al, 2011

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Neflamapimod Development Status

• Completed long-term animal toxicity studies– At 40 mg twice daily in humans, >5-fold safety margin to no-adverse-event

level in animal toxicity studies • Clinical safety data in ~175 healthy volunteers and patients

– Liver enzyme elevation dose-limiting in the clinic; seen at 10-15% incidence at doses ≥ 250 mg twice daily for 3 months

• 6-week to 12-week Phase 2a clinical studies in patients with early AD completed in 2017

– 40 mg twice daily identified as optimal dose for AD

• 161-patient Phase 2b clinical study in patients with early AD ongoing; enrollment complete, with results in Q4’2019

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Neflamapimod Reverses Inflammation-Induced Synaptic Dysfunction in Preclinical Models

Improvement in Neurologic Function in Rats after Ischemic Stroke

Journal of Alzheimer’s Disease, 2015; 48:219-27 American Academy of Neurology meeting, 2016

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Reversal of Cognitive Deficits in Morris-Water-Maze Test in Aged Rats

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Week 4 Week 6

** *** Vehicle Control

Neflamapimod1.5 mg/kg

Neflamapimod4.5 mg/kg

** p < 0.01

*** p < 0.001

Neu

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delta

(Day

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Treatment Day

Vehicle-treated Aged Rats

Neflamapimod-treated Aged Rats

Vehicle-treated Young Rats

*p=0.007 neflamapimod-vs. vehicle-treated aged rats

Robust Early Alzheimer’s Disease Phase 2a Program

• MCI or mild AD• PET amyloid (+)• MMSE 21 to 27• 16 patients

Study 302

• MCI or mild AD• Episodic memory

defect at entry• MMSE 20 to 28• 9 patients

Study 303

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12 WEEK TREATMENT 40 mg or 125 mg twice daily

6 WEEK TREATMENT 40 mg twice daily

Endpoints• Amyloid plaque

by PET scan• Wechsler Memory

Scale (WMS)

Endpoints• CSF inflammatory markers• Hopkins Verbal Learning Test

(HVLT)

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Successful Phase 2a Results

• Well tolerated, no safety signals

• Achieved target spinal fluid drug levels

• Demonstrated target engagement– Amyloid plaque load reductions– Effect on spinal fluid inflammatory markers

• Within-subject improvement in Episodic Memory function

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Baseline Day 14 Day 40

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Baseline Day 14 Day 40

N=8

Improvement in Episodic Memory Test (6-Week Study)

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HVLT - Total Recall

p=0.015

HVLT - Delayed Recallp=0.028

7 of 8 patients in 40 mg group and 6 of 7 in 125 mg group showed improvement from baseline at Day 84

8 of 8 patients in 40 mg group and 6 of 7 in 125 mg group showed improvement from baseline at Day 84

Improvement in Episodic Memory Test Results (12-Week Study)

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40mg 125mg All

Baseline Day 28 Day 84

WMS-Immediate Recall Composite

p=0.054

p=0.026

p=0.005

Mea

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40mg 125mg All

WMS-Delayed Recall Composite

p=0.007

p=0.013

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WMS -Immediate

WMS - Delayed HVLT-R TotalRecall

HVLT-R DelayedRecall

Effect Size Analysis Demonstrates Medium to Large Treatment Effects on Episodic Memory

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Effe

ct S

ize

(ES)

12-week study 6-week studyES =

Mean end-of-treatment − MeanBaseline

SDaverage

Prins et al AAIC, 2017; Scheltens et al ACTN, 2018

Effect Size cut-offs0.2 – small treatment effect0.5 – medium treatment effect0.8 – large treatment effect

Overview of Ongoing Phase 2b Trial

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• MCI or mild AD• Documented

memory deficit• MMSE 20 to 28• Spinal fluid (+) for

amyloid & tau• Enrollment

complete at 161 patients

Patients24 WEEK TREATMENT 40 mg or placebo twice daily

Endpoints• 1º: episodic memory

(Hopkins Verbal Learning Test)

• 2º: Clinical Dementia Rating Scale, Wechsler Memory Scale, MMSE, CSF biomarkers (p-tau, tau, NFL, A𝛽𝛽40, A𝛽𝛽42 )

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Poised for Success in AD Phase 2b

Potent, highly selective oral drug that inhibits p38α kinase• Highly-validated mechanism that

is directly involved in synaptic function and memory

• Potential for both reversing disease and slowing progression

• Reverses cognitive deficits in animal models

Positive Phase 2a clinical data in patients with Alzheimer’s disease• Blood-brain-barrier penetration

• Target engagement

• Improvement in episodic memory function

• No safety signals

• Optimal dose identified: 40 mg twice daily

Phase 2b trial designed in accordance with Feb’18 FDA guidance on developing drugs for Early AD

Early Stage Huntington’s disease• Scientific Rationale: Hippocampal functional

deficit prominent in early stages• Proof-of-principle study to start Q2’19• Patients with established cognitive deficits,

but no motor deficits• Primary endpoint:

cognitive testing

Dementia of Lewy Bodies• Scientific Rationale: Role of

neuroinflammation similar to that in AD; p38 role in alpha-synuclein induced toxicity

• Proof-of-concept study to start mid-2019• Patients on cholinesterase

inhibitor therapy > 12 months• Cognitive endpoints,

CDR-SB, Parkinson’s motor scales, FDG-PET

Broad Potential of Neflamapimod

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Corporate Summary

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Experienced Leadership TeamJohn Alam, MDPresident, CEO & Founder• 25+ years in industry. Physician-scientist

biopharmaceutical executive• Led Sanofi R&D in Alzheimer’s Disease and

other age-related disorders • Former Chief Medical Officer & EVP Medicines

Development at Vertex Pharmaceuticals• Led clinical development of Avonex® for

multiple sclerosis at Biogen

Sylvie Grégoire, PharmD Co-Founder, Exec. Chair of the Board• 30+ years in industry. Former President of

Shire Human Genetic Therapies (HGT); former Executive VP, Technical Operations at Biogen

• Board member – Novo Nordisk, Perkin-Elmer, Corvidia Therapeutics (Chair)

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Kelly BlackburnVP, Clinical Development• 25+ years in clinical development. Former VP, Clinical

Affairs at aTyr Pharma; VP, Clinical Development Operations at Vertex

• Global clinical operational responsibility for Kalydeco®,Incivek®, and Velcade®

Kevin Sarney VP, Finance and Administration• 18+ years in life sciences industry in early-stage & publicly

traded companies, including SEC reporting responsibility at Nitromed. Previously audit supervisor at PwC.

Darryl Patrick DVM, Phd – VP, Non-clinical Development• 30+ years in industry. Former head of global drug

safety (toxicology) evaluation at Merck• Former head of exploratory drug development

at Vertex

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Board and SAB

Board of Directors• Executive Chair: Sylvie Grégoire

• John Alam, President & CEO

• Tatjana May (ex-Shire general counsel; non-executive director, Indivior)

• Jeff Poulton (ex-Shire CFO; ex-CFO, Indigo Ag)

• Frank Zavrl (non-executive director, Puma Biotechnology)

Scientific Advisory Board• Chair: Ole Isacson,

Harvard Medical School

• Lewis Cantley, Weill Cornell Medical School

• Jeff Cummings, Cleveland Clinic

• Heidi McBride, McGill University

Financial Overview• Leveraging prior work by Vertex

• Series A - $5.7M in 2016/2017– Funded Phase 2a studies

• Series B - $20.5M in April 2018– Led by Access Industries– Funds Phase 2b study

• Closed on $11.2M in financing in April 2019– Supports Phase 2 studies in HD and DLB

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2018 2019 2020

Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Alzheimer’s Disease

Phase 2b – Reverse SD

Phase 3

Dementia of Lewy Bodies

Phase 2

Huntington’s Disease

Phase 2a

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EIP Pharma Clinical Milestones

Enrollment completed Results

Start Results

ResultsStart

Start

June 2019

Reversing Inflammation-Induced Synaptic Dysfunction in

Neurodegenerative Diseases

Slide Number 1Company OverviewAt the Forefront of a Fundamental Shift in the AD FieldWhy Target Synaptic Dysfunction?Inflammation in the Brain Is Key Driver of Synaptic Dysfunction in ADRecent Mechanistic Understanding �of Hippocampal Synaptic DysfunctionP38α Inhibition Reverses Synaptic Dysfunction and Restores Cognitive FunctionReversing Synaptic Dysfunction Provides Ability to Demonstrate Proof-of-Concept in Six Month Clinical StudyNeflamapimod: �Oral, Potent p38⍺ Kinase InhibitorNeflamapimod Development StatusNeflamapimod Reverses Inflammation-Induced Synaptic Dysfunction in Preclinical ModelsRobust Early Alzheimer’s Disease Phase 2a ProgramSuccessful Phase 2a ResultsImprovement in Episodic Memory Test (6-Week Study)Slide Number 15Effect Size Analysis Demonstrates Medium to Large Treatment Effects on Episodic MemoryOverview of Ongoing Phase 2b TrialPoised for Success in AD Phase 2bBroad Potential of NeflamapimodSlide Number 20Experienced Leadership TeamBoard and SABFinancial OverviewEIP Pharma Clinical MilestonesSlide Number 25