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4 t h A n n u a l C o m p l e m e n t - b a s e d D r u g D e v e l o p m e n t S u m m i t

Leveraging Biomarkers to De-risk Clinical Development in Complement Mediated Diseases: Progress with Anti-C1q Inhibitor ANX005

O c t o b e r 1 5 , 2 0 2 0

Sanjay C. Keswani, MBBS FRCP BScChief Medical OfficerAnnexon Biosciences

Annexon Founded on Pioneering Research on Complement-Mediated NeurodegenerationWell-researched role of C1q inhibition to protect against synapse loss and neurodegeneration

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Ben Barres, M.D., Ph.D.Discoverer of C1q TechnologyScientific Co-Founder, Annexon

“…complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration…”

- Eric Huang, UCSF 2016

Our Pioneering Platform Targets Two Distinct Disease ProcessesTargeting aberrant C1q activity in both autoimmune and neurodegenerative disorders

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NormalC1q Function

DiseaseC1q Dysfunction

Aberrant Triggers

Amplifies antibody activity for normal immune function

Auto-antibodies Removes healthy cells/tissueAnti-C1q potentially protects against

cell & organ damage

Antibody-mediated

autoimmunedisease

Sculpts the brain and retina in development

Neuronal Stress

Complement-mediated

neurodegen-eration

Removes functioning synapsesAnti-C1q potentially protects against

synaptic loss

Macrophage

Microglial cell

C1q

C1q

C1q

Why Target C1q?Initiates the classical complement cascade, a key driver of autoimmune and neurodegenerative diseases

1. C1q directly binds to the surface of tissues in disease

2. Inhibiting C1q upfront blocks downstream activity of the classical cascade

3. Anti-C1q allows normal immune function of other complement pathways

4. C1q and classical complement activation can be measured utilizing established biomarkers

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Neurons

C1q anchors classical cascade activation to tissues sites in disease

C1q Targeting SynapsesAnnexon data on file

C1q Inhibition Works Upstream for Valuable Downstream BenefitsKey differentiation: Shutting down powerful inflammatory activities of the classical cascade

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Membrane damageC3 C5Classical Pathway C1q

Enzymatic amplification

C2C1r C1s C6-C9FB

C4

Immune cell recruitment(macrophage/microglia)

Immune cell attack(macrophage/microglia)

Inhibiting C1q upstream

ANNEXON’s Key Differentiation

Potential Efficacy Advantages:

✓ Anti-C1q stops the cascade before it starts1

✓ Shuts down tissue-damaging components of classical pathway (C1q, C4, C3, C5)1

✓ C1q levels are 10-fold lower than C32

1Data on file; 2Glovsky, Ann Allery Asthma Immunol 2004, 93:513

Potential Safety Advantage of Anti-C1q vs. Downstream Complement Approaches

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C3 C5Classical Pathway C1q

C2C1r C1s C6-C9FB

C4

Inhibiting C1q upstream

ANNEXON’s Key Differentiation

Lectin pathway

Alternative pathway

Potential Safety Advantage:

✓ Allows normal immune functions of lectin and alternative complement pathways1

1 Annexon data on file

Key differentiation: Selectively blocking C1q while allowing other pathways to provide immune protection

• GBS (Guillain-Barré Syndrome)

• CIDP (Chronic idiopathic demyelinating

polyneuropathy)

• MMN (Multifocal Motor Neuropathy)

• PMS (Progressive Multiple Sclerosis)

• ON (Optic neuritis)

• GA (Geographic atrophy)

• GLA (Glaucoma)

• wAIHA (warm autoimmune hemolytic anemia)

• CAD (cold agglutinin disease)

• Lupus Nephritis• Bullous Skin Diseases• HIT (Heparin induced thrombocytopenia)

• Rheumatoid Arthritis• Crohn’s Disease

• ALS (Amyotrophic lateral sclerosis)

• HD (Huntington’s disease)

• SMA (Spinal muscular atrophy)

• FTD (Frontal Temporal Dementia)

• AD (Alzheimer’s disease)

• TBI (Traumatic Brain injury)

Broad Platform Potential Across Mechanistically-Related DiseasesCurrent indications and future opportunities in both orphan and large patient populations

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AUTOIMMUNE NEURODEGENERATION

Current Indications

OPHTHALMOLOGY

Increasing Probability of Success with Biomarker-led Development*

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Right Indication & Patient Selection

Optimal Dose & Dosing Regimen

Objective Measures of Treatment Effect

• Classical complement activation markers enable precision medicine approach in autoimmune diseases

• Measuring target engagement & pharmacodynamic activity in blood, CSF & eye

• NfL (Neurofilament Light Chain) for neurodegeneration

• Hemoglobin (hemolytic anemias)

• Proteinuria (nephritic diseases)

*Annexon data on file

Inhibition of C1q observed in CSF at 18-75 mg/kg

Classical complement and disease markers can be objectively measured in patients

Neurofilament light chain (NfL) Biomarker Underpins our Neurological Approach

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Significantly Informs Clinical Development

✓ Sensitive measure of neuronal damage / degeneration

✓ Correlates w/ patient disability and predicts outcomes in several diseases (e.g., SMA1, MS2, GBS3, HD4, ALS5)

✓ Reduced by effective therapies for MS and SMA within 3 months of treatment

✓ Annexon reduced NfL in preclinical (HD) and clinical (GBS) studies

✓ Decision-enabling biomarker and value driver in upcoming GBS, HD and ALS Phase 2 trials

1Olsson, 2019 J Neurol 266:2129–2136; 2Gunnarsson 2011 Ann Neurol 69:83; Ferraro 2020 Acta Neurol Scand 141:16; 3Martín-Aguilar, 2020 medRxiv 10.1101/2020.03.24.20042200; 4Byrne, 2017 Lancet Neurol 16: 601; ALS; 5Benatar 2018 Ann Neurol 84:130

12K patients diagnosed annually in North America/Europe

Acute antibody attack of peripheral nerves and roots triggers complement deposition and neurodegeneration• Rapid onset of neuromuscular paralysis

No approved therapy in U.S.

Off-Label IVIg and plasma exchange are standard of care with poor patient outcomes• 5% mortality in North America/Europe• ~20-30% require mechanical ventilation• Half of patients have motor/sensory impairment after

two years, 1/3 of patients experience pain

GBS: A Devastating Neuromuscular Autoimmune Disease

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INCIDENCE

DISEASE PROFILE

TREATMENT

*2011 estimates

Phase 1b Safety, Dose-Ranging Trial of ANX005 in GBS Patients

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• Safety / tolerability / PK

• C1q target engagement

• NfL reduction

• N = 31

TRIAL OBJECTIVES ANX005 DATA SUMMARY

• ANX005 well-tolerated at all dose levels

▪ Infusion-related reactions observed (transient skin rash)

• Single dose completely inhibited C1q and classical cascade in blood and CSF

• Significantly reduced levels of neurofilament light chain (NfL)—a predictive biomarker that correlates with patient disability in GBS and predicts long-term prognosis

• Consistent positive trends across key GBS clinical measures

• Global natural history study of ~2,000 GBS patients (IGOS) informing clinical development

Gateway indication that informs future autoimmune and neurodegenerative indications

ANX005Received Fast Track

& Orphan Drug Designations

for GBS

Annexon data on file

ANX005 Demonstrated Full Target Engagement— Blocking C1q & Entire Classical Complement Pathway in Blood & CSF

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Complete Inhibition of C1q / Complement Activity in Blood

Data from a Patient Receiving 75 mg/kg*

Inhibition of C1q in CSF at 18-75 mg/kg

0 1 2 3 4

0.3

3

30

300

3000

0

20

40

60

80

100

Time (weeks)

Seru

m A

NX

005 (

ug

/mL

)

C1q

fun

ctio

n(%

hem

oly

tic a

ctiv

ity)

C1q activity not detectable when ANX005 was present in the circulation

(Data from 75 mg/kg patient)

Serum level ANX005

Serum activity C1q

Subsequent analyses focused on 18-75 mg/kg cohorts

*Double blind, placebo-controlled study with 5 cohorts 3, 9, 18, 36 & 75 mg/kg. ANX005 inhibited C1q at all dose levels for varying durations

Dose Dependent Decrease of CSF Free C1q

Early NfL Reduction with ANX005 Correlated with GBS-DS Outcome

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ANX005 Led to Significant Early NfL Reduction (Weeks 2 – 4)

High Dose ANX005 (18-75 mg/kg)

vs Placebo

Annexon data on file

Early Reduction in NfL Correlated with Improved GBS-DS Outcome

Change in NfL (wk 2 – 4) vs. Overall Change in GBS-DS (wk 2 – 8)

-100 -50 0 50 100

-5

-4

-3

-2

-1

0

1

Delta NfL wk 2-4

Delt

aG

BS

wk0-8

Change in NfL wk 2 - 4 vs.

Overall Change in GBS-DS (wk 2 - 8)

p=0.028

r=0.431

n=26

* r is a statistical measure for the correlation of two variables that ranges from

-1 to 1. The closer r is to 1 or -1, the more closely the variables are related.

Mean Change in MRC ScoreWeek 1 from Baseline

ANX005 Associated with Early, Dose-Dependent Improvement of Muscle Strength (MRC Sum Score) in GBS Patients

• Dose dependent improvement of muscle strength (MRC) within 1 week of treatment

• Most significant predictor of future functional outcomes (mEGOS)*

• Improvement in MRC correlated with the change in GBS-DS functional score

Place

bo 3 9 18 36 75-20

0

20

40

Dose ANX005 (mg/kg)

MR

C c

han

ge f

rom

baselin

e

Mean change in MRC scoreWeek 1 from baseline

*Walgaard, et al., 2011

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ANX005 Signal for Disability Score Improvement in GBS Patients GBS-Disability Score (DS) Improvement— primary clinical endpoint for approval in GBS

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• Patient treatment groups largely balanced at baseline

• Percent of patients demonstrating improvement of ≥ 3 points on GBS-DS at week 8:

▪ 28% patients on high-dose ANX005

▪ 0% patients on placebo

6 Death5 ventilated4 bedbound3 walking assisted

GBS-DISABILITY SCALE

2 walking unassisted1 running0 normal

*Annexon data on file

28% of High Dose ANX005-Treated Patients Improved by ≥ 3 pts on GBS-DS by Week 8

(18-75 mg/kg)*

ANX005 GBS Phase 1b Summary

Neuronal Damage

Neurofilament Light

Muscle Weakness

MRC Sum Score

Neurological Disability

GBS Disability Score

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Reduction in NfLEarly Improvement in

MRC sum scoreImprovement in

GBS-DS at week 8

Treatment with ANX005 demonstrated consistent, positive trends in clinical measures

Huntington’s Disease (CNS)

Huntington's Disease & ALS: Severe Neurodegenerative DiseasesNeurodegenerative indications with high baseline NfL

Progressive movement disorder, dementia, psychosis

• ~35,000 U.S. patients (Orphan)

• C1q activity potentially drives synaptic loss and disability

• Potential to treat both early and late HD patients

• Monotherapy & complementary to HTT ASO approaches

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ALS (PNS & CNS)

Rapidly progressive weakness of limb and respiratory muscles

• ~30,000 patients globally (Orphan)

• C1q activity potentially drives synaptic/ NMJ loss and disability

Markers of Disease Activity in HD Patients Reduced by ANX005 in HD Mice Classical Complement Activation, Elevated NfL and Synapse Loss

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Annexon data on file. Collaboration with Dr. Ed Wild, UCL Byrne, 2017 Lancet Neurol 16: 601

Progressive Synapse Loss in Huntington'sIncreased Complement Activation w/ Disease Progression Increased NfL in the CSF with Disease Progression

CSF NfL (pg/mL) Synapse number (% Control)

Unpublished Data, Dan Wilton and Beth Stevens, Harvard

CSF C4a (ng/mL)

Annexon data on file; Collaboration w/ Dan Wilton and Beth Stevens, Harvard

Fold-Change in Complement Deposition on Synapses

IgG ANX0050.0

0.5

1.0

1.5

2.0

2.5

Fo

ld-c

han

ge in

nu

mb

er

of

C3d

+ p

un

cta

*

Annexon data on file. Study run in R6/2 model

Decreased Complement Activation w/ ANX005

CSF NfL (pg/mL)

IgG ANX0050

200

400

600

800

CS

F N

fL (

pg

/mL

)

**

Annexon data on file; Collaboration w/ Dan Wilton and Beth Stevens, Harvard

Decreased Levels of CSF NfL w/ ANX005

Fold Change Synapse Number

IgG ANX0050.0

0.5

1.0

1.5

2.0

2.5

Fo

ld-c

han

ge in

nu

mb

er

of

syn

ap

ses

*

Protection Against Synapse Loss w/ ANX005

PATI

ENTS

MIC

E

* p < 0.05; ** p < 0.01; **** p < 0.0001

Increased Complement Activation in HD Brain TissueManifest HD tissue C3

Manifest HD tissue iC3b

Contr

ol

Ear

ly P

re.

Late

Pre

.

Ear

ly H

D

Moder

ate

HD

0

10

20

30

40

ng

/mL

CSF C4a

p=0.011

p=<0.0001

Complement activation increases with progression of disease

Clinical endpoints p-value

Total functional score (tfs) 0.0333

Total motor score (tms2) 0.0181

Disease burden score (dbs) 0.1310

CAGxAge (cap) 0.0097

Symbol digit mod. Test (sdmt) 0.0324

Verbal fluency 0.0255

Stroop color naming (scn) 0.0454

Stroop word recall (swr) 0.0710

Motor & functional

Cognitive scales

CSF C4a is correlated with multiple clinical endpoints

Unpublished Data,Dan Wilton and Beth Stevens, Harvard

Unpublished DataAnnexon Collaboration with Ed Wild UCL

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C1q Deposition Correlated w/ Muscle Weakness in Mouse Model and Preceded Denervation in ALS Patients; NfL Elevated w/ Disease

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Serum NfL Elevated in ALS Patients a Year Prior to Symptom Onset

C1

q L

eve

ls

C1q Levels in NMJ of ALS Mouse Model Correlate with Weakness

Muscle Strength (N)

r=-0.6624*** P=0.0003

Reference ALS animal model: Lee et al., (2018) J Neuroinflam 15:171 Reference ALS patient data: Benatar, et al., 2018, Ann Neurol 84:130

C1q Deposition in NMJ of ALS Patients Prior to Denervation

Bahia El Idrissi et al. Journal of Neuroinflammation (2016) 13:72

ControlALS

NMJ

Phase 2a Trials of ANX005 in HD & ALS initiated in 2020Efficient, biomarker-driven trials to assess C1q target engagement and impact on NfL

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• HD and ALS Phase 2a clinical trials to measure key biomarkers after three months treatment

▪ CNS target engagement

▪ Significant NfL reduction from baseline

• Close partnership established with key academic consortia: HSG and NEALS

• HD and ALS INDs activated

• Development informed by large natural history cohorts

• Data informs initiation of registrational trials and other indications

PHASE 2aANX005 INHD & ALS

GEOGRAPHIC ATROPHY (GA)

Geographic Atrophy, a Neurodegenerative Disease of the RetinaSelective classical complement approach targeting loss of retina neurons and photoreceptors in GA

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• Loss of central vision due to loss of photoreceptor cell neurons

• ~1 million U.S. patients; ~5 million patients worldwide

• No approved therapies for disease onset or progression

• Complement validation in Phase 2 GA trials

• Aberrant C1q activity results in damage to photoreceptors

• Anti-C1q efficacious in GA models

Phase 1b: ANX007 (IVT) Demonstrated Complete C1q Inhibition / Target Engagement in Patients Inhibition at low & high doses support monthly or less frequent dosing

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Free C1q Levels in Aqueous Humor

ANX007 DATA SUMMARY

• ANX007 well-tolerated at all dose levels

• Single intravitreal (IVT) injection inhibited C1q in aqueous humor for at least 28 days at both low and high doses

• Repeat doses, N = 17

D1 = Day 1 (before ANX007 dosing)

D29 = Day 29 (post-1st dose)

D1 D29 D1 D29 D1 D29

0

50

100

150

C1q

in

Aq

ueo

us H

um

or

(%P

re-d

ose levels

)

Free C1q in Aq humor

(% Day 1 levels)

Sham 2.5 mg 5 mg

Annexon data on file

Phase 2 Trial of ANX007— Neuroprotective Therapy in Geographic Atrophy

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PHASE 2ANX007 IN GEOGRAPHIC ATROPHY

• Randomized, controlled Phase 2 trial in GA

• Leveraging experience from related complement trials

▪ Natural history of progression well understood

▪ Objective primary endpoint – change in area of geographic atrophy on FAF

▪ Enriching for patients with high rate of progression

▪ Evaluating Q 1 month and Q 2 month dosing

• Assessing extended release formulations to enable infrequent dosing