Arvinas : Corporate Presentation - February, 2020

Leading the Way

in Targeted Protein

Degradation

Therapeutics

FEBRUARY 2020

Safe harbor and forward‐looking statements

This presentation contains forward‐looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the development and regulatory status of our product candidates, such as statements with respect to our lead product candidates, ARV‐110 and ARV‐471, and the timing of clinical trials and data from those trials for our product candidates, and our discovery programs that may lead to our development of additional product candidates, the potential utility of our technology and therapeutic potential of our product candidates, the potential commercialization of any of our product candidates, the potential benefits of our arrangements with Yale University, our collaborative partnerships, and the Bayer joint venture, and the sufficiency of our cash resources. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward‐looking statements. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "might," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions are intended to identify forward‐looking statements, although not all forward‐looking statements contain these identifying words.

We may not actually achieve the plans, intentions or expectations disclosed in our forward‐looking statements, and you should not place undue reliance on our forward‐looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward‐looking statements we make as a result of various risks and uncertainties, including but not limited to: whether we will be able to successfully conduct Phase 1 clinical trials for ARV‐110 and ARV‐471, complete other clinical trials for our product candidates, and receive results from our clinical trials on our expected timelines, or at all, whether our cash resources will be sufficient to fund our foreseeable and unforeseeable operating expenses and capital expenditure requirements, each party's ability to perform its obligations under our collaborations and/or the Bayer joint venture, our expected timeline and other important factors, any of which could cause our actual results to differ from those contained in the forward‐looking statements, discussed in the "Risk Factors" section of the Company's quarterly and annual reports on file with the Securities and Exchange Commission. The forward‐looking statements contained in this presentation reflect our current views as of the date of this presentation with respect to future events, and we assume no obligation to update any forward‐looking statements except as required by applicable law.

The Arvinas name and logo are our trademarks. We also own the service mark and the registered U.S. trademark for PROTAC®. The trademarks, trade names and service marks appearing in this presentation are the property of their respective owners. We have omitted the ® and ™ designations, as applicable, for the trademarks named in this presentation.

2

Clinical‐stage leader in protein degradation, a powerful new modality

Novel PROTAC® (proteolysis‐targeting chimera) degrader platform

• Elimination of disease‐causing proteins, instead of inhibition
• Power of genetic medicines with small‐molecule benefits

Strategic, discovery‐stage partnerships with Pfizer, Genentech, and Bayer

• Pharmaceutical partnerships across multiple therapeutic areas
• Joint venture (Oerth Bio) with Bayer for agricultural applications
• Up to $2.1B in total potential milestones plus tiered royalties

Platform‐enabled pipeline of oncology and neuroscience programs

• ARV‐110 for men with metastatic castration‐resistant prostate cancer
• • Phase 1 initiated 1Q19
• ARV‐471 for patients with estrogen receptor‐positive / HER2‐negative locally advanced or metastatic breast cancer
• • Phase 1 initiated 3Q19
• Initial clinical safety/PK data for both ARV‐110 and ARV‐471 shared in October 2019
• Brain‐penetrant PROTAC programs targeting tauopathies, α‐ synucleinopathies, and other neurological disorders
• All programs fully owned by Arvinas

Strong cash and intellectual property positions

• ~$298M in pro forma cash, cash equivalents, and marketable securities as of 9/30/191
• Platform IP complemented by specific product IP

Leader in targeted protein degradation

• Two clinical‐stage programs
• Brain‐penetrant and orally bioavailable degraders
• Aggressively investing in the platform to maintain leadership position
• Nearly 150 employees fully dedicated to targeted protein degradation

1 Pro forma to include proceeds from a public offering of common shares closed on 11/12/19

3

High potential PROTAC® pipeline, focused on cancer and neurology

ONCOLOGY

CENTRAL	NERVOUS SYSTEM

		Program	Discovery	Lead Optimization	IND Enabling	Phase 1	Phase 2/3
Prostate Cancer	ARV‐110
		Androgen Receptor
		Next Generation Degrader
		Androgen Receptor
		AR Variant Degrader
		AR‐V7
Breast Cancer	ARV‐471
		Estrogen Receptor
Additional	Multiple Indications
Oncology Programs	Undisclosed Targets
FTLD‐Tau1, PSP2,	Tau
Alzheimer's
MSA3, Parkinson's	α‐synuclein
Additional	Undisclosed Targets
Neurology Programs

1 FTLD‐tau, frontotemporal lobar degeneration‐tau. 2 PSP, progressive supranuclear palsy. 3 MSA, multiple systems atrophy	4

PROTAC® Protein Degrader Platform

What is a PROTAC® protein degrader?

A proteolysis‐targeting chimera (PROTAC) degrader is a chimeric, modular small molecule

engineered to induce the degradation of disease‐causing proteins by the ubiquitin‐proteasome system

Protein ligand domain ("warhead") targets a specific protein

A linker region orients the target protein and E3 ligase to enable activity

Ligase ligand recruits a specific E3 ubiquitin ligase

All three regions of the PROTAC degrader play a role in the specificity and potency of target degradation

6

PROTAC® protein degraders harness the ubiquitin‐proteasome system to induce the degradation of disease‐causing proteins

1 PROTAC protein degraders function inside cells

Target Protein

4	Targeted protein is
	degraded by the
PROTAC®	proteasome
Ubiquitination
E3 Ligase
	Proteasome

Iterative PROTAC degrader activity

2 Formation of trimer complex and ubiquitination of target protein

3 Multiple ubiquitin molecules "tag" target protein for degradation

7

PROTAC® protein degraders combine the advantages of gene‐based medicines with the benefits of small molecule therapies

PROTAC protein degraders have distinct advantages over both small molecule inhibitors and gene‐based medicines

PROTAC	Small
Protein	Molecule	Gene‐Based
Degraders	Inhibitors	Medicines

Eliminate pathogenic proteins		
Target scaffolding function		
Potential to treat "undruggable" proteins		
Iterative mechanism of action			
Broad tissue penetration			
Orally bioavailable			
Ease of manufacturing			

8

Potential advantages of PROTAC® protein degraders over inhibitors

Overcome Target Protein Overexpression

PROTAC degraders can disable this common tumor resistance mechanism

•	Lapatinib alone results in HER2‐overexpression, but a
HER2
	PROTAC created with lapatinib as the "warhead" degrades
	natural and overexpressed HER2
•	HER2 degraded despite increased RNA levels

Selectively Eliminate Mutated Proteins

PROTAC degraders can differentiate between mutant and wild type proteins

• The three mutants of BRAF shown (V600E, K601E, G466V) differ from the wild type by a single point mutation, but are degraded by a BRAF‐targeted PROTAC that spares the wild type

1 hMito is a protein not targeted to degrade (loading control)	9

Arvinas is making substantial investments in platform expansion and its pipeline, including in undisclosed pipeline targets

Platform Investment and Expansion

• Enhanced prediction of degradation selectivity
• • Rapid narrowing of "zone of ubiquitination"
  • Improve speed to mutant vs. wild type specificity
• DEL screening and other approaches to incorporating tissue and disease‐specific E3 ligases
• Expansion into new disease areas, e.g., immuno‐oncology, either independently or with partners

Undisclosed "Undruggable" and Difficult‐to‐Drug Targets

• Many (up to ~80%) proteins have not been traditionally addressable by small‐molecule inhibition
• • Since PROTAC degraders do not require tight target binding, the "undruggable" space may be available
• PROTAC degraders also advantageous for "difficult to drug" targets where existing therapies leave substantial unmet need

10

Leading the way in targeted protein degradation therapeutics

Track Record	Targets validating the	95% success rate at degrading
of Success	PROTAC® mechanism	proteins of interest
	and platform

Two clinical‐stage programs with initial safety/PK data

Strategic Target Selection

• Recalcitrant targets where PROTAC technology shows differential biology
• Targets requiring exquisite selectivity
• Pipeline balances benefit and risk

Creating Degraders, Including Against "Undruggable" Targets

• Premier ligand discovery technologies
• Database of E3 ligase attributes to guide library expansion
• Predictive dynamic models and structural biology

Turning Degraders into Drugs

• Brain‐penetrant and orally bioavailable degraders
• Mechanism and proteomic analytics
• State‐of‐the‐art, disease‐ specific degradation assays
• Working "Beyond the Rule of 5" since our founding

11

Clinical‐stage Oncology Programs: ARV‐110

ARV‐110 is Arvinas' AR degrader for men with metastatic castration‐resistant prostate cancer (mCRPC)

Androgen Receptor (AR) Activity Drives Prostate Cancer

• Prostate cancer is the second leading cause of cancer death in men in the US1
• Current agents work by decreasing androgen levels (abiraterone) or blocking androgen binding to AR (enzalutamide)
• 15‐25% of patients never respond to abiraterone or enzalutamide (intrinsic resistance)
• Acquired resistance mechanisms to abiraterone and enzalutamide include:
• • AR gene amplification (40‐60% of patients)
  • AR gene enhancer amplification (>70% of patients)
  • AR point mutations (~15% of patients)
  • Intra‐tumoral androgen production

PROTAC® Degrader ARV‐110

• First‐in‐class AR degrader being tested in men with metastatic castration‐resistant prostate cancer who have progressed on standards of care (enzalutamide, abiraterone)
• In preclinical models, overcomes known resistance mechanisms to enzalutamide and abiraterone
• Highly selective degradation of AR; not brain penetrant
• Received FDA "Fast Track" designation in May 2019
• Initial safety/pharmacokinetic data shared Oct. 2019
• Phase 1 dose escalation data expected 2Q20

DHEA		Testosterone	DHT	AR
	AR
			ARE	PSA
								AR
										AR	AR
	Abiraterone					Enzalutamide

1 According to the American Cancer Society; https://www.cancer.org/cancer/prostate‐cancer/about/key‐statistics.html	13

ARV‐110 inhibits tumor growth in an in vivo model of acquired enzalutamide resistance

• In vivo mouse xenograft model of acquired enzalutamide resistance developed at Arvinas
• In this model, VCaP tumors acquired resistance to enzalutamide after being continuously propagated in castrated, enzalutamide treated mice for ~3 years
• Daily and orally delivered ARV‐110 significantly inhibited tumor growth (at right)
• • 10 mpk ARV‐110: 70% tumor growth inhibition

Tumor Volume (mm3)

Tumor Growth Inhibition in an Enzalutamide‐Resistant

VCaP Xenograft Model

500 Vehicle

Enzalutamide, 20 mpk PO, qd

ARV‐110, 10 mpk PO, qd

1. ARV‐110, 3 mpk PO, qd

200

100

0

0

4

7

11

14

18

21

25

28

Days of Treatment

14

ARV‐110 demonstrates efficacy and plasma PSA reduction in an enzalutamide‐insensitive patient derived xenograft model

Growth Inhibition in an Enzalutamide‐Insensitive PDX Model (TM00298)

600

		Vehicle
	500	Enzalutamide, 20 mpk PO, qd
	ARV‐110, 10 mpk PO, qd
)
3
(mm	400
Volume	300
Tumor
200

100

0

0	3	5	9	13	16	20
		Days of Treatment

Orally delivered ARV‐110 significantly inhibited tumor growth in these intrinsically enza‐insensitive tumors (TGI: 100%)

(ng/mL)	p < 0.00011
PSA

Plasma PSA levels following ARV‐110

treatment significantly decreased vs. mice

treated with vehicle or enzalutamide

1 p value refers to ARV‐110 vs. enzalutamide	15

ARV‐110 pharmacokinetics are dose proportional, and exposure has reached the predicted efficacious range

Preclinical Efficacious Exposure Range

Initial clinical data as of 10/23/19

Dose (po, qd)	AUC0‐24 (ng*hr/ml)	Cmax (ng/ml)
1 mpk	3628	224
3 mpk	8106	507

Phase 1 Data

Dose	Day 1 AUC0‐24 (ng*h/mL)	Day 1 Cmax (ng/ml)	Day 15 AUC0‐24 (ng*h/mL)	Day 15 Cmax (ng/ml)
po, qd	Mean	Mean	Mean‡	Mean
35 mg	160.5	11.1	1701	83
70 mg	300	19.6	2538	141
140 mg	865	54	5023	353

• Accumulation occurs between Day 1 and Day 15
• Exposure at 140 mg entered the preclinical efficacious range associated with tumor growth inhibition

‡ Day 15 AUCs calculated using imputed 24 hour values	16

ARV‐110 Phase 1 dose escalation: Day 15 pharmacokinetics

	600
	500
	400
(ng/mL)	300
Mean
	200
	100
	0

0	3	6	9	12	15	18	21	24
				Time (h)
† Time to reach maximum concentra	on (Cmax)
‡ Effec ve half‐life: rate of accumulation or elimination of a pharmacologic substance

Initial clinical data as of 10/23/19

Tmax† = 4 ‐ 8 hours

t1/2‡ = Estimated 3 ‐ 7 days

Cohort 3 (140 mg)

Cohort 2 (70 mg)

Cohort 1 (35 mg)

24 hour values are imputed from time zero

17

In the first 3 cohorts of the ARV‐110 Phase 1 dose escalation, we observed an overall favorable safety profile

Initial clinical data as of 10/23/19

(AEs)

AEs

AEs

1. Orally, once daily
2. Data not 100% source data verified
3. Not including 1 non‐evaluable patient (discontinued on day 1; patient's condition had worsened in the interval from screening to the morning of treatment initiation consistent with rapid progression of his cancer)

evaluation

18

Clinical‐stage Oncology Programs: ARV‐471

ARV‐471 is Arvinas' ER degrader for patients with locally advanced or metastatic breast cancer

Breast cancer is the second most common cancer in women1

• ~276,000 women are expected to be diagnosed with invasive breast cancer in the US in 20201
• Metastatic breast cancer accounts for ~6% of newly diagnosed cases2
• 80% of breast cancers are estrogen receptor (ER) positive3
• Fulvestrant has demonstrated the value of ER degradation in breast cancer. However, after 6 months of fulvestrant treatment, up to 50% of ER baseline levels remain4

PROTAC® Degrader ARV‐471

• ARV‐471 is in development for the treatment of patients with ER+ locally advanced or metastatic breast cancer
• Ph 1 trial initiated in 3Q2019, and initial clinical data shared October 2019
• Next data from the Phase 1 dose escalation planned for 2H20

~80% ER+

All Breast

Cancers1

1. American Cancer Society; 2 Malmgren, J.A., Breast Cancer Res Treat (2018) 167:579-590; 3 National Cancer Institute, Hormone Therapy for Breast Cancer; 4 Gutteridge et. Al., Breast Cancer Res Treat 2004;88 suppl 1:S177

20

ARV‐471: Superior tumor growth inhibition versus fulvestrant in a Y537S (ER gene mutation) PDX model

ARV‐471 In Vivo Preclinical Development

• Oral, daily dose of ARV‐471 inhibited tumor growth by 99% at 10 mpk and 106% at 30 mpk in an ESR1 mutant PDX model (at right)
• Superior inhibitor of tumor growth compared to fulvestrant1
• In corresponding quantitative western blots, ER is reduced by 79% and 88% in the 10 mpk and 30 mpk arms, respectively, vs. 63% for fulvestrant

Mean Tumor Volume (mm3)

TumorTumorGrowthGrowthInhibitionbitionin Patientin an EnzalutamideDerived Xenograft‐ResistantModel withVCaPY537SXenograftESR1 Mutationodel

2500

Vehicle

Fulvestrant (200 mpk)

2000

ARV‐471 (10 mpk qd)

ARV‐471 (30 mpk qd)

1500

1000

500

0

0

3

6

10

13

17

20

24

27

Days of Treatment

1 Fulvestrant schedule: 2x weekly x2 / q7dx2	21

In combination with palbociclib, ARV‐471 exhibits superior tumor shrinkage versus fulvestrant

ARV‐471 In Vivo Preclinical Development

• Achieved significant tumor shrinkage in combination with palbociclib (131% TGI) in an MCF‐7 xenograft mouse model
• • In all 10 mice in experiment, tumors reduced by >80%
• Superior tumor shrinkage (in combination with palbociclib) compared to fulvestrant (108% TGI)

1 Palbociclib arm: 60 mpk po qd; 94% TGI.

2 Fulvestrant + Palbociclib arm: Fulvestrant 200 mpk sc biwx 2, qwx 3 + palbociclib 60 mpk po qd; 108% TGI

3 ARV‐471 + Palbociclib arm: ARV‐471 30 mpk po qd + palbociclib 60 mpk po qd; 131% TGI

Tumor Growth Inhibition

in MCF‐7 Xenograft Mouse Model

	800
	700				Vehicle1
				Palbociclib
)
3	600				Fulvestrant + Palbociclib2
(mm
Volume	500				ARV‐471 + Palbociclib3
Tumor	400
300
Mean	200
	100
	0
	0	3	7	10	14	17	21	24	28

Days of Treatment

22

In the first cohort of the ARV‐471 Phase 1 dose escalation, exposure reached the predicted efficacious range

Initial clinical data as of 10/23/19

Preclinical Efficacious Exposure Range

Dose (po, qd)	Mean AUC0‐24	Mean Cmax
(ng*hr/ml)	(ng/ml)
3 mpk	658	84
10 mpk	2538	312
30 mpk	5717	962

Phase 1 Data

Dose	Day 1 AUC0‐24 (ng*h/mL)	Day 1 Cmax (ng/ml)	Day 15 AUC0‐24 (ng*h/mL)	Day 15 Cmax (ng/ml)
po, qd	Mean	Mean	Mean1	Mean
30 mg	1690	109	4100	224

• Accumulation occurs between Day 1 and Day 15
• Exposure at 30 mg entered the preclinical efficacious range associated with tumor growth inhibition

1 Day 15 AUCs calculated using imputed 24 hour values	23

Pharmacokinetics of the first cohort of the ARV‐471 Phase 1 dose escalation

(ng/mL)

300

200

Initial clinical data as of 10/23/19

Tmax = 4 hours

t1/2 = estimated to be ~24 hours

Day 1

Mean

‡

100

0

Day 15‡

0

5

10

15

20

25

Time (hr)

‡Day 15 24 hour value is imputed from time zero	24

No treatment‐related AEs or DLTs were observed in the first cohort of ARV‐471

Initial clinical data as of 10/23/19

Dose Level+	N		Key Safety Findings
30 mg‡	3	•	No DLTs
• No Treatment Related AEs
60 mg	3	•	TBD

• As of October 2019, the first cohort was through the 28 day dose limiting toxicity evaluation period

+ Orally, once daily		25
‡ Data not 100% source verified

Neurology Research Programs

Mutant‐specific PROTAC® degraders may reduce intra‐ and extracellular tau, creating a strong opportunity in neuroscience

PROTAC degraders may overcome the limitations of other platforms,PROTAC including antisense oligonucleotides (ASO) and monoclonal antibodies (Ab)

			.
		.	. . . .
		.
	.					. . .
ASO
					MAPT	.
					.
			.
• Degrades mRNA, impacting
intra‐ and extracellular tau

Ab

• Blocks only extracellular pathologic tau
• IV dosing results in only 0.5% in CSF

• Does not discriminate between wild type and pathologic tau
• Requires intrathecal dosing

Tau

PROTAC Potential

• Reduce intra‐ and extracellular pathologic tau
• Discriminate between wild type and pathologic tau
• Oral administration with BBB biodistribution

ASO, antisense oligonucleotide; Ab, antibody; CSF, cerebrospinal fluid; BBB, blood‐brain barrier	27

In vivo, tau‐directed PROTAC® degraders eliminate >95% of pathologic tau following parenteral administration

	Tau Detection (protein capillary electrophoresis)		Pathologic tau in Tg25081 mouse cortex
kDA	Vehicle		PROTAC‐A 15 mpk3 24 hrs	PROTAC‐B 30 mpk 24 hrs

Tau (%AUC2)

100%

<5%

<5%

24 hours post dose:

• >95% of pathologic tau is degraded
• No significant change in total soluble tau 24 h post dose (data not shown)

1 Tg2508 is a murine pathologic tau model (P301L). 2 AUC, area under the curve; 3 mpk, milligrams per kilogram	28
**** Tukey's multiple comparisons test P < 0.0001

Tau‐directed PROTAC® protein degraders inhibit ex‐vivo tau seeding

Tau Seeding Reporter Assay

Tau Seed

(Pre‐formed fibrils2 or Cortex Lysates3)

Modified from Holmes et al., 2014

24h

OR

‐ Tau /‐ PFF Seeding

+Tau /+ PFF Seeding

Dox‐inducible Tau P301L CHO‐K11

		PROTAC Treatment Inhibits Tau Seeding ex‐vivo4
			Cortex - Vehicle
	Per Cell		Cortex - PROTAC A - 24 hours
		Cortex - PROTAC B - 24 hours
	IntensityAvgSpot		No P301L5, No PFFs2
	4
	MC1

1 Tau P301L CHO‐K1 is a cell line expressing a doxycycline‐inducible tau mutation linked to FTDP‐17 (frontotemporal dementia and parkinsonism
linked to chromosome 17). 2 Pre‐formed fibrils (PFFs) are used to "seed" tau aggregation. 3 Cortex lysates are from Tg2508 mice. 4 MC1 is an
antibody that detects a pathologic conformation of tau. 5 "No P301L," no doxycycline induction.
**** Tukey's multiple comparisons test P < 0.0001. Comparisons are between the Cortex‐Vehicle value and all other values (individually)	29

Oligomer‐specific PROTAC® molecules human α‐synuclein aggregates in primary rat neurons

PROTAC molecules degrade oligomeric

α‐synuclein species

PROTAC‐1 and PROTAC‐2 degrade α‐synuclein aggregates in primary rat neurons expressing human α‐synuclein

PROTAC degraders were identified that specifically remove oligomeric α‐synuclein

[ng/ml]	600
oligomers	400
200
‐synuclein
0
α
DOX	5	4	3	2	1
			PROTAC degraders 1‐5
			@ 1 µM

Identify and select nuclei

Identify aggregates

Ratio: α‐syn total intensity / cell mask1

Neuronal α‐	200
synuclein	150
+PFF
induction
assays1	100
Intensity and	50
area features
of α‐syuclein
aggregates	0
calculated

PROTAC‐1PROTAC‐2

concentration concentration

1 Assay is of primary rat neurons expressing A53T human α‐synuclein, with pre‐formed fibrils (PFF) added or not. In the absence of α‐synuclein‐
specific PROTAC degraders, α‐synuclein forms aggregates induced by PFFs (green fluorescence in cellular images). When PROTAC degraders specific		30
for oligomeric α‐synuclein are added, the ratio of oligomeric α‐synuclein:cell mask (background fluorescence) is decreased (right panel).

Arvinas' approach in neuroscience reduces risk while proving the concept of protein degradation

Prove the concept with PROTAC® degraders in defined populations while pursuing larger, multifactorial indications

Conceptual

Tau	FTDP	Progressive	ApoE4 AD risk	Alzheimer's
	(~3K)	supranuclear palsy	allele carriers	(~6M)1
		(~20K)	(600‐900K)
α‐synuclein	Synuclein mutations,	Multiple systems	GBA PD risk	Parkinson's
	e.g., duplication/	atrophy	allele carriers	(~1M)4
	triplication (~4K)2	(~50K)3	(~500K)

FTDP, frontotemporal dementia and parkinsonism; GBA, glucocerebrosidase gene; AD, Alzheimer's disease; PD, Parkinson's disease

1. Alzheimer's Association: "2019 Alzheimer's Disease Facts and Figures" video; https://www.alz.org/alzheimers‐dementia/facts‐figures
2. Kowal. Movement Disorders 2013, 28: 311‐319; Nishioka. Intechopen 2011
3. NINDS; https://www.ninds.nih.gov/Disorders/Patient‐Caregiver‐Education/Fact‐Sheets/Multiple‐System‐Atrophy

4 Parkinson's Foundation: http://parkinson.org/Understanding‐Parkinsons/Causes‐and‐Statistics/Statistics

31

Corporate Overview

Financial snapshot

$298.2 Million1	Guidance1	39.0 Million1	Analyst Coverage2
Pro forma cash, cash	Expect pro forma cash,	Pro forma common	BMO, Cantor, Citibank,
equivalents, and	cash equivalents, and	shares outstanding	Evercore, Goldman Sachs,
marketable securities	marketable securities to	(as of 9/30/19)	Guggenheim,
(as of 9/30/19)	fund planned operations		HC Wainwright, Piper
	into 2022		Sandler, Roth, Wedbush

1 Financials, guidance, and shares outstanding include $115M from the public offering of common shares closed 11/12/19 (includes shoe exercise).
2 The foregoing list includes the names of all brokerage firms known by the company as of 2/12/20 to have analysts covering the company. This list may not be
complete and is subject to change as firms add or delete coverage. Please note that any opinions, estimates or forecasts regarding the company made by these
analysts are theirs alone and may not represent the opinions, estimates or forecasts of the company.	33

Strategic partnerships are validating our PROTAC® protein degrader technology

SEPTEMBER 2015

(expanded in November 2017)

• Target discovery deal
• Upfront, development, and commercial milestone aggregate payments in excess of $650M
• Tiered royalties

DECEMBER 2017

• Target discovery deal
• Upfront, development, and commercial milestone aggregate payments up
  to $830M
• Tiered royalties

JUNE 2019

• Pharma target discovery deal, including cardiovascular, gynecologic,
  and oncologic disease
• Private equity placement
• $60M in upfront, committed funds, and private placement of common stock

JUNE 2019

• Agricultural JV; 50:50 ownership
• >$55M in committed funds from Bayer

Potential for nearly $2.1 billion in milestones

34

Arvinas: Leading the way in protein degradation therapeutics

• Shared the first clinical data on targeted protein degraders
• Leading platform and product IP, driven by nearly two decades of PROTAC protein degradation research
• First to publish data on orally available PROTAC protein degraders
• Leadership team with experience getting drugs to market
• Strong financial position to advance the platform and product candidates

35

Thank You!

36

Appendix

Our strategic approach to proving and delivering a novel technology platform

Clinically validate the PROTAC® protein degrader concept with well‐defined targets

Prioritize targets where	Treat patients with
degradation has the	diseases inaccessible to
potential to be superior	current therapies by
to existing modalities	degrading "undruggable"
	targets

• Invest in our pipeline and our platform and grow our IP to expand our leadership in protein degradation
• Selectively collaborate with strong partners to expand the impact of PROTAC protein degraders into new areas

38

Weak or promiscuous ligands can be converted into potent and selective PROTAC® degraders

When developed into PROTAC degraders, weak binders can become potent degraders

• Foretinib is a relatively weak binder to p38α
• PROTAC 1 is a foretinib‐based PROTAC degrader with a p38α binding affinity of 11 μM
• Despite its 11 μM binding affinity, PROTAC 1 has a DC50 of 210 nM1
• • Based on experience, optimization of potency better than 210 nM is likely

A PROTAC degrader based on foretinib has a nanomolar DC50 despite a 11 μM binding affinity

DC50 = 210 nM1

When developed into PROTAC degraders, promiscuous ligands can become selective degraders

• Foretinib binds to 133 protein kinases (left panel)
• In cells treated with a foretinib‐based PROTAC degrader, only a small subset of cellular proteins are degraded (blue‐shaded quadrant of the right panel)

Binds 133 Kinases

Degrades <10 Proteins

1 hMito is a protein not targeted to degrade (loading control)	39

ARV‐110 inhibits AR‐dependent tumor growth in xenograft models with oral, daily dosing

Castrated VCaP

Enzalutamide Resistant VCaP

20 mpk

mpk = mg/kg

Intact (Non-castrated) VCaP

Dose	Mean AUC0‐24	Mean Cmax
po, qd	ng*hr/ml1	ng/ml2
1 mpk	3628	224
3 mpk	8106	507

† AUC0‐24 or Area Under the Curve is a measurement of total exposure from 0‐24 hours after last dose	Values represent total drug concentrations	40
‡ Cmax is a measurement of peak concentration

ARV‐110 selectively degrades AR

Orally bioavailable androgen receptor‐ targeted PROTAC protein degrader

Selective Degradation of AR by ARV‐110 in VCaP Cells

• ARV‐110 is in development for the treatment of men with mCRPC who have progressed on abiraterone and/or enzalutamide
• Appears to overcome mechanisms of resistance to current standards of care
• DC50 = 1 nM in VCaP cells1

ARV‐110 Selectively Degrades AR

• After 8 hours of treatment of VCaP cells with 10 nM ARV‐110 in vitro, AR was the only degraded protein among the nearly 4,000 proteins measured
• • 85% Dmax2
  • p‐value: 3x10‐9

1 VCaP, Vertebral Cancer of the Prostate

ARV‐110 increases abundance

ARV‐110 decreases abundance

Fold Change (ARV‐110 : vehicle)

4

3

2

1

0 ‐1 ‐2 ‐3 ‐4 ‐5 ‐6 ‐7

‐8

1.E‐09

AR

1.E‐07 1.E‐05 1.E‐03 1.E‐01

p‐value

2 Dmax, maximal degradation

41

ARV‐110: Phase 1 Study

First patient dosed March 2019

DESIGN

• "3 + 3" dose escalation; starting dose = 35 mg, orally, once daily (po, qd) with food
• Dose increases dependent on toxicities: range 25% (if 1 DLT in 6 pts) to 100% (≤Grade 1 Adverse Events)

KEY ENTRY CRITERIA

• Men with mCRPC
• At least two prior systemic therapies, at least one of which was abiraterone or enzalutamide
• Disease progression on most recent therapy
• • Rising PSA or 2+ new lesions upon bone scan

KEY OBJECTIVES

• Maximum Tolerated Dose/ Recommended Phase 2 Dose/ Safety
• Pharmacokinetics
• Anti‐Tumor Activity (PSA,
  RECIST)
• Biomarkers

BIOMARKERS

• AR degradation in circulating tumor cells (CTCs) and pre‐ vs post‐treatment biopsies (when available)
• AR (and other) gene mutations, amplifications in circulating tumor DNA (ctDNA)
• AR‐V7 in CTCs

PSA, Prostate specific antigen. RECIST, Response evaluation criteria in solid tumors	42

Orally dosed ARV‐471 shrinks tumors and robustly degrades ER in MCF7 xenografts

			Western Blot PD	% ER Reduction
			(18 hours post last dose)
			3 mpk	95
			10 mpk	97
		TGI	30 mpk	94
		85%
		98%
mpk = mg/kg		124%
Dose	Mean AUC0‐24	Mean Cmax
po, qd	ng*hr/ml‡	ng/ml‡
3 mpk	658	84
10 mpk	2538	312
30 mpk†	5717	962

† Single dose		43
‡ Values represent total drug concentra ons

ARV‐471: Phase 1 Study

First patient dosed August 2019

DESIGN

• "3 + 3" dose escalation; starting dose = 30 mg orally, once daily (po, qd) with food
• Dose increases dependent on toxicities: range 25% (if 1 DLT in 6 pts) to 100% (≤Grade 1 Adverse Events)

KEY ENTRY CRITERIA

• ER+/HER2‐ advanced breast cancer
• At least two prior endocrine therapies in any setting, and a CDK4/6 inhibitor
• Up to three prior cytotoxic chemotherapy regimens

KEY OBJECTIVES

• Maximum Tolerated Dose/ Recommended Phase 2 Dose/Safety
• Pharmacokinetics
• Anti‐tumor activity (RECIST, CBR)
• Biomarkers

BIOMARKERS

• ER gene (ESR1) mutational status in ctDNA and/or tumor tissue
• ER, Progesterone Receptor and Ki‐67 levels in pre‐ and post‐treatment tumor biopsies in patients with accessible tumor tissue

CBR, clinical benefit rate	44

PROTAC® degraders can be engineered to cross the blood‐brain barrier (BBB)

• Micromolar rodent brain exposure achieved	PROTAC	Species	Dose	[Plasma 1h]	[Brain 1h]	B/P ratio
after peripheral (IV) administration			(mg/kg)	(ng/ml)	(ng/g)
1	mouse	10	309	227	0.8
• Brain‐to‐plasma ratio >0.5 achievable with
2	mouse	10	843	3920	4.7
PROTAC degraders
	3	mouse	10	285	1425	5.0

Over a 4‐hour time course, PROTAC degraders are more durable in the brain than in plasma

4,000	3,920	3,550

2,470

2,000

0

1,000 843

500	520
279

Brain (ng/g)		0
Time (hours)		1	2	4
Plasma (ng/mL)	B/P Ratio		4.7	6.8	8.9

45

Seasoned leadership with expertise in advancing novel technologies

Leadership Team

Board of Directors

John G. Houston, PhD

President & CEO

Angela Cacace, PhD

VP Neuro and Platform Biology

John A. Grosso, PhD

VP Chemistry, Mfg. & Controls

Ronald Peck, MD

Chief Medical Officer

Ian Taylor, PhD

Chief Scientific Officer

Kimberly Wehger

VP Information Technology

Matthew Batters, JD

VP Bus. Development & Counsel

Sean Cassidy, CPA, MBA

Chief Financial Officer

Marcia Dougan Moore, MPH

SVP Strategic Operations

Larry Snyder, PhD

ED Medicinal Chemistry

Randy Teel, PhD

VP Corporate Development

Steve Weiss

VP Human Resources

Timothy Shannon, M.D. Chairman

John G. Houston, Ph.D.

Ted Kennedy, Jr., J.D.

Jakob Loven, Ph.D.

Brad Margus

Briggs Morrison, M.D.

Leslie Norwalk, Esq.

Liam Ratcliffe, M.D., Ph.D.

Laurie Smaldone Alsup, M.D.

46

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