Download pdf - Curative Innovations for Hepatitis B and Other Viral Diseases

Curative Innovations for

Hepatitis B and Other

Viral Diseases

September 2021

HBV Remains

a Formidable

Challenge

Despite decades of ongoing effort,

the current standard of care is still

unable to provide a functional cure

for HBV infection

Achieving this for the vast majority of HBV patients is the key unmet

need and aspiration of the marketplace

2

Deeply

Experienced,

Results-

Driven

Leadership

ABEL DE LA

ROSA, PHDChairman I Senior Scientific &

Strategic Advisor

Coinventor of ATI-2173

Cofounder

PHARMASSET

• SVP Business Development

& Scientific Affairs

• Executive team member that

helped build company from

$30MM valuation through

development of Sofosbuvir for

HCV, IPO, and $11B acquisition

by Gilead

EMORY UNIVERSITY—

DRIVE

•Chief Scientific Officer

• Visible Genetics

GREG MAYESChief Executive Officer

ENGAGE THERAPEUTICS

• Founder and CEO

• $40MM raised, acquired by

UCB in 2020 for $270MM

following positive phase 2b

study

ADVAXIS

IMMUNOTHERAPIES

•Chief Scientific Officer

• Visible Genetics

VP,PRODUCT

DEVELOPMENT

• Acquired by Bayer

IMCLONE SYSTEMS

• VP, General Counsel, and

Chief Compliance Officer

• Acquired by Eli Lilly for $6.5B

DOUG MAYERS, MDChief Medical Officer

Cofounder

IDENIX

•Chief Medical Officer

• Acquired by Merck for $3.9B

COCRYSTAL PHARMA, INC.

•Chief Medical Officer

• NASDAQ: COCP

BOEHRINGER INGELHEIM

• Therapeutic Area Head and

International Vice President of

Virology

TAMRA ADAMSChief Financial Officer

ACCOUNTING CONCEPTS

• Founder

• Consulting CFO for Engage

Therapeutics until sale to UCB

GOLDMAN SACHS

• Senior Accounting Officer

ERNST & YOUNG

• Senior Auditor

Board of Directors

Benjamin Rovinski David Canner Iyona Rajkomar Patrick Higgins Scott Morenstein

3

ANTIOS Investment Highlights

Clinical-stage biopharma company focused on innovative therapies to treat and cure hepatitis B

• 250MM to 300MM individuals infected with chronic HBV worldwide require lifelong therapy; larger market than

hepatitis C and HIV combined

Accomplished leadership team: Cofounder helped build Pharmasset’s curative hepatitis C franchise

Lead drug candidate ATI-2173 has potential to become the cornerstone of curative, once-daily HBV therapy

• ATI-2173 is the only active site polymerase inhibitor nucleotide (ASPIN) in development

• ASPIN mechanism is complementary to all other approaches—potential to completely shut down viral

replication and cure hepatitis B

Phase 2 program informed by compelling phase 1b proof-of-concept data

• Efficacy—Potent, “next-generation ASPIN” antiviral activity confirmed, sustained beyond treatment cessation

• Safety—ATI-2173 liver-targeted active metabolite; finite duration of treatment; well tolerated

Solid interest from investor group with relevant experience

• Investors include RA Capital, Adage, Pontifax, and Aisling

• Regular phase 2 data readouts expected through 2022

4

Supported by Leading Healthcare Investors

5

Our Vision Is

a World

Liberated

From the

Burden of HBV

ATI-2173

THE CORNERSTONE OF CUREBecoming the critical component for achieving functional cure

for nearly all people living with hepatitis B

• The first stone set, serving as

a reference for all others

• Cornerstones serve as the

guiding light that determines

the position or direction of

everything that follows

6

Chronic HBV is a Greater Global Burden Than HCV

and HIV Combined

End-stage liver disease

(~20% of patients)

Death (~900K annually)

Source: WHO; CDC; ClearView Analysis.

Globally, 250MM to 300MM

adults have chronic HBV

1.0MM 1.8MM 77MM

Failure to successfully manage HBV leads to:

Low worldwide treatment rates

represent an opportunity-35% -35% -10%

7

Development of hepatocellular

carcinoma in ~50% of patients

Source: Tang, LSY, et al.2018 JAMA

Viable

Solutions

Promise

Substantial

Rewards

Source: WHO; CDC; ClearView Analysis.

Market Research Suggests >$9 Billion

Cumulative ATI-2173 Sales Potential

From US, China and EU

Base Case Cumulative Sales for ATI-2173

(2026-2042, US, EU3, China)

0 1 2 3 4 5 6 7 8 9

HBV

Revenue ($B)

$3.4 (US) $1.8 (EU3) $2.7 (China)

8

Chronic HBV Currently Demands Complex,

Lifelong Therapy To Sustain Viral Suppression

HBV complexity will almost

certainly require combination

therapy to effect a true cure

SOC chain-terminating nucleoside

analogues (tenofovir and entecavir)

control replication—but >90% of

patients relapse quickly on treatment

discontinuation

HBV:DNA virus with cccDNA that

stays inside the nucleus and

acts as a reservoir to

sustain the infection

CURE COMPLEXITYLESS MORE

HIV:Retrovirus that

integrates into the host

genome resulting in

lifelong infection

HCV: An RNA virus with

no reservoir

9

Poised to Repeat Transformational HCV Treatment Success in HBV

10

Prior to 2014:

• Very low HCV cure rates (10-50%); commensurately low product sales

• Injectable interferon was the backbone of treatment

Sofosbuvir-based regimens were the inflection point that changed HCV

treatment forever

• 1st approved oral nucleotide achieved cure rates >85%

• Eliminated the need for interferon

• >400,000 patients treated in first 36 months post launch

• 8x increase in patient initiation from 2013 to 2015

• Peak sales in US: ~$12B

Previous Pharmasset, Idenix, and Abbvie leadership are now at

Antios to repeat history with ATI-2173 for HBV

HCV Milestones: Improved Safety and Efficacy

Mavyret

Telbivudine

Protease Inhibitor

(Boceprevir or

Telaprevir) with INF/RIVINF-alpha 2b

(IFN)

INF-alpha 2b and

ribavirin Combination

(IFN + RBV)

First commercially

available HBV vaccine

INF-alpha

Adefovir

Entecavir

Tenofovir Tenofovir

alafenamide

Harvoni

Viekira Pak

1990’s 2010’s 2020

HBV Milestones

Lamivudine

(Nuc)

2000’s

Sovaldi

Olysio

The HBV Market is Well Positioned to Parallel the

Innovation Seen in HCV

Sofosbuvir-based regimens were the inflection

point that changed HCV treatment forever

1st approved oral nucleotide achieved cure rates >85%

>400,000 patients treated in first 36 months post launch

8x increase in patient initiation from 2013 to 2015

Peak sales in US: ~$12B

HCV Classes: PI, Nuc, NS3/4A, NS5A, NS5B

New Classes: ASPIN, CAM, STOP, RNA destabilizer, siRNA/ASO

HCV

SVR

Rates

<10% <46% <56-60%

Addition of Interferon Free All-Oral regimens

85-98%

11

The Only ASPIN in Development Leverages a Unique

Mechanism To Empower Combination Therapy

Chain-terminating nucleoside analogues

like tenofovir and entecavir compete for

positions in the replicating viral DNA,

expending themselves through incorporation

to block some DNA synthesis through

chain termination

ATI-2173 actively binds to and distorts

the HBV polymerase enzyme’s active

site to catastrophically disrupt ALL

aspects of polymerase activity (protein

priming, chain elongation, and DNA

synthesis)

12

Combination

Therapy is

Within Reach

ATI-2173 combined with a complementary

mechanism, in a convenient, once-daily

regimen, could completely shut down HBV

replication—and potentially cure HBV

infected individuals

13

Arbutus Bio (AB-729)

Antios Partner

Arrowhead (JNJ-3989)

Vir Biotech (VIR-2218)

Assembly Bio (ABI-H0731)

Assembly Bio (ABI-H3733)

Arbutus Bio (AB-836)

Enanta (EDP-514)

Aligos Ther (ALG-00184)

ETV, entecavir; siRNA,

small/short interfering

ribonucleic acid; TDF,

tenofovir.

ATI-2173 Creates Wide Opportunity for Powerful

Combination Regimens

14

Building On Experience to Optimize

Treatment Potential

*Yoo, et al. Hepatol 2007; 45:1172-1178, Yoo, et al. Hepatol 2007; 46:1041-1048.†Clevudine was first approved in South Korea in 2006.

ATI-2173

• Clevudine demonstrated sustained off-treatment antiviral efficacy vs SOC in HBV-infected patients in

South Korean trials*,†

• However, Pharmasset voluntarily discontinued further development due to reversible proximal skeletal

muscle myopathy seen in some patients after long-term dosing

• ATI-2173 is a liver-targeted phosphoramidate prodrug of clevudine

• ATI-2173 is ion-trapped in the liver as clevudine monophosphate,

leading to:

▪ High liver clevudine triphosphate levels

▪ Low systemic clevudine exposure

• 1-year finite duration of therapy further reduces potential myopathy risk

ATI-2173 leverages that sustained potency, while enhancing safety

15

ATI-2173 Significantly Reduces Systemic

Clevudine Exposure

Squires et al. 2021 EASL; Abstract 1240, *Lim, S. G. et al. 2008 Aliment Pharmacol Ther

• In a phase 1B study, ATI-2173 was rapidly

cleared from the blood within 4 to 6 hours

• Clevudine exposure was dose proportional

and multiple-fold below 30 mg dose of

clevudine

• 56 ng/mL was the historical clevudine

Cmin during treatment*

0 8 16 24

0

20

40

60

80Clevudine

56 ng/mL

Pla

sm

a C

once

ntr

ation

(n

g/m

L)

Hours

50mg–Day 28

25mg–Day 28

16

ATI-2173 Phase 1b Safety Data Similar to Placebo

Mayers et al. 2021 EASL; Abstract 1251.

TEAE, treatment-emergent adverse event.

No serious adverse events or adverse events leading to study drug discontinuation

MedDRA System Organ Class

Preferred Term

All Cohorts

Placebo

(n=7)

n (%)

Cohort C

10 mg

(n=6)

n (%)

Cohort A

25 mg

(n=5)

n (%)

Cohort B

50 mg

(n=6)

n (%)

Subjects with any TEAE 5 (71.4) 1 (16.7) 3 (60.0) 4 (66.7)

Thrombocytosis 0 1 (16.7) 0 0

Secondary thrombocytopenia 0 0 0 1 (16.7)

External ear pain 0 0 0 1 (16.7)

Nausea 0 0 0 1 (16.7)

Fatigue 0 0 1 (20.0) 0

Inflammation 1 (14.3) 0 0 0

Flu 0 0 0 1 (16.7)

Common cold 1 (14.3) 0 0 0

Coronavirus infection 0 0 1 (20.0) 1 (16.7)

ALT/AST high 2 (28.6) 0 0 0

Blood creatine phosphokinase increased 1 (14.3) 0 0 0

Bone pain 0 0 1 (20.0) 0

Headache 1 (14.3) 0 2 (40.0) 1 (16.7)

17

All Doses of ATI-2173 Demonstrated Potent

Antiviral Activity

*Marcellin, P et. al. 2004. Hepatology


Viral reductions with ATI-2173

corresponded to those seen

previously with clevudine

treatment: 2.5 to 3 log10*

• 25 mg ATI-2173 (n=5): 2.7 log10

• 50 mg ATI-2173 (n=6): 2.7 log10

• Placebo (n=7): 0.2 log10 increase

Ch

an

ge

Fro

m B

aselin

e (

HB

V D

NA

lo

g1

0IU

/mL

)

0 7 14 21 28

-5

-4

-3

-2

-1

0

1

Day

25mg

Placebo

50mg

18

Prolonged HBV RNA suppression with ATI-2173

demonstrates potential cccDNA activity

• 28-day ATI-2173 (25 or 50mg) treatment

decreases HBV RNA in all subjects

• Two subjects were below level of quantification

(BLQ) at baseline and throughout most of

study, thus were excluded from analysis

• Missing data from one subject

• RNA decreased on treatment and continued to

decrease off treatment for one month, similar to

DNA

• Reduction in HBV RNA was sustained for ATI-

2173-dosed subjects

• All ATI-2173 (25 or 50mg) treated subjects are

BLQ by W4 off-treatment and slowly trend toward

baseline by W24 off-treatment

• Placebo treatment is associated with no pattern of

change in HBV RNA

• One subject was BLQ at baseline and

throughout study, thus is excluded from

analysis

Sustained BLQ D28 W4 (D55) W12 (D111) W24 (D195)

Placebo subjects, N 6 6 5 5

Active subjects, N 8 8 7 7

Placebo, n (% of N)1

(17%)0

(0%)1

(20%)0

(0%)

25/50mg with BLQ, n (% of N)

5(63%)

8(100%)

7(100%)

3(43%)

Off treatment

19

Change by subject to EOTHBV RNA suppression correlates to reduced

cccDNA activity and may predict off-

treatment SVRs

0 28 56 84 112 140 168 196

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

Day

HB

V R

NA

(lo

g10 c

op

ies/m

L)

Ch

an

ge f

rom

Baselin

e

Change from Baseline

Placebo

ATI-2173 25 or 50mg

0 28 56 84 112 140 168 196

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

Day

HB

V R

NA

(lo

g10 c

op

ies/m

L)

Ch

an

ge f

rom

Baselin

e

Change from Baseline

Placebo

ATI-2173 25 or 50mg

ALT Normalizes With ATI-2173 Therapy

As expected, antigen levels remained unchanged during short duration of treatment

100

80

60

40

20

0

AL

T, U

/L

Day

0 7 14 21 28 35 42 49 56

ULN

Range

Placebo (n=7) ATI-2173 25 mg (n=5) ATI-2173 50 mg (n=6)

White shading indicates the 28-day treatment period. ALT, alanine aminotransferase; ULN, upper limit of normal.

20

ATI-2173 Showed Extended Off-treatment Responses


• 25 mg and 50 mg show equivalent

HBV DNA suppression

• One patient achieved SVR24

in 25 mg arm and was followed

until relapse

21

n treatment ff treatment

B

Placebo

B B B B

B B B B B B B

B B B B B B B B

B B B b B B

A I mg

B B B B B B

B B B

B B B B B

B B B B B

B B B B

B I m ebound detectable NA after B A flare

AT

I-2

17

3 2

5 m

g

Study Design

• ATI-2173 + TDF will be administered orally, once daily for 90 days in treatment naïve patients then stopped

• Treatment will be restarted for HBV-infected subjects during follow-up if viral rebound or a hepatic flare

• SVR24 data for HBV DNA will be available in mid-2022

• Addition of 2 cohorts, 1 with an siRNA and 1 with a core inhibitor in late-2021 (SAVE-2)

End of

Study

Follow-Up

24 weeks

Treatment

12 weeksScreening ≤8 weeks

SAVE-1 and SAVE-2 (Sustained Antiviral Efficacy) Trial

Cohort A: 25 mg HBV

Fully enrolled

ATI-2173 25 mg + TDF (n=8)

Placebo 25 mg + TDF (n=2)

Cohort B: 50 mg HBV

Fully enrolled

ATI-2173 50 mg + TDF (n=8)


Cohort C: 50 mg HBV/HDV

Enrolling

ATI-2173 50 mg + TDF (n=8)


Cohort E (other partner ): 25 mg

HBV

Start up

ATI-2173 25 mg + CI + TDF (n=8)

Placebo + TDF (n=2)

Cohort D (Arbutus): 25 mg HBV

Start up

ATI-2173 25 mg + siRNA + TDF

(n=8)

Placebo + TDF (n=2)

SA

VE

-1

SA

VE

-2

Phase 2a Study Design

22

Future Phase 2 Studies to Commence in H2 2022

Study Design

• Phase 2 studies with HBV mono-infected patients dosing for 1 year with ATI-2173 + TDF

• Treatment naïve study to include patients who have had no HBV treatment or have been off HBV treatment for > 6 months

• Treatment experienced study to include patients who have been controlled on NRTIs for > 1 year

• Studies will include both HBeAg positive and negative patients

• Global reach with sites in US, EU, and Asia

• Flexible approach allows additional studies with novel HBV agents.

Treatment

Experienced

Approximately n=140

TDF + Placebo

ATI-2173 + TDF

Follow-Up 24 weeksTreatment Duration up to 1 yearScreening ≤ 8

weeks

Primary Endpoint:

HBV DNA SVR 24 weeks

post-treatment

Secondary Endpoint:

HBsAg Loss

Treatment Naïve

Approximately n=100

23

TDF + Placebo

ATI-2173 + TDF

ATI-2173 Proprietary Manufacturing

Process in Place

API manufacture:

• Developed and optimized an 8 linear step chiral

process from the GMP starting material

• Used to produce 3 separate 25+ kg batches of API

• API produced is >99.7% pure

• Low cost of goods

• Primary supplier of API engaged; several potential

backup suppliers have been identified

Drug product manufacture:

• DP formulation developed

• Currently used to manufacture 25 mg capsules

• 2+ year shelf life for capsules

24

24

ATI-2173—Extended, Multilayer IP Protection

• ATI-2173: 9 patents issued (US and

international) including composition of

matter, method of use, and synthesis;

IP protection expected to 2042;

17 applications pending

• ATI-2173 combination: 1 patent

issued with protection to 2042;

15 applications pending

Robust portfolio of patents granted worldwide

(August 2021)

US, Japan, S Africa, Israel, Singapore, Australia,

Eurasia (Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Russia, Tajikistan, and Turkmenistan).

25

Inflection-point Progress Continues to add Value

2021 2022

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

1Q21: Series

B/Crossover

Financing

1Q21:

Phase 2a First

Patient Dosed

2Q21:

EASL 2021

Phase 1b Data

Presentations

3Q21:

SAVE-2:

Clinical Trial

Collaborations

Announced

2Q22:

SVR24

Off-treatment

Combination

Data

2Q21:

Chronic Tox

Skeletal Muscle

Histopath

3Q21:

Phase 2a

On-treatment

Combination

Data

1Q22: Phase 2a End-of-

treatment

Virology

Endpoints

Q422:

Off Treatment

Triplet

Combination

Data

Q421:

New Product

Announcement

3/4Q22:

First Patient

Dosed In

Phase II

26

Antios Vision—A Cure for HBV

ATI-2173 has demonstrated potent HBV viral suppression with durable off-treatment suppression in early studies

Liver-targeting offers the potential for an enhanced safety profile for ATI-2173 by lowering systemic exposure to clevudine

The only active site polymerase inhibitor nucleotide (ASPIN) in development—a potential future cornerstone for curative HBV combination therapy

Cumulative sales potential exceeds $9B in US, China, and EU

Antios maintains a robust IP portfolio, wholly-owned proprietary manufacturing process, and strategic flexibility to pursue beneficial biopharmaceutical partnerships

ATI-2173 could be combined with a complementary drug class to create an oral regimen that sustainably shuts down all viral replication

27

Thank you

Curative Innovations for Hepatitis B and Other Viral Diseases