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©2019 ASSEMBLY BIOSCIENCES, INC.
Elimination of Residual HBV Replication
and Prevention of cccDNA Generation with
the Combination of NrtI and Core Inhibitors
HBV Cure Workshop
November 6, 2019
Richard Colonno
Cautionary Note Regarding Forward-Looking Statements
The information in this presentation contains forward-looking statements regarding future events, including statements about the clinical and therapeutic potential of Assembly Biosciences’ HBV-cure program, the therapeutic potential of core inhibitors, including ABI-H0731, ABI-H2158, ABI-H3733, and the plans, strategies and intentions related to its HBV-cure program and proposed stages to cure. Certain forward-looking statements may be identified by reference to a future period or periods or by use of forward-looking terminology such as “potential.” Such forward-looking statements, which are intended to be covered by the safe harbor provisions contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, are just predictions and are subject to risks and uncertainties that could cause the actual events or results to differ materially. These risks and uncertainties include, among others: the scientific theory for our therapeutics is unproven and novel; outcomes of clinical studies are uncertain; results of earlier preclinical and nonclinical studies and early clinical studies may not be predictive of future clinical studies results. These and other potential risks and uncertainties that could cause actual results to differ from the results predicted are more fully detailed under the heading “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2018 and our Quarterly Report on Form 10-Q for the quarter ended June 30, 2019, each filed with the Securities and Exchange Commission (the “SEC”) and any additional reports filed with the SEC following the date of this presentation. It is not possible for Assembly Biosciences management to predict all risks nor can it assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this presentation may not occur and actual results could differ materially and adversely from those anticipated. Any forward-looking statement speaks only as of the date on which it is made, and no obligation to update or revise any forward-looking statement is assumed, whether as a result of new information, future events or otherwise, except as required by law.
Prolonged NrtI Therapy Fails to Eliminate Viral Replication
0
10
20
30
40
50
60
70
80
90
100
Pa
tie
nts
HB
V D
NA
“T
arg
et
De
tec
ted
” (
%)
HBeAg pos Patients
HBeAg neg Patients
2 53 4
Treatment Years
TDF Clinical Studies
102 (HBeAg-) and 103 (HBeAg+)1
• PCR-detectable HBV DNA persists in 70-80% of
patients despite TDF treatment for 5 years1
• Detected DNA represents infectious virus!2
• Residual viremia refractory to elimination by NrtIs
• Accounts for poor cure rates
1Marcellin, et al, AASLD 2014, Poster 18612Burdette, et al, EASL 2019, PS-150
Infe
cti
ou
s V
iru
s Treatment Period
HBV DNA LLQ
Time (years)
Critical Inhibitory Elements of New Treatment Paradigms
Eliminate Residual Virus Replication
….To Stop New Infection of Hepatocytes
Block Generation of New cccDNA
….To Stop Generation of New cccDNA and
Allow Decay of Existing cccDNA
Core Inhibitors Block Viral Replication and cccDNA Establishment
Core Protein Inhibitors (CIs)
• Bind to dimer-dimer interface of Core
protein
• Trigger formation of aberrant capsids,
preventing packaging of pgRNA and
production of virus
• Disrupt trafficking of nucleocapsids to
nucleus, blocking the generation of
cccDNA
Covalently Closed Circular DNA (cccDNA)
Packaging
of pgRNA Core
Relaxed CircularDNA (rcDNA)
Polymerase
PregenomicRNA (pgRNA)
Trafficking
to nucleus
ASMB Portfolio of CIs
• ABI-H0731 (Phase 2)
• ABI-H2158 (Phase 1b)
• ABI-H3733 (IND-enabling)
NrtI
Inhibition
Program Objectives - Targeted Steps Toward Cure
• Demonstrate safety, PK supporting QD dosing, and potent inhibition of HBV
DNA levels with monotherapy (Phase 1)
• Demonstrate ability to eliminate residual viral replication refractory to NrtI
therapy (DNA to “Target not Detected”) (Phase 2)
• Demonstrate decrease in cccDNA population as reflected by significant
reductions in pgRNA levels and other surrogate markers in absence of ALT
flares (Phase 2)
• Demonstrate further decline of viral antigens during consolidation (Phase 2)
• Following consolidation, demonstrate sustained viral DNA/RNA suppression
off therapy (Phase 2)
Overview of ABI-H0731 Phase 2a Clinical Studies
ETV + Pbo (n=12)
ETV + 731 300 mg (n=13)
ETV + 731 300 mg (n=11)
Study 211*
ETV + 731 300 mg (n=10)
NrtI + Pbo (n=18)
NrtI + 731 300 mg (n=29)
NrtI + 731 300 mg (n=15)
NrtI + Pbo (n=10)
NrtI + 731 300 mg (n=16)
NrtI + 731 300 mg (n=10)
NrtI + 731 300 mg (n=27)
NrtI + 731 300 mg (n=14)
Treatment Wks0 24 76
*n values represent the 87 patients who transitioned to 211 and remain on treatment and included in this analysis
Study 20147 HBeAg pos patients
on SOC NrtI therapy
Study 20225 HBeAg+ Rx-naïve
viremic patients
1:1
Study 20126 HBeAg neg patients
on SOC NrtI therapy
3:2
3:2
Blinded Open Label
Study 202: Superior DNA/RNA Declines with 731 Combination
0
1
2
3
4
5
6
7
8
0 4 8 12 16 20 24
ETV 731 + ETV
Faster HBV DNA Declines
4.19
5.30
Me
an
HB
V D
NA
Re
du
cti
on
(lo
g10 IU
/mL
)
Treatment Week
HBV DNA assessed by Roche Cobas qPCR; LOQ = 20 IU/mL
0
1
2
3
4
5
6
0 4 8 12 16 20 24
ETV 731 + ETV
Treatment Week
Me
an
HB
V R
NA
Re
du
cti
on
(lo
g10 U
/mL
)
Significant pgRNA Declines
0.61
2.34
HBV RNA assessed by RT qPCR; LOQ = 135 U/mL
Mechanism
Based
Inhibition
cccDNA
Depletion?
Study 201: Reduction of Refractory Virus with 731 Combo Therapy
NrtI Monotherapy
731 + NrtI Therapy
Residual viremia not eliminated by NrtI
Patient Treatment Week
Nuc M 0 2 4 8 12 16 20 24
1
TDF
2
TAF
3
TDF
4
TDF
Patient Treatment Week
Nuc M 0 2 4 8 12 16 20 24
5
TAF
6
TAF
7
ETV
8
TAF
9
TDF
10
TAF
At Week 24, longitudinal serum samples were assayed for detectable virus using sensitive PCR assay
Residual viremia decline below detection (5 IU/mL)
Lalezari et al. Oral LB-07 EASL Apr 2019
50 20 10 5 2 1 0
Gel Assay Standardization and Validation
Input DNA IU/mL of WHO Standard
Highly sensitive semi-quantitative PCR assay developed
Study 201: DNA/RNA Declines in NrtI-Suppressed Patients
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
0 5 10 15 20 25
ETV 731 + ETV
Treatment Week
Me
an
HB
V R
NA
Re
du
cti
on
(lo
g10 U
/mL
)
Significant pgRNA Declines on Combination
1.74
Deeper HBV DNA Declines on Combination
• 22 of 27 (81%) 731+NrtI patients achieved “TND” by Wk 24
NrtI Treatment
731 + NrtI Treatment
• 0 of 12 NrtI-treated patients achieved “TND” by Wk 24
• Highly sensitive semi-quantitative PCR assay developed to detect
viral DNA levels to 5 IU/mL to monitor loss of residual virus
Individual patient gel results; “Target Detected” or “Target Not Detected”
1 2 3 4 5 6 7 8 9 10 11 12Baseline
Wk 24
1 2 3 4 5 6 7 8 9 10 11 12 13 14
15 16 17 18 19 20 21 22 23 24 25 26 27
Baseline
Wk 24
Baseline
Wk 24
Further DNA/RNA Declines in Study 202/211 Patients
0
1
2
3
4
5
6
7
8
0 10 20 30 40 50
ETV
ETV+731
ETV to Combo
Treatment Week
Me
an
HB
V D
NA
Lo
g R
ed
uc
tio
n
HBV DNA Levels
Study 202 211
9 patients with
DNA <20 IU/mL
0
1
2
3
4
5
6
0 10 20 30 40 50
ETV
ETV+731
ETV to Combo
Treatment Week
Me
an
HB
V R
NA
Lo
g R
ed
uc
tio
n
HBV pgRNA Levels
Study 202 211
4 patients
with pgRNA
<135 U/mL
DNA/RNA Declines to Highly Suppressed Levels Study 201/211
HBV RNA “<35 U/mL” (LLOQ 35 U/mL)
0
10
20
30
40
50
60
70
80
90
100
% P
ati
en
ts w
ith
HB
V p
gR
NA
<3
5 U
/mL
BL W24 BL W24≥W40 ≥W40
N=29
N=27
Treatment NrtI NrtI Combo Combo Combo Combo
Study 201 201 211 201 201 211
N=17
N=17
N=29
N=15
24%18%
73%
14%
59%
70%
% P
ati
en
ts w
ith
HB
V D
NA
“T
ND
”
0
10
20
30
40
50
60
70
80
90
100
HBV DNA “Target Not Detected” (<5 IU/mL)
Treatment NrtI NrtI Combo Combo Combo Combo
BL W24 BL W24 ≥W40≥W40
N=15
N=27
Study 201 201 211 201 201 211
29% 29%
53%
7%
83%85%
N=17 N=17
N=29
N=29
BL = Study Entry
Study 202: Summary of Results at Time of AASLD Submission
• Antigen declines appear to be correlated with pgRNA declines
• Various levels of expression of HBsAg from integrated sequences limits ability of HBsAg
to serve as a surrogate for cccDNA in some patients/populations
• Please visit the LB-1 Poster at AASLD on Monday for updated results
HBeAg Positive Patients in Study 202-211
Viral Antigen Mean Reduction Individual Patients
HBeAg ≥0.6 11/22 (50%) ≥0.5, with 4 ≥1.0 log
HBcrAg ≥0.8 7/22 (32%) ≥ 1.0, with 3 ≥ 2.0 logs
HBsAg ≥0.4 7/22 (32%) ≥0.5, with 3 ≥1.0 log
Program Objectives - Targeted Steps Toward Cure
• Demonstrate safety, PK supporting QD dosing, and potent inhibition of HBV
DNA levels with monotherapy (Phase 1)
• Demonstrate ability to eliminate residual viral replication refractory to NrtI
therapy (DNA to “Target not Detected”) (Phase 2)
• Demonstrate decrease in cccDNA population as reflected by significant
reductions in pgRNA levels and other surrogate markers in absence of ALT
flares (Phase 2)
• Demonstrate further decline of viral antigens during consolidation (Phase 2)
• Following consolidation, demonstrate sustained viral DNA/RNA suppression
off therapy (Phase 2)
AASLD 2018
AASLD 2019
EASL 2019
ASMB Core Inhibitor Program Summary
• Core inhibitors have the potential to be the backbone of future HBV regimens
─ Highly potent antivirals that disrupt viral replication at multiple steps
─ Potential to eliminate residual viremia (refractory to NrtI therapy)
─ Inhibit the generation of new cccDNA
• Summary of Interim Data for Phase 2a Studies on ABI-H0731
─ Favorable safety profile
─ Combination of 731+NrtI demonstrated superior antiviral activity vs. NrtI monotherapy
• In Rx-naïve patients, faster and deeper declines in HBV DNA observed
• Reduction of residual HBV DNA (virus) using high-sensitivity PCR assay present in NrtI
“suppressed” patients
• Significant HBV pgRNA (surrogate marker of cccDNA) declines in both studies
• Decreases in HBV antigen levels
Acknowledgements
• The Patients
• The (many) clinical study teams
• Assembly Biosciences
Office of Xiaoli Ma
Quest Clinical Research
(GI) Research and Education
Asia Pacific Liver Center
Schiff Center for Liver Diseases
Toronto General Hospital
Queen Mary Hospital
Southern California Research Center
Thomas Jefferson University Hospital
Toronto Liver Center
Icahn School of Medicine at Mount Sinai
Medical Associates Research Group
Johns Hopkins University School of Medicine
Stanford University Medical Center
Infectious Disease Care
King's College Hospital
GI Research Institute
NYU Langone Medical Center
Digestive Disease Associates
Office of S Chan, MD
Waikato Hospital
Pfleger Liver Institute at UCLA
Cedars-Sinai Medical Center
Auckland Clinical Studies
Virology: Qi Huang, Ran Yan and Dawei Cai
Clinical: Uri Lopatin, Steve Knox, Katia Alves, Linda Baher and
Vivian Huey
Regulatory: Eric Ruby, Christina Schmidt, Na Yu
DMPK: Dongmei Qiang, Marc Evanchik
Thank You!