RO7020531, a novel prodrug of a toll-like receptor 7 agonist,
demonstrated desirable pharmacodynamics responses in both
AAV-HBV mice and healthy volunteers
Lu Gao1, Lue Dai1, Youjun Yu1, Xue Zhou1, Lili Gu1*, Yuyan Jin1, Yonghong Zhu1, Joseph F. Grippo2, Miriam Triyatni3, Ilia
Folitar3*, Ruchi Upmanyu4, Katerina Glavini3, Eoin Coakley2*, Tomas Racek3, Edward J. Gane5
1. Roche Innovation Centre Shanghai, China, 2. Roche Innovation Center New York, USA; 3. Roche Innovation Center Basel, Switzerland; 4. Roche Innovation Center Welwyn, UK; 5.
Auckland Clinical Studies, New Zealand; *Former Roche employee
Cure
Virus Targeted Approach
CpAM Class I RO7049389
VIRAL CYCLE
Immunoenhancers
TLR7 Agonist RO7020531
ActivationViral-mediated
suppression
Peg-IFN
Existing SoC
Virus Targeted asset
Immunoenhancer asset
Functional impairment of anti-HBV immune responses is a key feature of chronic HBV infection.
Development of a finite HBV cure will likely require combinations of novel compounds which inhibit HBV replication,
reduce antigen production and enhance HBV-specific immune responses2
HBV LNA
Nucleos(t)ide
Roche Approach Toward Combination Therapy for HBV Cure
Novel molecule
Novel molecule
CpAM: core protein allosteric modulator; LNA: locked nucleic acid; SoC: standard of care; IFN: interferon; TLR: toll-like receptor
Roche TLR7 agonist is positioned to be differentiated as an oral
double prodrug selectively converted in the liver
• TLR7 agonist induces broad immuno-modulatory effects including:
– Activation of IRF7, NFκB, and AP-1 transcription factors
– Differentiation of plasmacytoid dendritic cells (pDCs), and upregulation of co-stimulatory molecules and secretion of type 1-IFN and other
cytokines/chemokines leading to activation of T-cells and NK cells
– Differentiation of B-cells to antibody-producing plasma cells
• RO7020531 is an orally available double pro-drug of a TLR7 agonist which also activates TLR8 with lower potency
• It was safe and well tolerated in healthy volunteers with a favorable PK profile in single and multiple QOD doses up to 170 mg
Hydrolysis
Esterase
Oxidation
Aldehyde Oxidase
hTLR7 reporter EC50: 55.2 ±22.5 M
hTLR8 reporter EC50: 296 ±45 M
PBMC MEC IFNα induction: 3-6 M
CC50: > 1000 M
RO7020531
Double pro-drugSingle pro-drug Active form
Dai, L. et al. [poster]. EASL 2018; SAT-345; Gane, E. et al. [poster]. EASL 2018; FRI-3373
In the AAV-HBV mouse model, oral combination treatment with TLR7
agonist RO7020531 and CpAM RO7049389 leads to sustained viral
load suppression and HBsAg loss
4
Vehicle
TLR7 agonist 100
mg/kg QOD
CpAM
20 mg/kg QD
Combo
(n=7)
200
150
100
50
14 21 28 35 42 49 56 63 70 77 84Days
mIU
/ml
Treatment end
0
6
5
4
3
2
0 7 14 21 28 35 42 49 56 63 70 77 84
Days
Lo
g10
IU/m
l se
rum
Treatment end
LLOQ
*
Dai et al EASL 2018; SHC 2018, GHS 2018
• The combination of RO7049389 and RO7020531 reduced HBsAg level to below LLOQ at the end of treatment in 5 of 7 animals, which sustained
during 6-week off-treatment follow-up.
Results are presented as meanSEM (n = 7). LLOQ = lower limit of quantification; QD = once a day; QOD = every other day
Log 1
0co
pie
s/m
l ser
um
10
9
8
7
6
5
0 7 14 21 28 35 42 49 56 63 70 77 84Days
Treatment end
LLOQ
HBV DNA HBsAg Anti-HBs antibody
RO7020531 increases the number of germinal center B cells and
HBsAg-specific B and T cells in the spleen of AAV-HBV infected mice
• HBsAg-specific B cells were captured and measured by ELISPOT with HBsAg-coated plate.
• HBsAg-specific T cells were measured by IFN- γ ELISPOT in the presence of HBsAg peptides.
Weeks
-4 4-3 -2 0-1 1 2 3
AAV-HBV injection Oral treatment
5
Dai et al EASL 2018, SHC 2018, GHS 2018
The anti-HBV activity of RO7020531 in AAV-HBV infected mice relies on
functional adaptive immune response (B- and T- cells)
C57B/Bl6 (wild type mice) SCID (T- and B-cell deficient mice)
• Note: no change on HBeAg level was observed.
• Increasing dose levels of RO7020531 in SCID mice up to 300 mg/kg did not demonstrate anti-HBV activity.
• Plasma exposure of TLR7 agonist and innate immune responses (mRNA upregulation of interferon induced genes) in both
SCID and C57B/Bl6 mice were comparable6
Dai et al EASL 2018, SHC 2018, GHS 2018
The PD response of TLR7 signalling is observed in a dose-dependent
manner in RO7020531-treated AAV-HBV mice
* Mouse blood samples were collected at 6 hours post dose on day 28 for mRNA and cytokine tests.
TLR7 agonist RO7020531 Phase 1 umbrella study (NP39305)
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• First-in-human study for
RO7020531
• 110 healthy volunteers
dosed in Part 1
• HBV patient part initiated
in 2018 (cohort 1 to 3 in
Nuc-suppressed patients
completed)
Part
1:
Co
mp
lete
d
150 mg QOD
Cohort 1
Cohort 2
Cohort 3
SAD in HV1 single dose
MAD in HV2 weeks of QOD dosing
Safety / PD Study in HBV Patients6 Weeks QOD treatment
6 Weeks follow-up
N total =110 (88:22)
Cohort 4
Cohort 2
Cohort 1
Cohort 3
Cohort 5
Cohort 6
Cohort 7
Cohort 8
170 mg
3 mg
10 mg
20 mg
40 mg
60 mg
100 mg
140 mg
Cohort 1
Cohort 2
Cohort 3
170 mg QOD
100 mg QOD
140 mg QOD
Part
2:
co
ho
rt 1
to
3
co
mp
lete
d
N per cohort =10 (8:2)
150 mg QOD
170 mg QOD
150 mg QOD Rx naive Cohort 4
Gane, E. et al. [poster]. EASL 2018; FRI-337
Gane, E. et al. SHC, 2018
Jin, Y. et al. APASL STC, 2019
RO7020531 has a favorable pharmacokinetics profile
• Dose proportional exposure across the
full RO7020531 dose range (3 mg–170 mg)
in SAD and MAD
• The active TLR7 agonist appears rapidly in
plasma with a median Tmax of ~0.5 hrs, is
cleared within 12 hours post dose (mean
half life ~ 3.0 hr)
• Stable RO7011785 exposure over a two
week dosing with no drug accumulation
• Following multiple QOD RO7020531
doses, there was no evidence for
RO7011785 accumulation, and PK
parameters on Day 1 and Day 13 in the
MAD were comparable
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Concentration-time profiles for RO7011785 (active
agonist) following multiple QOD RO7020531 doses
0
500
1000
1500
2000
2500
3000
0 4 8 12 16 20 24
Time Post Dose (hr)
100 mg
140 mg
170 mg
0
500
1000
1500
2000
2500
3000
0 4 8 12 16 20 24
Time Post Dose (hr)
Day 1 Day 13
RO7011785 (ng/mL) RO7011785 (ng/mL)
Gane, E. et al. SHC, 2018; Jin, Y. et al. APASL STC, 2019
Pharmacodynamic activity first demonstrated at 100 mg (SAD)
• PD Evaluations: TLR activation markers in serum (IFN-α, IL-6, TNF-α, IL-10, IL-12p40, IP-10 and
neopterin) and expression of ISG15, OAS-1, MX1 and TLR7 mRNAs in whole blood
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• Following a single 100 mg RO7020531 dose, 3/8 subjects exhibited increases in IFN-α indicative of TLR7
activation (Panel A)
• These changes in IFN-α were accompanied by increases above baseline for other markers of TLR7
activation including ISG-15 and OAS-1 shown as an example for Subject 1 (Panel B) following the
expected temporal pattern after the appearance of plasma RO7011785
Panel A Panel B
0.00
0.05
0.10
0.15
0.20
0.25
0
5
10
15
20
25
30
35
0 4 8 12 16 20 24
Time Post Dose (hr)
ISG15
OAS-1
Interferon
RO7011785
Fold
ch
an
ge
fro
m b
ase
line
(IS
G1
5 a
nd
OA
S-1
) Inte
rfero
n (p
g/m
L)
RO
701
17
85
(ug
/mL
)
0.00
0.05
0.10
0.15
0.20
0.25
0 4 8 12 16 20 24
Inte
rfe
ron (
pg
/mL
)
Time Post Dose (hr)
Subject 1
Subject 2
Subject 3
Baseline Value (dashed line)
Gane, E. et al. SHC, 2018; Jin, Y. et al. APASL STC, 2019
Higher RO7020531 doses yields more ‘responders’ and with a
greater amplitude of response (SAD cohorts)
With increasing single dose, the fraction of subjects exhibiting TLR7 PD activity and the magnitude of
response increased with a plateau of geometric mean response magnitude at 170 mg
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Dose (mg)
ISG15 OAS1
Fraction
responding
Geometric mean fold
change (range)
Fraction
responding
Geometric mean fold
change (range)
Placebo 0/16 - 0/16 -
3 1/8 2.4 (2.4–2.4) 0/8 -
10 0/8 - 0/8 -
20 1/8 2.6 (2.6–2.6) 0/8 -
40 1/8 2.9 (2.9–2.9) 0/8 -
60 1/8 2.6 (2.6–2.6) 2/8 2.4 (2.0–2.9)
100 6/8 5.9 (2.3–29.3) 5/8 3.8 (1.9–6.9)
140 8/8 11.6 (2.3–48.0) 8/8 5.5 (2.2–18.1)
170 8/8 11.2 (2.5–132.2) 8/8 5.5 (2.0–19.0)
Gane, E. et al. SHC, 2018; Jin, Y. et al. APASL STC, 2019
PD activity maintained across multiple biomarkers with QOD
dosing of RO7020531
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INF-α ISG15 mRNA
0
2
4
6
8
10
12
14
16
18
20
0 2 4 6 8 10 12 14
Inte
rfe
ron
(p
g/m
L)
Study Day
100 mg 140 mg 170 mg
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14Fo
ld C
ha
ng
e F
rom
Ba
se
line
Study Day
100 mg 140 mg 170 mg
In the MAD cohorts, biomarker response was maintained over the 2 week QOD dosing
Jin, Y. et al. APASL STC, 2019
Summary
• RO7020531 is a novel double pro-drug of a TLR7 agonist.
• In the AAV-HBV mouse model, RO7020531 induced both innate PD responses and adaptive
immune responses which are important for therapeutic effects. The oral combination of the
CpAM and TLR7 agonist demonstrated robust suppression of both HBsAg and HBV DNA levels
and with the additional emergence of anti-HBs antibodies in several animals
• RO7020531 appears to be safe and tolerable with a predictable PK profile for the active TLR7
agonist in human.
• PD effects in human are observed with doses starting at 100 mg. At higher doses, more
responders and greater amplitude of response are observed.
• These promising preclinical results and Phase 1 clinical data provide encouragement to further
explore RO7020531’s therapeutic effect in chronic hepatitis B patients in combination with direct
acting antiviral agents.
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