Update on safety and efficacy in the REP 401...
Transcript of Update on safety and efficacy in the REP 401...
Update on safety and efficacy in the REP 401 protocol:
REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha 2a in treatment naïve Caucasian patients with chronic HBeAg
negative HBV infection
M. Bazinet, V. Pantea, G. Placinta, I. Moscalu, V. Cebotarescu, L. Cojuhari, P. Jimbei,L. Iarovoi, V. Smesnoi, T. Musteata, A. Jucov, A. Krawczyk, A. Vaillant
Infectious DiseaseClinic
Toma CiorbăHospital
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Disclosures
M. Bazinet, A. Vaillant: employees and shareholders in Replicor Inc.
All other authors: no conflicts of interest to declare.
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Particle production in HBV
Infectedhepatocyte
Virions + filaments
HBeAg
Capsids
cccDNA
SUBVIRAL PARTICLES: The bulk of circulating HBsAgHBsAg is an immunosupressor:
•Masks anti-HBs response
•Blocks signalling mechanisms in innate and adaptive immunity
•Blocks the effect of immunotherapies
•HBsAg clearance is critical to achieving functional control
M. Bazinet et al., 2016 Hepatology 64: S912AAl-Mahtab et al., 2016 PLOS One 11: e0156667Shi et al. 2012 PLOS One 7: e44900Woltman et al. 2011 PLOS One 6: e15324Op den Brouw et al., 2009. Immunology, 126: 280-289Wu et al., 2009. Hepatology, 49: 1132-11 Xu et al., 2009. Molecular immunology, 46: 2640-2646Cheng et al., 2005. Journal of Hepatology, 43:4 65-471Vanlandschoot et al., 2002. J. Gen. Virol., 83: 1281-1289
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Infectedhepatocyte
Virions + filaments
HBeAg
Capsids
cccDNA
NAPs block subviralparticle release
Efficient HBsAg clearancefrom the blood
Vaillant, 2016. Antiviral Res. 133: 32-40Al-Mahtab et al., 2016 PLOS One 11: e0156667M. Bazinet et al., 2016 AASLD Abstract 1848.Reesink et al., 2016 Hepatol. Int. 10: S2Noordeen et al., 2015 PLOS One 10: e0140909
Critical effects of HBsAg clearance:
•Unmasking anti-HBs response
•Elimination of HBsAg mediated immunosupression
• Improved response to immunotherapy
•Functional control can be established in most patients
Nucleic Acid Polymers (NAPs)
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REP 401 Design
Primary efficacy endpoints:
Initial follow up scheduled 4, 12, 24 and 48 weeks after all treatment is stopped
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REP 2139-Mg / REP 2165-Mg (1:1)PegasysTDF
Patients with< 3 log HBsAgresponse at49 weeks
PegasysTDF
PegasysTDF
Wee
k 1
Wee
k 25
Wee
k 49
Wee
k 73
Wee
k 97
Follo
w-u
pFo
llow
-up
Follo
w-u
p
EXPERIMENTAL(20 patients)
ADAPTIVECOMPARATORCONTROL(20 patients)
TDF
REP 2139-Mg / REP 2165-Mg (1:1)
(≥ 6 months HBsAg < 1 IU/ml, HBV DNA < 1000 copies / ml)
• Serum HBsAg reduction• Appearance of anti-HBs• Functional control maintained after treatment withdrawal
Dosing: • TDF 300mg PO qD• Pegasys 180ug SC qW• NAPs: REP 2139-Mg or REP 2165-Mg 250mg IV qW• REP 2165 = REP 2139 variant with improved tissue clearance
15/ 20 control patients have crossed over to NAP therapy
Clinicaltrials.org # NCT02565719Randomized, open label, active comparator controlled3 trial sites (Chisinau, Moldova)
Patient population:• Treatment naive• HBeAg negative• Fibrotic (not cirrhotic)
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REP 401 patient demographics
ParameterAdaptive comparator
control(TDF + peg-IFN)
Experimental(TDF + peg-IFN +
NAPs)Age
(average / median) Average 36.9 / 36 38.6 / 39.5
Sex 27M / 3F 26M / 4F
HBV genotypeA 1 2
D 19 18
Metavir score(based on Fibroscan)
F0-F1 12 10
F2 3 6
F2-F3 0 3
F3-F4 3 1
Virologic baseline(average / median)
HBV DNA (IU/mL) 3.6x107 / 8.7x104 4.8x106 / 4.8x104
HBsAg (IU/mL 14775.7 / 9302.5 9018.1 / 8743
Anti-HBs (mIU/mL) 0.78 / 0.1 2.778 / 0.1
7
1.E-011.E+001.E+011.E+021.E+031.E+041.E+051.E+061.E+071.E+081.E+09
-5 5 15 25 35 45 55 65 75
Seru
m H
BV D
NA (
IU /
ml)
Weeks of treatment
1.E-011.E+001.E+011.E+021.E+031.E+041.E+051.E+061.E+071.E+081.E+09
-5 5 15 25 35 45 55 65 75
Seru
m H
BV D
NA (
IU /
ml)
Weeks of treatment
LLOQ
TND
LLOQ
TND
Interim Efficacy data (serum HBV DNA)
LLOQ = lower limit of quantification (10 IU / ml)TND = HBV DNA target not detected
REP 2139 REP 2165TDF
peg-IFN
REP 2139
TDFpeg-IFN
REP 2139
TDFpeg-IFN
REP 2165
TDFpeg-IFN
REP 2165
8
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
Interim Efficacy data (serum HBsAg)
LLOQ
TND
LLOQ
TND
LLOQ = lower limit of quantification (0.05 IU / mL)TND = HBsAg not detected (0.00 IU / mL)
REP 2139 REP 2165TDF
peg-IFN
REP 2139
TDFpeg-IFN
REP 2139
TDFpeg-IFN
REP 2165
HBsAg response > 4 log: 8/9 0/7HBsAg loss (≤0.01 IU/mL): 7/9 0/7
HBsAg response > 4 log: 6/10 2/8HBsAg loss (≤0.01 IU/mL): 5/10 1/8
TDFpeg-IFN
TDFpeg-IFN
REP 2165
TDFpeg-IFN
2 patients
9
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75Se
rum
ant
i-HBs
(mIU
/ m
l)
Weeks of treatment
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75Se
rum
ant
i-HBs
(mIU
/ m
l)
Weeks of treatment
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75Se
rum
ant
i-HBs
(mIU
/ m
l)
Weeks of treatment
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m a
nti-H
Bs (m
IU /
ml)
Weeks of treatment
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m a
nti-H
Bs (m
IU /
ml)
Weeks of treatment
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
-5 5 15 25 35 45 55 65 75
Seru
m a
nti-H
Bs (m
IU /
ml)
Weeks of treatment
Interim Efficacy data (serum anti-HBs)
Prot. Imm.
Prot. Imm. = Architect defined threshold for protective immunity (10 mIU / mL)absent = no significant anti-HBs present (≤ 0.1 mIU / mL)
REP 2139 REP 2165
Prot. Imm.
absent absent
Elevation in serum anti-HBs correlated with extent of HBsAg reduction
peg-IFN
REP 2139
TDFpeg-IFN
REP 2139
TDFpeg-IFN
REP 2165
peg-IFN peg-IFN
REP 2165
peg-IFNTDF TDF
10
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
LT (U
/ L)
Weeks of treatment
Interim Efficacy Data (serum ALT)
upper limit of normal
REP 2139 REP 2165TDF
peg-IFN
REP 2139
TDFpeg-IFN
REP 2139
TDFpeg-IFN
REP 2165
TDFpeg-IFN
REP 2165
Elevation in serum ALT correlated with HBsAg reduction(self-resolving with continued therapy)
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
LT (U
/ L)
Weeks of treatment
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
LT (U
/ L)
Weeks of treatment
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
LT (U
/ L)
Weeks of treatment
(1748, 1425)
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0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
ST (U
/ L)
Weeks of treatment
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
ST (U
/ L)
Weeks of treatment
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
ST (U
/ L)
Weeks of treatment
Interim Efficacy Data (serum AST)REP 2139 REP 2165
TDFpeg-IFN
REP 2139
TDFpeg-IFN
REP 2139
TDFpeg-IFN
REP 2165
TDFpeg-IFN
REP 2165
upper limit of normal
Elevation in serum AST correlated with HBsAg reduction(self-resolving with continued therapy)
(1284)
0
200
400
600
800
1,000
-5 5 15 25 35 45 55 65 75
Seru
m A
ST (U
/ L)
Weeks of treatment
12
0
100
200
300
400
500
600
-5 5 15 25 35 45 55 65 75
GG
T (U
/ L)
Weeks of treatment
0
100
200
300
400
500
600
-5 5 15 25 35 45 55 65 75
GG
T (U
/ L)
Weeks of treatment
0
100
200
300
400
500
600
-5 5 15 25 35 45 55 65 75
GG
T (U
/ L)
Weeks of treatment
0
100
200
300
400
500
600
-5 5 15 25 35 45 55 65 75
GG
T (U
/ L)
Weeks of treatment
Interim Efficacy Data (serum GGT)REP 2139 REP 2165
TDFpeg-IFN
REP 2139
TDFpeg-IFN
TDFpeg-IFN
REP 2165-Mg
TDFpeg-IFN
REP 2165
upper limit of normal
Elevation in serum GGT correlated with HBsAg reduction
REP 2139
13
Interim REP 401 Safety Data (liver function)RE
P 21
39RE
P 21
65
Bilirubin (μmol / L) Albumin (g / L) INR
upper limit of normal / normal range
Liver function normal during transaminase flares
0
10
20
30
40
-5 5 15 25 35 45 55 65 75
Tota
l bili
rubi
n (u
mol
/ L)
Weeks of treatment
0
10
20
30
40
-5 5 15 25 35 45 55 65 75
Tota
l bili
rubi
n (u
mol
/ L)
Weeks of treatment
0
20
40
60
80
100
-5 5 15 25 35 45 55 65 75Se
rum
alb
umin
(g
/ L)
Weeks of treatment
0
20
40
60
80
100
-5 5 15 25 35 45 55 65 75
Seru
m a
lbum
in (
g / L
)
Weeks of treatment
0
1
2
-5 5 15 25 35 45 55 65 75
INR
Weeks of treatment
0
1
2
-5 5 15 25 35 45 55 65 75
INR
Weeks of treatment
14
Interim REP 401 Safety Data(kidney function)
Creatinine (μmol / L)BUN (mmol / L) Uric acid (umol / L)
upper limit of normal / normal range
REP
2139
REP
2165
Kidney function not altered by the presence of NAPs
0
2
4
6
8
10
-5 5 15 25 35 45 55 65 75
Seru
m B
UN (m
mol
/ L)
Weeks of treatment
0
50
100
150
-5 5 15 25 35 45 55 65 75Se
rum
cre
atin
ine
(µm
ol /
L)Weeks of treatment
0
50
100
150
-5 5 15 25 35 45 55 65 75
Seru
m c
reat
inin
e (µ
mol
/ L)
Weeks of treatment
0
2
4
6
8
10
-5 5 15 25 35 45 55 65 75
Seru
m B
UN (m
mol
/ L)
Weeks of treatment
0
100
200
300
400
500
600
-5 5 15 25 35 45 55 65 75
Seru
m u
ric a
cid
(um
ol /
L)
Weeks of treatment
0
100
200
300
400
500
600
-5 5 15 25 35 45 55 65 75
Seru
m u
ric a
cid
(um
ol /
L)
Weeks of treatment
15
Platelets (1012 / L)
Interim REP 401 Safety Data (hematology)
Hemoglobin (g / L) RBC (1012 / L) WBC (109 / L)
normal range
REP
2139
REP
2165
Thrombocytopenia and leucopenia consistent with the introduction of peg-IFN(not altered by presence of NAPs)
020406080
100120140160180200
-5 5 15 25 35 45 55 65 75
Hem
oglo
bin
(g /
L)
Weeks of treatment
020406080
100120140160180200
-5 5 15 25 35 45 55 65 75
Hem
oglo
bin
(g /
L)
Weeks of treatment
0123456789
10
-5 5 15 25 35 45 55 65 75
RBC
(mil
/ µL)
Weeks of treatment
0123456789
10
-5 5 15 25 35 45 55 65 75
RBC
(mil
/ µL)
Weeks of treatment
050
100150200250300350400450500
-5 5 15 25 35 45 55 65 75
Plat
elet
s (m
il / µ
L)
Weeks of treatment
050
100150200250300350400450500
-5 5 15 25 35 45 55 65 75Pl
atel
ets
(mil
/ µL)
Weeks of treatment
02468
101214161820
-5 5 15 25 35 45 55 65 75
WBC
(mii
/ µL)
Weeks of treatment
02468
101214161820
-5 5 15 25 35 45 55 65 75
WBC
(mii
/ µL)
Weeks of treatment
Is peg-IFN induced leucopeniaassociated with immune exhaustion?
16
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m a
nti-H
Bs (m
IU /
ml)
Weeks of NAP exposure
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m a
nti-H
Bs (m
IU /
ml)
Weeks of NAP exposure
NAP-induced HBsAg reduction as a tool for examining response to immunotherapy?
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
Seru
m H
BsAg
(IU
/ m
l)
1.E-03
1.E-02
1.E-01
1.E+00
1.E+01
1.E+02
1.E+03
1.E+04
1.E+05
Seru
m H
BsAg
(IU
/ m
l)
TDF
peg-IFNNAP
TDF
peg-IFNno peg-IFN
REP 2139 REP 2165
HBsAg
Anti-HBs
Comparable HBsAg and anti-HBs response
NAP
(Synchronization of virologic response to start of NAP therapy)
NAPs started 24 weeksafter peg-IFN
NAPs started withpeg-IFN
LLOQ
TND
LLOQ: lower limit of quantification (0.05 IU / mL)TND: HBsAg not detected (0.00 IU / mL)Prot. Imm.: Architect defined threshold for protective
immunity (10 mIU / mL)Absent: no significant anti-HBs present (≤ 0.1 mIU /
mL)
LLOQ
TND
Prot. Imm.
absent
Prot. Imm.
absent
17
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
LT (U
/ L)
Weeks of NAP exposure
0
100
200
300
400
0 4 8 12 16 20 24 28 32 36 40 44 48
GG
T (U
/ L)
Weeks of treatment
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
ST (U
/ L)
Weeks of NAP exposure
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
ST (U
/ L)
Weeks of NAP exposure
0
100
200
300
400
0 4 8 12 16 20 24 28 32 36 40 44 48
GG
T (U
/ L)
Weeks of NAP exposure
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
LT (U
/ L)
Weeks of NAP exposure
Liver flares are attenuated with initial NAP exposure after 24 weeks of peg-IFN
ALT (U/L) AST (U/L) GGT (U/L)
REP
2139
REP
2165
NAPs started with peg-IFN
NAPs started 24 weeks after peg-IFN
(1748, 1425)(921, 1284)
(591)
Continued peg-IFN exposure may impede immune response to HBsAg clearance upper limit of normal
(Synchronization of serum transaminases to start of NAP therapy)
0
100
200
300
400
0 4 8 12 16 20 24 28 32 36 40 44 48
GG
T (U
/ L)
Weeks of NAP exposure
0
100
200
300
400
0 4 8 12 16 20 24 28 32 36 40 44 48
GG
T (U
/ L)
Weeks of treatment
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
LT (U
/ L)
Weeks of NAP exposure
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
ST (U
/ L)
Weeks of NAP exposure
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
ST (U
/ L)
Weeks of NAP exposure
0
200
400
600
800
0 4 8 12 16 20 24 28 32 36 40 44 48
Seru
m A
LT (U
/ L)
Weeks of NAP exposure
18
Adverse events
NAP administration has been well tolerated to date • Infusion reactions which spontaneously developed in 2 patients were self
resolving after 3-4 weeks with supportive therapy during infusion – may be related to the onset and resolution of concomitant seasonal infections
Peg-IFN therapy is associated with weakness, thrombocytopenia and neutropenia• not altered by combination therapy with REP 2139 or REP 2165• otherwise asymptomatic• managed with supportive therapy and peg-IFN dose reduction
Serious adverse events to date:• transient profound weakness (1 patient, peg-IFN related)• appendicitis (1 patient, not treatment related)• community acquired bronchopneumonia (1 patient, not treatment related)
19
Summary
REP 2139 and REP 2165 are well tolerated in triple combination with TDF and peg-IFN
Antiviral effect of REP 2139 is conserved with the more rapidly cleared REP 2165
NAP therapy is associated with:• multilog reduction or clearance of serum HBsAg• increases in serum anti-HBs• increased incidence and magnitude of serum transaminase flares
(otherwise asymptomatic and self resolving)
NAP therapy started after 24 weeks peg-IFN results in attenuated transaminase flares with HBsAg clearance.
• immune exhaustion may be occurring with continued exposure to peg-IFN
Upcoming analyses to be presented:• HBcrAg and HBV RNA analysis (EASL 2017)