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

2

Disclosures

M. Bazinet, A. Vaillant: employees and shareholders in Replicor Inc.

All other authors: no conflicts of interest to declare.

3

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

4

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)

5

REP 401 Design

Primary efficacy endpoints:

Initial follow up scheduled 4, 12, 24 and 48 weeks after all treatment is stopped

40

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)

6

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)


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


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)

11

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


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


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)


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)


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)


0

200

400

600

800

0 4 8 12 16 20 24 28 32 36 40 44 48

Seru

m A

ST (U

/ L)


0

100

200

300

400

0 4 8 12 16 20 24 28 32 36 40 44 48

GG

T (U

/ L)


0

200

400

600

800

0 4 8 12 16 20 24 28 32 36 40 44 48

Seru

m A

LT (U

/ L)


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)


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)


0

200

400

600

800

0 4 8 12 16 20 24 28 32 36 40 44 48

Seru

m A

ST (U

/ L)


0

200

400

600

800

0 4 8 12 16 20 24 28 32 36 40 44 48

Seru

m A

ST (U

/ L)


0

200

400

600

800

0 4 8 12 16 20 24 28 32 36 40 44 48

Seru

m A

LT (U

/ L)


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)

update on safety and efficacy in the rep 401...

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