Arrowhead Pharmaceuticals : EASL 2022 JNJ-3989 REEF-1

Effects of the siRNA JNJ-3989 and/or the Capsid Assembly Modulator JNJ-6379 on Viral Markers of Chronic Hepatitis B: Results From the REEF-1 Study

Man-Fung Yuen,1,* Tarik Asselah,2 Ira M. Jacobson,3 Maurizia Brunetto,4 Harry L.A. Janssen,5 Tetsuo Takehara,6 Jin Lin Hou,7 Thomas N. Kakuda,8 Tom Lambrecht,9

Ronald Kalmeijer,10 Carine Guinard-Azadian,9 Cristiana Mayer,10 John Jezorwski,10 Thierry Verbinnen,9 Oliver Lenz,9 Umesh Shukla,10 Michael Biermer9

1Department of Medicine & State Key Laboratory of Liver Research, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; 2Université de Paris, INSERM UMR1149 and Hôpital Beaujon, APHP, Clichy, France; 3New York University Grossman School of Medicine, New York, NY, USA; 4University of Pisa, Pisa, Italy; 5University of Toronto, Toronto, Canada;	*Presenting author.
6Osaka University Graduate School of Medicine, Osaka, Japan; 7Nanfang Hospital, Southern Medical University, Guangzhou, China; 8Janssen Research & Development, LLC, South San Francisco, CA, USA; 9Janssen Research & Development, Beerse, Belgium; 10Janssen Research & Development, LLC, Titusville, NJ, USA.

Key Findings

>	Similar to HBsAg, a
JNJ-3989dose-response
	relationship was observed

Introduction

• JNJ-73763989(JNJ-3989) is a liver-targetedshort-interfering RNA (siRNA) designed to target all hepatitis B virus (HBV) RNAs for degradation, thereby reducing all HBV viral proteins and pregenomic RNA1
• JNJ-56136379(JNJ-6379) is a capsid assembly modulator that interferes with HBV replication by causing the formation of structually normal capsids that are devoid of HBV DNA and RNA (CAM-N)2
• The phase 2b REEF-1 study (ClinicalTrials.gov Identifier: NCT03982186) assessed the efficacy and safety of 48 weeks of JNJ-3989 and/or JNJ-6379 in combination with nucleos(t)ide analogues (NA) in patients with chronic hepatitis B (CHB)3
• • JNJ-3989treatment resulted in a dose-dependent reduction in hepatitis B surface antigen (HBsAg) through follow-up Week 24; the greatest decline was observed with the subcutaneous (SC) 200 mg dose received every 4 weeks (Q4W)
  • There was no beneficial effect of coadministration with JNJ-6379 on HBsAg decline
  • JNJ-3989and/or JNJ-6379 were safe and well tolerated

Objective

• To assess JNJ-3989- and/or JNJ-6379-induced changes to viral markers in CHB patients
  who were not currently treated (NCT) or virologically suppressed (VS) with NA treatment and who were hepatitis B e antigen (HBeAg)+ or HBeAg-

Methods

Study Design and Participants

•	REEF-1 is a phase 2b, multicenter, double-blind,active-controlled, randomized study; results
	through follow-up Week 24 are reported here
•	Eligible patients included those aged 18 to 65 years

• • Patients were randomized to 6 treatment arms (Figure 1), all of which included NA, and received study treatment for 48 weeks
• Patients who met the criteria for stopping NA treatment at Week 44 (primary endpoint; Figure 1) terminated NA treatment at the Week 48 visit and began a 48-weekNA-freefollow-up phase
• Patients could stop NA treatment and enter a 48-weekNA-freefollow-up phase at any time if NA stopping criteria were met
• Patients having met NA stopping criteria and having stopped NA treatment were monitored for HBV DNA and alanine aminotransferase (ALT); NA treatment restarted based on predefined NA retreatment criteria

Figure 1. Study design.

Inclusion criteria:		PBO (n = 45)	Analysis up to follow-up Week 24
• Active CHB (NCT or VS)		JNJ-6379 250 mg PO QD (n = 48)
• HBsAg >100 IU/mL at screening
	JNJ-3989 40 mg SC Q4W (n = 93)	NA continued when NA stopping criteria† not met
• Fibrosis stage F0-F2
		†ALT <3x ULN, HBV DNA HBeAg-, and HBsAg <10 IU/mL
Stratification:		JNJ-3989 100 mg SC Q4W (n = 93)
	NA stopping criteria reassessed at every follow-up visit
• HBeAg+ vs HBeAg-
	JNJ-3989 200 mg SC Q4W (n = 96)
• Treatment history (NCT vs VS)
	JNJ-3989 100 mg SC Q4W + JNJ-6379 250 mg PO QD (n = 95)

All patients received NA* during treatment

0

12

24

36

48

F12

F24

F36

F48

Weeks

Primary endpoint: Proportion of patients meeting NA stopping criteria (ALT <3x ULN, HBV DNA HBeAg-, and HBsAg <10 IU/mL) at Week 48

ETV, entecavir; F, follow-up; LLOQ, lower limit of quantitation; PBO, placebo; PO, oral; QD, daily; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal.

*NA = ETV/TDF/TAF.

Results

Participants

• A total of 470 patients with CHB were included, with a mean age of 43 years and a mean duration of CHB infection of 25.4 years; 66% were male and 40% were Asian (Table 1)
• 95% of patients enrolled completed the 48-week treatment phase, with no differences across treatment groups

Table 1. Baseline Demographics and Clinical Characteristics by Treatment History and HBeAg Status at Screening

	NCT			VS
	HBeAg+	HBeAg-	HBeAg+	HBeAg-
Characteristic*	(n = 75)	(n = 97)	(n = 67)	(n = 231)

Primary Endpoint

• 19.1% (18/94) and 29.8% (28/94) of patients (all of whom were VS, except for 7) met NA stopping criteria with JNJ-3989 200 mg at Week 48 and until follow-up Week 24, respectively
• • For HBeAg- patients, the main reason for not meeting NA stopping criteria was not achieving HBsAg <10 IU/mL
  • For HBeAg+ patients, the main reasons for not meeting stopping criteria were not achieving HBeAg seroclearance and/or HBsAg <10 IU/mL and, in those who were also NCT, not achieving HBV DNA <>
• 2 of 63 (3.2%) patients who met NA stopping criteria and stopped NA treatment subsequently met NA restarting criteria through follow-up Week 24

Changes in HBsAg

• Consistent with the overall population,3 JNJ-3989 reduced HBsAg in a dose-dependent manner in subgroups by treatment history and HBeAg status (Figure 2); the greatest mean declines were generally seen with the 200 mg dose
• The largest reductions of HBsAg were observed in NCT HBeAg+ patients (Figure 2)

Figure 2. Mean change in HBsAg (±SE) from baseline by treatment history and HBeAg status.

NCT HBeAg+

VS HBeAg+

		1									Mean (SE) Mean (SE)			1									Mean (SE) Mean (SE)
										Follow-up	Change	Change											Follow-up	Change	Change
										Week 48	FU Week 24											Week 48	FU Week 24
		0													0									0.04 (0.025)	-0.04 (0.037)
HBsAg	IU/mL												HBsAg	IU/mL										-0.08 (0.028)	-0.14 (0.049)
									-0.43 (0.306)	-0.40 (0.295)
																				-1.27 (0.114)	-0.91 (0.094)
(SE) change in	10	-1											(SE) change in	10	-1
baseline, log									-0.80 (0.795)	-1.02 (0.985)	baseline, log
									-1.77 (0.138)	-1.32 (0.198)										-1.78 (0.128)	-1.43 (0.138)
																				-2.01 (0.169)	-1.39 (0.259)
-2									-2.52 (0.270)	-2.04 (0.256)	-2
								-2.55 (0.263)	-2.10 (0.365)									-2.61 (0.175)	-2.18 (0.259)
Mean	from										-3.56 (0.355)	-2.63 (0.339)	Mean	from
		-3													-3
		-4													-4
		0	4	8	12	16	20 24	28	32	36 40 44 48 F4 F8 F12 F16 F20 F24					0	4	8	12	16	20 24	28	32	36 40 44 48 F4 F8 F12 F16 F20 F24
										Weeks													Weeks

									NCT HBeAg-													VS HBeAg-
		1									Mean (SE) Mean (SE)			1									Mean (SE) Mean (SE)
											Follow-up	Change	Change											Follow-up	Change	Change
											Week 48	FU Week 24											Week 48	FU Week 24
		0										-0.03 (0.072)	-0.15 (0.070)			0									0.01 (0.016)	-0.09 (0.015)
HBsAg											HBsAg										-0.11 (0.033)	-0.11 (0.028)
IU/mL											-0.13 (0.110)	-0.13 (0.113)	IU/mL
										-1.40 (0.126)	-0.90 (0.107)
(SE) change in	10	-1										(SE) change in	10	-1									-1.51 (0.065)	-0.98 (0.051)
baseline, log										-1.40 (0.107)	-1.08 (0.111)	baseline, log
																	-1.71 (0.080)	-1.30 (0.079)
										-2.16 (0.163)	-1.53 (0.192)										-1.93 (0.072)	-1.34 (0.079)
										-2.22 (0.141)	-1.48 (0.136)										-2.41 (0.128)	-1.62 (0.113)
-2												-2
Mean	from	-3												Mean	from	-3
		-4														-4
		0	4	8	12	16	20 24	28	32	36 40 44 48 F4 F8 F12 F16 F20 F24					0	4	8	12	16	20 24	28	32	36 40 44 48 F4 F8 F12 F16 F20 F24
										Weeks														Weeks
							PBO		JNJ-6379	JNJ-3989 40 mg	JNJ-3989 100 mg		JNJ-3989 200 mg	JNJ-3989 100 mg + JNJ-6379

FU, follow-up; SE, standard error.

• The JNJ-3989 200 mg arm had the highest proportion of patients who achieved HBsAg reduction ≥2 log10 and ≥3 log10 at Week 48 (73.6% and 27.5%, respectively; Figure 3A) and at the time of follow-up Week 24 (37.3% and 10.8%, respectively; Figure 3B)

Figure 3. Individual changes in HBsAg from baseline at (A) Week 48 and at (B) follow-up Week 24 in individual patients by HBeAg status.

A.

PBO

JNJ-6379

JNJ-3989 40 mg

JNJ-3989 100 mg

JNJ-3989 200 mg

JNJ-3989 100 mg

+ JNJ-6379

48,

1

Week

0

Treatment Arm

at

-1

PBO HBeAg+

baseline

PBO HBeAg-

IU/mL

-2

JNJ-6379 HBeAg+

JNJ-6379 HBeAg-

JNJ-3989 40 mg HBeAg+

HBsAg from

-3

JNJ-3989 40 mg HBeAg-

10

JNJ-3989 100 mg HBeAg+

log

-4

JNJ-3989 100 mg HBeAg-

JNJ-3989 200 mg HBeAg+

JNJ-3989 200 mg HBeAg-

-5

JNJ-3989 100 mg + JNJ-6379 HBeAg+

in

JNJ-3989 100 mg + JNJ-6379 HBeAg-

Change

-6

-7

B.

JNJ-6379

JNJ-3989 40 mg

JNJ-3989 100 mg

JNJ-3989 200 mg

JNJ-3989 100 mg

+ JNJ-6379

Treatment Arm

72,

PBO HBeAg+

0

PBO HBeAg-

Week

JNJ-6379 HBeAg+

JNJ-6379 HBeAg-

JNJ-3989 40 mg HBeAg+

at

-1

JNJ-3989 40 mg HBeAg-

baseline

JNJ-3989 100 mg HBeAg+

IU/mL

-2

JNJ-3989 100 mg HBeAg-

JNJ-3989 200 mg HBeAg+

JNJ-3989 200 mg HBeAg-

HBsAgfrom

-3

JNJ-3989 100 mg + JNJ-6379 HBeAg+

10

log

-4

JNJ-3989 100 mg + JNJ-6379 HBeAg-

Figure 4. Mean (±SE) change in HBeAg over time in HBeAg+ patients (A) NCT or (B) VS.

A.											B.
HBeAg		0								Follow-up	HBeAg		0
IU/mL									IU/mL
-0.5										-0.5
(SE) change in	10	-1.0										(SE) change in	10	-1.0									Follow-up
baseline, log										baseline, log
-1.5										-1.5
-2.0										-2.0
Mean from	-2.5										Mean from	-2.5
		-3.0	0	4	8	12	16	20 24 28	32	36 40 44 48 F4 F8 F12 F16F20F24			-3.0	0	4	8	12	16	20 24	28	32	36 40 44 48 F4 F8 F12 F16F20F24
									Weeks												Weeks
			PBO		JNJ-6379	JNJ-3989 40 mg	JNJ-3989 100 mg	JNJ-3989 200 mg	JNJ-3989 100 mg + JNJ-6379

Table 2. Baseline and Change From Baseline HBeAg Values

				NCT and HBeAg+							VS and HBeAg+
							Change								Change
			Change		Change		from BL				Change		Change		from BL
			from BL		from BL		at FU				from BL		from BL		at FU
		BL,	at W24,	<>	at W48,	<>	W24,			BL,	at W24,	<>	at W48,	<>	W24,
	N	log10	log10	at W24,	log10	at W48,	log10	FU W24,	N	log10	log10	at W24,	log10	at W48,	log10	FU W24,
	IU/mL	IU/mL	n/N (%) IU/mL n/N (%)	IU/mL	n/N (%)	IU/mL	IU/mL	n/N (%) IU/mL n/N (%)	IU/mL	n/N (%)
PBO	7	1.92	-0.97	0/7	-1.45	1/7	-1.50	1/7	6	-0.02	-0.15	0/6	-0.39	1/6	-0.35	1/6
(0.54)	(0.35)	(0.63)	(14.3)	(0.64)	(14.3)	(0.07)	(0.07)	(0.40)	(16.7)	(0.36)	(16.7)
JNJ-6379	8	1.60	-1.27	1/7	-1.49	1/7	-1.56	1/8	7	-0.11	-0.18	0/6	-0.20	0/7	-0.26	0/7
(0.42)	(0.31)	(14.3)	(0.31)	(14.3)	(0.28)	(12.5)	(0.18)	(0.08)	(0.16)	(0.26)
JNJ-3989	15	1.86	-0.69	1/15	-1.03	2/13	-1.13	2/15	15	0.67	-0.39	1/15	-0.54	1/14	-0.43	1/12
40 mg	(0.38)	(0.12)	(6.7)	(0.17)	(15.4)	(0.19)	(13.3)	(0.22)	(0.05)	(6.7)	(0.35)	(7.1)	(0.36)	(8.3)
JNJ-3989	14	2.77	-1.53	1/14	-2.09	2/14	-2.06	2/13	11	0.29	-0.60	3/11	-0.75	3/10	-0.64	3/10
100 mg	(0.22)	(0.13)	(7.1)	(0.25)	(14.3)	(0.24)	(15.4)	(0.30)	(0.10)	(27.3)	(0.39)	(30.0)	(0.40)	(30.0)
JNJ-3989	16	2.65	-1.60	0/15	-2.22	1/14	-2.52	2/14	14	0.40	-0.70	1/14	-0.78	1/14	-0.75	1/13
200 mg	(0.25)	(0.23)	(0.30)	(7.1)	(0.33)	(14.3)	(0.22)	(0.12)	(7.1)	(0.56)	(7.1)	(0.53)	(7.7)
JNJ-3989 +	13	2.52	-1.66	0/15	-2.48	1/12	-2.59	1/12	14	0.02	-0.39	2/14	-0.52	4/14	-0.49	1/13
JNJ-6379	(0.25)	(0.20)	(0.25)	(8.3)	(0.26)	(8.3)	(0.69)	(0.12)	(14.3)	(0.48)	(28.6)	(0.50)	(7.7)

BL, baseline; W, Week.

Values are mean (SE) unless otherwise noted; LLOQ = 0.11 IU/mL = -0.96 log10 IU/mL.

Changes in HBV DNA

• A numerically greater decline in HBV DNA was seen with JNJ-3989 100 and 200 mg and JNJ-6379-containing arms compared to control in NCT HBeAg+ patients (Figure 5A)
• Assessment of mean change from baseline in HBV DNA in NCT HBeAg- patients was limited by a high proportion of patients reaching HBV DNA Figure 5B and Table 3)

Figure 5. Mean (±SE) change in HBV DNA over time in patients NCT and (A) HBeAg+ or (B) HBeAg-.

A.										B.
DNA		0							Follow-up	DNA		0											Follow-up
IU/mL								IU/mL
-1									-1
-2									-2
HBV	10	-3									HBV	10	-3
Mean (SE) change in	from baseline, log									Mean (SE) change in	from baseline, log
-4									-4
-5									-5
-6									-6
-7									-7
-80									-8
		4	8	12	16	20 24 28	32	36 40 44 48 F4 F8 F12 F16F20F24			0	4	8	12	16	20	24	28	32	36	40 44 48 F4	F8 F12 F16F20F24
								Weeks													Weeks
		PBO		JNJ-6379	JNJ-3989 40 mg	JNJ-3989 100 mg		JNJ-3989 200 mg		JNJ-3989 100 mg + JNJ-6379

Table 3. Baseline and Change From Baseline HBV DNA Values

				NCT and HBeAg+							NCT and HBeAg-
							Change								Change
			Change		Change		from BL				Change		Change		from BL
			from BL		from BL		at FU				from BL		from BL		at FU
		BL,	at W24,	<>	at W48,	<>	W24,			BL,	at W24,	<>	at W48,	<>	W24,
	N	log10	log10	at W24,	log10	at W48,	log10	FU W24,	N	log10	log10	at W24,	log10	at W48,	log10	FU W24,
	IU/mL	IU/mL	n/N (%)	IU/mL	n/N (%)	IU/mL	n/N (%)	IU/mL	IU/mL	n/N (%)	IU/mL	n/N (%)	IU/mL	n/N (%)
PBO	7	7.92	-5.03	2/7	-5.46	4/7	-5.72	5/7	9	5.20	-3.81	5/9	-4.07	9/9	-4.11	8/9
(0.49)	(0.56)	(28.6)	(0.90)	(57.1)	(0.82)	(71.4)	(0.47)	(0.43)	(55.6)	(0.48)	(100)	(0.47)	(88.9)
JNJ-6379	8	8.03	-6.17	1/7	-6.72	5/7	-6.72	6/8	10	5.24	-4.22	7/9	-4.83	8/8	-4.39	9/9
(0.35)	(0.38)	(14.3)	(0.43)	(71.4)	(0.42)	(75.0)	(1.74)	(0.47)	(77.8)	(0.50)	(100)	(0.55)	(100)
JNJ-3989		7.57	-5.28	2/15	-5.89	8/14	-6.12	8/15		4.87	-3.84	15/16	-3.96	15/16	-4.02	16/16

Figure 6. Mean (±SE) change in HBcrAg over time by treatment history and HBeAg status in patients with HBcrAg >LLOQ at baseline who received treatment with either PBO or JNJ-3989 200 mg.

		0												Follow-up
HBcrAg
IU/mL	-0.5
-1.0
Mean (SE) change in	10
from baseline, log	-1.5
-2.0
-2.5
-3.0
-3.5
		0	4	8	12	16	20	24	28	32	36	40	44	48	F4	F8	F12	F16	F20 F24
										Weeks

PBO: NCT HBeAg+	PBO: NCT HBeAg-	PBO: VS HBeAg+	PBO: VS HBeAg-
JNJ-3989: NCT HBeAg+	JNJ-3989: NCT HBeAg-	JNJ-3989: VS HBeAg+	JNJ-3989: VS HBeAg-

Table 4. Baseline and Change From Baseline Mean (SE) HBcrAg by Subgroup for NA and JNJ-3989 200 mg Treatment Arms in Patients With HBcrAg >LLOQ at Baseline

			Change from BL		Change from BL		Change from BL
		BL,	at W24,		at W48,		at FU W24,
	N*	log10 IU/mL	log10 IU/mL	n/N (%)	log10 IU/mL	n/N (%)	log10 IU/mL	FU W24, n/N (%)
NCT HBeAg+
PBO	7	7.76 (0.47)	-1.31 (0.33)	0/7	-1.69 (0.53)	0/7	-1.71 (0.59)	0/7
JNJ-3989 200 mg	16	8.43 (0.28)	-2.01 (0.18)	0/15	-2.56 (0.25)	0/14	-2.74 (0.30)	0/14
NCT HBeAg-
PBO	8	4.8 (0.55)	-1.23 (0.32)	3/8 (37.5)	-1.26 (0.43)	3/8 (37.5)	-1.24 (0.45)	3/8 (37.5)
JNJ-3989 200 mg	16	4.71 (0.37)	-1.58 (0.37)	6/16 (37.5)	-1.59 (0.35)	7/16 (43.8)	-1.60 (0.36)	6/15 (40.0)
VS HBeAg+
PBO	6	5.42 (0.14)	-0.12 (0.04)	0/6	-0.23 (0.08)	0/6	-0.18 (0.04)	0/6
JNJ-3989 200 mg	14	5.80 (0.22)	-0.82 (0.14)	0/14	-0.91 (0.17)	0/14	-0.76 (0.15)	0/14
VS HBeAg-
PBO	11	3.73 (0.19)	-0.17 (0.06)	3/11 (27.3)	-0.14 (0.10)	1/11 (9.1)	-0.12 (0.10)	1/11 (9.1)
JNJ-3989 200 mg	22	3.92 (0.12)	-0.41 (0.07)	4/22 (18.2)	-0.23 (0.13)	2/22 (9.1)	-0.33 (0.09)	4/18 (22.2)

*Patients with detectable levels of HBcrAg at baseline.

Values are mean (SE) unless otherwise noted; LLOQ = 3 log10 IU/mL.

Changes in HBV RNA

• JNJ-3989200 mg resulted in pronounced reduction of HBV RNA across all patient populations, with up to 3.66 log10 reduction in NCT HBeAg+ patients (Figure 7 and Table 5)
• Reductions in HBV RNA were sustained through 24 weeks of follow-up
• Assessment of RNA reduction in VS patients was hampered by a high proportion of patients achieving HBV RNA

Figure 7. Mean (±SE) change in HBV RNA over time by treatment history and HBeAg status in patients with HBV RNA >LOD at baseline who received treatment with either PBO or JNJ-3989 200 mg.

Follow-up

HBV RNA	copies/mL	0
-1
in	10	-2
Mean (SE) change	from baseline, log
-3
-4
-5
		0	4	8	12	16	20	24	28	32	36	40	44	48	F4	F8	F12	F16	F20 F24
										Weeks

PBO: NCT HBeAg+	PBO: NCT HBeAg-	PBO: VS HBeAg+	PBO: VS HBeAg-
JNJ-3989: NCT HBeAg+	JNJ-3989: NCT HBeAg-	JNJ-3989: VS HBeAg+	JNJ-3989: VS HBeAg-

Table 5. Baseline and Change From Baseline Mean (SE) HBV RNA by Subgroup for PBO and JNJ-3989 200 mg Treatment Arms in Patients With HBV RNA >LOD at Baseline

						Change from
		Change from BL		Change from BL		BL at
	BL,	at W24,		at W48,		FU W24,	FU W24,
N*	log10 copies/mL	log10 copies/mL	n/N (%)	log10 copies/mL	n/N (%)	log10 copies/mL	n/N (%)

	for HBeAg, HBcrAg,
	HBV DNA, and HBV RNA
	The greatest reductions
> in viral markers were
	observed during the
	48-week treatment phase
	and in patients who were
>	NCT and HBeAg+
The reductions in HBeAg,
HBcrAg, and HBV RNA
	generally remained stable
	or declined during the
	24-weekfollow-up phase
	Safety results have been
> previously reported and
	showed that all regimens
	were generally safe and
	well tolerated3

Conclusions

>	JNJ-3989, with or without
JNJ-6379, reduced all viral
	markers, with the strongest
	effect observed for HBsAg
	This study supports the
> continued development of
	JNJ-3989 in combination
	therapies that may provide

Male, n (%)	45 (60.0)	61 (62.9)
Asian, n (%)	42 (56.0)	16 (16.5)
Age, years	37.2 (10.99)	40.6 (10.17)
HBsAg, log10 IU/mL	4.48 (0.79)	3.95 (0.50)
HBV DNA, log10 IU/mL	7.93 (1.11)	5.07 (1.37)
ALT, U/L	107.1 (103.16)	92.5 (94.08)
HBeAg, log10 IU/mL	2.31 (1.16)	-
HBcrAg, n (%) <>	0	19 (19.8)
HBV RNA, n (%) <>§	0	30 (31.9)
Liver stiffness,II kPa	6.30 (1.88)	5.90 (1.45)

49 (73.1)	155 (67.1)
48 (71.6)	84 (36.5)
41.7 (9.06)	46.2 (10.21)
3.61 (0.58)	3.46 (0.61)
Not applicable†	Not applicable†
24.4 (11.60)	23.7 (12.21)
0.27 (0.79)	-
0	110 (48.2)
23 (34.8)	202 (89.0)
4.84 (1.33)	4.92 (1.38)

in	-5
Change
-6
	-7

Patients who achieved HBsAg loss are noted with red dots.

Changes in HBeAg

•	Declines in HBeAg were observed across all treatment arms and sustained during follow-up, with reductions
	being JNJ-3989 dose dependent (Figure 4). Of note, the combination arm of JNJ-3989 100 mg + JNJ-6379 had the
	numerically greatest decline among NCT patients
•	Reductions were most pronounced in NCT patients, potentially due to higher baseline HBeAg levels (Figure 4
	and Table 2)
•	The number of patients in each treatment arm who achieved HBeAg

40 mg	15	(0.38)	(0.25)	(13.3)	(0.29)	(57.1)	(0.29)	(53.3)	18	(0.30)	(0.29)	(93.8)	(0.36)	(93.8)	(0.33)	(100.0)
JNJ-3989	14	7.77	-5.44	3/14	-6.41	8/14	-6.40	8/13	19	5.29	-4.08	15/18	-4.22	13/18	-4.31	13/16
100 mg	(0.29)	(0.28)	(21.4)	(0.22)	(57.1)	(0.25)	(61.5)	(0.33)	(0.23)	(83.3)	(0.36)	(72.2)	(0.42)	(81.3)
JNJ-3989	16	8.29	-6.07	2/15	-6.56	3/14	-6.82	7/14	19	5.26	-4.16	14/18	-4.28	16/18	-4.24	15/17
200 mg	(0.21)	(0.16)	(13.3)	(0.20)	(21.4)	(0.26)	(50.0)	(0.35)	(0.32)	(77.8)	(0.35)	(88.9)	(0.38)	(88.2)
JNJ-3989 +	13	8.04	-6.00	2/13	-6.72	6/12	-6.87	9/12	20	4.62	-3.63	18/19	-3.60	17/18	-3.71	18/18
JNJ-6379	(0.28)	(0.19)	(15.4)	(0.24)	(50.0)	(0.27)	(75.0)	(0.24)	(0.26)	(94.7)	(0.29)	(94.4)	(0.29)	(100)

Values are mean (SE) unless otherwise noted.

Changes in HBcrAg

• JNJ-3989 200 mg resulted in pronounced reduction of HBcrAg in NCT patients, with up to 2.56 log10 reduction at

Week 48 in the HBeAg+ subgroup, while HBcrAg decline in VS patients was limited, potentially due to lower baseline

levels (Figure 6 and Table 4)

NCT HBeAg+
PBO	6	6.90 (0.67)	-1.12 (0.53)	0/6	-1.34 (0.57)	0/6	-1.54 (0.62)	0/6
JNJ-3989 200 mg	16	7.33 (0.23)	-2.96 (0.26)	2/15 (13.3)	-3.66 (0.30)	4/14 (28.6)	-3.70 (0.31)	5/13 (38.5)
NCT HBeAg-
PBO	5	5.02 (0.32)	-2.11 (0.47)	2/5 (40.0)	-2.59 (0.34)	3/5 (60.0)	-2.89 (0.33)	3/4 (75.0)
JNJ-3989 200 mg	13	4.64 (0.32)	-2.31 (0.30)	10/13 (76.9)	-2.37 (0.30)	11/13 (84.6)	-2.23 (0.36)	10/11 (90.9)
VS HBeAg+
PBO	5	3.31 (0.47)	-0.10 (0.20)	1/5 (20.0)	-0.41 (0.14)	3/5 (60.0)	-0.18 (0.12)	1/5 (20.0)
JNJ-3989 200 mg	9	4.29 (0.44)	-1.69 (0.26)	5/9 (55.6)	-1.95 (0.35)	7/9 (77.8)	-1.87 (0.30)	6/8 (75.0)
VS HbeAg-
PBO	3	3.25 (0.47)	0.20 (0.40)	1/3 (33.3)	0.29 (0.41)	1/3 (33.3)	0.46 (0.18)	0/2

functional cure to patients

with CHB

HBcrAg, hepatitis B core related antigen; LOD, limit of detection; SD, standard deviation. *Mean (SD) unless otherwise noted.

†98% of patients had HBV DNA 10 IU/mL = 20 IU/mL). ‡LLOQ = 3.0 log10 IU/mL.

§LOD = 2.49 log10 copies/mL.

IIMeasured with FibroScan® Paris, France.

patients, with the greatest proportion of patients reaching HBeAg JNJ-3989 100 mg (n = 3, 30.0%)

and JNJ-3989 100 mg + JNJ-6379 (n = 4, 28.6%) treatment arms in VS patients (Table 2)

• The proportion of patients reaching HBcrAg

JNJ-3989 200 mg (Table 4)

JNJ-3989 200 mg

9

3.13 (0.14)

-0.84 (0.15)

8/9 (88.9)

-0.88 (0.17)

8/9 (88.9)

-0.75 (0.26)

5/7 (71.4)

*Patients with detectable levels of HBV RNA at baseline.

Values are mean (SE) unless otherwise noted; N = patients with detectable HBV RNA at baseline; LOD = 2.49 log10 copies/mL.

References	Acknowledgments	Disclosures
1.	Gane E, et al. Presented at: European Association for the Study of the Liver (EASL)	This study was supported by Janssen Research & Development, LLC. Medical writing	M-FY serves as advisor/consultant for AbbVie, AlloVir International, Arbutus Biopharma, Bristol Myers Squibb, ClearB Therapeutics, Dicerna Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, and Spring Bank Pharmaceuticals; and receives grant/research
	Digital International Liver Congress™; August 27-29, 2020; Virtual. Oral GS10.	support was provided by Kim Caldwell, PhD, of Cello Health Communications/MedErgy,	support from Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myers Squibb, Fujirebio Diagnostics Inc., Gilead Sciences, Merck Sharp & Dohme, Roche, Spring Bank Pharmaceuticals, and Sysmex Corp. TA serves as advisor/consultant for AbbVie, Antios Therapeutics, Enyo Pharma,
2.	Berke JM, et al. Antimicrob Agents Chemother. 2020;64(5):e02439-19.	and was funded by Janssen Global Services, LLC.	Gilead Sciences, GlaxoSmithKline, Janssen, and Roche. IMJ serves as a consultant for Aligos, Arbutus, Janssen, and Gilead; has received research funds from Janssen and Assembly Biosciences; and serves on a data monitoring committee for GlaxoSmithKline. MB serves as a consultant and speaker for
3.	Yuen MF, et al. Presented at: American Association for the Study of Liver		AbbVie, Gilead Sciences, Janssen, Esai, MSD, and Roche. HLAJ received grants from AbbVie, Arbutus, Gilead Sciences, Janssen, and Roche; and is a consultant for Arbutus, Arena, Enyo, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, Vir Biotechnology Inc., and Viroclinics. TT has received
	Diseases (AASLD) The Liver Meeting; November 12-15, 2021; Virtual. Oral LO10.		lecturer fees from Bristol Myers Squibb, Gilead Sciences, and GlaxoSmithKline; research funding from Janssen; and consulting fees from Janssen. JLH serves as advisor/consultant for Aligos, Assembly, Gilead Sciences, Johnson & Johnson, and Roche; and receives grant/research support from
			Bristol Myer Squibb. TNK, TL, RK, CG-A, CM, JJ, TV, OL, US, and MB are employees of Janssen Pharmaceuticals and may be Johnson & Johnson stockholders.

Scan the QR code

https://www.congresshub.com/IDV/EASL2022/ChronicHepatitisB/Yuen The QR code is intended to provide scientific information for individual reference, and the information should not be altered or reproduced in any way.

Presented at the European Association for the Study of the Liver (EASL) International Liver Congress™; June 22-26, 2022; London, UK & Online.