Arrowhead Pharmaceuticals : EASL 2022 JNJ-3989 REEF-2

Efficacy and Safety of Finite 48-week Treatment With the siRNA JNJ-3989 and the Capsid Assembly Modulator JNJ-6379 in HBeAg Negative Virologically Suppressed Chronic Hepatitis B Patients:

Results from the REEF-2 Study

Kosh Agarwal,1 Maria Buti,2 Florian van Bömmel,3 Pietro Lampertico,4 Ewa Janczewska,5 Marc Bourliere,6

Thomas Vanwolleghem,7,8 Oliver Lenz,9 Thierry Verbinnen,9 Thomas N. Kakuda,9 Cristiana Mayer,9 John Jezorwski,9 Maria Beumont,9 Ronald Kalmeijer,9 Michael Biermer,9 Isabelle Lonjon-Domanec9

1Institute of Liver Studies, King's College Hospital, London, England; 2Hospital Universitario Valle de Hebrón, Barcelona, Spain;

3University Hospital Leipzig, Leipzig, Germany; 4Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 5Faculty of Health Sciences, Medical University of Silesia, Katowice, Poland; 6Hôpital Saint Joseph, Marseille, France; 7Antwerp University Hospital (UZA), Edegem, Belgium; 8Viral Hepatitis Research Group, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium; 9Janssen Research & Development.

Oral presentation at the European Association for the Study of the Liver (EASL) International Liver Conference™; June 23-26, 2022.

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June 24, 2022

REEF-2: Introduction

• JNJ-3989is an siRNA that targets all HBV RNAs, thereby reducing levels of all viral proteins1
• JNJ-6379is a CAM-N that inhibits viral replication by inducing the formation of structurally normal, non- infectious viral particles consisting of empty nucleocapsids2
• In the REEF-1 study (NCT03982186), JNJ-3989, with or without JNJ-6379, demonstrated strong dose-dependent HBsAg decline in a 48-week regimen3
• In virologically suppressed, NA-treated,non-cirrhotic, HBeAg negative CHB patients, discontinuation of NA treatment may result in increased rates of functional cure (HBsAg seroclearance), especially in the subset of patients with low HBsAg levels at the end of treatment4
• The REEF-2 study (NCT04129554) assessed the efficacy and safety of 48 weeks of the combination of JNJ-3989,JNJ-6379, and NA in this population, with 48 weeks of follow-up after discontinuation of all treatment
• • Here, we report Follow-up Week 24 data

CAM-N, capsid assembly modulator - normal capsid structure; CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus;

NA, nucleos(t)ide analogues; siRNA, small interfering RNA.

1. Yuen MF, et al. Submitted. 2022. 2. Berke JM, et al. Antimicrob Agents Chemother. 2020; 64(5):e02439-19. 3. Yuen MF, et al. AASLD: The Liver Meeting; Nov, 2021; abstract LO10. 4. Van Bommel F and Berg, T. Hepatology Commun. 2021;0:1-17.

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REEF-2 (NCT04129554): Study Design

NA Suppressed/HBeAg negative

CHB who received NA treatment ≥2 years ALT <2.0 ULN, HBV DNA <60 IU/mL HBsAg >100 IU/mL at screening Non-cirrhotic (Fibrosis Stage F0-F2)

NA = ETV/TDF/TAF according to label

7 Countries in Europe

		Primary Endpoint: HBsAg
		seroclearance at Week 72
Study intervention			End of
	without restarting NA
stopped (including NA)	treatment		study

JNJ-3989* + JNJ-6379† + NA (N = 85)	Follow-up
(Active arm)
JNJ-3989 placebo + JNJ-6379 placebo + NA (N = 45)‡	Follow-up
(Control arm)

Week	0	12	24	36	48	60	84	96
Number of patients per analysis visit	130	119	118	117	117	120	119

HBsAg seroclearance defined as HBsAg † 250 mg PO daily.

All analyses were performed for the ITT population.

ETV, entecavir; ITT, intention-to-treat; LLOQ, lower limit of quantitation; PO, oral; SC, subcutaneous; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal.

‡Referred to as NA treatment.

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REEF-2: NA Retreatment Criteria

After stopping NA treatment (Week 48), participants were to restart NA treatment:

• If the below results were confirmed at least 4 weeks apart:
• • HBeAg seroreversion
  • Post-treatmentincreases in HBV DNA >2,000 IU/mL and ALT >5× ULN
  • Post-treatmentincreases in HBV DNA >20,000 IU/mL
• Immediately, in case of signs of decreasing or impaired liver function based on laboratory findings or clinical assessment

Additional retreatment criteria were added to the protocol during the course of the study:*

• Immediately with an HBV DNA value >100,000 IU/mL (irrespective of confirmation and/or ALT increase)

*Prompted by a single patient in the control arm who experienced severe liver deterioration and had to undergo transplant after stopping NA even though NA retreatment began in accordance with retreatment criteria in the original protocol.

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REEF-2: Demographics and Baseline Characteristics

Percentages or	Placebo + NA	JNJ-3989 + JNJ-6379
+ NA	Total
Mean Value (SD)	(Control)
(Active)
N		45		85	130
Demographics
Female vs. Male (%)	35.6/64.4	31.8/68.2	33.1/66.9
Age, years	47.4	(10.55)	45.3	(10.10)	46.0	(10.27)
White (%)	66.7	65.9	66.2
Disease Characteristics
HBsAg, log10 IU/mL	3.49	(0.703)	3.43	(0.530)	3.45	(0.594)
HBV DNA	100	100	100
HBV RNA †	97.7	92.8	94.4
HBcrAg ‡	75.0	65.9	69.0
ALT, U/L	23.9	(10.75)	24.2	(10.89)	24.1	(10.80)
Fibroscan score, kPa	5.02	(1.301)	5.23	(1.482)	5.16	(1.420)
Duration of NA at study entry, years	8.1	(4.48)	8.4	(4.79)	8.3	(4.67)
Stratification Factors
Asian vs. Non-Asian (%)	17.8/82.2	21.2/78.8	20.0/80.0
Type of NA: ETV vs. TDF/TAF (%) §	37.8/62.2	38.8/61.2	38.5/61.5
HBsAg level: <1,000 vs. ≥1,000 IU/mL (%)	24.4/75.6	20.0/80.0	21.5/78.5

ALT, alanine transaminase; HBcrAg, hepatitis B core related antigen.

*HBV DNA, LLOQ = 20 IU/mL. † HBV RNA, LOD = 2.49 log10 cp/mL. ‡HBcrAg, LLOQ = 3.0 log10 U/mL. §2 patients were on TAF.

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