Arrowhead Pharmaceuticals : EASL 2023 JNJ-3989 REEF-D

Treatment With siRNA JNJ-73763989 Plus Nucleos(t)ide Analogue (NA) Decreases HBsAg and HDV RNA Levels in Patients With Chronic Hepatitis D (CHD): Part 1 of the REEF-D Study

Heiner Wedemeyer,1 Ed Gane,2 Kosh Agarwal,3 Ömer Fehmi Tabak,4 Xavier Forns,5 Ulus Salih Akarca,6 Viacheslav Morozov,7 Soo Aleman,8 Maria Buti,9 Gurdal Yilmaz,10 Pietro Lampertico,11,12 Julia Niewczas,13 John Jezorwski,14 Thomas N. Kakuda,15 Isabelle Benoot,16 Nonko Pehlivanov,17 Oliver Lenz,16 Michael Biermer16

1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany; 2New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand; 3Institute of Liver Studies, King's College Hospital, London, England; 4Istanbul University, Istanbul, Turkey; 5Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain; 6Division of Gastroenterology, Department of Internal Medicine, University of Ege School of Medicine, Izmir, Turkey; 7Medical Company Hepatolog Ltd, Samara, Russia; 8Department of Infectious Diseases, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden; 9Hospital General Universitari Valle Hebron and CIBER-EHD del Instituto Carlos III, Barcelona, Spain; 10Trabzon Karadeniz Technical University Farabi Hospital, Trabzon, Turkey; 11Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; 12CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; 13Janssen-Cilag, Solna, Sweden; 14Janssen Research & Development, LLC, Titusville, NJ, USA; 15Janssen Research & Development, LLC, Brisbane, CA, USA; 16Janssen Pharmaceutica NV, Beerse, Belgium; 17Janssen Research & Development, LLC, Raritan, NJ, USA.

Final abstract number: OS-030

Oral presentation at the European Association for the Study of the Liver (EASL) International Liver Conference™; June 21-24, 2023; Vienna, Austria.

June 22, 2023

REEF-D: Chronic Hepatitis D (CHD)

• Hepatitis D is the most severe form of chronic viral hepatitis
• • High risk for developing liver cirrhosis, decompensation, and HCC1,2
• PegIFN-αand bulevirtide (conditional approval in the European Union) can be used to treat hepatitis D3
• Limitations of current therapies:
• • PegIFN-α:low efficacy, side effects4
  • Bulevirtide: daily injections, long-term treatment, no effect on HBsAg levels5
• HDV requires HBsAg to form infectious viral particles6
• Therefore, targeting HBsAg could be a therapeutic option for delta co-infection

CHD, chronic hepatitis D; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HDV, hepatitis D virus; pegIFN, pegylated interferon.

1. Kamal H, et a. Liver Int. 2022. doi: 10.1111/liv.15467. 2. Alfaiate D, et al. J Hepatol. 2020;73(3):533-539. 3. EASL Clinical Practice Guidelines on hepatitis D. J Hepatol. 2023, epub June 24. 4. Sandmann L, Wedemeyer H. Liver Int. 2022 Aug 24. doi: 10.1111/liv.15410. 5. Lampertico P, Roulot D, Wedemeyer H. J Hepatol. 2022;77(5):1422-1430. 6. Urban S, Neumann-Haefelin C, Lampertico P. Gut. 2021;70(9):1782-1794.

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REEF-D: siRNA JNJ-3989 in CHD

• JNJ-3989is a liver-targeted siRNA that targets all HBV RNAs for degradation, thereby reducing all HBV proteins and pregenomic RNA1
• Results from phase 2a (NCT03365947, AROHBV1001)2 and phase 2b ( NCT03982186, REEF-1; NCT04129554, REEF-2)3,4 clinical trials in patients with CHB have demonstrated pronounced reductions in HBsAg with JNJ-3989(REEF-1: 48 weeks; 40, 100, and 200 mg; REEF-2: 48 weeks; 200 mg) in combination with NA
• In REEF-D, patients with CHD are treated with 100 mg JNJ-3989 Q4W SC + NA QD for up to 144 weeks
• • This is the first time an HBsAg targeting siRNA is used to treat patients with CHD
  • Here, we report the 48-week interim analysis of Part 1 and available data after Week 48

CHB, chronic hepatitis B; HBV, hepatitis B virus; JNJ-3989,JNJ-73763989; NA, nucleos(t)ide analogue; Q4W, every 4 weeks; QD, daily; SC, subcutaneous; siRNA, small interfering RNA.

1. Gane E, et al. Presented at: European Association for the Study of the Liver (EASL) Digital International Liver Congress™; August 27-29, 2020; Virtual. Oral GS10.
2. Yuen MF, et al. J Hepatol. 2022;77(5):1287-1298. 3. Yuen MF, et al. Lancet Gastroenterol Hepatol. 2023. Accepted manuscript.

4. Agarwal K, et al. Presented at: American Association for the Study of Liver Diseases (AASLD) - The Liver Meeting®; November 4-8, 2022. Abstract 5012.

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REEF-D (NCT04535544): Study Design

Phase 2, multicenter, randomized (4:1), 2-part,double-blind,placebo-controlled, parallel

Interim analysis

primary endpoint

JNJ-3989 100 mg SC Q4W + NA* PO QD (immediate active treatment arm) n = 17

Part 1 EOT		Part 1 EOS

Follow-up + NA

• Patients aged 18 to 65 years

Placebo SC Q4W + NA*

JNJ-3989 100 mg SC Q4W + NA* PO QD

Follow-up + NA

• Chronic hepatitis D: HDV RNA >1,000 IU/mL

PO QD

(deferred active treatment arm) n = 5

• ALT >ULN and <10 ×ULN

• Patients with compensated cirrhosis were

Week 0

48 52

96

144

148

F48 F48

eligible for Part 1 (platelets >100/nL)

Double-blind

Open-label

Assessment of antiviral

activity † to start Part 2‡

Primary endpoint: HDV RNA ≥2 log10 IU/mL decline from baseline or HDV RNA TND with normal ALT at Week 48

Part 2‡ with identical design

ALT, alanine transaminase; EOS, end of study; EOT, end of treatment; ETV, entecavir; F, follow-up; LLOQ, lower limit of quantification; PO, oral; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TND,

*ETV/TDF/TAF according to label. † ≥8 JNJ-3989-treated patients with ≥0.5 log10 reduction from baseline in HBsAg and HDV RNA and 4 of those with ≥1 log10 reduction in HDV RNA. ‡Part 2 of the study will be presented at a later date.

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REEF-D: Demographic and Baseline Characteristics

	Immediate active	Deferred active	Total
Characteristic*	treatment arm	treatment arm
N	17		5	22
Demographics
Male, n (%)	9 (52.9)	2 (40.0)	11 (50.0)
Age, years	40.9	(10.4)	44.2	(11.9)	41.6	(10.6)
White, n (%)	13 (76.5)	4 (80.0)	17 (77.3)
Disease characteristics
HBsAg, log10 IU/mL	4.1	(0.5)	3.8	(0.6)	4.0	(0.5)
HDV RNA, log10 IU/mL	5.1	(1.0)	5.1	(0.9)	5.1	(0.9)
HBV DNA <_lloq2c_ n="">†	11 (64.7)	5 (100)	16 (72.7)
ALT, U/L	74.9	(48.0)	95.0	(87.2)	79.5	(57.2)
HBeAg positive, n (%)	3 (17.6)	1 (20.0)	4 (18.2)
NA treatment, n (%)‡	7 (41.2)	3 (60.0)	10 (45.5)
FibroScan® score, n (%)
≥2 and <12.5 kPa	12 (70.6)	4 (80.0)	16 (72.7)
≥12.5 kPa	5 (29.4)	1 (20.0)	6 (27.3)

HBeAg, hepatitis B e antigen; SD, standard deviation.

*Mean (SD) unless otherwise noted. † HBV DNA ‡Patients on NA treatment at screening.

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