Arbutus Biopharma : AB‐729, a GalNAc‐siRNA, results in robust reductions of HBV DNA and HBsAg in subjects with chronic hepatitis B infection APASL 2021

AB‐729, a GalNAc‐siRNA, results in robust reductions of HBV DNA and HBsAg in subjects with chronic hepatitis B infection

• Gane,1 E Berliba,2 YJ Kim,3 J Holmes,4 Y‐S Lim,5 S Strasser,6 W Sukeepaisarnjaroen,7 C Schwabe,1 A Jucov,2 ACH Lee,8 EP Thi, 8 T Harasym, 8 GR Pamulapati, 8 P Wattamwar, 8 J Kunta, 8 M Sofia , 8 H Sevinsky, 8 K Gray, 8 T Eley, 8 G Picchio, 8 KD Sims, 8 MF Yuen9

1 Auckland Clinical Studies, New Zealand; 2 Arensia Exploratory Medicine, Moldova; 3 Seoul National University Hospital, South Korea; 4 St. Vincent's Hospital, Melbourne, Australia; 5 Asan Medical Center, Seoul, South Korea; 6 Royal Prince Alfred Hospital, Sydney, Australia; 7 Srinagarind Hospital, Khon Kaen, Thailand; 8 Arbutus Biopharma, Warminster, PA, USA; 9 Queen Mary Hospital, Hong Kong

BACKGROUND

• Chronic hepatitis B (CHB) can result in the development of cirrhosis,

RESULTS

Figure 2: Individual and mean change from baseline HBsAg (A) and HBV DNA (B) following a single dose of AB‐729 90 mg in HBV DNA+ subjects (Cohort D)

hepatocellular carcinoma, and progression to end‐stage liver

disease.1,2

• Current therapies slow or prevent the development of HBV‐related

liver complications,3,4,5 but do not typically lead to a cure. Thus,

there is an unmet medical need for new HBV therapies that have

the potential to provide a functional cure for CHB.

• AB‐729 is a subcutaneously administered single trigger GalNAc‐

conjugated RNA interference therapeutic candidate. The

proprietary GalNAc liver targeting technology ensures high affinity

and uptake into hepatocytes via the asialoglycoprotein receptor

(ASGPr).

• In preclinical models, AB‐729 reduced all HBV transcripts and

antigens thereby inhibiting HBV replication,6 and was shown to

have activity against all HBV genotypes in vitro.

• AB‐729‐001 is a 3‐part study examining the safety and

pharmacodynamics (PD) of AB‐729 (Figure 1).

- Single doses of AB‐729 (Cohorts A, B, C) and repeat dosing of

AB‐729 60 mg every 4 weeks (Q4W, Cohort E) in virologically‐

suppressed CHB subjects have been previously reported.7

A 1.0
	0.5						individual
(IU/mL)	0.0						mean (N=5)
HBsAg	‐0.5						‐1.02 (0.13) log10 IU/mL
‐1.0
							Mean (SE) at Week 12:
10							Maximum mean (SE)
∆log	‐1.5
					at Week 18:
							‐1.25 (0.11) log10 IU/mL
	‐2.0						3/5 subjects HBsAg
	‐2.5						< 100 IU/mL at nadir
	0	4	8	12	16	20	24
				Week

B 1.0
	0.5
(IU/mL)	0.0
‐0.5
DNA
HBV	‐1.0
10	‐1.5
∆log
	‐2.0
	‐2.5
	0	4	8	12	16	20	24
				Week

individual mean (N=5)

Mean (SE) at Week 12: ‐1.53 (0.24) log10 IU/mL

Maximum mean (SE)

at Week 10:

‐1.57 (0.21) log10 IU/mL

• Here we report safety and PD through:

- 24 weeks following a single dose of AB‐729 90 mg in HBV DNA+

CHB subjects, in the absence of nucleos(t)ide analogue (NA)

therapy (Cohort D)

- 24 weeks with repeat dosing of AB‐729 60 mg every 4 weeks

(Q4W) in virologically‐suppressed subjects (Cohort E)

- 16 weeks with repeat dosing of AB‐729 60 mg every 8 weeks

(Q8W) in virologically‐suppressed subjects (Cohort F).

AB‐729‐001 STUDY DESIGN

Figure 1. AB‐729‐001 Study Design

In Part 2, AB‐729 was administered to subjects as single doses of

60 mg - 180 mg on Day 1. In Part 3, repeat doses of AB‐729 60 mg or 90 mg were administered at varying dosing intervals for 20 weeks.

Part 1: Single Ascending Dose	Part 2: Single Doses	Part 3: Repeat Doses
Healthy Subjects	CHB Subjects (open‐label)	CHB Subjects (open‐label)
Dose 1 (60 mg)	Cohort A: 180 mg	Cohort E
60 mg Q4W
n=6; 4 active: 2 PBO	HBV DNA‐ n=6
HBV DNA‐ n=7

Figure 3: Individual HBsAg, HBV DNA, and ALT

following administration of a single dose of AB‐729 90 mg in HBV DNA+ subjects (Cohort D)

	1.0			12																200
	0.5
			Week																	(U/L)ALT
	0.0																		150
(IU/mL)	‐0.5																		100
	‐1.0
	‐1.5																			50
DNA	‐2.0
‐2.5																			0
HBV	0	4	8	12	16	20	24 0	4	8	12	16	20	24	0	4	8	12	16	20	24
1.0			Week						Week				200			Week
HBsAg,																HBsAg
0.0													150
	0.5
10	‐0.5														(U/L)ALT
∆log													100			HBV DNA
‐1.0
	‐1.5													50				ALT *
	‐2.0
	‐2.5													0
	0	4	8	12	16	20	24 0	4	8	12	16	20	24
				Week						Week

*dotted horizontal line represents ALT ULN (43 U/L for females, 48 U/L for males)

Figure 4: Individual maximum HBV RNA decline

within the first 12 weeks following administration of a single dose of AB‐729 90 mg in HBV DNA+ subjects (Cohort D)

0

U/mL)
10	‐0.5
(log
	ⱡ,b	#,c
decline		#,a
RNA	‐1
HBV			#,b
Max
	‐1.5			c
HBV RNA samples below the lower the limit of quantitation
(1.65 log10 U/mL, ⱡ) or target not detected (#) assigned

a value of 1.64 log10 U/mL for the purpose of this assessment.

Last available HBV RNA timepoint at Week 12 (a), Week 8 (b), and Week 10 (c)

≥ Day 15 Safety		≥ Day 15 Safety	Cohort F
			60 mg Q8W
Dose 2 (180 mg)		Cohort B: 60 mg	HBV DNA‐	n=7
n=6; 4 active: 2 PBO		HBV DNA‐ n=6	Cohort G
			90 mg Q8W
≥ Day 15 Safety		≥ Day 15 Safety	HBV DNA+	n=7
			Cohort I
Dose 3 (360 mg)		Cohort C: 90 mg	90 mg Q8W	n=7
n=6; 4 active: 2 PBO		HBV DNA‐ n=6	HBV DNA‐
		Cohort D: 90 mg	Cohort J
		60 mg Q12W
		HBV DNA+ n=5*
		HBV DNA‐	n=7

Q4W: every 4 weeks, Q8W: every 8 weeks; Q12W: every 12 weeks

*One subject removed from analysis due to spontaneous HBV flare prior to dosing (pre‐dose Day 1 ALT elevated to 149 U/L from Screening value of 24 U/L, TDF initiated by investigator on Day 8), thus data presented are for N=5

Key Inclusion Criteria:

•	All Cohorts: HBeAg positive or negative; HBsAg ≥ 250 IU/mL
•	Virologically‐suppressed Cohorts (A, B, C, E, F, I, J): HBV DNA < LLOQ,
	on stable NA treatment for ≥ 6 months
•	HBV DNA+ Cohorts (D, G): HBV DNA ≥ 1000 IU/mL
•	Single dose Cohorts (A, B, C, D): ALT/AST ≤ 5xULN

Figure 5: Mean (SE) ∆log10 HBsAg following repeat dosing of AB‐729 60 mg Q4W (Cohort E) and Q8W (Cohort F)

	0.5
(IU/mL)	0				AB‐729 60 mg Q4W (N=7)
				AB‐729 60 mg Q8W (N=7)
‐0.5
HBsAg
‐1
10
∆log
mean(SE)	‐1.5
‐2
	‐2.5
	0	4	8	12	16	20	24
60 mg Q4W
60 mg Q8W
				Week

Table 2. Safety Results

	Cohort D	Cohort E	Cohort F	TOTAL
	(90 mg SD
Subjects, n (%)	(60 mg Q4W)	(60 mg Q8W)
HBV DNA+)	[N=19]
	[N=7]	[N=7]
	[N=5]
Subjects with any TEAE	3 (60)	4 (57)	4 (57)	11 (58)
Subjects with related TEAEs	1 (20)	2 (29)	4 (57)	7 (37)
(all Grade 1)
Most common related TEAEs
(in ≥ 2 subjects):
Injection site pain	0	0	2 (29)	2 (3)#
Injection site erythema	0	2 (29)	1 (14)	4 (6)#
Injection site bruising	1 (20)	2 (29)	0	3 (4)#
Laboratory Abnormalities
(in ≥ 2 subjects):
ALT elevation	2 (40)	2 (29)	1 (14)	5 (26)
Grade 1
Grade 2‡	0	2 (29)	1 (14)†	3 (16)
AST elevation (Gr 1)	0	2 (29)	2 (29)	4 (21)
Sodium (low, Gr 1)	0	1 (14)	1 (14)	2 (11)
TEAE: treatment‐emergent adverse event

Grading criteria based on Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1

#n, % is number of events out of 70 total AB‐729 doses administered ‡Grade 2 ALT eleva ons were transient and all improved to Grade 1 †Subject had history of pre‐study Grade 1 ALT abnormalities

•	Repeat dose Cohorts (E, F, G, I, J): ALT/AST ≤ 2xULN

RESULTS

Table 1. Baseline Characteristics

Baseline	Cohort D	Cohort E	Cohort F
90 mg SD	60 mg Q4W	60 mg Q8W
Measure
HBV DNA+ [N=5]	[N=7]	[N=7]
Age in years,	43.6	45.1	44.0
mean (range)	(35 - 57)	(33 - 63)	(31 - 59)
Male gender, n (%)	3 (60%)	4 (57%)	4 (57%)
BMI mean (SD)	29.2 (5.42)	27.7 (5.01)	23.7 (2.17)
Race, n (%)
Asian	0	1 (14%)	5 (71%)
White	4 (80%)	6 (86%)	1 (14%)
Black	0	0	1 (14%)
Other	1 (20%)	0	0
ALT (U/L)	31.6 (13.4)	22.4 (10.5)	23.4 (15.2)
mean (SD)
HBV eAg‐, n (%)	5 (100%)	7 (100%)	6 (86%)
HBsAg (IU/mL)	2336	5372	5354
mean (range)	(317 - 6,451)	(584 - 11,761)	(667 - 18,605)
HBV DNA (IU/mL)	86,840	N/A	N/A
mean (range)	(1,220 - 360,560)
SD: single dose

Table 3. Summary PD data for AB‐729 60 mg administered every 4 weeks or every 8 weeks

Visit	AB‐729 60 mg Q4W [Cohort E, N=7]	AB‐729 60 mg Q8W [Cohort F, N=7]
Week 16	Mean (SE) ∆log10 HBsAg:	4/7 HBsAg < 100 IU/mL	Mean (SE) ∆log10 HBsAg:	3/7 HBsAg < 100 IU/mL
‐1.44 (0.18) IU/mL	4/7 > 1.5 log10 HBsAg decline	‐1.39 (0.07) IU/mL	3/7 > 1.5 log10 HBsAg decline
Week 24	Mean (SE) ∆log10 HBsAg:	5/7 HBsAg < 100 IU/mL	not yet available
‐1.84 (0.16) IU/mL	6/7 > 1.5 log10 HBsAg decline

CONCLUSIONS

• In HBV DNA+ CHB subjects administered a single dose of AB‐729 90 mg in the absence of NA therapy:
• • HBsAg remained suppressed in all subjects up to 24 weeks post‐dose; however HBV DNA rebound was observed in some subjects post‐Week 12.
  • HBV RNA declined in all subjects up to 12 weeks post‐dose (the last time point available for HBV RNA), with 4/5 subjects reaching either undetectable or unquantifiable HBV RNA at some point.
  • ALT elevations were benign and did not appear to correlate with either HBsAg or HBV DNA profiles, including HBV DNA rebound.
  • These data continue to support AB‐729 dosing in combination with other agents at intervals up to every 12 weeks.
• In virologically suppressed CHB subjects administered AB‐729 60 mg every 4 weeks (Cohort E) or every 8 weeks (Cohort F):
• • Mean (SE) HBsAg declines were similar up to Week 16, providing further evidence that AB‐729 can be dosed less frequently than every 4 weeks.
  • Mean HBsAg continued to decline through Week 24 following repeat dosing of AB‐729 60 mg every 4 weeks.
  • • 7/7 subjects have consented to participate in a treatment extension arm where they will continue to receive AB‐729 for an additional 6 months.
    • Based on single dose PD data presented previously,7 the dosing interval of AB‐729 60 mg was increased to every 12 weeks for the extension period.
• AB‐729 was well tolerated after single doses in HBV DNA+ subjects and after multiple doses in virologically suppressed CHB subjects:
• • All TEAEs were Grade 1 excepting one case of unrelated COVID‐19 with fever (Grade 2).
  • Transaminase elevations were modest and transient, none were symptomatic or were accompanied by bilirubin elevations or other clinically relevant laboratory changes and were not assessed as TEAEs.

REFERENCES	ACKNOWLEDGEMENTS
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2Yuen MF, et al. Nat Rev Dis Primers,2018.4:p.18035.	and site staff, Novotech, Covance, Maks Chernyakhorvskyy, Deana Antoniello, and the
3European Association for the Study of the Liver, EASL 2017 Clinical Practice	AB‐729 Research and Clinical Development Teams.
Guidelines on the management of hepatitis B infection. J Hepatol,	CONTACT INFORMATION AND DISCLOSURES
2017.67(2):370‐398.
4Sarin SK, et al. Hepatol Int, 2016.10(1):p:1‐98.	•Heather Sevinsky, Senior Director, AB‐729 Compound Development Lead and Clinical Pharmacology
5Terrault N, et al. Hepatol,2018.67(4)p:1560‐1599.	•Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA 18974
6Lee ACH. EASL 2018.	•Email: [e-mail]
•Tel: +1‐267‐420‐2603
7Yuen MF, et al. AASLD 2020.	•Authors affiliated with Arbutus Biopharma are employees and may own company stock.
	www.arbutusbio.com