Arrowhead Pharmaceuticals : NLA 2020 ARO-APOC3

Pharmacodynamic effect of ARO-APOC3, an investigational hepatocyte-targeted RNA interference therapeutic targeting apolipoprotein C3, in patients with hypertriglyceridemia and multifactorial chylomicronemia

P Clifton1, D Sullivan2, J Baker3, C Schwabe4, S Thackwray5, R Scott6, J Hamilton7, T Chang7, B Given7, J San Martin7, S Melquist7, N Rajicic7, GF Watts8, I Goldberg9, D Gaudet10, JW Knowles11, RA Hegele12, C Ballantyne13

1Royal Adelaide Hospital, Adelaide, Australia; 2Royal Prince Alfred Hospital, Sydney, Australia; 3Middlemore Hospital, Auckland, New Zealand; 4Auckland Clinical Studies, Auckland, New Zealand; 5University of the Sunshine Coast, Sippy Downs, Australia; 6Lipid and Diabetes Research Group, Christchurch, New Zealand; 7Arrowhead Pharmaceuticals, Inc., Pasadena, United States; 8University of Western Australia, Perth, Australia; 9NYU School of Medicine, NYU Langone Health, New York City, United States; 10Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, Canada; 11Stanford Division of Cardiovascular Medicine and Cardiovascular Institute, School of Medicine, Stanford, United States; 12University of Western Ontario, London, Canada; 13Baylor College of Medicine,

Houston, United States

Financial Disclosure

Presenter: C Ballantyne

Grant/Research Support- All significant. (All paid to institution, not individual): Abbott Diagnostic, Akcea, Amgen, Esperion, Novartis, Regeneron, Roche Diagnostic, NIH, AHA, ADA.

Consultant- Abbott Diagnostics, Althera, Amarin*, Amgen, Arrowhead, Astra Zeneca, Biotech, Corvidia, Denka Seiken*, Esperion, Genentech, Gilead, Matinas BioPharma Inc, New Amsterdam*, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, Sanofi- Synthelabo* (*Significant where noted (>$10,000))

Co-authors:

P. Clifton, J. Baker, C. Schwabe, S. Thackwray and R. Scott

report no relevant disclosures

D. Sullivan reports grants and/or consulting fees from Regeneron, Amgen, Astra-Zeneca, Amarin, Espirion, Arrowhead, Sanofi, and Novartis

J Hamilton, T Chang, B. Given, J San Martin, S Melquist and

N Rajicic are all current or former employees of Arrowhead Pharmaceuticals

GF Watts reports consulting fees from Amgen, Novartis, Arrowhead, Kowa and Astra Zeneca

D.Gaudet reports grants and personal fees from Arrowhead during the conduct of the study; and grants and/or personal fees from Acasti, Akcea, Amryt Pharma, Esperion, Gemphire, Ionis, HDL Therapeutics, Kowa, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi and UniQure outside the submitted work.

I Goldberg has been on a scientific advisory boards for Arrowhead, Esperion and Amgen. He has received funds from Arrowhead for preclinical studies.

JW Knowles reports consulting fees from Arrowhead

RA Hegele reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Novartis, Pfizer, Regeneron and Sanofi

APOC3 is a key regulator of triglyceride-rich lipoproteins (TRLs) through lipoprotein lipase (LPL)-dependent and -independent pathways

• Severe hypertriglyceridemia (SHTG) is characterized by triglyceride (TG) levels ≥ 500 mg/dL, which can lead to acute pancreatitis
• • SHTG may be caused by a combination of genetics (i.e., chylomicronemia), diet, and comorbid conditions (e.g., metabolic syndrome, diabetes)
  • Reduction and maintenance of TG levels below 500 mg/dL can reduce the risk of acute pancreatitis and is a goal of therapy1
• APOC3 is a key regulator of TG metabolism
• • SHTG is characterized by excess levels of Apolipoprotein C3 (APOC3)-containing particles, such as chylomicrons or VLDL
  • Loss-of-functionmutations in APOC3 are associated with lower TG, lower post-prandial lipemia and decreased incidence of coronary artery disease
• ARO-APOC3is designed to specifically target and silence the APOC3 gene, thereby reducing TG levels
• • ARO-APOC3is an investigational synthetic, double-stranded,hepatocyte-targeted RNA interference trigger designed to specifically target APOC3 mRNA transcripts

1NCEP 2002. Circulation 106:3143-3421

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ARO-APOC3 specifically targets and silences the APOC3 gene, reducing TG levels

Silencing of liver APOC3 mRNA	Reduced APOC3 stimulates LPL
reduces APOC3 protein in	dependent & independent
Triglyceride rich lipoproteins	clearance pathways

DIETARY LIPIDS	(TRLs)
		APOC3
SMALL
INTENSTINE
		LPL DEPENDENT
	CHYLOMICRON
LIVER		LPL INDEPENDENT
FREE FATTY ACIDS	VLDL	APOC3
	ARO-
	APOC3

Decreased TRLs and

remnants

CHYLOMICRON

REMNANTS

LDL

IDL

Increased remnant clearance by liver

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Phase 1 study to evaluate the effect of ARO-APOC3 in patients with hypertriglyceridemia (HTG) or chylomicronemia (CM)

Study Endpoints

Safety (Primary):

• Incidence and frequency of adverse events

Key Pharmacodynamics (PD) and

Lipid Parameters:

• Change from baseline over time in APOC3

• Change from baseline over time in the following key parameters: Triglyceride, HDL- C, non-HDL-C

Data cut date: 31 Aug 2020

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ARO-APOC3 results in substantial and sustained reduction of APOC3 and TG

APOC3

HTG

TG

Data cut date: 31 Aug 2020

APOC3 (mg/dL)

80
60								8%
40								80%
							98%
20								98%
							99%
0								LLOQ
0	2	4	6	8	10	12	14	16
				Week

Triglyceride (mg/dL)

2500
2000	*
1500								19%
1000								74%
							92%
500								85%
0								87%
0	2	4	6	8	10	12	14	16
				Week

Pooled Placebo (n=7) 10 mg ARO-APOC3 (n=6) 25 mg ARO-APOC3 (n=4) 50 mg ARO-APOC3 (n=7)

100 mg ARO-APOC3 (n=8) * Vertical error bar is

truncated for 25 mg ARO-APOC3 cohort, Vertical error bars are truncated if they cross below zero

Chylomicronemia

					APOC3									TG
(mg/dL)APOC3	80									(mg/dL)Triglyceride	4000
60								96%	3000
	40										2000
	20										1000
																			88%
	0								LLOQ		0
	0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16
					Week										Week

50 mg ARO-APOC3 (n=16)

Only subjects with baseline + >1 additional visit are included in

graphs

Mean values +/- SD are plotted for each cohort ;% values are maximum mean reductions for each cohort (n>1 subject	6
at a visit date)

ARO-APOC3 substantially reduces non-HDL-C and increases HDL-C

				non-HDL-C				HTG						HDL-C
non HDL-C (mg/dL)	500											100
400	*									HDL-C (mg/dL)	80
								0%
300									60
								41%
200									60%	40
									45%
100									39%	20
	0											0
	0	2	4	6	8	10	12	14	16			0	2	4	6	8	10
					Week											Week
								Chylomicronemia
				non-HDL-C										HDL-C
	500											100

		9%
		95%
		116%
		96%
		110%
12	14	16

Data cut date: 31 Aug 2020

Pooled Placebo (n=7) 10 mg ARO-APOC3 (n=6) 25 mg ARO-APOC3 (n=4) 50 mg ARO-APOC3 (n=7) 100 mg ARO-APOC3 (n=8)

* Vertical error bar is truncated for 25

mg ARO-APOC3

cohort

-(mg/dL)C	400	C(mg/dL)	80
300	60

50 mg ARO-APOC3 (n=16)

nonHDL	200									59%	HDL-	40
100										20
	0											0
	0	2	4	6	8	10	12	14	16			0	2	4	6	8	10
					Week											Week

120%

12 14 16

Only subjects with

baseline + >1 additional visit are included in graphs

Mean values +/- SD are plotted for each cohort ;% values are maximum mean reductions for each cohort (n>1 subject at a visit	7
date)

Summary interim safety findings in HTG and CM patients

								CM
			HTG Cohorts (TG>300 mg/dL)	TG>880mg/dL
			10 mg	25 mg	50 mg	100 mg
	TEAEs Reported in > 1		Cohort	Cohort	Cohort	Cohort	Pooled	50 mg Cohort	Total
	subject, AE Term (MedDRA		1b	4b	2b	3b	Placebo	5	Active
	Preferred Term)		n = 5	n = 5	n = 7	n=8	N=8	n=16	n = 41
	Injection site reaction -				2
	erythema, rash,		0	2 (40%)	2 (25%)	0	2 (12.5%)	8 (19.5%)
		(28.5%)
	discoloration, pain, bruising
	ALT, LFT, transaminase
	increased, Liver function test		0	1 (20%)	1 (14%)	2 (25%)	0	3 (19%)	7 (17%)
	increased
	Headache		1 (20%)	2 (40%)	2	1	0	0	6 (15%)
		(28.5%)	(12.5%)
	Upper respiratory tract		0	1 (20%)	2	0	0	1 (6%)	4 (10%)
	infection		(28.5%)
	Rash		0	0	0	2 (25%)	0	1 (6%)	3 (7%)
	Abdominal distention		0	2 (40%)	0	0	0	0	2 (5%)
	Diarrhea		1 (20%)	0	1 (14%)	0	0	0	2 (5%)
	Hyperglycemia		0	1 (20%)	1 (14%)	0	0	0	2 (5%)
	Paresthesia		1 (20%)	0	0	1	0	0	2 (5%)
		(12.5%)
	Safety data cutoff 11 Sep 2020

• AEs at injection site were all mild
• ALT elevations were generally asymptomatic and transient, returning towards baseline by end of study
• • Only two subjects had ALT >3X ULN at two sequential visits with return to pre- dose baseline by Day 113 (EOS).
  • The highest ALT was in a subject with a history of cholelithiasis and biliary colic. Baseline ALT of 22 U/L, elevation on Day 85 to 230 U/L with return to 36 U/L on Day 99 and 33 U/L at Day 113 (EOS) Subject subsequently underwent elective cholecystectomy
• No clinically significant adverse changes in platelets, total bilirubin or creatinine
• No drug discontinuations
• 1 SAE of pancreatitis
• • Not related to ARO-APOC3
  • History of pancreatitis, type 2 diabetes mellitus and gall stones
  • MRCP/endoscopic ultrasound indicated pancreatolithiasis as probable cause

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ARO-APOC3, an investigational RNAi therapeutic that silences APOC3 mRNA transcripts results in favorable lipid changes in patients

• In patients with hypertriglyceridemia, 10 mg, 25 mg, 50 mg and 100 mg SC doses of ARO- APOC3, resulted in robust and sustained reductions in TGs and Non-HDL-Cwith HDL-Cincreases
• • Maximal mean reduction of -80% to -99% in APOC3
  • Maximal mean reduction of -74% to -92% in TG, -39% to -62% in non-HDL-C
  • Maximal mean increase of +95% to +116% in HDL-C
• In patients with chylomicronemia, 50 mg ARO-APOC3 SC achieves similar levels of reduction of
  APOC3 and changes in key lipid parameters
• • Maximal mean reduction of -98% in APOC3
  • Maximal mean reduction of -88% in TG, -59% in non-HDL-C
  • Maximal mean increase of +120% in HDL-C
• The effect of ARO-APOC3 is maintained >12 weeks post second dose regardless of patient population
• ARO-APOC3safety profile supportive of later stage clinical development based on interim Phase 1 study results

ARO-APOC3 may prove useful as a therapeutic option in patients with hypertriglyceridemia,

severe hypertriglyceridemia and chylomicronemia

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