Arrowhead Pharmaceuticals : NLA 2020 ARO-ANG3

Pharmacodynamic effect of ARO-ANG3, an investigational RNA interference therapeutic targeting hepatic angiopoietin-like protein 3, in patients with dyslipidemia

GF Watts1, C Schwabe2, R Scott3, P Gladding4, D Sullivan5, J Baker6, P Clifton7, J Hamilton8, B Given8, J San Martin8, S Melquist8, T Chang8, N Rajicic8, I Goldberg9, D Gaudet10, JW Knowles11, RA Hegele12, C Ballantyne13

1University of Western Australia, Perth, Australia; 2Auckland Clinical Studies, Auckland, New Zealand; 3Lipid and Diabetes Research, Christchurch Hospital, Christchurch 8011, New Zealand; 4Waitemata District Health Board, Auckland, New Zealand; 5Royal Prince Alfred Hospital, Sydney, Australia; 6Middlemore Hospital, Auckland, New Zealand; 7Royal Adelaide Hospital, Adelaide, Australia; 8Arrowhead Pharmaceuticals, Inc., Pasadena, United States; 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

INTRODUCTION

• Dyslipidemia is a major risk factor for cardiovascular disease (CVD), and residual risk of CVD persists even with current standard of care (including PCSK9 inhibitors)
• ANGPTL3 is a key regulator of lipid and lipoprotein metabolism with multiple potential nodes of action, including inhibition of Lipoprotein Lipase (LPL) and Endothelial Lipase (EL) (see figure below)
• Loss-of-functionmutations in ANGPTL3 lead to enhanced LPL and EL activity, resulting in:
• • Low TG, LDL-C,VLDL-C, and HDL-C
  • Reduced risk of CVD, and
  • No known adverse phenotype associated with genetic deficiency in ANGPTL3
• ARO-ANG3 is an investigational synthetic, double-stranded,hepatocyte-targeted RNA interference (RNAi) trigger designed to specifically silence ANGPTL3 mRNA expression in the liver
• AROANG1001 is a phase 1 study designed to evaluate the safety, tolerability and pharmacodynamic effects of ARO-ANG3 on healthy volunteers and patients with dyslipidemia

STUDY ENDPOINTS

Safety (Primary):

• Incidence and frequency of adverse event

Key Pharmacodynamic and Lipid Parameters:

• Change from baseline over time in ANGPTL3
• Change from baseline over time in the following parameters: fasting Triglycerides, LDL-C, non- HDL-C, and HDL-C

Patient Populations

• HeFH - Heterozygous Familial Hypercholesterolemia (HeFH) patients - genetically confirmed or
  Dutch lipid clinic network score ≥ 6
• Non-FH - Patients on stable statin regimen that are not at LDL-C goal (LDL-C > 70 mg/dL)
• HTG - Hypertriglyceridemia patients with TG >300 mg/dL at screening

Baseline characteristics of HeFH, Non-FH and HTG patient cohorts

				HeFH Patients		Non-FH Patients	HTG Patients
		100 mg ARO-	200 mg ARO-	300 mg ARO-	200 mg ARO-
	Mean (range)	ANG3	ANG3	ANG3	ANG3	Placebo	200 mg ARO-
	Fasting values	(n=6)	(n=6)	(n = 5)	(n=6)	(n=3)	ANG3 (n=6)
	Age (years)	43.5 (19-61)	49.3 (25-65)	45.2 (20-70)	51.7 (31-62)	58.7 (51-63)	62.8 (51-69)
	Male (%)		50	50	60	83	67	67
	BMI (kg/m2 )	29.9 (25.1-35.0)	28.0 (21.0-36.9)	25.6 (19.4-29.8)	26.8 (21.5-36.4)	28.8 (28.0-29.5)	31.2 (27.8-36.9)
	ANGPTL3	71	(45-91)	96 (76-127)	74 (36-134)	87 (59-112)	91 (69-131)	107 (68-161)
	(ng/mL)
	Triglycerides	196	(94-360)	86 (66-118)	138 (38-441)	87 (68-130)	198 (121-271)	973 (189-2743)
	(mg/dL)
	LDL-C (mg/dL)	129	(95-191)	146 (91-171)	126 (96-174)	96 (68-198)	98 (56-132)	79 (13-179)
	(direct assay)
	Non-HDL-C	171 (121-229)	168 (109-207)	163 (105-230)	112 (84-217)	131 (83-180)	236 (141-385)
	(mg/dL)
	HDL-C (mg/dL)	45	(32-59)	60 (46-86)	44 (30-57)	43 (34-53)	57 (54-61)	37 (10-75)
	ApoB (mg/dL)	132	(88-202)	106 (73-138)	100 (75-135)	78 (64-133)	87 (60-124)	106 (71-149)

Phase 1 Study to evaluate the effect of ARO-ANG3 in patients with dyslipidemia	Clinicaltrials.gov identifier:
	NCT03747224

RESULTS																																		Data cutoff: 30 Apr 2020
ARO-ANG3 substantially reduces ANGPTL3, TG, LDL-C and non-HDL-C in HeFH and non-FH patients
																TG				HeFH				LDL-C
				ANGPTL3																											Non HDL-C
	140											400										200									(mg/dL)HDLnonC-	250								100 mg ARO-ANG3 (n=6)
ANGPTL3(ng/mL)									88%	Triglyceride(mg/dL)	50								29%	(mg/dL)C-LDL
20
	120											350																				200								200 mg ARO-ANG3 (n=6)
												300										150																		300 mg ARO-ANG3 (n=5)
	100											250																		29%		150
	80											200										100								33%										31%
	60																														100								34%
											150								47%										35%
																																						35%
	40									78%		100									50
																	39%											50
	0									88%		0										0										0
	0	2	4	6	8	10	12	14	16			0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16
					Week											Week										Week										Week
																				Non-FH													Non HDL-C
				ANGPTL3										TG										LDL-C
	140											400										200									(mg/dL)HDLnonC-	250								Placebo (n=3)
ANGPTL3(ng/mL)										Triglyceride(mg/dL)	50								42%	(mg/dL)C-LDL
20
	120											350																				200								200 mg ARO-ANG3 (n=6)
	100											300										150
	80											250																				150
											200										100
	60											150																		32%		100								30%
	40											100										50										50
										90%																						0
	0											0										0
	0	2	4	6	8	10	12	14	16			0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16

Week

Week

Week

Week

ARO-ANG3 substantially reduces ANGPTL3, TG and non-HDL-C in HTG patients

HTG

				ANGPTL3									TG												LDL-C									Non HDL-C
	140										2000											150										(mg/dL)HDLnonC-	400								200 mg ARO-ANG3 (n=6)
ANGPTL3(ng/mL)									Triglyceride(mg/dL)	250									75%	(mg/dL)C-LDL
20
	120										1750
	100										1500											100											300
											1250
	80										1000																				5%		200
	60
										750											50
																																							56%
	40										500																					100
								83%
	0										0											0											0
	0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16			0	2	4	6	8	10	12	14	16		0	2	4	6	8	10	12	14	16
					Week										Week												Week										Week

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

RESULTS

Summary of interim safety data

	HeFH	Non-FH		HTG
TEAEs Reported in > 2	All Doses	200 mg	Placebo	200 mg	Total
subjects, AE Term	Active	Active
(MedDRA Preferred Term)	n = 17	n=6		n=3	n=6	n = 29
Headache	4 (23.5%)	0	1	(33%)	1 (17%)	5 (17%)
Contusion	4 (23.5%)	0		0	0	4 (14%)
Oropharyngeal pain	3 (18%)	0		0	1 (17%)	4 (14%)
Vascular access site	2 (12%)	1 (17%)		0	1 (17%)	4 (14%)
bruising/hematoma
Injection site erythema,	3 (18%)	0	1	(33%)	0	3 (10%)
bruising, pain, swelling
Dizziness	2 (12%)	1 (17%)	1	(33%)	0	3 (10%)
Muscle spasm	1 (6%)	0		0	2 (33%)	3 (10%)
Presyncope, Syncope	3 (18%)	0		0	0	3 (10%)
Upper respiratory tract	1 (6%)	2 (33%)	1	(33%)	0	3 (10%)
infection, Respiratory tract
infection

• Two subjects reported SAEs (1 case of ketosis related to dapaglifozin and dehydration, 1 case of syncope with fibula fracture), both cases not related to ARO-ANG3.
• Two AEs of ALT elevation were reported. One case was asymptomatic (baseline 34 U/L, peak 91 U/L). The other (baseline 30 U/L, peak 238 U/L Day 29, 68 U/L Day 43 and 34 U/L at Day 113/EOS) was transient and associated with gastroenteritis. Neither associated with clinically significant elevations in total bilirubin.
• No clinically significant adverse changes in platelets
• No drug discontinuations
• Contusion AEs (n=4)

•2 events related to mechanical fall

•1 event related to NSAID treatment

CONCLUSIONS

• ARO-ANG3,an investigational RNAi therapeutic targeting ANGPTL3 mRNA transcripts results in sustained favorable lipid changes
• ARO-ANG3maintained reductions in these lipid parameters for >12 weeks post second dose, regardless of patient population
• ARO-ANG3had a favorable safety and tolerability profile
• ARO-ANG3produces a substantial and prolonged reduction of LDL-C,non-HDL-C and TGs, and may prove useful as a therapeutic option in patients with dyslipidemia

ACKNOWLEDGEMENTS

The study sponsors would like to acknowledge the help and participation of all patients who agreed to take part in this study, as well as the work and dedication of the staff at the clinical sites.