Table 1.

Disease Targets and Nucleic Acid Therapeutic Candidates in the Development Pipeline

Indication(s)	Therapeutic Name	Target	Type	Delivery	Administration Route	Clinical Status	Company	NCT Number	References
Familial amyloidotic cardiomyopathy	ALN-TTRsc/Revusiran	TTR	siRNA	STC-GalNAc conjugate	s.c.	phase III, terminated	Alnylam	NCT01814839, NCT02292186, NCT01981837, NCT02319005, NCT02595983	J.D. Gillmore, et al., 2015, J. Am. Coll. Cardiol., abstract; 64, 65, 70
Hypercholesterolemia	ALN-PCSsc	PCSK9	siRNA	ESC-GalNAc conjugate	s.c.	phase II	Alnylam	NCT02314442, NCT02597127	K.J. Pasi et al., 2016, Haemophilia, abstract; K. Fitzgerald et al., 2015, Circulation, abstract; 74, 110
Hemophilia and rare bleeding disorders	ALN-AT3/Fitusiran	AT	siRNA	ESC-GalNAc conjugate	s.c.	phase I/II	Alnylam	NCT02035605, NCT02554773	K.J. Pasi et al., 2016, Haemophilia, abstract; 71, 72, 111
Paroxysmal nocturnal hemoglobinuria	ALN-CC5	C5	siRNA	ESC-GalNAc conjugate	s.c.	phase I/II	Alnylam	NCT02352493	75, 112
Alpha-1 antitrypsin deficiency	ALN-AAT	AAT	siRNA	ESC-GalNAc conjugate	s.c.	phase I/II, terminated	Alnylam	NCT02503683	66
Primary hyperoxaluria type 1	ALN-GO1	GO (HAO1)	siRNA	ESC-GalNAc conjugate	s.c.	phase I/II	Alnylam	NCT02706886	76, 77, 113
Hepatitis B virus infection	ALN-HBV	conserved region of HBV	siRNA	ESC-GalNAc conjugate	s.c.	phase I/II	Alnylam	NCT02826018	L. Sepp-Lorenzino et al., 2015, Hepatology, abstract;78, 79, 114
Hepatic porphyrias	ALN-AS1	ALAS1	siRNA	ESC-GalNAc conjugate	s.c.	phase I	Alnylam	NCT02452372	80, 81, 115
Familial amyloidotic cardiomyopathy	ALN-TTRsc02	TTR	siRNA	ESC-GalNAc conjugate	s.c.	phase I	Alnylam	NCT02797847	116
Alpha-1 antitrypsin deficiency	ALN-AAT02	AAT	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam
β-Thalassemia/iron overload disorders	ALN-TMP	Tmprss6	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam		J. Butler et al., 2013, Blood, abstract
Hereditary angioedema	ALN-F12	F12	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam		Akinc et al., 2016, J. Allergy Clin. Immunol., abstract
Thromboprophylaxis	ALN-F12	F12	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam
Hypertriglyceridemia	ALN-AC3	ApoC3	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam		74
Mixed hyperlipidemia/hypertriglyceridemia	ALN-ANG	ANGPTL3	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam		W. Querbes et al., 2013, Circulation, abstract
Hypertension/pre-eclampsia	ALN-AGT	AGT	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam
Hepatitis D virus infection	ALN-HDV	HDV genome	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam
Chronic liver infection	ALN-PDL	PD-L1	siRNA	ESC-GalNAc conjugate	s.c.	preclinical	Alnylam
Hepatitis B virus infection	ARC-520	conserved region of HBV	siRNA	GalNAc-masked DPC	i.v.	phase IIb	Arrowhead	NCT01872065, NCT02535416, NCT02065336, NCT02604199, NCT02604212, NCT02452528, NCT02738008, NCT02577029	11, 89, 117
Hepatitis B virus infection	ARC-521	integrated DNA of HBV genome	siRNA	GalNAc-masked DPC	i.v.	phase I/IIa	Arrowhead	NCT02797522
Alpha-1 antitrypsin deficiency	ARC-AAT	AAT	siRNA	GalNAc-masked DPC	i.v.	phase I	Arrowhead	NCT02363946	89
Thrombosis and angioedema	ARC-F12	F12	siRNA	GalNAc-masked DPC	i.v.	preclinical	Arrowhead		S. Melquist et al., 2016, J. Allergy Clin. Immunol., abstract
Primary hyperoxaluria type 1	DCR-PHsc	HAO1	siRNA	DsiRNA-GalNAc conjugate	s.c.	preclinical	Dicerna		91
Orphan genetic disease	DCR-undisclosed	undisclosed target	siRNA	DsiRNA-GalNAc conjugate	s.c.	preclinical	Dicerna		91
Cardiovascular disease	DCR-PCSK9	PCSK9	siRNA	DsiRNA-GalNAc conjugate	s.c.	research	Dicerna		91
Alpha-1 antitrypsin deficiency	DCR-AAT	AAT	siRNA	DsiRNA-GalNAc conjugate	s.c.	research	Dicerna		91
Fibrotic liver diseases	DCR-HMGB1a	HMGB1	siRNA	DsiRNA-GalNAc conjugate	s.c.	research	Dicerna		91
Hepatitis B virus infection	DCR-HBVa	conserved region of HBV	siRNA	DsiRNA-GalNAc conjugate	s.c.	research	Dicerna		91
Chronic liver diseases (liver fibrosis)	DCR-β-catenina	CTNNB1	siRNA	DsiRNA-GalNAc conjugate	s.c.	research	Dicerna		91
Rare genetic diseases/metabolic disorder/multiple liver-related diseases	GalXC UDT #1–#8	eight undisclosed targets	siRNA	DsiRNA-GalNAc conjugate	s.c.	research	Dicerna		91
Unknown	unknown	undisclosed targets	siRNA	siRNA-GalNAc conjugate	s.c.	research	Silence
Rare genetic diseases 1	unknown	undisclosed targets	unknown (ASO or RNAi)	GalNAc-conjugated molecule	NA	research	Wave Life Science
Rare genetic diseases 2	unknown	undisclosed targets	unknown (ASO or RNAi)	GalNAc-conjugated molecule	NA	research	Wave Life Science
Hepatitis C virus infection	RG-101	microRNA-122	anti-miR	anti-miR-GalNAc conjugate	s.c.	phase II	Regulus	NA	M.H. van der Ree et al., 2015, Hepatology, abstract;92
NASH/type 2 diabetes/pre-diabetes	RG-125	microRNA-103/107	anti-miR	anti-miR-GalNAc conjugate	s.c.	phase I	Regulus/AstraZeneca	NA	M. Sundqvist et al., 2015, Diabetologia, abstract; B. Wagner et al., 2015, Diabetologia, abstract;93
High lipoprotein(a)	IONIS-APO(a)-LRx	Apo(a)	ASO	ASO-GalNAc conjugate	s.c.	Phase I/IIa	Ionis/Akcea	NCT02414594	97, 98, 99
Mixed dyslipidemias	IONIS-ANGPTL3-LRX	ANGPTL3	ASO	ASO-GalNAc conjugate	s.c.	phase I/II	Ionis/Akcea	NCT02709850	98
Ocular disease	IONIS-GSK4-LRx	Undisclosed targets	ASO	ASO-GalNAc conjugate	s.c.	phase I	Ionis/GSK	NA
Hepatitis B virus infection	IONIS-HBV-LRx	HBV genome	ASO	ASO-GalNAc conjugate	s.c.	phase I	Ionis/GSK	NA	100, 101
Severe high triglycerides / High triglycerides with type 2 diabetes	IONIS-APOCIII-LRX	ApoC3	ASO	ASO-GalNAc-conjugate	s.c.	preclinical	Ionis/Akcea
Acromegaly	IONIS-GHR-LRx	GHr	ASO	ASO-GalNAc conjugate	s.c.	preclinical	Ionis		102
β-Thalassemia	IONIS-TMPRSS6-LRx	Tmprss6	ASO	ASO-GalNAc conjugate	s.c.	preclinical	Ionis		103
Treatment-resistant hypertension	IONIS-AGT-LRx	AGT	ASO	ASO-GalNAc conjugate	s.c.	preclinical	Ionis

Abbreviations: TTR, transthyretin amyloidosis; PCSK9, proprotein convertase subtilisin/kexin type 9; AT, antithrombin; C5, complement component 5; AAT, alpha-1 antitrypsin; HAO1 (GO), hydroxyacid oxidase (glycolate oxidase) 1; ALAS1, aminolevulinic acid synthase 1; Tmprss6, transmembrane protease serine 6; F12, factor XII; ApoC3, Apolipoprotein C3; ANGPTL3, Angiopoietin-like 3; AGT, angiotensinogen; PD-L1, programmed death-ligand 1; HMGB1, high mobility group box 1 protein; CTNNB1, catenin beta-1 or β-catenin; GHr, growth hormone receptor; s.c., subcutaneous; i.v., intravenous; NCT, national clinical trial; NA, not available.

^aPredicted name.