Table 1.

Failed clinical trials of RNA therapies due to safety issues.

Drug candidate	Payload	Delivery platform	Indication	Safety issue	Major events	Status	Company
CALAA-01 [141]	Anti-R2 siRNA	Tumor-targeted nanocomplex	Solid tumors	Phase 1a: DLTs in 2 patients Phase 1b: DLTs in other patients	Grade3,4: Lymphopenia, Hypersensitivity, ischemic colitis, hyponatremia	Phase 1 terminated (NCT00689065)	Calando Pharmaceuticals
ARC-520 [142]	Anti HBV cccDNA siRNA	Cholesterol-targeted siRNA conjugate+ARC-EX1	HBV	Phase 2: Death of NHPs with high doses of another investigational RNAi therapeutic with ARC-EX1 excipient	Early termination of study	Phase 2 terminated	Arrowhead pharmaceuticals
TKM-ApoB [148]	Anti APoB siRNA	SNALP	Hypercholesterolemia	Phase 1: potential of immune stimulation with dose escalation	Immune-mediated adverse events	Phase 1 terminated (NCT00927459)	Tekmira Pharmaceuticals
TKM-080301 [152]	anti-PLK1 siRNA	SNALP	Solid tumors	Phase 1/2: - Dose 0.9 mg/kg: DLTs including grade 3 CRS - Dose 0.75 mg/kg: 2 patients grade 4 thrombocytopenia - Dose 0.6 mg/kg: well-tolerated but limited efficacy	Thrombocytopenia, peritoneal hemorrhage, sepsis, hepatic failure	Phase 1/2 completed (NCT02191878)	Tekmira Pharmaceuticals
Revusiran [156]	Anti-TTR siRNA	GalNac-conjugate	hATTR cardiomyopathy	Phase 3: unbalanced death between the treatment and placebo group	Cardiac failure, Hepatic and renal events, Peripheral neuropathy	Phase 3 terminated (NCT02319005)	Alnylam
MRX34 [16]	Anti-miR-34	Liposome	Solid tumors	Phase 1: SAEs in 5 patients, causing death of 4	Immune-mediated adverse events in lung and colon, multi-organ failure, generalized seizure, CRS	Phase 1 terminated (NCT01829971)	Mirna therapeutics
RG-101 [15]	Anti – miR122	GalNac-conjugate	HCV	Phase 1b: 2 patients developed jaundice	High levels of bilirubin in the blood	Phase 1 terminated	Regulus Therapeutics