TY - JOUR
T1 - Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9)
T2 - a first-in-human randomized, placebo-controlled trial
AU - van Poelgeest, Eveline P
AU - Hodges, Michael R
AU - Moerland, Matthijs
AU - Tessier, Yann
AU - Levin, Arthur A
AU - Persson, Robert
AU - Lindholm, Marie W
AU - Dumong Erichsen, Kamille
AU - Ørum, Henrik
AU - Cohen, Adam F
AU - Burggraaf, Jacobus
N1 - © 2015 The British Pharmacological Society.
PY - 2015/12
Y1 - 2015/12
N2 - AIMS: LDL-receptor expression is inhibited by the protease proprotein convertase subtilisin/kexin type 9 (PCSK9), which is considered a pharmacological target to reduce LDL-C concentrations in hypercholesterolaemic patients. We performed a first-in-human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9.METHODS: In this randomized, placebo-controlled trial, 24 healthy volunteers received three weekly subcutaneous administrations of SPC5001 (0.5, 1.5 or 5 mg kg(-1)) or placebo (SPC5001 : placebo ratio 6 : 2). End points were safety/tolerability, pharmacokinetics and efficacy of SPC5001.RESULTS: SPC5001 plasma exposure (AUC(0,24 h)) increased more than dose-proportionally. At 5 mg kg(-1), SPC5001 decreased target protein PCSK9 (day 15 to day 35: -49% vs. placebo, P < 0.0001), resulting in a reduction in LDL-C concentrations (maximal estimated difference at day 28 compared with placebo -0.72 mmol l(-1), 95% confidence interval - 1.24, -0.16 mmol l(-1); P < 0.01). SPC5001 treatment (5 mg kg(-1)) also decreased ApoB (P = 0.04) and increased ApoA1 (P = 0.05). SPC5001 administration dose-dependently induced mild to moderate injection site reactions in 44% of the subjects, and transient increases in serum creatinine of ≥20 μmol l(-1) (15%) over baseline with signs of renal tubular toxicity in four out of six subjects at the highest dose level. One subject developed biopsy-proven acute tubular necrosis.CONCLUSIONS: SPC5001 treatment dose-dependently inhibited PCSK9 and decreased LDL-C concentrations, demonstrating human proof-of-pharmacology. However, SPC5001 caused mild to moderate injection site reactions and renal tubular toxicity, and clinical development of SPC5001 was terminated. Our findings underline the need for better understanding of the molecular mechanisms behind the side effects of compounds such as SPC5001, and for sensitive and relevant renal toxicity monitoring in future oligonucleotide studies.
AB - AIMS: LDL-receptor expression is inhibited by the protease proprotein convertase subtilisin/kexin type 9 (PCSK9), which is considered a pharmacological target to reduce LDL-C concentrations in hypercholesterolaemic patients. We performed a first-in-human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9.METHODS: In this randomized, placebo-controlled trial, 24 healthy volunteers received three weekly subcutaneous administrations of SPC5001 (0.5, 1.5 or 5 mg kg(-1)) or placebo (SPC5001 : placebo ratio 6 : 2). End points were safety/tolerability, pharmacokinetics and efficacy of SPC5001.RESULTS: SPC5001 plasma exposure (AUC(0,24 h)) increased more than dose-proportionally. At 5 mg kg(-1), SPC5001 decreased target protein PCSK9 (day 15 to day 35: -49% vs. placebo, P < 0.0001), resulting in a reduction in LDL-C concentrations (maximal estimated difference at day 28 compared with placebo -0.72 mmol l(-1), 95% confidence interval - 1.24, -0.16 mmol l(-1); P < 0.01). SPC5001 treatment (5 mg kg(-1)) also decreased ApoB (P = 0.04) and increased ApoA1 (P = 0.05). SPC5001 administration dose-dependently induced mild to moderate injection site reactions in 44% of the subjects, and transient increases in serum creatinine of ≥20 μmol l(-1) (15%) over baseline with signs of renal tubular toxicity in four out of six subjects at the highest dose level. One subject developed biopsy-proven acute tubular necrosis.CONCLUSIONS: SPC5001 treatment dose-dependently inhibited PCSK9 and decreased LDL-C concentrations, demonstrating human proof-of-pharmacology. However, SPC5001 caused mild to moderate injection site reactions and renal tubular toxicity, and clinical development of SPC5001 was terminated. Our findings underline the need for better understanding of the molecular mechanisms behind the side effects of compounds such as SPC5001, and for sensitive and relevant renal toxicity monitoring in future oligonucleotide studies.
KW - Adult
KW - Aged
KW - Dose-Response Relationship, Drug
KW - Double-Blind Method
KW - Female
KW - Humans
KW - Kidney/drug effects
KW - Male
KW - Middle Aged
KW - Oligonucleotides, Antisense/adverse effects
KW - Proprotein Convertase 9
KW - Proprotein Convertases/antagonists & inhibitors
KW - Serine Endopeptidases
UR - http://www.scopus.com/inward/record.url?scp=84957434512&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/bcp.12738
DO - https://doi.org/10.1111/bcp.12738
M3 - Article
C2 - 26261033
SN - 0306-5251
VL - 80
SP - 1350
EP - 1361
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 6
ER -