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.
RCT Entities:
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.
Authors: Jonathan Cohen; Alexander Pertsemlidis; Ingrid K Kotowski; Randall Graham; Christine Kim Garcia; Helen H Hobbs Journal: Nat Genet Date: 2005-01-16 Impact factor: 38.330
Authors: William G Herrington; Denis C Talbot; Michael M Lahn; John T Brandt; Sophie Callies; Ray Nagle; Christopher G Winearls; Ian S D Roberts Journal: Am J Kidney Dis Date: 2010-12-21 Impact factor: 8.860
Authors: Zhenze Zhao; Yetsa Tuakli-Wosornu; Thomas A Lagace; Lisa Kinch; Nicholas V Grishin; Jay D Horton; Jonathan C Cohen; Helen H Hobbs Journal: Am J Hum Genet Date: 2006-07-18 Impact factor: 11.025
Authors: Eliano Pio Navarese; Michalina Kolodziejczak; Volker Schulze; Paul A Gurbel; Udaya Tantry; Yingfeng Lin; Maximilian Brockmeyer; David E Kandzari; Julia M Kubica; Ralph B D'Agostino; Jacek Kubica; Massimo Volpe; Stefan Agewall; Dean J Kereiakes; Malte Kelm Journal: Ann Intern Med Date: 2015-07-07 Impact factor: 25.391
Authors: Kevin Fitzgerald; Maria Frank-Kamenetsky; Svetlana Shulga-Morskaya; Abigail Liebow; Brian R Bettencourt; Jessica E Sutherland; Renta M Hutabarat; Valerie A Clausen; Verena Karsten; Jeffrey Cehelsky; Saraswathy V Nochur; Victor Kotelianski; Jay Horton; Timothy Mant; Joseph Chiesa; James Ritter; Malathy Munisamy; Akshay K Vaishnaw; Jared A Gollob; Amy Simon Journal: Lancet Date: 2013-10-03 Impact factor: 79.321
Authors: Meike H van der Ree; Adriaan J van der Meer; Joep de Bruijne; Raoel Maan; Andre van Vliet; Tania M Welzel; Stefan Zeuzem; Eric J Lawitz; Maribel Rodriguez-Torres; Viera Kupcova; Alcija Wiercinska-Drapalo; Michael R Hodges; Harry L A Janssen; Hendrik W Reesink Journal: Antiviral Res Date: 2014-09-08 Impact factor: 5.970
Authors: Eveline P van Poelgeest; Reinout M Swart; Michiel G H Betjes; Matthijs Moerland; Jan J Weening; Yann Tessier; Michael R Hodges; Arthur A Levin; Jacobus Burggraaf Journal: Am J Kidney Dis Date: 2013-04-03 Impact factor: 8.860
Authors: Thazha P Prakash; Mark J Graham; Jinghua Yu; Rick Carty; Audrey Low; Alfred Chappell; Karsten Schmidt; Chenguang Zhao; Mariam Aghajan; Heather F Murray; Stan Riney; Sheri L Booten; Susan F Murray; Hans Gaus; Jeff Crosby; Walt F Lima; Shuling Guo; Brett P Monia; Eric E Swayze; Punit P Seth Journal: Nucleic Acids Res Date: 2014-07-03 Impact factor: 16.971
Authors: Yingnan Zhang; Mark Ultsch; Nicholas J Skelton; Daniel J Burdick; Maureen H Beresini; Wei Li; Monica Kong-Beltran; Andrew Peterson; John Quinn; Cecilia Chiu; Yan Wu; Steven Shia; Paul Moran; Paola Di Lello; Charles Eigenbrot; Daniel Kirchhofer Journal: Nat Struct Mol Biol Date: 2017-08-21 Impact factor: 15.369
Authors: Haibo Xie; Ka Yang; Gabrielle N Winston-McPherson; Donnie S Stapleton; Mark P Keller; Alan D Attie; Kerry A Smith; Weiping Tang Journal: Eur J Med Chem Date: 2020-08-04 Impact factor: 6.514
Authors: Steffen Schmidt; Sandra F Gallego; Iris Daphne Zelnik; Sergey Kovalchuk; Nanna Albæk; Richard R Sprenger; Charlotte Øverup; Yael Pewzner-Jung; Anthony H Futerman; Marie W Lindholm; Ole N Jensen; Christer S Ejsing Journal: Mol Ther Date: 2021-08-14 Impact factor: 12.910
Authors: Eveline P van Poelgeest; Michael R Hodges; Matthijs Moerland; Yann Tessier; Arthur A Levin; Robert Persson; Marie W Lindholm; Kamille Dumong Erichsen; Henrik Ørum; Adam F Cohen; Jacobus Burggraaf Journal: Br J Clin Pharmacol Date: 2015-10-24 Impact factor: 4.335
Authors: Tom T G Nieskens; Otto Magnusson; Patrik Andersson; Magnus Söderberg; Mikael Persson; Anna-Karin Sjögren Journal: Arch Toxicol Date: 2021-05-07 Impact factor: 6.168