Delving into the Latest Updates on SPC-5001 with Synapse

Overview

Basic Info

Drug Type

ASO

Synonyms

Target

PCSK9

Mechanism

PCSK9 inhibitors(Proprotein convertase subtilisin kexin type 9 inhibitors)

Therapeutic Areas

NeoplasmsCongenital DisordersEndocrinology and Metabolic Disease+ [3]

Active Indication-

Inactive Indication

Hereditary Leiomyomatosis and Renal Cell CancerHypercholesterolemiaHyperlipoproteinemia Type II

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization-

Inactive Organization

Roche Innovation Center Copenhagen A/S

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure

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A First-in-Human (FIH), Randomized, Dose-Escalation, Double-Blind, Placebo-Controlled Study to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPC5001 Administered to Healthy Subjects and Subjects with Familial Hypercholesterolemia (FH) - SPC5001 in healthy subjects and subjects with FH

Start Date11 Apr 2011

Sponsor / Collaborator

Santaris Pharma

100 Clinical Results associated with SPC-5001

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100 Translational Medicine associated with SPC-5001

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100 Patents (Medical) associated with SPC-5001

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4

Literatures (Medical) associated with SPC-5001

01 Jun 2021·Archives of ToxicologyQ2 · MEDICINE

Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip

Q2 · MEDICINE

Article

Author: Andersson, Patrik ; Magnusson, Otto ; Nieskens, Tom T G ; Sjögren, Anna-Karin ; Söderberg, Magnus ; Persson, Mikael

Antisense oligonucleotides (ASOs) are a promising therapeutic modality. However, failure to predict acute kidney injury induced by SPC5001 ASO observed in a clinical trial suggests the need for additional preclinical models to complement the preceding animal toxicity studies. To explore the utility of in vitro systems in this space, we evaluated the induction of nephrotoxicity and kidney injury biomarkers by SPC5001 in human renal proximal tubule epithelial cells (HRPTEC), cultured in 2D, and in a recently developed kidney proximal tubule-on-a-chip. 2D HRPTEC cultures were exposed to the nephrotoxic ASO SPC5001 or the safe control ASO 556089 (0.16-40 µM) for up to 72 h, targeting PCSK9 and MALAT1, respectively. Both ASOs induced a concentration-dependent downregulation of their respective mRNA targets but cytotoxicity (determined by LDH activity) was not observed at any concentration. Next, chip-cultured HRPTEC were exposed to SPC5001 (0.5 and 5 µM) and 556089 (1 and 10 µM) for 48 h to confirm downregulation of their respective target transcripts, with 74.1 ± 5.2% for SPC5001 (5 µM) and 79.4 ± 0.8% for 556089 (10 µM). During extended exposure for up to 20 consecutive days, only SPC5001 induced cytotoxicity (at the higher concentration; 5 µM), as evaluated by LDH in the perfusate medium. Moreover, perfusate levels of biomarkers KIM-1, NGAL, clusterin, osteopontin and VEGF increased 2.5 ± 0.2-fold, 3.9 ± 0.9-fold, 2.3 ± 0.6-fold, 3.9 ± 1.7-fold and 1.9 ± 0.4-fold respectively, in response to SPC5001, generating distinct time-dependent profiles. In conclusion, target downregulation, cytotoxicity and kidney injury biomarkers were induced by the clinically nephrotoxic ASO SPC5001, demonstrating the translational potential of this kidney on-a-chip.

01 Dec 2015·British Journal of Clinical PharmacologyQ2 · MEDICINE

Antisense‐mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first‐in‐human randomized, placebo‐controlled trial

Q2 · MEDICINE

Article

Author: Moerland, Matthijs ; Lindholm, Marie W. ; Burggraaf, Jacobus ; Persson, Robert ; Tessier, Yann ; van Poelgeest, Eveline P. ; Ørum, Henrik ; Dumong Erichsen, Kamille ; Cohen, Adam F. ; Hodges, Michael R. ; Levin, Arthur A.

AimsLDL‐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.MethodsIn 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.ResultsSPC5001 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.ConclusionsSPC5001 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.

01 Oct 2013·American Journal of Kidney DiseasesQ1 · MEDICINE

Acute Kidney Injury During Therapy With an Antisense Oligonucleotide Directed Against PCSK9

Q1 · MEDICINE

Article

Author: Yann Tessier ; Michiel G.H. Betjes ; Jan J. Weening ; Jacobus Burggraaf ; Michael R. Hodges ; Eveline P. van Poelgeest ; Matthijs Moerland ; Reinout M. Swart ; Arthur A. Levin

Antisense oligonucleotides have been explored widely in clinical trials and generally are considered to be nontoxic for the kidney, even at high concentrations. We report a case of toxic acute tubular injury in a healthy 56-year-old female volunteer after a pharmacologically active dose of a locked nucleic acid antisense oligonucleotide was administered. The patient received 3 weekly subcutaneous doses of experimental drug SPC5001, an antisense oligonucleotide directed against PCSK9 (proprotein convertase subtilisin/kexin type 9) that is under investigation as an agent to reduce low-density lipoprotein cholesterol levels. Five days after the last dose, the patient's serum creatinine level increased from 0.81 mg/dL at baseline (corresponding to an estimated glomerular filtration rate [eGFR] of 78 mL/min/1.73 m(2)) to 2.67 mg/dL (eGFR, 20 mL/min/1.73 m(2)), and this increase coincided with the presence of white blood cells, granular casts, and minimal hematuria on urine microscopy. The patient's serum creatinine level peaked at 3.81 mg/dL (eGFR, 13 mL/min/1.73 m(2)) 1 week after the last oligonucleotide dose. Kidney biopsy showed multifocal tubular necrosis and signs of oligonucleotide accumulation. Upon conservative treatment, the patient's serum creatinine level gradually decreased and reached her baseline level 44 days after the last oligonucleotide was administered. The patient recovered fully and kidney function was normal at every follow-up visit.

100 Deals associated with SPC-5001

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hereditary Leiomyomatosis and Renal Cell Cancer	Phase 1	NL	Roche Innovation Center Copenhagen A/S	01 May 2011
Hypercholesterolemia	Phase 1	NL	Roche Innovation Center Copenhagen A/S	01 May 2011
Hyperlipoproteinemia Type II	Phase 1	NL	Roche Innovation Center Copenhagen A/S	01 May 2011