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An oral antisense o...
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Gennemark, PeterLinköpings universitet,Avdelningen för medicinsk teknik,Tekniska fakulteten,AstraZeneca, Sweden
(author)
An oral antisense oligonucleotide for PCSK9 inhibition
- Article/chapterEnglish2021
Publisher, publication year, extent ...
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AMER ASSOC ADVANCEMENT SCIENCE,2021
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:liu-176171
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-176171URI
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https://doi.org/10.1126/scitranslmed.abe9117DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Funding Agencies|AstraZenecaAstraZeneca; Ionis Pharmaceuticals
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Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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Walter, KatrinAstraZeneca, Sweden
(author)
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Clemmensen, NiclasAstraZeneca, Sweden
(author)
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Rekic, DinkoAstraZeneca, Sweden
(author)
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Nilsson, Catarina A. M.AstraZeneca, Sweden
(author)
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Knochel, JaneAstraZeneca, Sweden
(author)
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Holtta, MikkoAstraZeneca, Sweden
(author)
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Wernevik, LindaAstraZeneca, Sweden
(author)
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Rosengren, BirgittaAstraZeneca, Sweden
(author)
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Kakol-Palm, DorotaAstraZeneca, Sweden
(author)
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Wang, YanfengIonis Pharmaceut Inc, CA 92010 USA
(author)
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Yu, Rosie Z.Ionis Pharmaceut Inc, CA 92010 USA
(author)
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Geary, Richard S.Ionis Pharmaceut Inc, CA 92010 USA
(author)
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Riney, Stan J.Ionis Pharmaceut Inc, CA 92010 USA
(author)
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Monia, Brett P.Ionis Pharmaceut Inc, CA 92010 USA
(author)
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Isaksson, RikardAstraZeneca, Sweden
(author)
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Jansson-Lofmark, RasmusAstraZeneca, Sweden
(author)
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Rocha, Cristina S. J.AstraZeneca, Sweden
(author)
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Linden, DanielAstraZeneca, Sweden
(author)
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Hurt-Camejo, EvaAstraZeneca, Sweden
(author)
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Crooke, RosanneIonis Pharmaceut Inc, CA 92010 USA
(author)
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Tillman, LloydIonis Pharmaceut Inc, CA 92010 USA
(author)
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Ryden-Bergsten, TinaAstraZeneca, Sweden
(author)
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Carlsson, BjornAstraZeneca, Sweden
(author)
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Andersson, UlfAstraZeneca, Sweden
(author)
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Elebring, MarieAstraZeneca, Sweden
(author)
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Tivesten, AnnaAstraZeneca, Sweden
(author)
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Davies, NigelAstraZeneca, Sweden
(author)
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Linköpings universitetAvdelningen för medicinsk teknik
(creator_code:org_t)
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In:Science Translational Medicine: AMER ASSOC ADVANCEMENT SCIENCE13:5931946-62341946-6242
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Gennemark, Peter
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Walter, Katrin
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Clemmensen, Nicl ...
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Rekic, Dinko
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Nilsson, Catarin ...
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Knochel, Jane
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Holtta, Mikko
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Wernevik, Linda
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Rosengren, Birgi ...
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Kakol-Palm, Doro ...
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Wang, Yanfeng
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Yu, Rosie Z.
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Geary, Richard S ...
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Riney, Stan J.
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Monia, Brett P.
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Isaksson, Rikard
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Jansson-Lofmark, ...
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Rocha, Cristina ...
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Linden, Daniel
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Hurt-Camejo, Eva
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Crooke, Rosanne
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Tillman, Lloyd
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Ryden-Bergsten, ...
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Carlsson, Bjorn
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Andersson, Ulf
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Elebring, Marie
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Tivesten, Anna
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Davies, Nigel
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