title: A Highly Durable RNAi Therapeutic Inhibitor of PCSK9.
abstract: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.
  
  
  
  In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.
  
  
  
  The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).
  
  
  
  In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442 .).
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Suellen
authors.initials: S
authors.lastname: White
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Strahs
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Valerie
authors.initials: V
authors.lastname: Clausen
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Peter
authors.initials: P
authors.lastname: Wijngaard
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Jorg
authors.initials: J
authors.lastname: Taubel
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Ashley
authors.initials: A
authors.lastname: Brooks
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Chamikara
authors.initials: C
authors.lastname: Fernando
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kauffman
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: David
authors.initials: D
authors.lastname: Kallend
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Akshay
authors.initials: A
authors.lastname: Vaishnaw
authors.affiliation: From Alnylam Pharmaceuticals, Cambridge, MA (K.F., S.W., A. Borodovsky, B.R.B., A. Strahs, V.C., R.S.K., A.V., A. Simon); the Medicines Company, Parsippany, NJ (P.W., D.K.); University of Texas Southwestern Medical Center, Dallas (J.D.H.); Richmond Pharmacology, St. George's University of London, London (J.T.); and Covance Clinical Research Unit, Leeds, United Kingdom (A. Brooks, C.F.).
authors.forename: Amy
authors.initials: A
authors.lastname: Simon
mesh_terms: D000116:Acetylgalactosamine / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000096:biosynthesis / Q000097:blood; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000009:adverse effects; D034743:RNA-Induced Silencing Complex / Q000378:metabolism; D000067492:RNAi Therapeutics; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: C585830:ALN-PCS; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; D034741:RNA, Small Interfering; D034743:RNA-Induced Silencing Complex; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D000116:Acetylgalactosamine