title: Phase I trial of ISIS 104838, a 2'-methoxyethyl modified antisense oligonucleotide targeting tumor necrosis factor-alpha.
abstract: ISIS 104838 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that binds tumor necrosis factor-alpha (TNF-alpha) mRNA. It carries a 2'-methoxyethyl modification on the five 3' and 5' nucleotide sugars, with 10 central unmodified deoxynucleotides. ISIS 104838 was identified from a 264 ASO screen in phorbol myristate acetate-activated keratinocytes, and the dose response was assessed in lipopolysaccharide (LPS)-activated monocytes. Healthy males received multiple intravenous (i.v.) ISIS 104838 infusions in a placebo-controlled dose escalation trial (0.1-6 mg/kg). Additional volunteers received single or multiple subcutaneous (s.c.) injections. ISIS 104838 suppressed TNF-alpha protein by 85% in stimulated keratinocytes. The IC50 for TNF-alpha mRNA inhibition in stimulated monocytes was <1 microM. For i.v., C(max) occurred at the end of infusion. The effective plasma half-life was 15 to 45 min at 0.1 to 0.5 mg/kg and 1 to 1.8 h for higher doses. The apparent terminal plasma elimination half-life approximated 25 days. Obese subjects had higher plasma levels following equivalent mg/kg doses. For s.c. injections, C(max) occurred at 2 to 4 h and was lower than with equivalent i.v. dosing. Plasma bioavailability compared with i.v. was 82% following a 200 mg/ml s.c. injection. Transient activated partial thromboplastin time prolongation occurred after i.v. infusions and minimally after s.c. injections. Two subjects experienced rash, one a reversible platelet decrease, and mild injection site tenderness was noted. TNF-alpha production by peripheral blood leukocytes, induced ex vivo by LPS, was decreased by ISIS 104838 (p < 0.01). ISIS 104838, a second-generation antisense oligonucleotide, was generally well tolerated intravenously and subcutaneously. The pharmacokinetics support an infrequent dosing interval. Inhibition of TNF-alpha production ex vivo was demonstrated.
authors.affiliation: Isis Pharmaceuticals Inc., Carlsbad, California 92008-7208, USA. klsewell@isisph.com
authors.forename: K Lea
authors.initials: KL
authors.lastname: Sewell
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Glover
authors.forename: Timothy G K
authors.initials: TG
authors.lastname: Mant
authors.forename: Rosie Z
authors.initials: RZ
authors.lastname: Yu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tami
authors.forename: F Andrew
authors.initials: FA
authors.lastname: Dorr
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054735:Phosphorothioate Oligonucleotides; D012044:Regression Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C464616:ISIS104838; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D014409:Tumor Necrosis Factor-alpha