Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist.
CPG 10101 (ACTILON) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV.


OBJECTIVE
In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks.


RESULTS
A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2',5'-oligoadenylate synthetase were sustained for several days.


CONCLUSIONS
This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
Vicari
Alain P
AP
Coley Pharmaceutical Group, Wellesely, MA, USA. avicari@coleypharma.com
Schmalbach
Tess
T
Lekstrom-Himes
Julie
J
Morris
Mary Louise
ML
Al-Adhami
Mohammed J
MJ
Laframboise
Chantal
C
Leese
Philip
P
Krieg
Arthur M
AM
Efler
Susan M
SM
Davis
Heather L
HL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012016:Reference Values; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; C523579:CPG 10101; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9