Targeted Drugs Entered Phase I Clinical Trials
A large number of targeted therapeutics entered phase I clinical trials during the past year, and many more, currently in late stage preclinical testing, will soon follow.
In addition, of the 92 agents that entered monotherapy clinical trials in 2005, many have advanced to phase II monotherapy and phase I combination trials. This unprecedented phenomenon is driven by the ever expanding knowledge of genomics and proteomics, breakthrough advances in drug discovery/drug design, and new in vitro and in vivo testing methodologies that allow drugs faster entry into clinical trials. Because these agents do not appear to cause significant toxicities, they are easily obtaining IND approvals from the FDA to enter clinical trials.
The plethora of molecular targets implicated in malignancy and the numerous agents addressing these targets has generated an incredibly complicated picture of what therapeutic approaches are effective, or may be effective, for particular cancer indications. The potential combinations and permutations boggle the mind. Because currently approved targeted therapeutics provide mostly small benefits to patients, results from many early clinical trials with novel, developmental agents appear comparable to those of approved agents. As a result, many novel agents are viewed as promising, prompting the initiation of clinical trials with an increasing number of new drugs.
nm|OK has updated numerous records of agents about which clinical or preclinical data were presented at the 2007 meeting of the American Association of Cancer Research (AACR). Among targets being addressed are Akt (protein kinase B, PKB); Angiopoietin-2; Aurora B (Aurora-1); Bcr-Abl; BRaf (B-Raf); c-Kit; Cyclin-dependent kinase 2 (CDK2); Cyclin-dependent kinase 7 (CDK7); Cyclin-dependent kinase 9 (CDK9); Delta-like 4 (DLL4); Epidermal growth factor (EGFr); focal adhesion kinase (FAK); HEr2/neu; Kinesin-like spindle protein (KSP)/Eg5; c-Kit; Lymphocyte-specific protein tyrosine kinase (Lck); Lyn; Hepatocyte growth factor receptor (HGFr)/c-Met; Notch 1 (TAN1); NF.B; Phosphatase and tensin homolog (PTEN); Phosphatidylinositol 3 kinase (PI3K); Platelet-derived growth factor receptor alpha (PDGFrA); Raf; c-Src; Tie-2; Tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-r2, TRAILr2)/DR5; Vascular endothelial growth factor (VEGF) receptor (VEGFr); VEGFr2/KDR; VEGFr3/FLT4, etc.
Technologic advances in drug discovery and design are enabling small biotech companies to create rich pipelines. Two companies, Exelixis and ImClone Systems illustrate this phenomenon. Exelixis, a developer of orally available small molecule protein kinase inhibitors, is testing in clinical trials agents targeting Abl; Akt; Chk1; CHK2; A disintegrin-like and metalloprotease (ADAM)-TS10; EGFr; Ephrin B4 (EphB4); Fibroblast growth factor receptors (FGFr); Fms-like tyrosine kinase 3 (FLT3, FLT-3); Insulin-like growth factor 1 receptor (IGF1r); MAPK/extracellular signal-regulated kinase (ERK) kinases (MEK); Met; Raf; c-Src; VEGFr; and VEGFr2/KDR. ImClone Systems, a developer of intravenously administered monoclonal antibodies targeting extracellular receptors, has advanced into clinical trials agents targeting.