Targeted failure of the week. Post No 29-30. Avagacestat and GRN1005

Today we will present two targeted disasters: avagacestat and GRN1005

Bristol-Myers Squibb Co. (NYSE:BMY) discontinued development of avagacestat (BMS-708163) after data from Phase II trials evaluating the product for mild to moderate Alzheimer's disease and predementia AD did not "establish a profile that supported advancement" to Phase III testing.

And no doubts that avagacestat is extremely targeted drug: gamma secretase inhibitor BMS-708163 is an oral gamma secretase inhibitor. 

The gamma secretase inhibitor avagacestat was designed for the selective inhibition of amyloid beta synthesis.

But the second targeted disaster - GRN1005 - is really impressive! The idea behind this candidate is childishly mechanical but very sexy:

GRN1005 is a peptide-drug conjugate that is being developed for the treatment of tumors in the brain, including malignant glioma and brain metastases from solid tumors. GRN1005 is designed to deliver cytotoxic drug across the BBB and into tumors by exploiting a native transport mechanism by which essential substances, such as lipids and hormones, successfully enter the brain through receptors. GRN1005 is comprised of three molecules of paclitaxel, linked to a proprietary peptide that is designed to target lipoprotein receptor-related proteins (LRPs), specifically LRP-1, which is one of the most highly expressed receptors on the surface of the BBB. Binding to LRP-1 facilitates receptor-mediated transport, or transcytosis, across the BBB into the brain tissue. LRP-1 is also up-regulated in many tumors; therefore, once in the brain GRN1005 may gain entry into tumor cells using the same receptor by a process known as endocytosis. GRN1005 is a prodrug, which becomes activated in cells only after it is cleaved by esterases to release active paclitaxel from the peptide.

GRN1005 is a nice attempt to translate our mechanical simplified understanding to real physiology on its cell level – this reduction never works despite the attractiveness of this approach. Very sorry for GRN1005 but c'est la vie!