Clinical Pipeline
The following candidates are part of Abraxis' robust clinical development pipeline.
Abraxis Clinical Pipeline
Oncology
Abraxis is focused on the discovery and development of novel therapeutics and core technologies, such as its proprietary nab™ technology platform, for the treatment of cancer. By leveraging its rich research heritage, Abraxis strives to quickly and safely bring these breakthrough discoveries into the clinic and to market.
Docetaxel inhibits depolymerization of the microtubule while polymerization continues to occur. This disrupts cellular division and propagation by arresting the cell cycle during mitosis. Accumulation of microtubules (due to the lack of disassembly in the presence of docetaxel) leads to the initiation of apoptosis, as does docetaxel-mediated inhibition of the oncoprotein Bcl-2.
Docetaxel is currently formulated in the surfactant Tween® 80, which inhibits the binding of taxanes to albumin, possibly inhibiting albumin-based drug transport via the gp60 pathway.15 Tween 80 also has other toxicities. nab™ technology offers the ability to convert insoluble or poorly soluble drugs into nanoparticles, allowing them to become soluble and easier to deliver without the need for solvents.
Removing Tween 80 from docetaxel has the potential to enhance drug transport while eliminating toxicities associated with surfactants. This possibility led investigators at Abraxis to evaluate nab™-docetaxel for the treatment of solid tumors.
In preclinical studies, nab™-docetaxel has been tested in vivo with PC-3 human prostate carcinoma and HCT-116 human colon carcinoma xenografts.15 Abraxis has also evaluated the efficacy, toxicity, and pharmacokinetics of nab™-docetaxel vs standard docetaxel in preclinical studies.12 Results were presented at the 2006 American Association of Cancer Research (AACR) Annual Meeting by Desai et al, Abstract 5438.12
The investigational new drug (IND) application was filed, and phase I/II studies have been initiated.
mTOR is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on vascular endothelial growth factor (VEGF). Rapamycin is an mTOR antagonist that blocks the downstream signaling elements, which starves cancer cells and shrinks tumors.
At least 2 important effects occur as mTOR inhibitors bind to the mTOR kinase. First, mTOR is a downstream mediator of the phosphatidylinositol 3 (PI-3) kinase/Akt pathway. The PI-3 kinase/Akt pathway plays a critical role in cell survival and resistance to chemotherapy.5 This pathway is thought to be overactivated in numerous cancers and may account for the widespread response of various cancers to mTOR inhibitors.20 However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. The second major effect of mTOR inhibition is antiangiogenesis via the lowering of VEGF levels. These anticancer drugs have shown exceptional promise in cancer therapy and may change the way many types of cancer are treated.
The role of mTOR inhibition has led investigators at Abraxis to explore the use of nab™ technology to enhance the deregulation of mTOR signaling. Preclinical studies of single-agent nab™-rapamycin have evaluated tumor activity in breast cancer xenografts and in colon cancer xenografts. Results were presented at the 2007 AACR Annual Meeting by De et al, Abstract 4719.11 IND submission was filed in 2007. Phase I clinical studies will be initiated in 2007.
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the folding and maturation of key regulatory proteins including steroid hormone receptors, transcription factors, and kinases such as Src-kinase. Hsp70 and Hsp90 form a multichaperone complex in which both are connected by a third protein called Hop. The connection of and interplay between the 2 chaperone machineries are of crucial importance for cell viability. Hsp90 is strongly upregulated as part of the heat shock response, helping protect the cell from protein damage and interfering with apoptosis.
This molecular protein maintains the stability and function of many signaling proteins, including oncogenic proteins that are upregulated in tumors and promote the growth and survival of cancer cells.29 Hsp90 inhibitors can bind to Hsp90 and induce the degradation of its oncogenic proteins, thereby generating potent antitumor activity at well-tolerated doses.
Abraxis is currently investigating a novel nanoparticle version of the Hsp90 inhibitor 17-allylaminogeldanamycin (17AAG), which binds to Hsp90 and causes the destabilization and eventual degradation of Hsp90 client proteins such as Bcr-Abl, Raf-1, Akt, and HER2/ErbB2. nab™-17AAG may dramatically increase the in vivo efficacy of this standard chemotherapeutic agent.
Preclinical studies of nab™-17AAG have shown effects on suppressing HER2 expression and exhibiting significant antitumor activity. Preclinical studies required for the IND submission are underway.
A novel class of antimitotic agents has demonstrated a dual mechanism of action including the inhibition of microtubule polymerization and the disruption of topoisomerase-1 activity. Abraxis is investigating the conversion of these insoluble drugs to a nanoparticle form using nab™ technology.14 ABI-011 has the potential to represent an innovative tool in the fight against drug resistance to conventional antitumor agents.
ABI-011 was selected for its cytotoxic activity in nanomole range concentrations on several human tumor cell lines and, in particular, on a tumor cell line resistant to cisplatin and topotecan.3 This particular behavior was related to a dual mechanism of action. ABI-011 has the additional oncotherapeutic property of inhibiting topoisomerase-1 nuclear enzymes in a different manner than the classic topo-I inhibitors, camptothecins.31
In preclinical in vivo testing, ABI-011, formulated as a nanoparticle of albumin, was evaluated in human ovarian and colon carcinoma xenografts and compared with standard irinotecan. Results were presented at the 2005 AACR Annual Meeting by Desai et al, Abstract 3439.14 ABI-011 also possesses antiangiogenic properties as demonstrated in the study recently reported at the 2006 AACR Annual Meeting by Trieu et al, Abstract 3823.40
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