Earlier today, Ambit Biosciences (San Diego, USA) announced that it had started recruitment for two separate Phase I trials, the first one for AC430, a selective Janus Kinase 2 (JAK2) inhibitor, and the second for AC480 (also known as BMS-599626 ), a pan-HER inhibitor.

The Phase I trial for AC430 is a two part, placebo-controlled, single ascending, and multiple ascending dose trial in healthy volunteers. AC430 will be administered orally once-daily and doses escalated until a maximum tolerated or maximum feasible dose is established. In addition to evaluating the safety, tolerability, and pharmacokinetics of AC430, the study will also assess cytokine signal transduction.

AC430 was specifically developed to be a best-in-class JAK2 inhibitor. In preclinical studies, AC430 has exhibited potency against JAK2 in cell-based models that is at least equivalent, and in most cases superior to, competing JAK2 inhibitors, and also has excellent oral pharmacokinetic properties. In preclinical oncology and autoimmune models, AC430 is well tolerated and has significant efficacy at oral doses as low as 10 mg/kg/day. JAK2 has been implicated as a target for therapy in both oncology and autoimmune disease.

The second phase I trial for AC480 is a multi-center, dose escalation study with AC480 administered by intravenous infusion on days one and two of a 21 day cycle, either alone or in combination with docetaxel. The trial will assess safety, pharmacokinetics and anti-tumor activity of AC480 in patients with advanced solid tumors including metastatic breast cancer and non-small cell lung cancer, or NSCLC.

AC480 is a small molecule kinase inhibitor that selectively inhibits the HER family of receptors, HER1, HER2, HER3 and HER4 and may prevent downstream signaling and inhibit the proliferation of tumor cells that overexpress these receptors.

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Furthermore, researchers believe that AC480 may enhance the radiosensitivity of certain tumor cell types that express HER1 and HER2 through cell cycle redistribution in G1 phase and inhibition of DNA repair. Excessive HER signaling has been associated with the development of a wide variety of types of solid tumors, including those found in lung, breast, head and neck and brain cancers. Currently marketed HER inhibitors inhibit only one or two of the HER family members and a pan-HER inhibitor that inhibits all of the HER receptors may be effective in more cancer types.

Published data with oral HER inhibitors administered in combination with taxanes, such as docetaxel, demonstrate activity in clinical studies and these clinical data are supported by preclinical data demonstrating that combining HER inhibitors with taxanes produces synergistic anti-tumor activity. An intravenous formulation of a pan-HER inhibitor such AC480 enables high pulsatile doses to be administered in combination with taxanes.

“The initiations of these studies are important milestones,” said Alan Lewis, President and CEO Ambit Biosciences. “AC430 has demonstrated convincing efficacy in pre-clinical models of autoimmune and inflammatory diseases, and AC480 IV was developed to assess whether pulsatile doses of a pan-HER inhibitor administered in combination with a taxane such as docetaxal would produce synergistic anti-tumor activity.”

In October 2007 the company licensed exclusive worldwide rights to AC480 from Bristol-Myers Squibb Company. The drug candidate is being studied in an oral formulation in a Phase I clinical trial in patients with glioblastoma multiforme, or GBM.

For more information:
– Torres MA, Raju U, Molkentine D, Riesterer O, Milas L, Ang KK. AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo.Invest New Drugs. 2010 Feb 2. [Epub ahead of print]
– Kedrin D, Wyckoff J, Boimel PJ, Coniglio SJ, Hynes NE, et al. ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation. Clin Cancer Res. 2009 Jun 1;15(11):3733-9. Epub 2009 May 19.
– Gavai AV, Fink BE, Fairfax DJ, Martin GS, Rossiter LM, et al. Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases. J Med Chem. 2009 Nov 12;52(21):6527-30.
– Haluska P, Carboni JM, TenEyck C, Attar RM, Hou X, et al. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther. 2008 Sep;7(9):2589-98. Epub 2008 Sep 2.
– Wong TW, Lee FY, Yu C, Luo FR, Oppenheimer S, Zhang H, et al. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling.
Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93.
– Albanell J, Gasc?n P. Small molecules with EGFR-TK inhibitor activity. Curr Drug Targets. 2005 May;6(3):259-74. Review.

Clinical trials:
BMS-599626 in Treating Patients With Metastatic Solid Tumors (Study completed)
Pharmacokinetics (PK) Study of AC480 for Recurrent Glioma
Safety Study for Intravenous (IV) AC480 (AC480IV) to Treat Advanced Solid Tumors

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