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AMG706 (motesanib)

AMG 706 (generic name motesanib) from Amgen is a potent, oral, multi kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF, Kit and Ret receptors. A Phase I open label, two center, dose-escalation study was initiated to assess the safety, establish the maximum tolerated dose and generate pharmacokinetic profiles of oral AMG 706.  AMG 706 was generally well tolerated. Most adverse events were of mild to moderate severity and reversible. AMG 706 demonstrated favorable bioavailability and half life using a 125 mg dose. Once daily dosing generated sustained exposure sufficient to elicit effective tumor responses. At least half of the subjects with advanced metastatic cancer experienced disease stabilization while on AMG 706 therapy.

A Phase ll trial to determine the safety and effectiveness of AMG 706 in patients with advanced GIST was also conducted but has now been closed. Patients must have had documented treatment with imatinib mesylate (Gleevec) at least 600mg daily for at least 2 months, but the disease had progressed on this treatment.  No previous exposure was allowed to AMG706 or other tyrosine kinase inhibitors of c-kit (except imatinib mesylate) or VEGF (vascular endothelial growth factor) type (e.g., SU11248, PTK787) or anti-VEGF antibody (Avastin).

Limited information about how patients fared in the trial of AMG 706 against GIST has been released.  Amgen presented data from this trial at the CTOS 2006 international meeting, and the slides can be viewed at the CTOS website   The drug showed biological activity in GISTs. However, a company spokespeson told GSI that the data from the phase II trial as designed do not support registration for an indication (Gleevec resistant GISTs) in which Sutent is already on the  market. There are no current plans to pursue a first line of defense indication for GISTs. We can look for announcements about this drug for thyroid cancer, and ongoing trials for non small cell lung cancer and breast cancer.

In February 2008 Amgen announced the following:  Takeda Pharmaceutical of Japan is becoming the global partner on Amgen’s cancer drug motesanib, also called AMG 706. Takeda will pay Amgen $100 million up front for the motesanib rights and up to $175 in additional payments if certain goals are met. The two companies will split profits from the drug 50-50.

Following is an excerpt from an AMGEN press release.

"AMG 706: Interim data from the Phase 2 study in gastrointestinal stromal tumors (GIST) became available during the second quarter and will be presented in the fourth quarter of this year. The Company's review of the data indicates evidence of clinical activity. Based on the preliminary assessment, median follow-up at the time of analysis was only ten months and at that point median survival had not been reached.  The final overall analysis is still pending. The Company reported that it expects that the data will be included in any regulatory filing but that it cannot stand alone.

Additionally, the Company announced that cholecystitis and enlargement of the gall bladder have been observed in patients who have received AMG 706. Cholecystitis is inflammation of the gall bladder and is commonly due to a gallstone that cannot pass through the neck, or cystic duct, of the gall bladder. To date, approximately two to three percent of patients treated with AMG 706 alone or in combination with various other anti-cancer regimens have developed cholecystitis and these events have been managed with standard clinical practice. Ongoing studies are expected to continue, subject to protocol amendments. The Phase 3 studies in first-line breast cancer and first-line non-small cell lung cancer (two of the planned eleven mega-trials) which were expected to start in the fourth quarter have been delayed."

AMG706 is currently being studied in trials against several other cancers.  A trial for Japanese GIST patients is still listed as open.  The FDA has granted Fast Track designation to AMG 706. This should allow for streamlining of development and review of results by the FDA from the various trials.

We now have the poster of the abstract of AMG 706 available, courtesy of Amgen. Click here for the PDF file.

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