The US Food and Drug Administration has accepted EntreMed Inc’s investigational new drug (IND) application for ENMD-1198, a novel tubulin binding agent for which EntreMed intends to pursue clinical development. The company plans to enter into Phase I oncology clinical studies with the compound in 2006.

ENMD-1198 is a new chemical entity (NCE) based on a modified chemical structure of 2ME2 designed to increase antitumour and antiangiogenic properties and improve metabolism. ENMD-1198 is characterised by its multiple mechanisms of action, which include inducing apoptosis, binding microtubules, and inhibiting HIF-1alpha. HIF-1alpha is over-expressed in more than 70% of human tumours and its over-expression correlates with tumor aggressiveness, metastases and poor prognosis. Preclinical studies identified ENMD-1198 as an orally active, microtubule disrupting agent that leads to arrest of cell division and apoptosis in tumor cells. Additionally, ENMD-1198 exerts antiangiogenic activity that contributes to its overall antitumor effects, states a company release.

In preclinical studies, ENMD-1198 has demonstrated pronounced in vivo antitumor activity in models of human cancer. Oral daily treatment with ENMD- 1198 in an orthotopic MDA MB 231 breast cancer model led to a reduction in tumour burden equivalent to the positive control cyclophosphamide, disruption of microtubules within tumour cells, and a substantial decrease in HIF-1alpha. ENMD-1198 also reduced protein levels for two additional transcription factors, NFkB and Stat3, known to modulate HIF-1alpha protein levels in vitro. All three transcription factors are known to regulate multiple genes and their proteins that contribute to tumour growth and progression.

In preclinical tumour studies, serum proteins regulated by HIF-1alpha, NFkB and Stat3, were also reduced substantially following oral administration of ENMD-1198. Results from several studies demonstrate significantly (40-100%) decreased plasma or serum levels of human VEGF (secreted by tumour cells), a major proangiogenic growth factor, compared to control animals following therapy with ENMD-1198. Serum levels of human IL-6 were also decreased significantly (62-96%). Over-expression of IL-6 is associated with higher morbidity in breast cancers, bone metastases, increased aromatase synthesis, and increased cancer drug resistance. Tumour levels of a third tumour protein regulated by HIF-1alpha, carbonic anhydrase IX (CA IX), were also decreased, consistent with HIF-1alpha inhibition.

Carolyn F. Sidor, EntreMed vice president and chief medical officer, said, "We anticipate initiating Phase I oncology studies for ENMD-1198 in 2006. Last week, we announced results from our Phase Ib trials with our lead drug candidate, 2ME2 (Panzem NCD) and the planning of Phase II studies. This means EntreMed will have two drug candidates with antitumor and antiangiogenic properties in the clinic in 2006. Both clinical stage drug candidates, Panzem NCD and ENMD-1198, are multi-mechanism agents that inhibit HIF-1alpha, but with different safety and activity profiles. As such, we have a clear path to developing both compounds."

EntreMed Inc. is a clinical-stage pharmaceutical company developing therapeutic candidates primarily for the treatment of cancer and inflammation.