NEWS:
Medicinova announce completion of initial Phase I clinical study of MN-029 OXFORD-July 6th., 2006
On June 4th., 2006 at the American Society of Clinical Oncology (ASCO) meeting in Atlanta, Georgia, our partners MediciNova Inc. presented results from the first Phase I clinical trial of the Vascular Disrupting Agent (VDA) MN-029, licensed from Angiogene Pharmaceuticals Ltd. in 2002. In this open-label, dose-escalation, safety and pharmacokinetic study, MN-029 was administered as an intravenous infusion once every 3 weeks with a 20 day recovery period between doses to patients with a broad range of solid tumours for whom no standard therapy was available. The results presented at ASCO by Dr. Alejandro Ricart of the Institute for Drug Development, Cancer Therapy and Research Center in San Antonio, Texas (Poster Number: AA12, Abstract No: 3096) established a maximum tolerated dose (MTD) for MN-029 of 180 mg/m2. As with other VDAs the most common side effects observed included nausea, vomiting, fatigue and diarrhea. Nine of 34 patients had stable disease after 3 cycles of treatment, including 2 patients with carcinoid tumors who received 26 cycles and 23 cycles, respectively. Importantly, tumour blood flow, which is considered a potential predictor of clinical efficacy, was shown by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to be reduced at well-tolerated doses below MTD. Commenting on these encouraging results, Yuichi Iwaki, M.D., Ph.D., Executive Chairman and CEO of MediciNova, Inc. stated that “Demonstration of pharmacologic proof-of-concept and completion of the Phase I clinical program for MN-029 is an important milestone for MediciNova. Based upon these findings, we plan to initiate Phase II/III studies in more than one type of solid tumor cancer later this year.” Additional details can found in the associated Press Release on the MediciNova website.
Angiogene Reacquires Rights to ZD6126 (ANG453) from AstraZeneca OXFORD-March 7th., 2006
Angiogene announces that AstraZeneca has returned all rights to the Vascular Targeting Agent ZD6126 (previously ANG453). This novel agent for the therapy of solid tumours has been shown to markedly reduce tumour blood flow in Phase I studies and had advanced to Phase II. The clinical programme has been on hold pending the results of laboratory studies aimed at understanding and identifying management strategies for the side effect profile of ZD6126. These investigations have been successful.
AstraZeneca has subsequently made the decision to concentrate on other aspects of their pipeline and Angiogene is now seeking another partner for the development of this innovative experimental drug.
Peter Davis, Chief Executive Officer of Angiogene Pharmaceuticals said: "Although the clinical development of ZD6126 has had some difficulties, preclinical investigations carried out by AstraZeneca scientists have indicated a clear path forward for this programme. Tumour vasculature has been recently validated as a target by the approval of the antiangiogenic antibody bevacizumab. I am hopeful that the reduction in tumour blood flow, which will starve the tumour of essential oxygen and nutrients, will translate into clear patient benefit. We thank AstraZeneca for their efforts which have provided proof-of-principle for this strategy and now look forward to restarting this exciting project."
MediciNova announce initiation of a 2nd Phase I trial of MN-029 OXFORD-June 17th., 2005
MediciNova Inc. announced today the initiation of a second Phase I trial of the vascular disrupting agent MN-029, licenced from Angiogene in 2002. According to Dr. Richard E. Gammons the Chief Development Officer at MediciNova, “MN-029 has been well tolerated at each dosing level throughout the current Phase I clinical study, and we are planning in this second study to implement a more aggressive, yet simpler dosing schedule that will be compatible with a wide range of cancer treatment regimens". Further details can be found in the Press Release on the MediciNova website.
VIEWS:
ZD6126-induced hemodynamic changes and cardiovascular events can be prevented by anti-hypertensive therapy. OXFORD-March 26th., 2008
Although ZD6126 exhibits dramatic anti-tumor activity at well-tolerated doses, adverse cardiovascular events have been noted in a small number of patients in Phase I studies. In common with other vascular disrupting agents (VDA) that act by inhibiting tubulin polymerization, ZD6126 treatment is often associated with transient increases in blood pressure. In particular, pre-existing hypertension may be exacerbated and in rare instances, more severe cardiac events may occur including, most notably, increases in the circulating level of troponin I, a marker of cardiac damage.
Recently, Dr. Anderson Ryan and colleagues at AstraZeneca have employed a rat pre-clinical model to both investigate the mechanisms responsible for such cardiotoxicity and suggest ways in which it can be overcome. The results of these studies have recently been published in The Journal of the National Cancer Institute.
Briefly, administration of ZD6126 induced a rapid but short-lived increase in diastolic blood pressure in Wistar-derived Alpk:ApfSD rats. The timing and duration of this effect was similar to that seen in humans. In some animals, plasma troponin T levels were also elevated and histopathological examination of hearts removed 24 hours after treatment showed a corresponding increase in mild/moderate left ventricular myocardial necrosis. Importantly, pretreatment with the calcium channel blocker nifedipine and the beta-adrenoceptor antagonist atenolol ameliorated both the acute hemodynamic changes and the increase in troponin T levels and myocardial necrosis associated with ZD6126 administration. Most critically, such treatment did not inhibit the anti-tumor activity of ZD6126 as determined by the induction of tumor necrosis in a xenograft model.
Together these studies suggest that the induction of acute hemodynamic changes in response to ZD6126 administration is required for cardiac damage to occur. Further, although the application of careful patient selection criteria similar to those employed in relation to current VEGF-targeted anti-angiogenic therapies may avoid the need for intervention, the findings reported in this manuscript nevertheless suggest that ZD6126-induced cardiac events can be prevented through the use of simple and established anti-hypertensive therapies.
REFERENCE:
Gould, S., Westwood, F.R, Curwen, J.O. Ashton, S.E., Roberts, D.W., Lovick, S.C. and Ryan, A.J. (2007) Effect of pre-treatment with atenolol and nifedipine on ZD6126-induced cardiac toxicity in rats. J Natl Cancer Inst 99(22): 1724-1728. (Read Abstract)
Evaluating the therapeutic efficacy of vascular disrupting agents in early clinical studies OXFORD-July 3rd., 2007
The magnitude of the tumour cell death response produced by treatment with ZD6126 and other vascular disrupting agents (VDA) is critically dependent upon both the degree and duration of the blood flow shutdown that results. Although dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) analysis carried out in the course of Phase I studies revealed dramatic reductions in tumour perfusion at well tolerated doses of ZD6126, the precise relationship between particular DCE-MRI parameters and subsequent tumour necrosis was not clearly established. In a paper published in May 2007 in the journal Neoplasia, Bradley et al., addressed this important question using a well characterized rat xenograft model. Importantly, this study employed doses of ZD6126 that produce plasma levels of the biologically active ZD6126 phenol derivative equivalent to those seen in Phase I studies. The results obtained provide convincing evidence of a correlation between the proportion of hypoperfused voxels measured 24 hours post-ZD6126 treatment and the extent of the resultant necrotic response. These data help justify the use DCE-MRI as a non-invasive means of assessing the potential efficacy of VDA treatment in future clinical studies. In particular, the measurement of equivalent enhancing fraction (EHF) and the presence of hypoperfused voxels as estimated from fit failures in Ktrans are likely to prove especially informative.
REFERENCE:
Bradley, D.P., Tessier, J.J., Ashton, S.E., Waterton, J.C., Wilson, Z., Worthington, P.L. and Ryan, A.J. (2007) Correlation of MRI biomarkers with tumor necrosis in Hras5 tumor xenograft in athymic rats. Neoplasia 9(5): 382-391. (Read Abstract)