[2002]-[XR9576]-[P-Glycoprotein Inhibitor][XR9576/Tariquidar-How it works]
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Animation of XR9576
For an animation and explanation of how XR9576 works, please click here to see a Shockwave Flash movie.
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Scientific Background
The most common form of multi-drug resistance (MDR) is the result of over-production in the cancer cell membrane of P-gp, a protein which pumps the anti-cancer drug out of the cell. This may affect between 30 and 80 per cent of all cancer patients affected by MDR, depending on the cancer type. It is this type of MDR which is targeted by XR9576.
Clinical trials
Phase I clinical trials for XR9576 commenced in May 1998 in healthy volunteers using an intravenously administered formulation of XR9576. The initial studies were single dose, dose escalation studies to establish safety and tolerance and to evaluate the concentrations in the blood of XR9576. Phase I clinical trials using an oral dosing were completed in early 1999.
Phase IIa trials for XR9576 began early in 1999 and were completed in 2001. In these trials the pharmacokinetic behaviour of XR9576 was studied in combination therapy with a range of marketed cytotoxic agents, namely vinorelbine, doxorubicin and paclitaxel, three of the world’s best-selling cytotoxic drugs. The primary purpose of these trials, which were carried out at a number of centres in Europe and the US, was to assess the degree of interaction, if any, between XR9576 and the cytotoxic agent.
The successful conclusion of the Phase IIa trial involving XR9576 and paclitaxel in ovarian cancer patients was announced in March 2000.
Although not designed as an efficacy study, a significant response was observed in 6 of the 12 patients in this study.
Further positive data was announced in October 2000 for the second of the Phase IIa trials, in which XR9576 was administered in combination with doxorubicin.
Positive interim data was announced in February 2001 for the third and final Phase IIa trial, in which XR9576 was given in combination therapy with the cytotoxic drug vinorelbine.
Results of the paclitaxel and vinorelbine trials were presented at the 2001 annual meeting of the American Society of Clinical Oncology, in San Francisco, California, USA.
Phase IIa Studies: XR9576 + Vinorelbine
CT scan (10 March 2000):
Two large lesions in left half of the liver
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Phase IIa Studies: XR9576 + Vinorelbine
CT scan (17 May 2000):
One lesion in the liver disappeared, the other one is significantly reduced in size, following 2 cycles with XR9576 + vinorelbine
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No significant drug interaction in plasma has been observed, which it is believed significantly differentiates XR9576 from other drugs which modulate P-gp and which are undergoing clinical trials.
Xenova has been in discussions with the US FDA and with a number of regulatory agencies in Europe with respect to the further development of this compound and the establishment of pivotal Phase III registration studies in these countries.
34 Year Old Male With Adrenocortical Cancer:
Multiple Lung Metastases Imaged With XR9576
99mTc-Sestamibi Scan
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As announced in August 2001, Xenova has entered into an agreement with QLT Inc for the development and North American marketing of XR9576. This agreement could be
worth up to £75m (US$105m) for Xenova in the form of
licence and milestone payments and research and development funding to gain product marketing approval.
QLT Inc. will provide up to US$45m (£32m) in funding for all development activities related to Phase III clinical studies for XR9576 in North America and Europe. In addition, royalties in the range of 15 to 22 per cent, depending on the level of North American sales, are also payable to Xenova. Xenova retains the rights to commercialise XR9576 in Europe and the Rest of the World and intends to establish further collaborations to maximise the value of this potentially first-in-class drug. It is currently anticipated that XR9576 will enter Phase III clinical trials during the course of 2002.
Journal Articles and Abstracts 2000-2002
XR 9576 1) Clinical Cancer Research (2001) 7 Suppl 3739
A Study of the Novel P-Glycoprotein (P-gp) Antagonist, XR9576 in Combination with Vinorelbine.
2) Proceedings of 92nd AACR (2001)
A Phase IIA pharmacokinetic and pharmacodynamic study of the P-glycoprotein inhibitor, XR9576 in patients treated with doxorubicin chemotherapy.
3) Proceedings of 37th ASCO (2001)
A Phase IIA pharmacokinetic study of the P-glycoprotein inhibitor, XR9576 in combination with paclitaxel in patients with ovarian cancer.
4) Proceedings of 37th ASCO (2001)
A Phase I study of the Novel P-Glycoprotein (Pgp) Antagonist, XR9576 in Combination with Vinorelbine.
5) Cancer Research(2001) 61, 749-758
In Vitro and in Vivo Reversal of P-Glycoprotein-mediated Multidrug Resistance by a Novel Potent Modulator, XR9576
6) Clinical Cancer Research (2000) 6 4186-4191
Phase I Trial of XR9576 in Healthy Volunteers Demonstrates Modulation of P-glycoprotein in CD56+ Lymphocytes after Oral and Intravenous Administration
7) Biochemistry (2000), 39, 11901-11906
Drug Binding Sites on P-Glycoprotein Are Altered by ATP Binding Prior to Nucleotide Hydrolysis.
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