LONDON - Xenova Group plc started Phase I trials of XR9576 for the prevention of multidrug resistance (MDR) in cancer chemotherapy. The compound inhibits the action of P-glycoprotein, a transport protein which acts as a pump, expelling drugs from a cell before they have reached their target.

Paul Bevan, head of development for Xenova, of Slough, U.K., told BioWorld International, “We have done a lot of preclinical work on this. XR9576 is replacing an earlier candidate, 9051, because it has substantially better characteristics. We are quite excited by 9576, but until it is moved into human trials we won't know if it works.“

There has been substantial debate over whether P-glycoprotein inhibition is a good target in the prevention of MDR. Bevan noted Novartis AG, of Basel, Switzerland, recently began a multicenter Phase II study of a P-glycoprotein inhibitor in a single tumor type, involving 700 patients. “In this case we are glad to be second,“ he said. “We will, of course, be extremely interested in the progress of this trial.“

XR9576 is derived from a naturally occurring compound that has “been much modified,“ Bevan said. In preclinical models it was effective in a broad range of tumor types and in restoring sensitivity to a range of chemotherapy agents. It also displayed long duration of action and good tumor distribution.

Xenova, which specializes in discovery and development of small molecule drugs from microorganisms, is talking to the regulatory authorities about the design of patient trials and appropriate clinical endpoints.

“We can't do trials in every tumor type for every cytotoxic, so we have to achieve a consensus with regulators on how to prove the principle,“ Bevan said. “It is clear from our dialogue that there is a desire to see this sort of clinical capability being made available to medicine.“

Xenova started the trials as it released results for the quarter ended March 31, 1998, showing losses of £2.7 million, slightly up over the £2.6 million loss for the same period last year. Revenues increased sharply, to £1.9 million from £205,000, as a result of partnership deals.

Operating expenses increased substantially, to £4.7 million from £3.3 million. This appeared to indicate the company, with cash of £13.1 million, will run out of money before the end of 1998.

However, David Oxlade, who was appointed CEO in March 1998, told BioWorld International he expects revenues from drug optimization and high-throughput screening services to increase over the year.

He noted that in the past, Xenova has had a parallel investment strategy, spending to establish its platform technologies in natural product drug discovery, and on drug discovery and development. “The strategy going forward for this company is going to be to focus on proprietary product development in cancer and anti-infectives,“ he said. “We will reduce the cash investment into non-core business. Therefore, it is difficult to take the current cash burn numbers and run them ahead - it is not a valid projection.“

On this basis Xenova has sufficient funds “for 12 to 15 months of normal operation. We are considering the options on terms of further fund raising,“ Oxlade added. “We don't have to do it at the moment, but obviously we won't let the company get into the position that its back is against the wall.“ *