LONDON - Signaling a breakthrough in the pharmaceutical industry's acceptance of botanicals, Phytopharm plc and Pfizer Inc. signed a license deal for the development of P57, an appetite suppressant derived from an extract of a South African plant.

Under terms of the deal, New York-based Pfizer has an exclusive worldwide license to develop and market P57. Phytopharm, of Godmanchester, U.K., will receive up to US$32 million in license fees and milestone payments, plus royalties on sales. Pfizer will also contribute at least US$7 million between now and the end of 1999 to the Phase I trial, which Phytopharm is about to initiate.

“What's really encouraging is to see a multinational like Pfizer electing to take a botanical into development, rather than a single chemical entity,“ said Richard Dixey, CEO of Phytopharm. “This should open the gates to the acceptance of botanicals by the pharmaceutical industry.“

P57, a single plant extract, was licensed by Phytopharm under a milestone and royalty sharing agreement from the Council for Scientific and Industrial Research (CSIR) in South Africa, a publicly funded body. “The license gives us first right of refusal for all natural products coming out of the CSIR -in other words, this is a pipeline,“ Dixey said. Phytopharm has similar deals, which include the supply of raw materials, in China, Indonesia and India.

Unlike many botanicals, the phytochemistry of P57 is highly characterized, and the mode of action has been elucidated. However, Dixey declined to give details because the patents are just coming up for examination. “Plant families have a number of active molecules,“ he said. “In P57, we know some of them, but there may be others we don't know. What we can say about the mode of action is that it is different from the two existing classes of anti-obesity drugs. In other words, it is not an enzyme inhibitor which prevents the digestion of some element of the diet, and it is not a central stimulant which produces a feeling of satiety.“

Several other Phytopharm compounds, including P58 for the treatment of Alzheimer's disease, also have novel modes of action. This feature can be expected to make them attractive to pharmaceutical companies because of the development lead this confers.

The overall effect of P57 is to suppress appetite. “It is highly efficacious, to the extent that, in animal studies, rats can starve to death.“ Because P57 is highly biologically active, Dixey expects the dose in humans to be very low, and adds the animal toxicology makes him optimistic that side effects will be minimal. He said he does not believe P57 would necessarily be prescribed as part of a weight-loss regime, and pointed out the product would have potential for abuse. “It's too early to say how it would be introduced,“ he said.

Phytopharm expects to complete Phase I testing by the end of next year. If at that point it decides to carry out Phase II trials in the U.S., the project will be handed over to Pfizer. “If it is decided to do Phase II in the U.K., obviously Phytopharm has a track record, and we may do it here,“ Dixey said.

The deal is financially significant for Phytopharm, which had net cash of £4.3 million (US$7.05 million) at the end of February, with 11 products in development, and a burn rate approaching £4 million per annum. “This lowers the cash burn dramatically. The US$7 million will finance seven of our 31 staff full time,“ said Dixey.

However, Phytopharm still needs to raise more money, and Dixey said it would be up to shareholders to decide if the company should license early-stage compounds or raise cash for more advanced trials. “We will see how the market receives our next deal. I promise you, we have multinationals queuing up to talk to us, but the choice facing shareholders is whether they want to license early stage or invest in trials and get more for later-stage licensing,“ he said.

The stock price rose 13.5 pence to £1.29 when the deal was announced on Monday.

Phytopharm's most advanced product is Zemaphyte, a Chinese herbal treatment for severe refractory atopic eczema. This has completed Phase III study in the U.K. Although results were positive, the trials were carried out before the company had its GMP manufacturing facilities in place. The U.K. Medicines Control Agency has told Phytopharm that it will not consider a resubmitted product license application until the results of a U.S. Phase II multi-center trial, carried out with GMP-manufactured Zemaphyte, are available.

As a result, the project is currently on hold. Although Phytopharm has been granted acceptance of an investigational new drug application by the FDA, it cannot afford the U.S. trial. Dixey said there are negotiations in relation to Zemaphyte but he does not expect this to be the next compound to be licensed. *