The fates and fortunes of biotechnology firms can be as twisted as any crime novel's plot, but the treasure at the center of the action - some novel drug or set of patents - often remains preserved, like the jewel sought by desperate characters of fiction.

Last week, when Mpex Pharmaceuticals Inc. licensed rights to efflux pump inhibitors (EPIs) from Trine Pharmaceuticals Inc. for undisclosed terms, Mpex gained what the company called a leadership position in that field of research.

It could mean big things for the firm. Efflux pumps are transport proteins that eject toxic substances from cells - including antibiotics, unfortunately. Suppressing the pumps' action could make such drugs work better.

The EPI patent estate has some history.

Step back almost exactly three years ago, when a company called Microcide Pharmaceuticals Inc. was taking over another named The Althexis Company Inc. in a stock swap worth about $22 million. The new company, to be known as Essential Therapeutics Inc., garnered $60 million in private equity funding for infectious disease research.

Hopes were high. Mark Skaletsky, Althexis' chairman and CEO, became chairman and CEO of Essential, which combined Microcide's VALID Microbial Genomics platform for developing "antibiotic potentiators" (in the form of EPIs) with Althexis' target-validation system known as ACTT, which stands for Althexis Calorimetric Target Triage and deploys calorimetric methods to measure the function of drug-target proteins.

The road proved less than smooth. Essential managed to take over another company, Maret Pharmaceuticals Inc., in a deal worth up to $6.8 million disclosed in the spring of 2002. Maret was a development-stage firm with programs in hematology, oncology and infectious disease. The lead product - which became Essential's lead candidate - was MARstem, a peptide analogue of the human hormone angiotensin being explored for end-stage renal disease and breast cancer.

But a year later, Essential was staring down the barrel of Nasdaq delisting and was trying to offload some assets. Terms of its Series B preferred stock specify that if Nasdaq removes its common shares from listing, holders of the preferred shares could redeem them for $1,000 each - and Essential had 60,000 of those shares outstanding, or $60 million worth.

Trading at about 12 cents per common share, Essential had about $40 million in cash, with a net loss for the first nine months of 2002 of $34.3 million, which hardly put the firm in a position to pay out the $60 million to preferred shareholders.

Essential went under last year. After the bankruptcy, investors took the company private and Trine was born, still clutching its portfolio of EPI patents, some of which jointly were part of a 1995 deal entered by Microcide with Tokyo-based Daiichi Pharmaceutical Co. Ltd. The five-year Daiichi arrangement fizzled because of toxicity problems, but the companies were able to validate the target and achieve efficacy in animals.

Bill Gerhart, president and CEO of Mpex, said an early stage drug in the works may get around the toxicity problem. Meanwhile, Mpex - apart from the deal with Trine - has come up with a bacterial EPI for respiratory infections in patients with cystic fibrosis (CF) and ventilator-associated pneumonia. Called MP-601,205, it's an aerosol formulation of an approved drug that Mpex will disclose later. Last week, the firm disclosed that an investigational new drug application had been filed, and Phase Ib/IIa trials are about to begin.

The endpoint for the study starting in September is to prove that a dose projected to work was likely to be tolerated and safe in the broader CF population. Providing financial and administrative support is the Cystic Fibrosis Foundation, and the study will be conducted at the Adult Cystic Fibrosis Center at the University of California San Diego Medical Center.

If the Phase Ib trial meets its goal, Mpex aims to begin a Phase II trial testing MP-601,205 in combination with ciprofloxacin to treat pulmonary exacerbations in CF patients.

Hopes are high once again. In CF patients, deadly Pseudomonas aeruginosa is the bug that attacks the lungs. Physicians typically first try TOBI, the inhaled tobramycin solution from Chiron Corp., and the drug works until the patient develops resistance and needs to be hospitalized. In MP-601,205, Mpex may have a drug that's more potent and not easily resisted.

Mpex's drug is similar to Augmentin, a combination of amoxicillin and clavulanate potassium that has raked in profits aplenty for GlaxoSmithKline plc. Augmentin hit the market in 1987 and went off patent last year. But MP-601,205 provides a different mechanism of resistance and targets hospital-based, Gram-negative bacteria rather than community-based infections. The patent estate licensed from Trine covers the discovery, development and use of EPIs to enhance antibiotics.

Did Mpex go after the intellectual property mainly to protect its products already in the works, or to protect future ones?

"Both," Gerhart told BioWorld Financial Watch. "We have three programs right now, and the IP that we licensed in covers two of them. The first one, which is the aerosol product, is outside that IP."

The in-licensed portfolio "doesn't give us total protectability" by itself, but combined with patents filed by Mpex should seal up the company's position in the field.

A tricky aspect of EPIs is that P. aeruginosa as tested in the laboratory leads to overproduction of efflux pumps as high as 75 percent, which adds to the challenge of making antibiotics, or antibiotic boosters, that the pumps won't spit out of the cell. So far, the best solution has been to optimize the antibiotics as well as possible in formulation, or to combine them into substrates that are targeted by different pump systems. Overproduction of one in particular, called the MexX-MexY-OprM system, is the suspected culprit in the resistance P. aeruginosa develops to aminoglycosides, the class of antibiotics that includes TOBI.

"The nice thing about the aerosol inhibitor is that it inhibits all of the pumps," Gerhart said. "In other bacteria, there's only one pump that is clinically relevant. It's [determined] bacteria by bacteria."

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