A refocused Xoma Corp. is back in the clinic. The companyannounced Monday that it has begun Phase I testing of asecond-generation product to treat sepsis.
Xoma (NASDAQ:XOMA) of Berkeley, Calif., shifted course lastyear after FDA refused marketing approval for its E5 treatmentfor sepsis following a Phase III trial. This monoclonal antibodytargeted the endotoxin produced by Gram-negative bacteriathat lead to an often-fatal blood infection in some 200,000Americans annually.
The new product, recombinant bactericidal permeability-increasing protein (rBPI-23), also targets endotoxin. It is afragment of a natural human protein, manufactured usingrecombinant DNA techniques. While the natural version weighs55 kilodaltons, Xoma's drug weighs 23 kilodaltons. rBPI-23binds to endotoxin on the surface of Gram-negative bacteriaand may kill the invading microbes by rupturing the cell wall.
The Phase I trial will involve about 40 patients who willreceive a single dose of either rBPI-23 or placebo, said PatrickScannon, Xoma's vice chairman for scientific and medicalaffairs. The trial will probably study the effects of four doseranges, he said.
The Phase I study should provide a preliminary safety profileof the drug in humans, as well as information about its activityin the bloodstream. It is being conducted under aninvestigational new drug (IND) application filed with FDA lastDecember.
According to Scannon, Xoma may pursue rBPI-23 as atreatment for other clinical indications, in addition to Gram-negative sepsis. He said the product might also be used in acuteor chronic infections of a single organ, such as pneumonia orkidney infection.
"No one has really tested a potent anti-endotoxin yet," saidRandal Scott, vice president of research and development atIncyte Pharmaceuticals Inc. of Palo Alto, Calif., which holds twopatents covering human BPI in septic shock, leukopenia andadult respiratory distress syndrome. Incyte is developing a BPIproduct of a slightly different molecular weight than Xoma's.
Preclinical data showed that BPI blocks the lethal effects ofendotoxin and protects against septic shock, Scott said.
Although about half of all sepsis patients have Gram-positiveinfections, Scott said that most of the sicker patients areapparently infected by Gram-negative bacteria.
"Endotoxins are probably the most potent stimulators of theimmune system known to man," he said. Centocor Inc. andXoma both suffered setbacks with anti-endotoxin candidates,but Scott said expectations may have been too high.
Brandon Fradd, a biotechnology analyst with MontgomerySecurities in San Francisco, agreed. "It looks like using thenaturally occurring anti-endotoxin may help them with some ofthe problems they've had with E5 and Centoxin," Fradd said."But they face competition from companies that are already inPhase II trials in septic shock with compounds that cut acrossGram-negative and Gram-positive: Immunex (Inc.), Chiron(Corp.) with its TNF and Cortech (Inc.)."
However, Scott pointed to the complexity of sepsis and thepotential to use anti-cytokines to tone down the immunesystem's overreaction in sepsis.
Synergen Inc.'s drug for sepsis, an interleukin-1 receptorantagonist called Antril, is just such an anti-cytokine.Combination therapy may eventually be the most promisingapproach, Scott pointed out, perhaps including a blood pressureblock as well.
Using a rapid screening test to determine which sepsis patienthas a Gram-negative infection may be possible when the firstdrugs are available in four or five years, added Jim McCamant,publisher of the Medical Technology Stock Letter.
Xoma's stock closed Monday at $8.25 a share, up 50 cents.
-- Nancy Garcia Associate Editor
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