Since the mid-1980s, sepsis researchers and biotechnology companies have watched a succession of sepsis therapies fail, often late in the drug development process. Xoma Corp.'s E5 monoclonal antibody product, as a treatment for Gram-negative sepsis, proved to be no exception when, on Thursday, the company and its marketing partner, Pfizer Inc., determined they would discontinue the U.S. clinical trials of the drug.
Results of an interim analysis recently completed on 1,000 patients in a Phase III U.S. clinical trial conducted by Pfizer, of New York, did not support continuation of the trial, the company said.
Although there were no safety concerns and a benefit was shown for patients treated with E5, the results were not sufficient to meet the predetermined efficacy criteria necessary for continuation of the trial, Ellen Martin, director of corporate communications at the Berkeley, Calif., company, told BioWorld Today.
Xoma and Pfizer, Martin said, will discontinue clinical trials of E5 in the U.S., "and stay pretty much on hold." However, the E5 approval process will continue in Japan for endotoxemia.
"We don't know what will happen to E5 in the U.S.," Martin said. "Pfizer has left that door open, but it is not clear to me that anyone is going to step through it."
Martin said Xoma does not expect a significant financial impact from discontinuing E5 in the U.S., because E5-related payments in 1996 were approximately $300,000 to Pfizer for clinical trial expenses.
Additionally, as of Dec. 31, 1996, Xoma had a contingent liability of $22.4 million related to deferred legal and clinical trial costs to be repaid from future royalties on U.S. sales of E5. This contingent liability will now be canceled, Martin said.
Xoma, which began development of E5 in the mid-1980s, was described by Martin as a legacy drug of the old monoclonal antibody-oriented Xoma. "We have long ago ceased to be an E5 company," Martin said. "We are a BPI-derived product company with Neuprex going into its second Phase III trial later this year," Martin said.
BPI-derived products are those products derived from bactericidal/permeability-increasing protein, a human host-defense protein that kills bacteria, neutralizes bacteria and their endotoxins and enhances the effectiveness of many antibiotics.
BPI appears to act by punching holes in bacterial cell walls, then binding and neutralizing endotoxin, Martin said. Neuprex is recombinant bactericidal/permeability increasing protein, or rBPI.
Neuprex has multiple indications, such as hemorrhagic trauma, infectious complications of severe accidental blood loss, complications following partial hepatectomy, a type of liver surgery, and in combination with antibiotics to treat intra-abdominal infections, including those resistant to the antibiotic.
Martin said Xoma believed Neuprex showed potential as a second-generation sepsis drug, but because the "all-cause mortality" endpoint required for sepsis is the FDA-required measure of success, the company decided to take a new clinical strategy away from sepsis.
With the sepsis indication, Martin said, the all-cause mortality hurdle is so high, it is difficult for a drug to succeed. In the E5 trial, the all-cause mortality endpoint was a 28-day mark after being given the medication, at which point if the patient died, it counted against the drug. Sepsis patients, Martin explained, generally have many other underlying illnesses that could easily kill them. "Anybody who dies from whatever cause 28 days after the drug is given counts against the efficacy test of the drug," Martin said.
"Also, sepsis is a grab-bag, late-stage, you-have-been-infected-and-all-systems-have-broken-down kind of disease," Martin said.
Indications for Neuprex are related to sepsis, but at a much earlier stage of disease, when patients have a better shot at getting well, she said.
Both Xoma's technical and business focus have shifted to a new generation of drugs that attack the same problem, Martin said. The company thus far is only in the discussion stage with various companies concerning future collaborations.
Xoma, as of March 31, 1997, had $39 million in cash on hand, representing 18 to 20 months of burn, Martin said. Xoma's stock (NASDAQ:XOMA) closed Friday at $3.937, unchanged. *