By Frances Bishopp

Neurex Corp. and partner Warner-Lambert Co. stopped patient enrollment in the Phase III clinical trial of SNX-111 for severe head trauma after Phase I/II clinical trial data failed to demonstrate a clear risk/benefit ratio in the active group.

Paul Goddard, CEO and chairman of Neurex, told BioWorld Today the total Phase I/II clinical experience with intravenously administered SNX-111 is being assessed in combination with earlier observations to decide the future of the product for treatment of head trauma.

The Phase I/II study, which enrolled 70 patients, looked at three separate dose levels of SNX-111 in head trauma patients to establish both safety and feasibility. With 70 patients divided through three doses, however, it was always going to be impossible to show statistical evidence of efficacy of SNX-111 vs. placebo, Goddard said.

This fact did not stop several investigators from publishing data, that, they said showed promising results. This evidence, Goddard pointed out, "was anecdotal and not statistically based."

"At the end of the 70 patients, what we thought we had, based on advice from an independent safety review board, was the ability to go into a larger patient population," Goddard said. "It was on closer analysis after the unblinding of the Phase I/II study that we saw data that led us to temporarily halt the trial.

"What we were seeing [in the Phase I/II study] which gave us some concern," Goddard said, "was differentiation in outcomes between SNX-111 and placebo groups. We don't fully understand what that means at the moment and it is this data that is subject to further analysis."

He added the study had not been stopped because of any obvious side effects or toxicity with the drug.

"In terms of outcomes, we had some cause for concern based on the review of both the active and placebo groups and for that reason, we decided to stop the Phase III program until we understand exactly what we have," Goddard said.

The highest-risk, longest-term project Neurex has in development is SNX-111 for the treatment of head trauma, Goddard said. The company does not expect to complete the Phase III study in the next two years and does not plan to file a new drug application (NDA) until 2000, he said.

"Generally speaking, the analysts who follow the company have seen little or no value attributed to this program," Goddard said, "although, in the longer term, it could be important for us."

SNX-111 is a synthetic pain relief peptide based on a derivative from the venom of the Conus snail. The compound specifically blocks N-type calcium channels and inhibits neurotransmitter release. When administered intrathecally (into the fluid surrounding the spinal cord), SNX-111 has proven to be an effective analgesic.

SNX-111 also is being developed for the treatment of malignant and neuropathic chronic pain syndromes. Two Phase III analgesia clinical trials are under way in which SNX-111 is being administered by the intrathecal route at doses that are 10,000 times lower than those being employed intravenously in the head trauma study.

Neurex, of Menlo Park, Calif., in collaboration with Medtronic Inc., of Minneapolis, is using Medtronic's implantable pump to deliver the drug to the spine in an effort to prevent nerve cells from sending pain signals to the brain.

Goddard said Neurex expects to complete the Phase III studies for pain this year and file an NDA three to six months thereafter. "What has happened in the head trauma studies bears no relationship to the pain studies," Goddard said. "They are continuing at a good pace at the moment."

The Phase III study for head trauma was dealing with an extremely ill patient population, Goddard pointed out. "What we were trying to show in these patients was a demonstrable benefit with SNX-111. We don't want to do an 800-patient study when we have some concerns that we couldn't demonstrate a clear benefit," he said.

SNX-111 is intended to prevent inappropriate excited, toxic effects following ischemia. When ischemia occurs, whether it's due to head trauma, cardiac arrest, drowning or coronary artery bypass graft surgery, the lack of oxygen to the brain leads to inappropriate stimulation of the nerve cells.

If this condition continues, nerve cell death will result. SNX-111 may block the biochemical cascade of reactions that results in nerve cell death.

"We don't bring nerve cells back to life," Goddard said. "We believe we preserve them."

Goddard said Neurex and Warner-Lambert, of Morris Plains, N.J., have every intention of getting the study up and running again.

In June 1997, the Cardiovascular and Renal Drugs Advisory Committee of the FDA recommended approval of Neurex's lead product, Corlopam, a dopamine (DA-1) receptor agonist that allows precise blood pressure control through systemic vasodilation.

In January 1997, Warner-Lambert sold 375,000 shares of Neurex stock. (See BioWorld Today, Jan. 23, 1997, p. 1.) After the stock sale, Warner-Lambert still owned 1.49 million shares of Neurex stock.

As of March 31, 1997, Neurex had approximately $80 million in cash on hand. Neurex's stock (NASDAQ:NXCO) closed Tuesday at $11.625, down $0.546. *