By Karen Pihl-Carey

Almost six years after Synaptic Pharmaceutical Corp. and Merck & Co. began a collaboration to find a drug useful in treating urinary retention problems, the selected compound has come up short in clinical trials.

The alpha adrenergic drug development candidate demonstrated limited oral bioavailability and a potential for drug interactions, prompting Merck to discontinue development of oral formulations of the compound.

An assay that measures how much of the compound gets into the body was used, said Kathleen Mullinix, president and CEO of Synaptic, of Paramus, N.J. "The bioavailability of this - meaning what percentage of what goes in the bloodstream - is pretty good. It's not terrific."

A Phase IIa trial also found that the compound had the potential to interact with other drugs.

The discontinuation by Merck, of Whitehouse Station, N.J., will not affect its overall collaboration with Synaptic as Merck is attempting to identify additional compounds to replace the former lead compound.

Investors reacted negatively to the news, driving the stock price down 34 percent. The stock (NASDAQ:SNAP) dropped $3.062 Monday, closing at $5.875.

"It's kind of unfortunate, the trials and tribulation of pharmaceutical development," said David Molowa, an analyst with Bear Stearns Co. in New York. "They have a good product, a good efficacious drug without the cardiovascular side effects of lots of these other drugs. But unfortunately, it holds the potential for some drug-drug interactions."

Mullinix said "it's not clear right now" how far this sets the company back. Even though the lead compound has failed, she said, the trial did provide some important information for future development. It confirmed that of the three alpha adrenergic receptors, the alpha 1-a receptor is an appropriate target for benign prostatic hyperplasia (BPH). Clinical trials also indicated that other drugs on the market, which cause cardiovascular side effects not experienced with Synaptic's compound, do not selectively target the alpha 1-a receptor over other alpha adrenergic receptors. Synaptic's lead compound was "highly efficacious in increasing urine flow without the low blood pressure of the other drugs on the market," Mullinix told BioWorld Today.

Molowa also noted the efficaciousness of the compound and said Merck's decision to discontinue oral development is not a huge setback for the company.

"It's more of a psychological setback," he said, "because that tends to be what the market focuses on. But if you look at the company and try to value the separate parts, there's a lot of cash, a low burn rate and a lot of other opportunities to develop other partnerships."

Mullinix could not estimate how far away Merck is from identifying a new compound for testing.

"Clearly," she said, "with the mechanism being validated, a huge uncertainty as to whether this approach works has been lifted."

Synaptic holds several U.S. patents covering the use of alpha 1-a antagonists, the use of genetically engineered cells expressing the human alpha 1-a receptor to identify compounds that bind to the receptor, and genes encoding the three human alpha adrenergic receptors. Merck has a license under these patents to develop and market alpha 1-a antagonists.

Merck and Synaptic first collaborated in December 1993 in a three-year $20 million deal involving a series of compounds for treatment of BPH, a non-cancerous enlargement of the prostate gland. The agreement was extended in one-year increments and remains active. (See BioWorld Today, Dec. 20, 1993, p. 1; and Oct. 30, 1996, p. 1.)

Synaptic was founded under the name Neurogenetic Corp. in 1987 and changed its name in 1992. It went public in December 1995.

Among its other collaborations are a number of preclinical programs targeting pain with Grunenthal GmbH, of Aachen, Germany, and a preclinical program for obesity with Novartis AG, of Basel, Switzerland. Synaptic also is working with Eli Lilly & Co., of Indianapolis, in preclinical studies for depression, migraine and obesity, as well as a Phase I trial with serotonin drugs for depression. Lilly this year dropped development of a lead candidate in migraine before a Phase III trial after looking at animal toxicology data. (See BioWorld Today, March 22, 1999, p. 1.)