By Mary Welch

Sibia Neurosciences Inc. remained confident its compound for Parkinson's disease, SIB-1508Y, has promise despite two Phase II trials in which it failed to demonstrate statistical significance.

"This is not fatal," said Jeffrey McKelvy, executive vice president and chief scientific officer at Sibia. "This was not a pivotal trial but a very early trial in humans. We were collecting information so that we could go forward. We've seen tolerability and trends of efficacy. This drug should definitely go forward."

SIB-1508Y is designed to selectively regulate dopamine and acetylcholine, which are linked to progression of Parkinson's disease and cognitive dysfunction, respectively. Preclinical studies suggested lower doses of both the drug and L-Dopa had synergistic effects that increased efficacy.

The question, McKelvy said, becomes whether the company should go forward and how it does so.

The La Jolla, Calif.-based company strongly believes drug development should proceed. The Phase II trials would provide a wealth of information to design a pivotal study, McKelvy said.

In order to show efficacy, a trial should last between three to six months, "and we don't have the money to do that," he said.

Sibia is hoping one or both of its development partners, Meiji Seiki, of Tokyo, or Eli Lilly and Co., of Indianapolis, takes the drug back into the clinic.

In May, Sibia and Lilly signed a $20 million deal to develop compounds, including SIB-1508Y, for an array of central nervous system disorders. Lilly made a $5 million equity investment and pledged $5 million a year in research funding for three years. Lilly has two months to decide whether or not to develop SIB-1508Y. (See BioWorld Today, May 27, 1999, p. 1.)

"We would not lose money if they chose not to develop it, but we would not receive any future payments that might have come from the development," McKelvy said. "And, even if Lilly decides not to, we've already heard from several companies who are interested."

McKelvy said results of the trials should not have a negative impact on the company. "We believe the drug has shown some efficacy and that it will proceed forward," he said. "Plus, it hasn't affected our stock much, which shows that the industry is sophisticated enough to know that these are early trials and that efficacy wasn't our primary objective."

Sibia's stock (NASDAQ:SIBI) closed Wednesday at $4.875, down 37.5 cents per share, or about 7 percent.

The first study involved patients with early onset Parkinson's disease who had not yet taken the standard treatment, L-Dopa. The four-week trial was a placebo- controlled, multiple-dose study assessing safety and tolerability as well as looking at efficacy of SIB-1508Y (altinicline). Altinicline did not demonstrate statistically significant improvement relative to placebo.

"We were trying to show an improvement not only in motor skills but also cognitive ones," McKelvy said "We wanted to see how it affected early-stage patients so that we'd have a better idea of how it would behave in later stages. We did a range of dosing. But for our second objective, efficacy, we needed a longer-term exposure of patients to the drug to show it really worked and we couldn't support a longer trial. It became a Catch-22."

Adding to the trial's troubles was that the "placebo response rate was enormously high," McKelvy said. "In fact, it was almost equal to the L-Dopa results. It was really frustrating but it can happen."

Although the compound didn't demonstrate statistically significant improvement relative to placebo in the global analysis, it did show improvement relative to baseline measures and in some cases, to placebo, in certain motor and cognitive measures.

The second study involved not only more advanced cases but also a different protocol. It was a crossover design examining acute motor and cognitive performance over an eight-hour period in which the patients received half the usual dose of L-Dopa along with either one of three doses of altinicline in random order, or placebo, for four consecutive days.

Patients then were observed during the next eight hours. A week later, the procedure was repeated.

"Because these were people with more advanced and severe symptoms, we were able to use a higher range of doses and we still found good tolerability, which is important," McKelvy said.

The company had set an endpoint of 25 percent improvement in motor and cognitive skills. However, patients showed an improvement of only 10 percent.

"Again, we saw a trend that we're interpreting represents an effective drug," McKelvy said.