By Chris Delporte

Titan Pharmaceuticals Inc. and Novartis Pharma AG said they will initiate additional dose-related trials of their schizophrenia drug candidate, delaying regulatory filing.

The news of yearlong delay resulted in a 56 percent drop in Titan¿s stock (NASDAQ: TTP), which fell $15.30 to close at $11.95.

Deutsche Banc Alex. Brown Inc., Legg Mason Wood Walker Inc. and U.S. Bancorp Piper Jaffray Inc. were among the firms that downgraded Titan¿s stock on Tuesday.

¿We¿ve been worried about delays for awhile, but we didn¿t see this coming,¿ Stefan Loren, an analyst with Legg Mason, told BioWorld Today.

Titan, of South San Francisco, and Novartis, of Basel, Switzerland, said they hope to more fully profile iloperidone (Zomaril). The additional trials will be designed to further investigate once-a-day dosing in order to demonstrate a favorable safety profile when switching from other antipsychotic agents to Zomaril, as well as to support the competitive profile of the compound.

Despite this setback, however, analysts remain confident that Zomaril will make it to market. A report issued by Deutsche Banc Alex. Brown on Tuesday said that Zomaril sales could reach $750 million by 2005, and that with more than $100 million in cash, Titan has sufficient reserves to reach profitability.

Loren pointed out that the longer it takes to get Zomaril approved, the tougher the competition will get, and that competition in this sector of the industry continues to intensify. Pfizer Inc. recently launched its drug, called Geodon, which now has another year to get entrenched in the market. Loren also predicted that Zomaril¿s application will follow the filing of aripiprazole, Bristol-Myers Squibb Co.¿s schizophrenia therapy.

¿This is still an approvable drug, but there just needs to be more data,¿ Loren said. ¿We¿ve never really seen any full data on this. I don¿t see how they have a good marketing hook that is going to allow it [Zomaril] to launch quickly.¿

Analysts had expected Zomaril to be filed with the FDA in the fourth quarter. However, Titan and Novartis now anticipate submission in the U.S. around the end of next year, followed by filings elsewhere. FDA approval most likely would follow by mid-2004, analysts said.

The companies reported on the third Phase III clinical trial for Zomaril. The study investigated two dose ranges of the drug for six weeks. Both ranges reconfirmed the favorable safety and tolerability profile, with overall low incidence of extra-pyramidal symptoms and cardiovascular effects, low sedation and little weight gain, though the weight gains were still higher than some analysts expected.

Results from the high-dose arm (20-24 mg/day) showed statistically significant improvement in symptoms measured by the 18-item Brief Psychiatric Rating Scale and the Positive and Negative Symptom Scale.

The results from the low-dose arm (12-16 mg/day), however, were inconclusive. Statistical significance was not observed at week six, though there was steady improvement compared to placebo. Statistically significant results were recorded at weeks three, four and five.

The companies conducted a total of seven Phase III trials for Zomaril, involving more than 3,500 patients at approximately 300 sites around the world. The development program studied a range of doses from 4 to 24 milligrams per day.

Separately, Titan recently completed enrollment in its Phase III study of CeaVac for the treatment of colorectal cancer. More than 620 patients have been enrolled in the study, which is being conducted at more than 50 sites in the U.S. and Europe. In total, Titan has eight products in development for the treatment of cancer and central nervous system disorders. According to Deutsche Banc, that should enhance the company¿s long-term growth prospects.

Novartis acquired the worldwide rights to develop, manufacture and market iloperidone from Titan in November 1997. The original terms involved an up-front payment of $18 million in license fees and reimbursement of research and development costs, in addition to a $5 million equity investment in Titan. (See BioWorld Today, Nov. 21, 1997.)

Titan officials could not be reached for comment.

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