By Brady Huggett

NeoTherapeutics Inc. opened enrollment for a pivotal Phase III trial of its lead product, Neotrofin, in patients with mild to moderate Alzheimer's disease.

Approximately 500 patients will be enrolled at more than 50 U.S. sites, a process expected to take six months. If enrollment goes smoothly, the patients should complete the primary analysis period by the end of 2001.

Barring any glitches, that should allow NeoTherapeutics to file a new drug application for Neotrofin in Alzheimer's patients within two years, said Rajesh Shrotriya, president of NeoTherapeutics, of Irvine, Calif.

"This means a lot," Shrotriya said. "Lots of these small biotech and pharma companies are in a Petri dish or mice or have just started human trials. It takes typically 10-plus years and $200 million-plus to get a drug to [filing]. We are at a late stage. It feels great. Absolutely great."

Patients will receive 500 mg of Neotrofin or placebo twice a day for one week, then the dose will be bumped up to 1,000 mg twice a day. That level either will be maintained or dropped back down to 500 mg, depending on tolerability, and the optimal dose will be continued for the remainder of the first 12 weeks. A second 12-week period will follow, allowing the patients that received placebo to be administered Neotrofin.

The primary endpoint will be a measurement of loss of recent memory, Shrotriya said, and will be measured by the Alzheimer's Disease Assessment Scale-cognitive subscale. (ADAS-cog). The Alzheimer's Disease Cooperative Study Clinician's Global Impression of Change also will be used to measure the patients.

"The second measurement is the global assessment of the patients," Shrotriya said. "That is, overall, how these patients are doing. These are the standards the FDA has laid down in their guidelines [for testing Alzheimer's patients]."

Secondary efficacy endpoints will be measured by the Neuropsychiatric Inventory and the Alzheimer's Disease Cooperative Study Activities of Daily Living.

In March 2000, NeoTherapeutics initiated a 1,500-patient, 165-site, worldwide Phase II/III trial with Neotrofin in Alzheimer's to test four different doses of the drug. But data from three other trials hinted that the best dose for the drug was in the neighborhood of 500 mg to 1,000 mg, so that trial was scrapped. (See BioWorld Today, March 30, 2000, and Oct. 27, 2000.)

"[I stopped] the 1,500-patient trial after I joined the company," Shrotriya said. "That was because of the smaller dose. We had evidence that the higher the dose, the better the effect."

Shrotriya said NeoTherapeutics also is laying the groundwork for a one-year trial to measure the effect of Neotrofin on Alzheimer's disease progression.

"We plan to measure brain volume to see if [patients receiving Neotrofin] have less shrinkage of the brain," he said. He added that NeoTherapeutics plans to file a NDA for the Alzheimer's indication, then seek label expansions following the long-term-effect study.

NeoTherapeutics filed a $50 million shelf registration in January. It has about $14 or $15 million in the bank, Shrotriya said, and will go get money "as we need it," saying there is no desire to go raise funds considering the current market. (See BioWorld Today, Jan. 4, 2001.)

In the last six months, there have been changes specifically meant to drive burn rate down, Shrotriya said. The company added a new vice president and medical director, Jacob Huff, with neuroscience experience. It now has a head of data management and biostatistics in house. It has added seven new M.D.s into the mix and more than 15 Ph.D.s. All of this has helped stretch NeoTherapeutics' dollars, Shrotriya said.

"The company had depended on the outside contract with [other] companies," he said. "We had a [monthly] burn rate of $4 million. We had to pay for our clinical trials. We are doing all of our own clinical trials now."

Neotrofin also is being tested in two Phase II trials, one in Parkinson's disease and one in subacute, complete spinal cord injury. If all progresses well, Shrotriya said the company would try to get the spinal cord injury indication viewed on a fast-track basis because there is currently no treatment for it.

NeoTherapeutics' stock (NASDAQ:NEOT) rose 40 cents Tuesday to close at $6.35.

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