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Hardly had investor memories of Namenda's approval faded than Forest Laboratories Inc., trying to build a franchise in Alzheimer's disease, suffered a setback in the Phase III failure of its second AD drug, neramexane, which missed its primary and secondary endpoints.

"They probably thought it was going to work similarly or better than Namenda, and it didn't," said Michelle Grady, senior analyst with Decision Resources in Waltham, Mass., adding that "Forest will complain about this and has complained about it to me, but I don't find Namenda very impressive, either." The drug sold $57.4 million for the three months ended June 30.

Forest's stock (NYSE:FRX) closed Wednesday at $41.98, down $3.87.

Neramexane data will be analyzed further in the coming months. Meanwhile, the New York-based company is enrolling moderate to severe AD patients in a second Phase II/III study to try the compound as monotherapy compared to placebo.

The six-month, double-blind, parallel-group study was designed to evaluate the safety and efficacy of combination therapy with neramexane and any of the three most widely prescribed acetylcholinesterase inhibitors (AChEIs) compared to an AChEI alone in 415 outpatients with moderate to severe Alzheimer's disease.

Early analysis of data has found that patients receiving neramexane and an AChEI did not achieve a statistically significant difference compared to patients on an AChEI alone on the study's primary endpoints of cognition and function.

The primary endpoints were the Severe Impairment Battery, which is a measure of cognition, and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev), which is a measure of functionality. The secondary endpoint was the Clinician's Interview-Based Impression of Change Plus Caregiver Input.

Grady said of the secondary endpoint, "It's more subjective [than scientific]."

Like Namenda (memantine), neramexane is an N-methyl-D-aspartate (NMDA) antagonist, intended to work by selectively blocking effects associated with abnormal transmission of the neurotransmitter glutamate while allowing other functions to continue normally. Neramexane was licensed from Merz Pharmaceuticals GmbH, of Frankfurt, Germany, which co-markets Namenda for Alzheimer's disease in German-speaking countries.

Why one NMDA antagonist would apparently work so well and another would fail is a question researchers at Forest will be trying to answer. But even memantine, approved in October 2003 for Alzheimer's, didn't succeed in all indications. In May of that year, the drug failed in a pivotal study testing it against neuropathic pain, causing Forest's partner, Richmond, Calif.-based Neurobiological Technologies Inc., to lose more than 50 percent of its stock value. (See BioWorld Today, May 8, 2003, and Oct. 20, 2003.)

Memantine for AD "languished in clinical trials forever," Grady said. "We looked at it every year, and it was a shock to all of us that the drug ever [gained approval]. It works in Alzheimer's, but when you really look at it, the effect is very modest. It's not any miracle drug, to say the least."

But AD patients have few alternatives, she noted, and their caregivers are grateful for any advance.

"The fact that a patient can remember a daughter or son's name is enough for them," Grady said. "It's a depressing disease. You don't have to be the best drug in the world and people will try you."

Another NMDA antagonist already on the market is dextromethorphan, known as DM, the active ingredient in the popular over-the-counter cough medicine Robitussin DM. Avanir Pharmaceuticals Inc., of San Diego, has combined the drug with the enzyme inhibitor quinidine sulfate (which sustains DM levels in the body) to treat pseudobulbar affect in patients with amyotrophic lateral sclerosis and multiple sclerosis, and Phase III trials in the latter indication were finished in late June. (See BioWorld Today, July 1, 2004.)

NMDAs "work in different parts of the body and different parts of the brain," Grady noted, which makes predicting response that much more challenging.

AD "is a very attractive indication, in that none of the drugs work that well, so you don't have to do much to get use, and the patient population is huge, and it's only going to grow," she said.

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