Patients suffering from a seemingly hopeless affliction, and those around them, might gain a glimmer of hope on news of the FDA's approval of Namenda (memantine HCL) for Alzheimer's disease.
While four other drugs already are marketed for the steadily progressive neurological condition, Namenda is the first to receive approval to treat the moderate to severe stages of the disease. The others are indicated for mild to moderate Alzheimer's disease.
Forest Laboratories Inc., which will market the product in the U.S., and development partner Neurobiological Technologies Inc. (NTI) expect to make it available by January.
"The real winners are the patients, as all the existing drugs are in the same category," NTI President and CEO Paul Freiman told BioWorld Today, adding that the mild to moderate indication represents about 20 percent of the entire Alzheimer's population. "So 80 percent of patients are now in the category that our drug is approved in, which is not to say that the others are not used in moderate to severe Alzheimer's. But our drug has a totally different mechanism of action."
Namenda, an antagonist of the N-methyl-D-aspartate receptor, works by blocking abnormal effects of glutamate. The four previously approved drugs - Pfizer Inc.'s Aricept, Novartis AG's Exelon, First Horizon Pharmaceutical Corp.'s Cognex and Shire Pharmaceuticals Group plc's Reminyl - work by preventing the breakdown of acetylcholine. Both acetylcholine and glutamate play a role in learning and memory.
"I think there is an exciting future for Alzheimer's patients, with the caveat that this is not a cure," Freiman said. "Once a patient is diagnosed, they're on a slippery slope. But this elevates the angle of the slope, so that life and quality of life can be prolonged. In my mind, it's yet another step on the road to finding a cure, but we're sure not there yet."
Richmond, Calif.-based NTI and Forest received a unanimous FDA panel recommendation in favor of the drug last month. The Peripheral and Central Nervous System Drugs Advisory Committee based their decision on Namenda's safety and efficacy profile culled from data from two Phase III trials. (See BioWorld Today, Sept. 26, 2003.)
The data included a seven-month, 252-patient monotherapy study published earlier this year in the New England Journal of Medicine and a six-month, 401-patient study of Namenda when used with Aricept. In both trials, Namenda patients scored higher on measures of cognition, daily function and/or global performance.
"It improves quality-of-life measurements of basic things like getting dressed, using the toilet or eating," Freiman said. "That's the practical aspect. The scientific aspect is that on batteries of neurological tests improvement is shown."
Once available in pharmacies, Namenda will be administered orally at a recommended twice-daily dose of 10 mg following a four-week titration.
NTI will receive a 1 percent royalty on Namenda's U.S. sales, a task that falls to New York-based Forest, which must manufacture and package the product in advance of getting it out to the public. Freiman said many early sales estimates range between $500 million and $750 million, though he expects peak sales to reach $1 billion.
Late last year, Forest filed a new drug application that amended an initial application submitted in July 2002 but withdrawn two months later. (See BioWorld Today, Dec. 23, 2002.)
The drug has a long history in the U.S. and Europe, where it has been sold since the early 1980s. A privately held German firm, Merz Pharmaceuticals GmbH, synthesized and developed the compound in the 1970s and eventually began marketing it for Parkinson's disease as a dopamine agonist. Frankfurt-based Merz later began studying its use in Alzheimer's patients.
Merz received European Union approval of Namenda for Alzheimer's last year, triggering a $1.4 million payment to NTI. Copenhagen, Denmark-based H. Lundbeck A/S exclusively markets the product for Alzheimer's disease throughout most of Europe, while Merz co-markets it in German-speaking countries.
NTI is due a $2.8 million milestone payment from Merz following FDA approval. Their relationship dates to 1998 through a complex arrangement Freiman jokingly said would take an hour to fully explain.
In the U.S., NTI licensed Namenda's use patents for diabetic neuropathy, age-related dementia and Huntington's disease from Children's Hospital at Harvard University, which in the mid-1990s had taken a use patent on the compound in such indications. Merz's original patent had expired at that point.
NTI later fell into financial trouble, at which time Merz made a financial investment in NTI. In exchange, NTI returned its licensing rights to the hospital, which returned the rights to Merz. In the end, after the tripartite deal was ultimately established, NTI retained its single-digit royalty stake.
Merz eventually entered a direct marketing agreement with Forest, which shouldered the cost of the late-stage Alzheimer's trials. Any royalties NTI will receive will flow first from Forest to Merz, then to NTI.
A Forest-sponsored pivotal trial studying the drug's ability to treat neuropathic pain in diabetic patients failed earlier this year, though. The drug did not demonstrate a significant difference vs. placebo relative to the trial's primary endpoints. (See BioWorld Today, May 8, 2003.)
Freiman said Forest continues to debate whether to continue that program. Should the compound receive FDA approval in that indication, he said NTI stands to receive a 13 percent royalty.
Outside of Namenda, NTI's pipeline includes one other late-stage product - xerecept, for which it owns full rights. The peptide has received the FDA's orphan drug designation for peritumoral brain edema. The agency also has authorized protocols for two Phase III trials that NTI expects to begin by the end of the year, Freiman said.
"If everything went well, by 2006 we could have the product on the market," he said. "We have nothing early stage, and we're looking at potentially bringing into the company other [central nervous system] products that are at a medium to later stage as well."
NTI's stock (NASDAQ:NTII) fell 29 cents to close at $6.25. Forest's shares (NYSE:FRX) climbed 46 cents to close at $49.92.