Who Will be First With the Next New Alzheimers Treatment?

The race is on as big companies compete for the multi-billion dollar market for effective Alzheimers treatments!

The good news is that there are new drugs for the treatment of Alzheimer's in the pipeline, and big companies are racing frantically to get theirs out first!  There are two leading candidates, Flurizan by Myriad Genetics and Alzhemed by Neurochem. Right behind them is the entry of Ireland-based Elan Pharmaceuticals.  The first two of these contenders are pushing variants of a new class of drug candidates known as Selective Amyloid beta-42 Lowering Agents (SALAs).  Elan is pursuing stopping the disease through humanized monoclonal antibodies.  The best part is that both SALAs and vaccine/antibody approaches are aimed at treating probable causes and have shown promise in early trials.  All the currently approved and available Alzheimer's drugs treat the symptoms, not the causes.

Amyloid beta-42 (Abeta42) is the primary constituent of senile plaque that accumulates in the brain of patients with Alzheimer's disease.  It is suspected by many to be the key initiator of Alzheimer's disease.  This is because Abeta42 has the greatest tendency to aggregate, cause neuronal damage and initiate amyloid deposits in the brain. Most genetic mutations that cause early-onset Alzheimer's disease appear to do so by increasing production of Abeta42.  The idea behind SALAs is to attack and remove one of the primary root causes of Alheimer's disease by lowering the concentrations of Abeta42 in patients.

Let's look over the apparent leaders in this race:

Flurizan

Flurizan is described by its developer as the first in the new class of drug candidates known as Selective Amyloid beta-42 Lowering Agents (SALAs).  In early tests, Flurizan lowered levels of Abeta42 in cellular assays and animal models.  Now, after 21 months of clinical trials, the data show that study participants on 800 mg BID of Flurizan continued to demonstrate increasing benefit through month 21 in the area of cognition and memory loss and that they maintained more of their global function and activities of daily living than those on 400 mg BID of Flurizan or than the projected placebo. 

The Phase 2 study showed that the drug had apparently halted further decline in test subjects.  Its success prompted what AP called the "...largest-ever Alzheimer's drug trial", involving 1,800 people with mild to moderate cases of Alzheimer's disease.

Results of the Phase 2 study and a summary of the 9-months of follow-on data were presented at the 19th annual meeting of the American Association of Geriatric Psychiatry by Daniel Christensen, M.D., Clinical Professor of Psychiatry, Clinical Professor of Neurology and Adjunct Professor of Pharmacology at the University Neuropsychiatric Institute, Salt Lake City, Utah.

Flurizan is being developed by Myriad Genetics, Inc. http://www.myriad.com/, a biopharmaceutical company focused on the development and marketing of novel healthcare products. The Company, located in Salt Lake City, Utah, initially purchased commercial rights to Flurizan from its creators at Loma Linda University, near San Bernardino, because of its promise for fighting cancer. But it soon became clear in experiments with mice that the drug was also effective for Alzheimer's as Myriad scientists made key tweaks to the drugs. 

On June 29, 2005, Myriad Genetics, Inc. , announced the issuance of Patent No. 6,911,466 entitled, "AB42 Lowering Agents". Myriad holds exclusive rights to the patent under a licensing agreement with Mayo Clinic. The patent covers methods of using a broad class of compounds known as selective amyloid beta 42 lowering agents (SALAs) to lower levels of the toxic peptide.  Apparently there are various strategyms, agents and approaches for lowering Abeta42 which require sorting and testing.

Based on the positive Phase 2 results, Myriad is enrolling patients with mild Alzheimer's disease for a Phase 3 trial, at 130 centers across the United States.  Information on participation is available by calling (888) 459-4888.

Flurizan is currently in two phase 3 trials, including the U.S. trial that is expected to complete enrollment this summer and a European trial that just started.  The trials will involve over 3,000 patients in total.

Alzhemed

Tramiprosate (Alzhemed(TM)) is a small, orally-administered molecule known as an amyloid (B) antagonist that crosses the blood-brain-barrier, binds to soluble A(B) peptide and interferes with the amyloid cascade, inhibits A(B) protein deposition in the brain and provides protection against A(B)-induced neurotoxicity.  Alzhemed is being developed by Neurochem, Inc.  http://www.neurochem.com/

The Phase II clinical trial for Alzhemed, involving mild-to-moderate AD patients, continues to show clinically significant benefits on cognitive and global performance measures, with stabilization of the disease in a proportion of patients with mild cases of Alzheimer's (four out of nine) after three years of treatment. (April 24, 2006)

In addition to the capability of Alzhemed to bind to soluble amyloid (B) (A(B)) peptide and interfere with the amyloid cascade, data from in vitro studies have shown that Alzhemed has a protective effect on neuronal cells against A(B) peptide-induced toxicity and cell death. Tramiprosate (Alzhemed(TM)) decreases A(B)42-induced cell death and DNA damage in neuronal cell cultures by 38%.

There are two Phase III trials underway.  In the U.S. an 18-month Phase III clinical trial involving 1,052 mild-to-moderate AD patients, is being carried out at close to 70 clinical sites across the United States and Canada. To date, (April, 2006) more than 50 patients have completed the trial and more than 500 patients have completed 12 months on study medication. The trial is now scheduled to be completed by January 2007. 

The ongoing European Phase III clinical trial, a multi-center, international, randomized, double-blind, placebo-controlled and parallel designed study, to investigate the safety and efficacy of tramiprosate (Alzhemed(TM)) in some 930 mild-to-moderate AD patients, is progressing on schedule.  Enrollment is brisk with more than 230 patients already enrolled in the clinical trial and enrollment expected to be completed in the fall of 2006.

Then there is the Vaccine/antibodies approach--

Another strategy for combating Alzheimer's is to clear the brain of toxic assemblies of A-beta after the peptide is produced. One approach is active immunization, which involves recruiting the patient's own immune system to attack A-beta. In 1999 Dale B. Schenk and his colleagues at Elan Corporation in South San Francisco made a groundbreaking discovery: injecting A-beta into mice genetically engineered to develop amyloid plaques stimulated an immune response that prevented the plaques from forming in the brains of young mice and cleared plaques already present in older mice. The mice produced antibodies that recognized A-beta, and these antibodies apparently prompted the brain's immune cells--the microglia--to attack aggregates of the peptide. The positive results in mice, which included improvements in learning and memory, quickly led to human trials.

Unfortunately, although the injection of A-beta passed initial safety trials, several patients in the phase II tests developed encephalitis--inflammation of the brain--forcing a premature halt to the study in 2002. Follow-up research indicated that the therapy might have caused the inflammation by prompting the T cells of the immune system to make over-aggressive attacks on the A-beta deposits. Nevertheless, the investigation confirmed that many patients produced antibodies against A-beta and that those who did showed subtle signs of improved memory and concentration.

The safety concerns about active immunization led some researchers to try passive immunization, which aims to clear the peptide by injecting antibodies into patients. These antibodies, produced in mouse cells and genetically engineered to prevent rejection in humans, would not be likely to cause encephalitis, because they should not trigger a harmful T cell response in the brain. A passive immunization treatment developed by Elan Corporation using such humanized monoclonal antibodies has already advanced to phase II clinical trials, involving 180 patients.

Elan Pharmaceuticals, Inc. is a wholly-owned subsidiary of Elan Corporation, plc . Elan is a neuroscience-based biotechnology company.  As of July 26, 2005 their research programs included four approaches to modifying or halting the progression of Alzheimer's disease.  Two of these programs are in collaboration with Wyeth, focused on immunologic approaches to treating the disease. One of the programs that focuses on halting the progression of the disease through humanized monoclonal antibodies is the one now in Phase II clinical trials.

In Summary:

From the point of view of those of us who are at higher risk for Alzheimer's, this is all good news!  To have big companies competing to be first with Alzheimer's treatments that treat the causes is a very welcome development.  We ALL win if any of the competing products turns out to be effective and manages to pass through the hoops necessary for final approval and use.

The fallout from all the testing cannot help but be useful in further identifying what works and what doesn't.  Also, if ways are developed to lower concentrations of Abeta42 in Alzheimer's patients, the same methods are very likely to work as a prevention for pre-Alzheimer's candidates who have begun growing plaques.  That means that people like us, who don't want to wait until we have noticeable loss of mental function before acting, could use it to reduce cerebral plaques before they do damage!!

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