The quest for medications beyond the five currently approved by the FDA is ongoing, rigorous, and intense. It appears to be a matter of time before new therapies are approved. These are just a few of the drugs now being studied:
Alzhemed
The plaques inside the brain of a person with Alzheimer’s are a complex mix of proteins, remnants of neurons, and a substance called beta amyloid, a soluble protein fragment cleaved from a larger protein called amyloid precursor protein. When these beta amyloid fragments bind together, they form the plaques that are a hallmark of Alzheimer’s.
Some studies suggest that beta amyloid may be the root cause of Alzheimer’s, a finding that has spurred some biotech and pharmaceutical companies to focus their energies on finding treatments that interfere with the buildup of beta amyloid. If successful, these medications would be the first disease-modifying drugs that could potentially stabilize the course of the disease and even halt its progression.
In the summer of 2004, Neurochem Inc., the company that is testing Alzhemed, launched the phase III trial of Alzhemed, an ex-perimental drug that may interfere with the disease process in the early stages of Alzheimer’s.
Alzhemed works by binding to beta amyloid in the brain before plaques can form. It also helps to remove beta amyloid from the brain and blocks the inflammatory process associated with amyloid buildup in the disease process. Earlier studies found that patients who received the highest closes of Alzhemed were able to sustain, even improve, their scores on cognitive tests, while those who received a placebo experienced a decline. Studies so far have also found that the drug is safe and well-tolerated.
Leuprolide
As a hormone medication, leuprolide is prescribed to men who have prostate cancer, and women who have endometriosis or uterine fibroids. Leuprolide belongs to a class of drugs known as gonadotropin-releasing (LH-RH) hormone analogs. These drugs work by stopping the production of testosterone in men and estrogen in females, hormones that stimulate the growth of diseased cells involved in prostate cancer and endometriosis.
Scientists at Voyager Pharmaceuticals are wondering whether leuprolide may also help slow the progress of Alzheimer’s andimprove the cognitive function of people with Alzheimer’s Disease. People who have Alzheimer’s have elevated levels of hormones known as gonadotropins, hormones that some experts believe are linked to the breakdown of neuron function.
Studies are now underway to examine the effect of leuprolide on men with mild to moderate Alzheimer’s disease and whether it can improve cognitive function and slow the disease.
Ampalex
Glutamate is an amino acid and chemical messenger released by brain cells that acts to excite other cells. It plays a pivotal role in information processing, storage, and memory. To do that, glutamate attaches to special receptor cells called AMPA (alpha-amino-2, 3-dihydro-5 methyl 3-oxo-4-isoxazolepropanoic acid) receptors. In people who have Alzheimer’s, the brain cells that release glutamate are damaged, so that levels of glutamate are excessive or deficient. Inadequate amounts of glutamate has a negative impact on learning and memory.
Ampalex acts to compensate for that deficit by enhancing the ability of AMPA receptors to attach to glutamate. Early studies have found that Ampalex, also called CX516, enhanced learning and memory in healthy young and elderly adults. Studies are now underway to see whether Ampalex, or CX516, can improve the symptoms of Alzheimer’s and be safely tolerated.
Neramexane
Another experimental drug that acts on glutamate is neramexane, an N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptor antagonists work by regulating the activity of glutamate, which is involved in information processing, storage, and retrieval. Glutamate triggers NMDA receptors to allow a controlled amount of calcium to flow into a nerve cell, creating the chemical environment required for information storage. Too much glutamate overstimulates NMDA receptors to allow too much calcium into nerve cells, which destroys and kills the nerve cells. Neramexane may guard against excess glutamate by partially blocking NMDA receptors.
If approved, neramexane would join memantine (Namenda) as the second drug in this category approved for the treatment of Alzheimer’s.
SGS742
GABA, which stands for gamma-aminobutyric acid, is a chemical messenger in the brain that relays information back and forth from the sensory organs such as the eyes back to the brain. Scientists have found that not enough GABA can lead to the cognitive decline associated with Alzheimer’s.
Saegis Pharmaceuticals is currently testing a drug known as SGS742, a GABA receptor antagonist that binds to the receptors of GABA, which would then keep more GABA in the brain. Earlier clinical trials have shown that the drug improves attention and memory. SGS742 has also been found to improve learning in mice, rats, primates, and humans.
AN ANTI-EPILEPTIC DRUG FOR ALZHEIMER’S
For years, doctors have prescribed an anticonvulsant medication called Valproate for the treatment of seizures in epilepsy. The drug has also been used to treat the manic phase of bipolar disorder and to help prevent migraine headaches. Now, scientists are wondering if Valproate may lessen symptoms of agitation in Alzheimer’s and slow the cognitive decline associated with the disease.
The National Institutes of Health has launched a $10 million multi-center study to answer that question. The study will also examine whether Valproate can improve memory and daily functioning and provide protective benefits of neurological functioning. Unlike most experimental treatments that are focused on beta amyloid, this study will examine a drug’s potential to block neurofibrillary tangles, the other hallmark of Alzheimer’s, which are created by chemical changes in a protein called tau. Early studies show that the drug may work by interfering with molecular events that lead to the progression of Alzheimer’s.
PREVENTING PLAQUE FORMATION
Rather than wait for the plaques to form and to then work on reducing them, some companies are aiming to prevent their formation at all. Researchers believe that by inhibiting certain enzymes involved in plaque formation, Alzheimer’s disease could be effectively blocked. The two enzymes under scrutiny are gamma secretase and beta secretase, which is also called BACE1. Beta-secretase and gamma-secretase are responsible for cleaving amyloid precursor protein (APP), which leads to the production of beta amyloid. Scientists believe that inhibiting these enzymes might reduce the amount of beta amyloid in the brains of people with Alzheimer’s, which might then slow the progression of the disease. But these enzymes are also involved in other bodily processes, which could cause complications.
CAN NSAIDS STOP THE DECLINE?
Ever since the discovery of indomethacin in 1956, doctors and patients alike have turned to non-steroidal anti-inflammatory drugs for the relief of pain and swelling, and the reduction of fever. In fact, today, more than 20 million Americans regularly use an NSAID.
In recent years, scientists have begun to question whether NSAIDs may have a role in the treatment and prevention of Alzheimer’s. Long-term population studies have suggested that people who take NSAIDs for arthritis are at reduced risk for developing Alzheimer’s. Of particular interest is a drug called flurbiprofen (Flurizan), which was derived from a different formulation of a drug called Ansaid. As one of the weaker NSAIDs, Ansaid has been used to treat arthritis.
In January 2005, Myriad Genetics announced plans to begin a phase III clinical trial, nine months ahead of schedule. The trial, which will be conducted on about 750 patients with mild to moderate Alzheimer’s, will determine whether Flurizan can alter the course of the disease and slow the cognitive decline. Participants will be randomly assigned to receive 400 or 800 milligrams of Flurizan twice daily or a placebo. In earlier studies, Flurizan was found to reduce beta amyloid, the protein fragments believed to be the culprit behind the devastating plaques that damage the brain in Alzheimer’s.
According to the Alzheimer’s Association, several research questions still need to be addressed regarding the use of NSAIDs. What mechanisms of NSAIDs are relevant to Alzheimer’s Disease? Which of the currendy approved NSAIDS merit further research? Do some NSAIDS help prevent dementia? Can some NSAIDs treat dementia? Is inflammation in the brain an appropriate target for the treatment or prevention of Alzheimer’s? And, are new drugs needed for targeting inflammation?