Disease-modifying drugs for Alzheimer’s: Hope or hype?

(This article was first printed in the October 2007 issue of the Harvard Mental Health Letter.)

In many ways, Alzheimer’s disease is the biological equivalent of a slow-motion train wreck. Studies have revealed that the two hallmark brain lesions in Alzheimer’s — amyloid deposits and neurofibrillary tangles — appear decades before telltale symptoms such as memory impairment. (Indeed, an active area of both genetic and neuroimaging research is the identification of preclinical signs of Alzheimer’s in the brain, raising the hope of reliable diagnosis for those most at risk.)

The fact that Alzheimer’s takes so long to develop suggests that it may be possible to design drugs that work early in the disease process, perhaps to delay symptom onset and disability. For that reason, researchers have been testing a number of such “disease-modifying” drugs that target the earliest biological changes in Alzheimer’s.

None of the disease-modifying drugs in development will cure Alzheimer’s. But a number of them are in phase III clinical trials, the last stage before the FDA will consider approving the drugs for sale. Already the media hype has begun. In June 2007, for example, the AARP Bulletin trumpeted on its cover: “Finally, new drugs offer real hope for reversing the disease.”

Two experts advise more cautious optimism.

“On the one hand, I feel enormous excitement about the potential of these new drugs,” says Lennart Mucke, M.D., director of the Gladstone Institute of Neurological Disease in San Francisco, who has reviewed the research. “They’re in a whole new category from what we currently have available. They aim at the root cause of Alzheimer’s as we understand it, and that is reason for hope.”

But he also has concerns. “One question is whether these drugs will be effective enough to block this powerful disease and, at the same time, be safe enough to be taken for long periods of time.” The challenge is particularly daunting, he notes, because Alzheimer’s mainly affects the elderly, who may be taking medications for other chronic conditions. “A drug may be safe when given on its own, but if someone is taking multiple medications, you run the risk of a drug interaction.”

Daniel D. Christensen, M.D., professor of psychiatry, neurology, and pharmacology at the University of Utah Neuropsychiatric Institute, also sees reason for both hope and caution. The author of another review, he has served as a consultant to one of the drug companies involved in research on disease modifiers. “On the one hand, the basic science behind these drugs looks good, and there’s reason to believe that one if not several of them may succeed,” he says. “On the other hand, we won’t know for sure until a phase III trial confirms in people what we see in the lab.”

Seeking early targets

The five drugs currently FDA-approved for the treatment of Alzheimer’s — donepezil (Aricept), galantamine (Razadyne), memantine (Namenda), rivastigmine (Exelon), and tacrine (Cognex) — all target neurotransmitter deficits that occur relatively late in the disease process. They alleviate symptoms only modestly, and they do nothing significant to prevent disease progression.

The disease-modifying drugs in development target much earlier biological abnormalities, especially the sequence of events that contribute to the development of amyloid plaques (see table). Plaque formation begins when a brain protein, amyloid precursor protein (APP), is broken down into peptides by various enzymes, known as secretases. The plaques consist of several forms of beta-amyloid peptides, some relatively benign and others more toxic.

Usually the beta-amyloid peptide considered most toxic, Aβ42, makes up less than 5% of beta-amyloid load in the brain. But a combination of genetic and environmental factors may tip the balance toward greater Aβ42 production. According to a leading theory about Alzheimer’s, this sets in motion a cascade of biological events leading to buildup of toxic beta-amyloid plaque around neurons, which in turn triggers neurodegeneration in areas of the brain necessary for memory and thought.

The disease-modifying drugs in development work in different ways, but all seek either to decrease production of toxic beta-amyloid peptides or to prevent them from accumulating in the brain. The ultimate aim is to find whether — by blocking plaque — these drugs can delay cognitive or functional decline in people with Alzheimer’s.

Decreasing beta-amyloid production

One class of drugs seeks to reduce toxic beta-amyloid production by acting on particular enzymes that break down APP.

Gamma-secretase inhibitors. One compound for which a phase III clinical trial is planned is LY450139. Phase II studies of this compound investigating a range of drug doses in a small number of patients reported that this compound reduced levels of beta-amyloid in the blood in a dose-dependent manner. However, beta-amyloid levels did not decline in the cerebrospinal fluid that suffuses the nervous system, indicating that levels in the brain also may not have fallen. Further, no change was reported in participants’ cognitive functioning, although this may have been due to the short duration of the studies.

Some neuroscientists are also concerned that LY450139 is not a selective inhibitor of gamma-secretase, which breaks down not only APP but also other brain proteins. Research in mice and lower organisms has shown that such nonselective gamma-secretase inhibitors can cause problems in embryonic development and in the functioning of the immune system and the gastrointestinal system. Thus LY450139 and other nonselective agents might cause serious side effects that would counterbalance any benefit for people with Alzheimer’s.

Some researchers believe that more selective gamma-secretase inhibitors, in very early development, may prove to be better options as disease modifiers.

Selective Aβ42-lowering agents. These drugs specifically lower Aβ42 levels in the brain. The first drug in this class to reach late-stage testing is tarenflurbil (Flurizan), which is in phase III trials. The drug modulates gamma-secretase activity by shifting production away from Aβ42 without interfering with other proteins. Phase II studies in 207 people with mild to moderate Alzheimer’s suggested that those who took the higher of two doses of this medication showed slower decline in cognitive functioning and daily functioning. Results of the phase III trials should be available in 2008.

Preventing amyloid accumulation

Of course the problem is not just production of toxic beta-amyloid, but also the accumulation of these sticky peptides in amyloid plaques near neurons. Several drugs that prevent amyloid accumulation — either by increasing clearance of beta-amyloid or preventing aggregation of these peptides — are in development.

Vaccines. Experimental Alzheimer’s vaccines enlist the immune system to clear the brain of toxic beta-amyloid, but so far this approach has been perilous. Researchers halted clinical trials of a first-generation vaccine, AN-1792, after it caused a nonfatal brain inflammation in 6% of people who received immunizations.

Researchers are trying to develop a safer Alzheimer’s vaccine. The most promising strategy appears to be “passive” immunization, which involves injecting patients with ready-made antibodies to beta-amyloid. This way, researchers hope to avoid prodding a person’s immune system to produce cells that might attack healthy brain tissue, as happened in the case of AN-1792.

One such agent, bapineuzumab, is a monoclonal antibody that targets and clears beta-amyloid. Phase II studies under way involve more than 200 people with mild to moderate Alzheimer’s who are taking various doses of bapineuzumab. In Europe, 30 participants are also undergoing brain scans to determine whether the drug is clearing amyloid plaque deposits. A phase III study has been announced, but has not yet started.

Another passive immunization agent, intravenous immunoglobulin, is in phase II trials for Alzheimer’s. Because this substance is already FDA-approved to treat people with immune deficiencies, its safety profile is well known; whether it will be effective as a disease modifier in Alzheimer’s remains to be seen. Researchers are hopeful, however, because intravenous immunoglobulin has both anti-amyloid and anti-inflammatory properties that may be helpful in Alzheimer’s.

Anti-aggregation agent. Tramiprosate (Alzhemed) is a drug that prevents Aβ42 peptides from sticking together (one theory being that this is the stage at which they become particularly toxic). Although a phase II study generated optimism, researchers announced at the Alzheimer’s Association’s International Conference on Prevention of Dementia in June 2007 that results of a phase III study were hard to interpret. This has dampened expectations of success, although nothing has been published yet.

Looking ahead

	Click to enlarge		Harvard Mental Health Letter The Harvard Mental Health Letter is a unique resource that covers a wide range of mental health issues and concerns. It presents the latest thinking, treatment options, therapies and debate of interest to both mental health care professionals and the concerned public. Read more 12 monthly issues (Print+Electronic) $59.00 12 monthly issues (Electronic Only) $55.00