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PsychopharmacologyFull Access

Despite Setbacks, Search for Alzheimer’s Therapy Moves Forward

Abstract

The hope for anti-amyloid treatment now rests on aducanumab in long-term early Alzheimer’s studies, while anti-tau and other novel treatments face challenges to prove efficacy in patients.

Treatment targeting amyloid beta—a protein that has long been assumed to cause Alzheimer’s disease (AD) through its accumulation in the brain—remains a major focus of research on potential pharmacological treatments, but drug candidates aimed at alternative pathways are catching up in development. The list below describes some of the AD drugs in development you may hear more about in the coming year.

Breaking Up Amyloid Beta

After the disappointment of failed trials of the anti-amyloid drugs bapineuzumab and solanezumab, aducanumab gave a boost to the flagging amyloid theory. In a three-year extension of a phase 1 study, aducanumab reduced amyloid plaques in the brain in 143 patients with prodromal or mild AD, Biogen announced in August 2017. This effect was measured by positron emission tomography (PET) and appeared to be dose dependent.

Photo: scientists in laboratory
iStock/Skynesher

Other anti-amyloid drugs in phase 3 development include gantenerumab and crenezumab. These medications are monoclonal antibodies designed to bind to amyloid beta, which in turn prevents amyloid aggregation and promotes its clearance in the brain.

Solanezumab and gantenerumab are currently being tested in a large trial of people genetically predisposed to develop AD. In addition, gantenerumab and crenezumab are each in two ongoing phase 3 studies in patients with mild and prodromal AD. BAN2401, another anti-amyloid monoclonal antibody, failed to meet the primary endpoint after 18 months of treatment in a phase 2 study, according to a Biogen announcement in December 2017. The study enrolled more than 800 early AD patients. Full analyses, which may reveal whether the drug is worth additional exploration in a subgroup of patients, are expected later this year.

Several drug candidates take a slightly different approach to preventing amyloid plaque. One of these approaches is to block the enzyme known as beta-secretase (BACE), which cleaves the precursor protein that produces amyloid beta. A phase 2/3 study of verubecestat, an BACE inhibitor, was terminated by Merck in February 2017 because of the lack of efficacy, but drugs with similar mechanisms, including JNJ-54861911, elenbecestat, lanabecestat, and CNP520 are still in late-stage clinical development. Unlike the injected anti-amyloid monoclonal antibodies, BACE inhibitors are oral drugs.

A third approach to removing amyloid beta is vaccination. CAD106 is a vaccine that induces the body’s immune system to generate antibodies against amyloid beta. It is being tested in a phase 2/3 study in people who are genetically predisposed to develop AD.

As more results emerge from these immunotherapy studies, the question of whether anti–amyloid-beta treatment is a valid approach to AD may finally become clear.

Interest in Tau, Other Pathways Grows

Drug development that targets the aggregation of tau tangles, a protein fragment also associated with AD, are currently lagging anti-amyloid research, but the interest is growing. Two anti-tau monoclonal antibodies— ABBV-8E12 and BIIB092—were moved into phase 2 clinical trials during 2017. RO7105705 is an anti-tau antibody being tested in a phase 1 study. Other anti-tau therapies are moving from animal to human testing.

Among other classes of drugs, azeliragon is a small molecule that inhibits the receptor for advanced glycation end products (RAGE) that may interfere with inflammation and amyloid transportation into the brain. The company vTv Therapeutics is conducting a phase 3 trial of the drug in mild AD that will produce preliminary results in early 2018. Lumateperone is a molecule that hits several types of serotonin, dopamine, and glutamate receptors. It is being developed for the treatment of agitation in AD and other dementia, as well as schizophrenia.

Other novel pathways look promising but have not moved into human testing, including strategies that try to fix dysfunctions in mitochondria (produce energy for cells), endocytosis (transportation of molecules in and out of cells), and autophagy (self-cleaning process inside cells).

Failures Continue

Even as new drug candidates are tested in people, failures continue to be the norm in AD trials, including the anti-tau drugs LMTM and abeotaxane, the neurotrophic drug edonerpic, and ketone-producing tricaprillin (AC-1204). Two serotonin 5HT6 receptor antagonists, which researchers hoped might work synergistically with current cholinesterase inhibitors commonly prescribed to treat Alzheimer’s, also failed in 2017. Intepirdine did not meet efficacy endpoints as an adjunct to donepezil, as announced in October, while idalopirdine did not decrease cognitive decline in over 2,500 patients.

As a result of these and other failed trails, phase 3 AD trials are increasingly focused on preventing or delaying disease onset, rather than treatment, in people who have not developed AD or have only mild symptoms. Some experts believe that previous anti-amyloid treatments failed in clinical trial because the intervention came too late and patients with moderate to severe symptoms have too much amyloid plaque buildup in the brain. The challenge of prevention studies is the long duration of treatment before a convincing difference in AD occurrence can be detected between people on active drugs and on placebo. For example, CAD106and CNP520 are being tested against placebo in a study known as Generation S1, which began in 2015 and is expected to end in 2024. Participants will receive the experimental treatment for five years.

In parallel with these trials, new tools are being developed to sharpen the picture of a brain with AD. Many recent trials rely on cutting-edge biomarkers, either from PET imaging or molecules in cerebral spinal fluid, to find participants who have prodromal AD—since they have no apparent symptoms of the disorder. These biomarkers can also help diagnose AD early and measure disease progress with unprecedented accuracy. Refinement in genetic analysis may clarify different pathological processes in subgroups of AD patients and lead to more targeted treatment. ■