Borrowing from the cancer playbook to find treatment for Alzheimer's disease

It's been notoriously difficult to develop medicines for ...

Posted: Aug 2, 2018 6:38 AM
Updated: Aug 2, 2018 6:38 AM

It's been notoriously difficult to develop medicines for Alzheimer's disease, the sixth leading cause of death in the United States. Each year, it seems, pharmaceutical companies release data from studies of promising drug candidates that merit only a collective sigh of disappointment.

In search of fresh ideas, researchers have begun to borrow a phrase or two from the more familiar language of cancer treatment.

Alzheimer's disease

Behavior and cognition

Biochemistry

Brain science

Business and industry sectors

Business, economy and trade

Cancer

Chronic diseases

Diseases and disorders

Genes and chromosomes

Genetic biochemistry

Genetics

Health and medical

Intelligence and cognition

Medical fields and specialties

Medical treatments and procedures

Neurological disorders and injuries

Neurology and neuroscience

Personalized medicine

Pharmaceutical industry

Pharmaceuticals and biotechnology

Pharmaceuticals and prescription drugs

Science

Continents and regions

North America

The Americas

United States

Misconduct

Plagiarism

Society

Drug safety, efficacy and availability

Experimental drugs

Some scientists are studying precision medicine, or personalized medicine, which is routinely used to treat breast and colon cancers. Other researchers are focusing on immunotherapy, an effective form of medicine for skin, lung, kidney, bladder and other cancers.

This translation of the cancer-fighting vocabulary to Alzheimer's disease, though, is not always simple.

Adapting precision medicine

"In precision medicine, in order to apply the most effective treatment possible, doctors select treatments based on the patient's genetic profile," explained Dr. Christiane Reitz, assistant professor of neurology and epidemiology at the Columbia University Department of Neurology.

The first step when applying precision medicine to Alzheimer's disease is to learn "as many of the genetic variants as possible" that cause this common form of dementia, said Reitz, whose research focuses on identifying both genetic and non-genetic factors that contribute to changes in the brain.

"There are diseases that are caused by only one gene or very few genes," she said. Huntington's disease, a classic example, is caused by a single gene mutation: If you have the mutation, you will develop the disease.

Late-onset Alzheimer's, though, is nothing like Huntington's or even most diseases.

"There are likely more than a hundred genes involved in Alzheimer's," Reitz said. "We know some of them but not all. We need to identify the remaining ones."

In a recently published study, Reitz noted that scientists have mapped "27 susceptibility loci" for Alzheimer's disease: regions on the chromosome that are most likely to mutate and thereby contribute to the risk of that disease.

Since there may also be a variety of causes of Alzheimer's, scientists hope that they will be able to identify the specific cause of a patient's disease by sequencing his or her genetic profile, Reitz explained. "Then, the most effective treatment for that patient can be determined and applied."

Such is the case with one experimental drug presented last week at the 2018 Alzheimer's Association International Conference in Chicago.

Restoring 'cellular balance'

Dr. Harald Hampel, a professor at Sorbonne University in Paris, explained that the experimental drug, Anavex 2-73, a precision medicine candidate from specialty pharmaceutical company Anavex Life Sciences Corp., activates the Sigma-1 receptor.

A worthy target for precision medicine, the Sigma-1 receptor "is involved in several important pathways related to Alzheimer's disease," Hampel said. It reduces beta amyloid (the signature plaque deposits seen in the brains of deceased Alzheimer's patients) and hyperphosphorylated tau (the signature protein tangles also seen in patients' brains), he said. It also lessens oxidative stress and inflammation in the brain, both of which have been linked to aging and age-related diseases.

The advantage of targeting the Sigma-1 receptor is that it "activates the body's own defense mechanism to restore cellular balance," Hampel said.

In their study presented at the Alzheimer's conference, Hampel and his colleagues researched the drug's effect in 32 mild-to-moderate Alzheimer's disease patients. The study showed that "patients improved both cognition and activities of daily living" after taking the drug for 57 weeks.

"Some also experienced positive effects on insomnia, a common problem among Alzheimer patients, and improved sleep," Hampel said.

Beneficial effects, however, varied among patients based on their individual genetic profiles.

"We were able to identify certain genetic variations for certain patients that explain their improved response," Hampel said. Specific genetic features, shared by about 80% of the study participants, correlated with a strong, "clinically meaningful" response to the medicine, he said.

" 'Clinically meaningful' means that the improvements are noticeable for the patient and the people around the patient," Hampel said. Participants with the conducive genetic profile also showed improved scores on gold-standard tests of cognition and activities of daily living, the study presentation indicated.

Though only 32 Alzheimer's patients participated in the study, Hampel feels confident of the results.

"Genetic patient data is more precise, and therefore not many patients are required. Examples are genetic studies in oncology, where even smaller studies are performed," he said. The next step, which has already begun, is a larger safety study of the drug in 450 participants with Alzheimer's.

Ultimately, Hampel said, he and his co-authors follow the concept of precision medicine, which means "to treat the right patient with the right drug at the right time."

"Alzheimer's disease is a complex disease," he said. "The newest weapon in the fight against Alzheimer's disease might be your own body."

Lundbeck, a global pharmaceutical company focused on psychiatric and neurological disorders, also subscribes to this philosophy as it works to develop an immunotherapy for Alzheimer's patients.

Unleashing the body's natural response

It might be natural to think of the body's immune system as a guard dog, eager to attack any incoming pathogens. However, the immune system is less a dog and more a dance, an interaction of blood cells, chemicals and proteins -- a collaboration that is highly intelligent and carefully calibrated at once. Among the various proteins within the system are those known as "checkpoint proteins."

"There's a PD 1 checkpoint protein on an immune cell and a similar checkpoint protein, called PDL 1, on a normal cell," explained Dr. Doug Williamson, chief medical officer and vice president of US medical for Lundbeck. "This 'handshake' tells the immune system not to attack."

When it comes to cancer, these checkpoint proteins fail to do their job due to the fact that some tumors also produce PDL 1. By this simple act of identity theft, tumor cells can masquerade as normal cells and thwart the immune system.

Immune checkpoint inhibitors, then, are one type of cancer drug that is often made of antibodies able to trigger an immune response and which can turn off the ability of cancer cells to masquerade as normal.

Williamson and his colleagues at Lundbeck are developing a potential immune checkpoint inhibitor for Alzheimer's disease.

The theory behind the experimental immunotherapy drug is, why isn't the body attacking the toxic proteins, "recognizing them as foreign and toxic and eliminating them the way that it usually does?" Williamson said.

This immunotherapy, an antibody, could make the toxic proteins visible to the immune system, which could then destroy them and prevent them from causing cell death in the brain.

Though the drug has not been tested in humans, animal study data suggest that when antibodies bind to checkpoint inhibitors, they appear to reduce deposits of plaque in the brain, Williamson said. He added that "there's a lot of development work to go" before a safe and effective drug can be developed.

"I can't give you a specific timetable, but we're looking at six to 10 years before this treatment might become available," he said.

Clearing an FDA hurdle

Overall, he said, there is some good news yet also "a host" of challenges to develop effective and safe drugs for the treatment of Alzheimer's disease.

First among the difficulties is getting a drug across the blood-brain barrier, the membrane that surrounds the intellectual organ with the purpose of stopping that from happening, he said. Another challenge is monitoring what's happening inside the brain.

"Increasingly, there are imaging technologies that allow you to look at deposited amyloid plaque and even deposited tau in the brain," Williamson said. These deposits of amyloid plaque and tau tangles are considered "biomarkers" of Alzheimer's disease.

A past study as well as the new results for an experimental drug jointly produced by Eisai Co. Ltd. and Biogen Inc. have shown that certain treatments can reduce the buildup of plaque in the brain. But what has not been demonstrated to the satisfaction of the US Food and Drug Administration is an association between a reduction in the plaque biomarker (as seen on a scan) and positive changes in the mental functioning of patients, Williamson said.

The good news is that once a link has been established between changes in biomarkers and a beneficial change in a patient's cognitive abilities, the FDA has indicated it will no longer require drug developers to prove that each potential new drug can modify Alzheimer's disease, Williamson said.

Once a firm connection is established, drug developers will need only to show their candidate drugs affect the biomarkers.

"An analogy to this would be cholesterol-lowering drugs and heart disease," Williamson said. Once the link between lowering cholesterol and heart disease was established, scientists no longer needed to conduct thousands of patient studies to show that a drug reduced heart disease. "You just needed to show you could reduce cholesterol."

One final challenge when developing Alzheimer's drugs is recruiting patients.

Since none of the available treatments can slow or stop the progress of Alzheimer's, a lot of people don't really want to know whether they're going to develop it, Williamson said. Meanwhile, past studies have failed because the participants were in the later stages of the disease.

"If you wait until people have got significant cognitive problems, then the damage is already done," Williamson said. "I personally think it's going to get better once we have an effective treatment."

Mississippi Coronavirus Cases

Data is updated nightly.

Cases: 468498

Reported Deaths: 9100
CountyCasesDeaths
Harrison31907468
Hinds30552569
DeSoto29532342
Jackson22868335
Rankin21016355
Lee14393214
Madison13961263
Jones13053215
Forrest12879231
Lauderdale11244292
Lowndes10148171
Lamar9972122
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Hancock7110107
Oktibbeha6764117
Washington6756146
Neshoba6350200
Monroe6304156
Warren6267159
Panola6036122
Pontotoc599292
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Marshall5917115
Union558885
Pike5424133
Lincoln5192127
Alcorn509388
George454766
Scott447392
Leflore4377138
Tippah431780
Itawamba429192
Prentiss429074
Copiah423883
Simpson4238108
Wayne419663
Tate418999
Adams4174109
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Covington404891
Marion399699
Leake389784
Coahoma385996
Newton360273
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Stone342657
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Attala318285
Jasper308261
Winston298191
Clay282672
Chickasaw277464
Clarke271784
Holmes257685
Calhoun256939
Smith241546
Yalobusha215447
Tallahatchie213849
Walthall203457
Lawrence202431
Greene202045
Perry195053
Amite191251
Webster191141
Noxubee173437
Montgomery168652
Jefferson Davis164041
Carroll158936
Tunica146533
Benton137531
Kemper136538
Claiborne124134
Choctaw123824
Humphreys122036
Franklin114127
Quitman100925
Wilkinson98335
Jefferson85832
Sharkey61620
Issaquena1916
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Alabama Coronavirus Cases

Cases: 757893

Reported Deaths: 12784
CountyCasesDeaths
Jefferson1082301712
Mobile694251158
Madison47738562
Baldwin35347420
Shelby34758281
Tuscaloosa32576495
Montgomery32249645
Lee21576200
Calhoun19621363
Morgan19061307
Etowah18363413
Marshall17028252
Houston15881337
St. Clair14724270
Limestone13908178
Elmore13812239
Cullman13756228
Lauderdale12909263
Talladega12124200
DeKalb11705220
Walker10047303
Autauga9371119
Blount9272146
Jackson8970132
Coffee8550150
Colbert8229160
Dale8162142
Escambia632298
Tallapoosa6255165
Covington6214153
Chilton6152128
Russell586753
Franklin558292
Chambers5155127
Dallas4569173
Marion4490114
Clarke447070
Pike439188
Geneva415999
Lawrence4002101
Winston399982
Bibb388975
Barbour334667
Marengo317778
Monroe306844
Butler305878
Pickens296166
Henry288550
Randolph288255
Hale282981
Cherokee275649
Fayette268569
Washington241844
Crenshaw226962
Clay219260
Macon211154
Cleburne205746
Lamar184638
Conecuh173337
Lowndes167856
Coosa160031
Wilcox153033
Bullock145642
Perry132430
Sumter122635
Greene117941
Choctaw71925
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