Why is immunotheraphy not being used as a tool in the war against Alzheimer's Disease?

Editor's note: Alexander Roberts is a longtime contributor to lohud.com, The Journal News and the USA TODAY Network. This is the first of a regular, monthly series of columns titled The Roberts Report.

Are drug companies delaying a potential cure for Alzheimer’s Disease?

The most powerful weapon against disease is not a drug. It is the body’s own immune system that constantly senses and neutralizes a huge variety of external and internal threats, from pathogens to abnormal cells. Dr. James Allison, together with Dr. Tasuku Honjo, received the 2018 Nobel Prize in Medicine for demonstrating that boosting the body’s systemic immune system could fight cancer. Their research launched an explosion of life-saving immunotherapies that can treat formerly incurable cancers.

Curiously, the immunotherapy revolution has bypassed age-related neurodegenerative diseases like Alzheimer’s. Critics blame two factors: the stubborn myth that the blood- brain barrier prevents the immune system from operating in the brain, and a 25-year preoccupation--some would say obsession--with an Alzheimer’s treatment that has yielded minimal results.

Challenging the immune system’s lack of brain access

The myth of the immune system’s lack of access to the brain was debunked 25 years ago by a professor of neuroimmunology and her team at the Weizmann Institute of Science in Israel. Professor Michal Schwartz felt it made no sense that the blood’s cell repair system would be off limits to one of its most critical organs. She successfully challenged the myth with seminal discoveries that immune cells are guardians of the brain, needed for life-long brain maintenance and repair. Schwartz is recognized as one of the world’s foremost neuroimmunologists, receiving the Israel Prize, that nation’s highest honor for life sciences, and was listed last year in Forbes among the top 50 most influential women in science and technology.

How it works

After establishing the immune system operates in the brain, Schwartz set out to prove that the breakthrough drugs that jumpstart the body’s immune system to fight cancer could be modified to fight Alzheimer’s and other dementias.

When the immune system is overwhelmed or exhausted, switches in the blood called “checkpoints” that turn immune response on and off become stuck on “off.” The antibodies used by oncologists are directed to the checkpoints. They disable the checkpoint inhibitor proteins to get the T cells working again. By 2016, in experiments on mice that modeled Alzheimer’s Disease, Schwartz’s team used modified checkpoint antibodies to rejuvenate the immune system in the brain. They were able to arrest, and even reverse cognitive decline. The benefit did not depend on whether the Alzheimer’s was early or late stage. Mice ravaged by Alzheimer’s showed improved cognition and could navigate mazes from their youth.

Galvanized by those achievements, the Israeli scientist embarked on developing and testing an immune checkpoint inhibitor therapy for Alzheimer’s. She again encountered a roadblock.

The amyloid hypothesis

Schwartz began testing her understanding of the brain’s immune system amid ongoing attempts by numerous companies to develop a treatment that targets the accumulated Beta-amyloid and Beta-amyloid plaques associated with the brains of Alzheimer patients. It’s called the Amyloid Hypothesis that Beta-amyloid deposits cause Alzheimer’s. Beta-amyloid is a sticky protein known to interfere in the work of synapses and neurons. Despite disappointing results and over 20 anti-amyloid drugs that failed in clinical trials, the hypothesis persists. A 2019 article by Sharon Begley in the magazine STAT noted:

“The most influential researchers have long believed so dogmatically in one theory of Alzheimer’s that they systematically thwarted alternative approaches. Several scientists described those who controlled the Alzheimer’s agenda as a ‘cabal’.”

The FDA approves an anti-amyloid drug

Begley, an award-winning science writer whose resume included science columnist at the Wall Street Journal and science editor at Newsweek unfortunately did not live to see the excitement followed by controversy that erupted over the release of Aduhelm (aducanumab) by Biogen, the first drug shown to slow the disease by removing amyloid plaques.

That drug’s approval in June 2021 occurred over the objections of an advisory council of 15 senior FDA officials who cited weak clinical evidence of effectiveness and serious side effects. In a statement at the time, a former Biogen senior medical director who designed the late-stage clinical trials, Dr. Vissia Viglietta said, “This approval shouldn’t have happened. It defeats everything I believe in scientifically and it lowers the rigor of regulatory bodies.”

Biogen announced in January of this year it was discontinuing the drug.

Like Aduhelm, the only other approved drug for Alzheimer’s, Leqembi (lecanemab), must be taken very early by patients with mild cognitive impairment or mild dementia, when they can still function independently. Also based on removing amyloid plaques, Leqembi won’t improve cognition or halt progression of the disease, much less cure it. The drug slowed progression about 4 ½ months during the 18-month clinical trial compared to placebo. After the initial disease stages, Leqembi provides no benefit compared to placebo.

In March, the FDA was set to approve a third anti-amyloid drug, this one developed by Ely Lilly called donanemab. It had slightly better results in clinical trials, but its March approval was unexpectedly delayed by the FDA, pending an independent advisory committee review.

A new market for the Amyloid Hypothesis

Despite the modest results of their anti-amyloid medications, which all have serious side effects, such as brain swelling and in rare cases death, the drug companies are doubling down on the Amyloid Hypothesis. Clinical trials at Eli Lilly will purportedly suggest that donanemab should be taken by all non-cognitively impaired individuals with evidence of amyloid plaques. This despite studies indicating 30%-50% of elderly people (mean age of 85) have such plaques and will never suffer symptoms.

Research on immune checkpoint inhibitors for Alzheimer’s

With help from the Weizmann Institute, Schwartz founded ImmunoBrain Checkpoint, a clinical-stage biopharmaceutical company testing a new antibody specific to immune checkpoints called Aboo2. Tailored to treat Alzheimer’s disease, it blocks a checkpoint protein called PD-L1. According to a company spokesman, “Ab002 is the ONLY therapeutic agent in development for AD with preclinical data suggesting simultaneous therapeutic effects on Amyloid pathology, Tau pathology [another toxic protein associated with Alzheimer’s] and neuroinflammation.”

ImmunoBrain Checkpoint is now conducting a Phase 1 clinical trial with Alzheimer’s patients in the U.K., Europe and Israel. Based on a preclinical study, Schwartz says Aboo2 has a significantly lower potential for side effects compared to antibodies used in cancer therapies.

The company’s approach recently attracted significant support with a $5 million grant from the National Institute on Aging, a division of the National Institutes of Health, and $1 million from the Alzheimer’s Association.

According to Alzheimer’s Association media director Niles Frantz, “Providing a $1 million research grant clearly demonstrates that we believe the area of research shows promise. Many of the research projects funded by the Alzheimer's Association generate significant new and compelling data, which enables the researcher(s) to secure additional funding to extend the time and/or expand the scope of their work.”

With the cost of bringing a drug to market at $1 billion, companies like ImmunoBrain need a major pharmaceutical firm to back it, which would require a willingness to consider alternatives to the Amyloid Hypothesis.

More from Alexander Roberts: The anxiety epidemic: A manufactured crisis

The human cost of Alzheimer’s Disease

Christa Daniello has worked with Alzheimer’s patients for over 25 years at The Osborn Senior Living in Rye, New York, where she is a vice president, and said the cost of the disease is significant.

“You never forget it when the wife and children of a 65-year-old Harvard graduate stand before you crying, with a husband and father who no longer recognizes them. It’s heart-breaking and it’s time for the drug companies to try a different approach.”

Alexander Roberts is a former New York City television news reporter and founder and CEO emeritus of the nonprofit Community Housing Innovations, based in White Plains, New York.

This article originally appeared on Rockland/Westchester Journal News: Alzheimer's disease: Immunotherapy could be a tool