Expert: Is Alzheimer’s a Singular Disease?

Casey Lynch, CEO of Cortexyme, was on the panel at the Biotech Showcase on “Reexamining Alzheimer’s: Is it a singular disease?” The Investing News Network spoke to Lynch about her take on the panel, what her company is working on and how other trials may have failed.

“We all had fairly different positions,” Lynch said, but always with respect for each others focus to make a difference for the patients with Alzheimer’s disease (AD). Lynch and her company believe the majority of AD is a singular disease triggered by a pathogen, whereas others on the panel believe multiple approaches are necessary.

Other panelists included Barbara Tate, venture partner of the Dementia Discovery Fund and SV Life Sciences and Ken Moch, CEO of Cognition Therapeutics. The fund focuses on investing in novel science to create meaningful new medicines. Cognition has used its resources to develop small molecules capable of competitively blocking amyloid beta (Aβ) binding to sigma-2/PGRMC1. If successful, these drugs could reverse and prevent memory deficits in preclinical models.

Topics the panel covered included: is Alzheimer’s a complex web of disease-related dementias or is it a singular disease? How do investors view the evolving landscape and its risk-reward profile? And, how do new players fit into this AD drug developing market?

“There’s lots of different ways to target beta amyloid,” Lynch said, without success. She describes the variety of approaches to a “thread and needle around beta amyloid,” in a nutshell. This is done with different molecules and trial designs. Lynch added everyone on the panel seemed to agree that funding new approaches is necessary.

A 2016 study on AD describes Aβ as the “hallmark” of the disease. The discovery of Aβ is likely what forms neurotoxic pores that has led to a new paradigm of the disease and proves why previous therapeutics haven’t been successful, the study continued.

Scientists continue to learn more about AD, including new risk factors and aspects of the pathology in the brain. Little progress has been made in identifying the cause or treatment strategy to halt the disease progression. These all stand as evolving topics in the AD sphere. The US National Institute on aging believes AD is unlikely to be treated with any single drug. Most patients with AD are on multiple drugs to improve symptoms for a short period, but it doesn’t relate to altering disease progression. This is what Cortexyme aims to address with its drug candidates.

While the panel discussed a need for combination therapies that go after the plaques and inflammation, Lynch admits she’s biased with her company’s approach. As she describes it, there’s strength in asking what’s upstream of the neurodegeneration, plaques, inflammation and other pathology.

Instead of developing multiple therapies to treat these pathways in the AD brain, and “treating them as though they’re being triggered by different things, or disparate,” Lynch said the company is working to identify the driver of neurodegeneration and other immune system activation in the brain, including abeta production. Cortexyme believes the pathology is being triggered by one thing. “If you deal with that, you can deal with all the downstream pathology.”

Cortexyme’s approach doesn’t follow the same route many other AD companies are taking. The company has identified a bacteria called Porphyromonas gingivalis (Pg) in brains of AD patients, which is a keystone bacteria in periodontal disease, she said. The bacteria was found in the brain of more than 90 percent of patients’ brain samples. The company’s co-founder, Steve Dominy, discovered the bacteria in AD patients brains after many big epidemiological studies on AD were coming out about that identified periodontal disease as a risk factor for AD.

The reasons of why AD drugs in development fail is vast and has many answers. Lynch said a big reason why she believes most therapeutic drugs in development don’t work are the animal models. The translatability of some animal models, especially transgenic mice have “failed” the industry.

This discovery is what began, and is still the focus of Cortexyme. It doesn’t mean periodontal disease causes AD, it’s just the same bacteria that creates the degenerative condition in the brain. “That bacteria is not isolated to your mouth, it has systemic access,” she said. If the bacteria gets into the patient’s brain or not has to do with a complex interaction of the genetic risk factors, bacterial load immune response and more.

Lynch’s conclusion is that aside from many cases with truly genetic AD, the data is available to support that this is a singular pathogenic cause. When mice are infected with the bacteria Pg, “it gets into their brain,” Lynch explained. “It triggers the very pathology of Alzheimer’s including plaques, tangles, neurodegeneration and neuroinflammation.” This was shown in a study by the University of Illinois in 2018.

Virulence factors from the bacteria, Pg, is found in 96 percent of mild to moderate patients, Lynch said. It’s hard to invoke multiple causes with this high amount of patients that have a pathogen known to cause degenerative disease in their mouth and brain, she said. From the company’s current research, it has seen this bacteria’s DNA in cerebrospinal fluid (CSF) in live patients. “We’re ramping up for a big Phase 2/3 study,” she said. This will track the bacterial DNA in the CSF and look for response rates.

Lynch says the data the company has worked on has been “convincing and compelling for investors to support.” Investors span from “sophisticated family offices, big pharma — including both Johnson & Johnson (NYSE:JNJ) and Takeda (TSE:4502)—and some major funds like Sequoia.” So far the company has raised US$100 million, which Lynch said will fund the company through the Phase 2 trial.

On Wednesday (January 23), Cortexyme released an article it calls a “groundbreaking discovery” related to Pg, driving AD, which was published in Science Advances. The paper explains the role of Pg and its prevalence in the high amount of patients, supporting the idea of a singular disease. It also challenges those who disagree with calling it a singular disease.

It also explains how Cortexyme’s small molecule inhibitor plays a role as a potential inhibitor to block the pathogen from the bacteria. “For the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen, Pg, and Alzheimer’s pathogenesis, Dominy said in the press release. “[It] also demonstrates the potential for a class of small molecule therapies to change the trajectory of disease.”

The company has developed a library of small molecule therapies targeting gingipains. Researchers have demonstrated the inhibition by COR388, prevents neurodegeneration, abeta overproduction and neuroinflammation, which is Cortexyme’s lead compound in the series.

Researchers are still just touching the surface of AD’s causes and how to treat it. Investors interested in further development by Cortexyme can follow the company’s news in these developments of AD treatments.

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Securities Disclosure: I, Gabrielle Lakusta, hold no direct investment interest in any company mentioned in this article.

Editorial Disclosure: The Investing News Network does not guarantee the accuracy or thoroughness of the information reported in the interviews it conducts. The opinions expressed in these interviews do not reflect the opinions of the Investing News Network and do not constitute investment advice. All readers are encouraged to perform their own due diligence.