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Tuesday, July 16, 2019
AAIC19: Infectious Agents and Alzheimer’s Disease
For quite some time, the focus of the cause of Alzheimer’s disease was on beta-amyloid, a protein that accumulates in the brains of individuals with the disease and which appears to cause at least some of the damage that results in memory and cognition issues. There are other candidates, and research appears to be heating up on the role of inflammation—perhaps triggered by beta-amyloid—in Alzheimer’s.
But before beta-amyloid was implicated in 1984, many researchers believed that an infectious agent was involved in the disease and research continues in this area.
On July 16, the Alzheimer’s Association International Conference (AAIC) 2019 hosted a panel titled, “Is There a Causative Role for Infectious Organisms in Alzheimer’s Disease?”
Panelists included Ben Readhead, assistant professor, ASU-Banner Neurodegenerative Disease Research Center; Ruth Frances Itzhaki, Emeritus Professor, Faculty of Biology Medicine and Health, University of Manchester; Robert D. Moir, assistant professor in Neurology, Genetics and Aging Research Unit, McCance Center for Brain, Health MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospitaland Harvard Medical School; Todd Golde, director, Evelyn F. and William L. McKnight Brain Institute and director of 1Florida Alzheimer’s Disease Research Center; and Michael T. Heneka, professor of Clinical Neuroscience, Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology at University of Bonn Medical Center and the German Center for Neurodegenerative Disease (DZNE).
Robert Moir took time to speak with BioSpace ahead of the panel to discuss the subject of infectious agents and the role they may play in Alzheimer’s disease.
“In 1984, Abeta was identified as the protein generating amyloid in the Alzheimer’s disease brain,” Moir said,” the hallmark pathology. It was assumed at the time Abeta was only found in AD brain and the protein’s propensity to form amyloid was intrinsically abnormal. As an abnormal catabolic byproduct of disease, it was assumed the protein has no function. This had a big impact on the idea of infection as an AD etiological factor—essentially sidelined it.”
He went on to say that the amyloid model essentially presented three obstacles to an infection etiology for the disease. One, Moir said, “Who needs infection when it can be explained by an abnormal activity of Abeta?”
Second, there was no clear mechanism for how an infectious agent would drive amyloidosis and other pathologies. And third, no single pathogen has been identified that is present in the majority or overwhelming number of Alzheimer’s cases.
“For any particular pathogen,” Moir said, “uninfected AD patients can be identified with extensive beta-amyloid deposition. These long-standing concerns have stymied the serious consideration of infection as an etiological factor for AD.”
In 1990, however, researchers found that the pathway that creates beta-amyloid is a common one, not an abnormal pathway, and that it is involved in generating hundreds of important proteins. This undercut the rationale for a functionless beta-amyloid, and in fact, research found that the same beta-amyloid found in human brains was found in more than half of all vertebrates, and that in humans the genetic sequence is remarkably well conserved, being more than 400 million years old.
“Such remarkable evolutionary conservation suggests an important function and a protein highly optimized for its role,” Moir said. “Ten years ago, we identified beta-amyloid as an antimicrobial peptide whose job was to protect the brain against fungi, bacteria and viral infections. Moreover, it does it by trapping microbes in amyloid.”
This presents three strong theories. First, amyloid accumulation is a response to invading pathogens. Second, microbes directly “seed” the deposition of beta-amyloid. And third, bacterial, fungal and viral pathogens can “seed” amyloid in multiple different types of neuroinfection, which accelerates the accumulation of beta-amyloid.
“There have been multiple fungal, bacterial, and viral neuroinfections linked to Alzheimer’s,” Moir said. “The most studies (and arguably strongest data) is for herpes simplex 1. However, data showing microbes in Alzheimer’s brain raise the question of if the infection came before AD or after—pathogens making their way into and across a weakened blood-brain barrier. This remains to be resolved. However, the finding that microbes can seed amyloid suggest infection will accelerate the disease in either case.”
In terms of the current focus of the biopharma industry, Moir says that many are looking at anti-inflammatories as an approach to treatment and prevention, “and all but one has abandoned anti-Abeta drugs. Anti-infectives face the same problem as anti-Abeta drugs—it will need to be a prodromal administration and at present, there is no reliable way to identify people in the early stages of pre-dementia Alzheimer’s disease. It is early days for the anti-inflammatories, but stage III clinical trials are underway.”
Genentech Strikes Three Separate Drug Discovery Deals With Small Companies
It has been a deal-making morning for South San Francisco-based Genentech. The Rochesubsidiary struck three separate deals with small companies in order to boost drug development.
Genentech and Cleveland-based Convelo Therapeutics, Inc. entered into a collaboration to accelerate discovery and development of novel remyelinating medicines for patients with neurological disorders such as multiple sclerosis (MS). The two companies will work together to discover novel remyelination therapies for MS and other myelin disorders. Convelo will receive an undisclosed upfront payment and research support from Genentech. Under terms of the deal, Genentech will retain an option to potentially acquire the company for an undisclosed sum as well as downstream milestones.
James Sabry, global head of pharma partnering at Roche, said there have been significant advances in the treatment of multiple sclerosis, but many patients still experience a progression in their disability. Currently approved therapeutics are focused on preventing additional myelin damage by modulating the immune system, but there are no approved therapies that tackle the unmet clinical need to promote myelin regeneration.
“Novel medicines that regenerate the myelin around nerve cells could help address this significant need. We look forward to collaborating with Convelo to hopefully deliver new options to people with multiple sclerosis and other neurological disorders,” Sabry said in a statement.
While the financial terms of the Convelo deal were not disclosed, Genentech entered into another deal today worth up to $1 billion. Genentech and Japan-based Sosei Group teamed up to discover and develop novel medicines that modulate G protein-coupled receptor (GPCR) targets. GPCRs are the largest membrane receptors in eukaryotes. According to Nature, it is believed that between one-third and one-half of all marketed drugs act by binding to GPCRs. If that’s true, then it explains Genentech’s interest in the target.
Under terms of the deal, Sosei will only receive $26 million in an upfront payment, but the deal is heavily backloaded. As the two companies work across a range of undisclosed disease targets, Sosei could earn future milestone payments that amount to $1 billion. That could increase with royalties from any approved drug sales. As noted, the targets the companies are going after were undisclosed, but in the announcement, the companies said the “nominated targets represent promising new therapeutic intervention points across a range of diseases.” Genentech will be responsible for developing and commercializing potential new medicines for each novel target and will have exclusive global rights to these agents.
Sabry said Genentech believes GPCRs are an important target class for multiple diseases. He said Sosei brings unique capabilities to the collaboration to enable and accelerate GPCR drug discovery.
In its third deal of the day, Genentech formed an alliance with Waltham, Mass.-based Skyhawk Therapeutics to develop and commercialize small molecules that modulate RNA splicing. In the announcement, Skyhawk said it will use its SkySTAR technology platform to discover and develop innovative small-molecule treatments directed to certain oncology and neurological disease targets.
The financial terms of the deal were undisclosed but the agreement gives Genentech an exclusive worldwide license to develop and commercialize potential therapeutics directed to multiple targets. Genentech will be responsible for clinical development and commercialization.
“Modulation of RNA splicing represents a novel approach for difficult-to-treat diseases. Skyhawk has developed a unique expertise in splicing biology, and we are excited to work with their team to discover potential new medicines for patients with cancer and neurodegenerative diseases,” Sabry said.
Kite builds cell therapy manufacturing even as Yescarta sales grow slowly
So far, Gilead Sciences’ Kite Pharma has been buying from contractors the viral vector material needed for its chimeric antigen receptor T-cell (CAR-T) treatment Yescarta. But with an expanding pipeline of cell therapies, the company says it is time to be able to produce its own.
The drugmaker announced today that it will build a 67,000-square-foot facility at its Oceanside, California, biologics site just for developing viral vectors, the tools needed to deliver genetic material into cells. The company declined to disclose what it expects to invest in the facility or how many people it may employ but said it is slated to begin commercial manufacturing of viral vectors in the second half of 2021.
“Viral vectors are one of the key components in cell therapy production, however, the industry’s current development and manufacturing capabilities are not widely established and supply is limited,” Tim Moore, executive vice president of technical operations for Kite, said in a statement.
“By pursuing our own viral vector facility, we will be able to advance viral vector development and supply to allow for accelerated process development of current CAR T and future pipeline therapies, while continuing to partner with external suppliers,” Moore explained.
Gilead swept up Kite and Yescarta in a $12 billion deal in 2017. Approved for treating some patients with large B-cell lymphoma, Gilead has had trouble getting Yescarta established in the market. It generated $264 million last year but has trailed Novartis’ Kymriah, which won the first-ever cell therapy approval.
Still, Gilead is planning for a big future in cell therapies and has aggressively expanded its manufacturing capabilities to stay ahead of the curve.
In April, it announced it was building a 279,000-square-foot facility west of Baltimore in Frederick County, Maryland, to manufacture its next-gen oncology treatments including Yescarta and its prospective T-cell receptor therapies. The site will employ up to 800 workers.
The big biotech also is building a separate CAR-T manufacturing facility near an Amsterdam airport, a move that is designed to shorten shipping times in Europe for the sensitive product. It also acquired a new building in Santa Monica, California, from Astellas Pharma that it will use for clinical manufacturing and cell therapy R&D.
In addition, Gilead is muscling up its executive infrastructure to make its big move into the new market. Last week, it announced it will bring on Eli Lilly executive Christi Shaw to run Kite and move the effort forward, and last year the company nabbed Michael Amoroso from Eisai to be its SVP and head of worldwide commercial efforts in cell therapy. He oversees sales and marketing, doctor and patient services and “market access”—aka payer negotiations.
While Gilead has touted Kite’s cell therapy pipeline, it has had troubles there as well. Earlier this year Gilead dumped an anti-BCMA cell therapy for multiple myeloma that was part of its $12 billion acquisition of Kite and then took an $820 million impairment charge in the quarter.
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