Q&A: The ‘odd couple’ of Alzheimer’s disease and schizophrenia

Alzheimer’s disease and schizophrenia are not often linked in the same sentence, much less in the same scientific conversation, but in an interview with DDNews, Dr. Deborah Dunsire, president and CEO of Forum Pharmaceuticals, and her colleague Dr. Lon S. Schneider at USC tell us why perhaps they should be

Lloyd Dunlap
Alzheimer’s disease and schizophrenia are not often linked in the same sentence, much less in the same scientific conversation. The first is a disease primarily found in older people, while schizophrenia is typically first observed in those in their teens, 20s or 30s. But Dr. Deborah Dunsire, president and CEO of Forum Pharmaceuticals—the new name for the company that has been known as EnVivo Pharmaceuticals—notes that her company’s drug encenicline has thus far shown promise as a treatment in both disease states.
 
We began our discussion with Dunsire by asking about the reason for the change in the company’s name.
 
Deborah Dunsire, M.D.: Our new name, Forum Pharmaceuticals, suggests collaboration and working together so that new ideas emerge to be tested. Further, we think the name underscores our commitment to partnering with regulatory bodies, the research community and patients. One last note, Forum can be trademarked and EnVivo could not.
 
DDNews: How did you company come to focus on Alzheimer’s disease (AD) and schizophrenia?
Dunsire: We began 12 years ago using fruit flies (Drosophila melanogaster) to test chemicals. One drug came out of that but that platform was not as productive as hoped although we are very excited about the drug lead that came from it. We became interested in Alzheimer’s and schizophrenia, but our fundamental emphasis has not changed. We are committed to the discovery and long-term development of innovative drugs that improve function and change the course of disease in patients with dementias, schizophrenia and other neuropsychiatric disorders. Our approach is multitarget and multiprogram by design. With no therapies currently available to treat the underlying causes and mechanisms of many CNS diseases, the scientific expertise and drug discovery ability to pursue a variety of disease targets is key. Based on scientific expertise and drug discovery capabilities, we have built a robust and diverse pipeline that is focused on important neuropsychiatric conditions for which currently available therapies are insufficient and leave profound unmet needs, including Alzheimer’s disease, schizophrenia and others.
 
DDNews: What is an alpha-7 inhibitor and how does your drug encenicline work?
Dunsire: Encenicline-hydrochloride (formerly known as EVP-6124), a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors.
Encenicline is an orally administered, brain-penetrant, selective and potent agonist of the α7 receptor found on certain hippocampal and cortical neurons in the brain. Encenicline is believed to work in low concentrations as a co-agonist with naturally occurring acetylcholine to potentiate the response of α7 receptors—activated brain networks associated with sensory gating, attention and cognition—thus priming these networks for improved neural processing and improved cognitive performance in areas such as memory and executive function.
Encenicline is currently being evaluated in an ongoing Phase 3 COGNITIV clinical trial program to improve cognition in patients with Alzheimer’s disease (COGNITIV AD) and patients with cognitive impairment associated with schizophrenia (COGNITIV CIAS).
Forum’s preclinical research has demonstrated that memory deficits can be minimized or entirely reversed by activating the alpha-7 receptor with encenicline alone or in combination with other acetylcholinesterase inhibitors (for example, donepezil). Encenicline has also been shown to increase the release of important neurotransmitters, notably glutamate, which is believed to be important in the pathology of schizophrenia.
 
DDNews: Most drugs act as antagonists in the attempt to down-regulate an unwanted effect. We hear relatively little about drugs that act as agonists.
Dunsire: It depends on what the disease is doing. There are a couple beta-2 stimulators in asthma to help the airways relax and expand and agonists are used to treat an under-active thyroid. But since most disease states involve overproduction of an unwanted effect, antagonists are often called for.
 
DDNews: Can you explain for our readers how cognitive tests are conducted and what the important metrics are in terms of test results?
Dunsire: There are no objective tests in cognition—no tumor size or blood markers, no blood pressure or blood sugar. Cognition relies on a battery of tests. In one such test the patient runs a pencil through a maze against time with growing complexity of the maze until failure. Or they are asked to repeat a list of words. There are 10 such sub-tests for our schizophrenia primary endpoint, 13 for AD.
The Clinical Dementia Rating scale is used to quantify the severity of symptoms of dementia (i.e. its impact). It assesses a patient's cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Scores in each of these are combined to obtain a composite score ranging from 0 through 3. While the assessment is subjective in nature, the CDR appears to be a reliable and valid tool for assessing and staging dementia.
 
DDNews: How are AD and schizophrenia related, if indeed they are?
Dunsire: I’ll let my colleague Dr. Lon Schneider address that question from his perspective as a professor of psychiatry and behavioral sciences.
Lon Schneider, M.D.: You can take the position that they are unrelated based on age of onset and other factors. One is a neurodevelopmental disorder and the other neurodegenerative. But the brain is the brain. In both conditions, cognitive impairment is evident and, again in both, cholinergic expression plays a part. For example, in both conditions working memory—what we call executive function— is affected and may respond to the same therapies.
 
DDNews: How is the mechanism of action of encenicline different from other Alzheimer disease therapeutics?
Schneider: Overall, cholinergic inhibitors have not been clinically successful with studies, showing only small effects for a minority of patients. As far as the rest of the “big picture,” drugs with a range of other, non-cholinergic mechanisms have failed in Phase 2 to Phase 3 because of a lack of efficacy.
Drugs targeting nicotinic subtypes, such as α7 seem to show cognitive effects. And that’s where drugs such as encenicline stand, not as cures but as a means to improve function.
In a six-month, double-blind Phase 2b clinical trial that evaluated encenicline against placebo in patients with mild to moderate Alzheimer's disease, results demonstrated that dosing with encenicline resulted in statistically significant improvements in cognition and clinical function, meeting the trial's primary endpoints. The data also showed statistically significant results across some secondary endpoints of other cognitive and a clinical global measure.

Deborah Dunsire has more than 25 years of scientific, clinical, operational and commercial experience. Prior to joining EnVivo Pharmaceuticals (now Forum Pharmaceuticals) in 2013, she served as president and CEO of Millennium Pharmaceuticals Inc. The company was acquired by Takeda Pharmaceutical Co. Ltd. in 2008 for $8.8 billion—one of the largest biotech acquisitions at that time—and became Millennium: The Takeda Oncology Company. She has received numerous awards, including the 2001 American Cancer Society Excalibur Award, the 2009 Healthcare Businesswomen’s Association’s “Woman of the Year,” the 2011 MassBIO Innovator Award and the 2013 Boston CEO Conference Lifetime Achievement award.
 
Investigator Lon S. Schneider, M.D., is professor of psychiatry and behavioral sciences, neurology and gerontology at the Keck School of Medicine of the University of Southern California and director of the USC California Alzheimer’s Disease Center and clinical core of the USC NIH Alzheimer’s Disease Research Center.

Lloyd Dunlap

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