Investigational New Drug for Alzheimer’s Scheduled for First Study in Humans--Vanderbilt Scientists Take Investigational Drug Product From Bench To Clinical Trials in Humans

Newswise, February 13, 2017 — Vanderbilt University scientists have received notification from the U.S. Food and Drug Administration (FDA) that testing in humans may proceed for an investigational new drug after more than 10 years of research by scientists at Vanderbilt University and Vanderbilt University Medical Center.

It is relatively uncharted territory for an academic drug discovery group to take a molecule from the laboratory setting to the clinical trials stage.

“The movement to the clinical phase of the research is the result of tireless colleagues reaching across disciplines in pursuit of the shared goal of hoping to someday improve the lives of individuals with Alzheimer’s disease and possibly other brain disorders, such as schizophrenia,” Provost and Vice Chancellor for Academic Affairs Susan R. Wente, Ph.D. said.

“This work exactly illustrates the critical role that basic science conducted in partnership with a world-class medical center can play in advancing knowledge in an attempt to fight a devastating disease.”

For Alzheimer’s disease, the aim is for the investigational drug to target major pathologies of the disease and selectively activate a key receptor in the brain. The Vanderbilt researchers believe that the current standard of care for Alzheimer’s disease, cholinesterase inhibitors, has a different mechanism of action.

They are hoping to establish through future clinical testing that the molecule is broadly effective across a number of cognitive and neuropsychiatric disorders, including schizophrenia.

“This is the first instance I am aware of where an academic drug discovery group moved a molecule designed to hopefully treat a chronic brain disorder all the way from early discovery to human trials without there being, at some point along the way, a pharmaceutical partner,” said P. Jeffrey Conn, Ph.D., Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine and director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). 

“And that really is crossing what people refer to all of the time as the ‘Valley of Death,’ where good research discoveries have a hard time moving into the clinical testing phase due to lack of funding,” he said.

“Importantly, at this early stage, the FDA has only granted permission to assess potential safety of this investigational new drug in healthy volunteers” said Conn.

“We cannot predict the outcome, but if these studies are successful in demonstrating that the investigational drug can be safely administered to humans, this would pave the way to allow filing of additional applications with the FDA to seek permission to advance to testing for efficacy in improving cognitive function in patients suffering from Alzheimer’s disease, and possibly schizophrenia or other brain disorders.

“While we cannot predict the outcome of any future safety or efficacy studies, this decision by FDA allowing clinical research to begin represents a major milestone in allowing us to hopefully provide answers to those critical questions in the future,” Conn said.

VCNDD Co-Director Craig W. Lindsley, Ph.D., director of Medicinal Chemistry and William K. Warren, Jr. Professor of Medicine, said phase I testing will assess drug safety and tolerability in healthy volunteer participants, a process that could take a year.

If successful, the phase II and III studies would include efficacy assessments in patients with Alzheimer’s disease and could take 3-5 years to complete.

“We are hoping to address what we see as an unmet medical need,” Lindsley said.

“For Alzheimer’s patients, the standard of care for symptomatic treatment remains cholinesterase inhibitors, which are 25 years old at this point. There hasn’t been any real scientific advancement in this field in a long time.”

Lindsley and Conn credit The William K. Warren Foundation for its philanthropic investments along the way to make clinical trials for this investigational drug a reality.

“One of the most challenging things about doing this in an academic environment is funding,” Lindsley said.

“Every step requires funding and if there is a delay or break in funding, then everything sits idle and potentially innovative approaches for patient care do not advance.”

“Being matched with the Warrens happened serendipitously. They have invested so much in our programs, and it is wonderful to show them progress on their investments,” he said.

“Without the financial support from the Warrens, this investigational drug would not be poised to enter human clinical trials.”

The William K. Warren Foundation Chief Executive Officer John-Kelly Warren said he is gratified that FDA has allowed for the investigational drug to proceed to testing in human beings.

“Although this is an important sequential milestone, the only milestone that matters to us is the hope that one day we will learn that this investigational new drug has positively and safely changed the life of a patient suffering from a brain disorder such as schizophrenia or Alzheimer’s disease,” Warren said. 

“That day will warrant a celebration felt in the heavens. Until then, we are prepared to support the VCNDD research team until they can deliver the necessary results,” he said.

A NIH National Cooperative Drug Discovery/Development grant funded the early basic science and discovery of this investigational drug and the Alzheimer’s Drug Discovery Foundation and Harrington Discovery Institute helped support some of the key toxicity studies that FDA required, Conn said.

“The investigational new drug has the potential to improve cognitive functions with fewer unwanted side effects.

“This could someday be an important advance for the treatment of cognitive deficits in psychiatric disorders and Alzheimer’s disease,” said Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, which co-funded the research. 

Conn and Lindsley said Vanderbilt’s “team science” approach included contributions from the director of Translational Pharmacology and Development for the VCNDD and Assistant Professor Carrie K. Jones, Ph.D., who coordinated the IND drafting, submission, and subsequent development into Phase I, director of Molecular Pharmacology for the VCNDD and Research Associate Professor of Pharmacology Colleen Niswender, Ph.D., for the molecular pharmacology; Research Assistant Professor of Pharmacology Jerri Rook, Ph.D., for the behavioral studies; and Research Assistant Professor of Pharmacology Thomas Bridges, Ph.D., and Research Assistant Professor of Pharmacology Anna Blobaum, Ph.D., for drug metabolism and pharmacokinetic profiling.

Paul Newhouse, M.D., director of the Center for Cognitive Medicine at VUMC and Jim Turner Professor in Cognitive Disorders, is expected to lead the upcoming clinical study funded in part by the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation.

Deep Brain Stimulation Studies in Alzheimer’s Disease Pose Ethical Challenges

Penn researchers propose guidelines to better protect patients in DBS clinical trials

Newswise, February 3, 2017--A—Promising, early studies of deep brain stimulation (DBS) for the treatment of Alzheimer’s disease have paved a path for future clinical trials, but there are unique ethical challenges with this vulnerable population regarding decision making and post-study treatment access that need to be addressed as they ramp up, Penn Medicine researchers argue in a new review in the Journal of Alzheimer’s Disease.

Does the patient still have the capacity to make an informed decision half way through the trial? Are there any misconceptions about its therapeutic benefit? Will the device remain after the trial ends, and who will pay for it?

These are the questions posed in an ethics review piece that also lays out guidelines for investigators to consider when enrolling Alzheimer’s patients in DBS trials.

The article is authored Andrew M. Siegel, MD, an assistant professor of Clinical Psychiatry in the Perelman School of Medicine at the University of Pennsylvania, Marna S. Barrett, PhD, an adjunct associate professor of Psychology in Psychiatry at Penn, and Mahendra T. Bhati, MD, a former assistant professor of Clinical Psychiatry at Penn, who is now at Stanford University, in an ethics review piece that also lays out guidelines for investigators to consider when enrolling Alzheimer’s patients in DBS trials.

Approved for the treatment of movement and neuropsychiatric disorders, such as Parkinson’s disease, DBS is an invasive, surgical procedure involving the implantation of a microstimulator that sends electrical impulses to specific targets in the brain.

Driven by the urgent need for effective therapies and the success of recent studies, DBS has now emerged as a possible treatment for Alzheimer’s.

“As the number of people affected by Alzheimer’s continues to grow, along with its substantial costs to individuals, their families, and society, novel therapies are urgently needed. DBS is one such treatment modality that has shown promising early results,” Siegel said.

“However, this enthusiasm should be tempered by prudent ethical considerations to help better protect the patients.”

The authors call out three ethical issues that should be addressed and recommendations.

Ensuring the trial subjects possess adequate decision-making capacity is important, the authors said, because such individuals have cognitive deficits that may reasonably limit that capacity and thereby compromise informed consent.

DBS for trials must have a robust mechanism for both detecting loss of decision-making capacity and protecting the interest of the patients during the trial, they wrote.

Suggestions include an Institutional Review Board (IRB)-mandated use of a validated decision-making capacity assessment, such as the MacCAT-CR interview, and an “auxiliary consenter,” someone not affiliated with the study to determine the patient’s knowledge about the procedures, risks, and the device.

Therapeutic misconception is another concern. Patients with Alzheimer’s, desperate for relief and without an effective alternative, may agree to DBS as a last resort.

Such desperation may alter their perception that the primary goal of the study is for health benefits and not knowledge about the efficacy of the device. Left unchecked, it could distort patients’ understanding of the risks and benefits of DBS.

“It may be necessary to directly inform patients during study consent that ‘scientific goals will have priority over therapeutic goals’,” the authors wrote. A “cooling off” period, where patients have adequate time to process all the information that has been given to them, may also prove effective.

Another question to be asked at the end of the trial is whether patients who have benefited from the device should continue to receive treatment.

This question is particularly salient considering the high cost of DBS and the fact that the device may be with the patient for many years after the trial ends.

The authors believe denying a patient access to the only intervention known to alleviate their suffering is tantamount to violating the sacrosanct principle of “do no harm.”

“Providing post-trial access to the subset of patients shown to benefit in a failed trial is not only ethically appropriate,” Siegel said, “but it would allow for the collection of longitudinal safety and efficacy data not captured in the original study.”

Once post-trial access is accepted by a research team, the challenge is financial responsibility. Patients, together with sponsors, investigators, health care systems, insurance, governments, and non-profit organizations must partner to share responsibility and negotiate continued access arrangements prior to study enrollment, the authors said.

This model has worked in the past – the HIV Netherlands, Australia, Thailand Research Collaboration is one example.

“We hope this review facilitates the development of study designs and IRB oversight procedures that best protect research subjects,” Siegel said.

“A reasonable next step is for research centers and hospitals to examine their current practice and policies guiding DBS in Alzheimer’s research. Our review could act as a guide in helping them ask the relevant questions about their current state of oversight and to consider changes as appropriate.”

Protein in Urine Linked to Increased Risk of Memory Problems, Dementia

By Turbotorque (Own work) [Public domain], via Wikimedia Commons

Newswise, December 26, 2016-- People who have protein in their urine, which is a sign of kidney problems, may also be more likely to later develop problems with thinking and memory skills or even dementia.

Researchers looked at all available studies on kidney problems and the development of cognitive impairment or dementia.

“Kidney dysfunction has been considered a possible risk factor for cognitive impairment or dementia,” said Kay Deckers, MSc, of Maastricht University in the Netherlands, author of the systematic review and meta-analysis.

“Chronic kidney disease and dementia share many risk factors, such as high blood pressure, diabetes and high cholesterol, and both show similar effects on the brain, so they may have shared vascular factors or there may even be a direct effect on the brain from kidney problems.”

A total of 22 studies on the topic were included in the systematic review. Five of the studies, including 27,805 people, were evaluated in the meta-analysis on protein in the urine, also called albuminuria or proteinuria. The analysis showed that people with protein in the urine were 35 percent more likely to develop cognitive impairment or dementia than people who did not have protein in their urine.

For another marker of kidney function, estimated glomerular filtration rate, the results were mixed and did not show an association. For three other markers of kidney function, cystatin C, serum creatinine and creatinine clearance, no meta-analysis could be completed because the few studies available did not use the same methods and could not be compared.

“Protein in the urine was associated with a modestly increased risk of cognitive impairment or dementia,” Deckers said.

“More research is needed to determine whether the kidney problems are a cause of the cognitive problems or if they are both caused by the same mechanisms.”

The study was supported by the In-MINDD (Innovative Midlife Intervention for Dementia Deterrence) project funded by the European Union’s Framework Program Seven.

To learn more about the brain, visit www.aan.com/patients.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with 30,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

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