New drug trial aims to slow disease

A new approach to treating Alzheimer’s disease is being tested in a clinical trial with strong New Haven connections.

If it proves effective, the new drug, troriluzole, would help slow the progression of Alzheimer’s by protecting the brain’s neurons from an overabundance of a molecule called glutamate. Until now, treatments for Alzheimer’s have had a small effect on the disease, slowing but not stopping its progression.

“Compounds that have a neuroprotective effect, like the drug that we’re studying now, (are) very different from the compounds that we’ve studied that have taken the amyloid out of the brain, but have done nothing to affect the course of the illness,” said Alan Siegal, of Geriatric and Adult Psychiatry in Hamden, the first site in the United States to enroll patients.

“The damage, so to speak, had already been done. … (That) approach had not been fruitful. Frustrating would be a better word.”

Current medications, such as Aricept and Namenda, don’t “prevent the inevitable,” Siegal said. While medications “that would arrest and reverse the illness (are) the ultimate goal, we’re still not there. We hope this study will move us to the next phase of a more aggressive delay of progression.”

“We’d really like to broaden the way the field is coming at this disease,” said Dr. Adam Mecca, co-investigator at the Yale Alzheimer’s Disease Research Unit, the second Connecticut site where the trial is being conducted. Dr. Christopher van Dyck, director of the unit, is principal investigator there.

The biopharmaceutical company that is sponsoring the study, Biohaven Pharmaceuticals, is “based in New Haven. It was founded by people who live in and around New Haven and … its beginnings came from work at Yale,” said Dr. Robert Berman, chief medical officer of Biohaven.

“About a third of people over 80 have brains with Alzheimer’s pathology.” Dr. Robert Berman

Berman said the hope is that troriluzole “has the potential both to improve people’s symptoms soon … and to markedly delay the progression even, but that’s what the study will show us.”

Siegal, who was the founding director of Yale’s Alzheimer’s research unit, is the principal investigator at Geriatric and Adult Psychiatry, 60 Washington Ave., Suite 203, Hamden. The Yale Alzheimer’s unit is located at 1 Church St., Suite 600, New Haven.

He said family members and others close to Alzheimer’s patients don’t realize how much devastation the illness will wreak on their lives. A man might say, “If my wife could stay in this state, things would be OK,” Siegal said. “They don’t get it until it smacks them in the face.”

Almost 300 patients with mild to moderate Alzheimer’s will be enrolled in the trial, half receiving troriluzole, the other half a placebo. (The subjects do not have to stop their current medications to be enrolled.)

“They’ll be treated for 48 weeks and we will look to see how well they are thinking and functioning using specific scales for that purpose,” Berman said. The study is different from most Alzheimer’s trials that “are really focused on the pre-dementia phase,” Berman said. “We think the preclinical studies from the labs suggest that we will have an impact through all stages of the disease so we decided to start with the mild to moderate (phase).”

Alzheimer’s disease, which robs its victims of their mental and, ultimately, physical abilities, is increasing as a public health issue as the baby boom generation ages. But it is also occurring in younger and younger patients.

The cost of the disease is $50 billion a year, Berman said, “and it’s going to increase as the population ages. About a third of people over 80 have brains with Alzheimer’s pathology, even if they don’t have any dementia yet.”

“If this specific illness doesn’t come up with a cure in the next eight years, then we will spend more on health care than we will on defense,” Siegal said. “The vast majority of that will be dementia care.”

Siegal said he has 46 Alzheimer’s patients under 60. Years ago, “if I saw a half dozen it would be ‘Oh my God!’ We’re seeing 20 new patients a week here,” Siegal said, and his practice receives 300 referrals a month, at least one of them under 60.

“It’s not the illness I signed up to treat,” he said.

The reason younger people are developing Alzheimer’s is largely unknown. Pollution is cited as one cause. “You can pick up any newspaper. On any given day, there’s another

theory,” Siegal said.

The same is true of Parkinson’s disease, he said. “It scares everybody. It’s shifting.”

Glutamate is a molecule that acts as a neurotransmitter in the brain, carrying signals from one neuron to another. “It’s critical to normal brain function and there are more control mechanisms in the brain to make sure it’s not overabundant or underabundant,” said Berman — whom Siegal taught when he was a resident. Too much glutamate can spill outside the synapse between neurons and damage them, which may be a factor in developing Alzheimer’s. Troriluzole acts by regulating the amount of glutamate in the neural synapses.

“The active component of troriluzole has been studied in many labs across the world in models relevant to Alzheimer’s disease and shown compelling results,” Berman said.

“We’re really the only drug out there targeting glutamate,” he said. “It is a very compelling target. Ninety percent of your brain’s synapses are governed by glutamate. … We know from animal studies, it’s very well established that when glutamate spills outside of the synapses the neuron degenerates.”

Also, “we know early on in Alzheimer’s disease there’s a decrease in what’s called glutamate transporters. They’re the molecule that clears glutamate from the synapses … and our drug increases glutamate transport.”

The current trial is a phase two study. Data from preliminary trials was presented to the Alzheimer’s Disease Cooperative Study, which was formed in 1991 as “a consortium of academic and private sites that have expertise in Alzheimer’s disease,” Berman said. The consortium, based at the University of California at San Diego, agreed to design the study.

“Biohaven’s lucky that the ACDS agreed to take this on and New Haven’s lucky that we actually have two sites,” he said.

Enrolling in the study requires screening to make sure there aren’t other health factors that would make someone ineligible, such as cancer or diabetes. Also, according to Sylwia Lipior, clinical research coordinator at Yale’s Alzheimer’s Disease Research Unit, there are patients looking forward to the possibility of a more effective treatment.

“We do have sort of a pool of people who have already participated in studies at the ADRU and Dr. van Dyck takes from those people, and it’s really exciting because a lot of those people are sort of running out of options, so this study is very exciting in that regard,” Lipior said.

Andrea DeClement, the study coordinator at Geriatric and Adult Psychiatry, said, “My patients love being in research studies — the extra care, extra hands, more time spent. It’s just the extra attention.” Patients have their bloodwork done more often and, altruistically, it’s gratifying “just to be part of something that could be groundbreaking too,” she said.

“The patients themselves are excited,” DeClement said. “They’re excited and nervous.” At the same time, “caregivers are extremely excited and hopeful for the study” because of the potential that their burden will be lightened, she said.

For information about the clinical trial, go to www.t2protect.org. To inquire about being considered for the study at Geriatric and Adult Psychiatry, call DeClement at 203-288-0414 or email a.declement@gapcare.org. To enroll at the Yale Alzheimer’s Drug Research Unit, call Carol Gunnoud at 203-764-8100 or email carol.gunnoud@yale.edu.