Brown University-Led Investigational Team to Assess HIV Drug Impact on Alzheimer’s Patients in Phase I Clinical Trial

Feb 16, 2020 | Alzheimer's Disease, Alzheimer’s Association, Brown University, Butler Hospital, HIV Drugs

Brown University-Led Investigational Team to Assess HIV Drug Impact on Alzheimer’s Patients in Phase I Clinical Trial

The Alzheimer’s Association Part the Cloud Translational Research Funding Program granted $750,000 to a team of researchers from Brown University, Butler Hospital, and The Miriam Hospital to conduct a Phase I, 2.5-year clinical trial that will assess the potential therapeutic effect that a class of HIV drugs can have on the progression of Alzheimer’s disease. By using an “on the shelf” drug made by Gilead, to repurpose for another disease, positive results would indeed represent a promising breakthrough. The investigators await approval by the Institutional Review Board (IRB).

The Alzheimer’s Disease Crisis

According to the Alzheimer’s Association, nearly 5.8 million Americans of all ages have Alzheimer’s disease with 5.6 million of them aged 65 and older and approximately 200,000 individuals with young-onset Alzheimer’s. About one in ten people age 65 and older have Alzheimer’s dementia. By 2050, the number will rise to 14 million. Alzheimer’s is the 6th leading cause of death in the United States. In 2019 Alzheimer’s cost the economy $290 billion. Most horrifically, at a personal level, as people grow old the disease can snatch one’s memory—representing the most terrible of losses—those memories of one’s life, their loved ones, friends and experiences. There is no cure and hasn’t been a new treatment approved by the FDA for nearly a couple decades. There are only five FDA-approved treatments and these have minimal impact and in some cases considerable side effects. A new drug in China was approved recently but the true efficacy is not known with confidence

Neuroinflammation

Patients afflicted with Alzheimer’s disease (and other neurological conditions) have symptoms that include a greater amount of inflammation in the brain. The direct cause of the neuroinflammation isn’t truly understood at this point. The investigators in this study are operating from a hypothesis that in fact this neuroinflammation may originate from retrotransposable elements.

Background

Brown University has become a hub for early-stage Alzheimer’s disease research. The Brown team are part of an overall movement seeks to step back and think about Alzheimer’s research in new, but also pragmatic ways—stepping back and considering new approaches including the focus on inflammation’s association with the disease. As “an Alzheimer’s brain is an inflamed brain” Brown team seek innovative yet pragmatic approaches to progress the march toward a more effective Alzheimer’s treatment. Two key players operating in this research hub include John Sedivy, Hermon C. Bumpus professor of biology and professor of medical science and co-principal investigator and Stephen Salloway, director of neurology and the memory and aging program at Butler Hospital, Martin M. Zucker professor of psychiatry and human behavior, professor of neurology.

Previous Research at Brown

As reported by Rahma Ibrahim of The Brown Daily Herald, earlier experiments, led by John Sedivy, Hermon C. Bumpus professor of biology and professor of medical science and co-principal investigator of the current study, found that the HIV drug called Lamivudine could decrease inflammation in various mice tissues. Lamivudine (Epivir) blocks the activity of the HIV-linked reverse transcriptase enzyme, a molecular substance enabling HIV to replicate and include into an individual’s DNA. The research indicated that LINE-1—long interspersed nuclear elements and a type of retrotransposon—can lead to age-related inflammation. Apparently, a person’s cells recognize retrotransposons as foreign DNA and hence triggers a swift immune system response to eliminate the supposed invaders, leading to inflammation.

However, these out-of-place DNA molecules aren’t a one-time event—rather they continuously trigger immune responses increasing inflammation levels over time. Hence it could be understood, suggests Sedivy’s research, that these actions lead to “sterile inflammation.” Not a reaction to any infection, this observed Sterile inflammation, the hypothesis goes, is now believed to exacerbate diseases normally associated with old age noted Sedivy. Hence, the team’s impetus to center the study attention on how to address inflammation associated with Alzheimer’s disease. If the brain inflammation associated with the neurodegenerative disease can be positively impacted, perhaps other symptoms can be as well.

Study Drug (Emtricitabine)

An HIV drug made by Gilead, emtricitabine (Emtriva) is similar to Lamivudine, however, emtricitabine is reported to have fewer side effects and hence one reason why it was selected. Prescribed to millions of people as an HIV therapy, it has overall been “very well tolerated,” noted John Sedivy. In the current study, participants are elderly and diagnosed with Alzheimer’s—a different target population. Hence, the need to carefully monitor for side effects of any kind is important. It should be noted however, that many elderly people with HIV have been using this class of drug without experiencing adverse reactions greater than those of the younger prescribers so Sedivy declared “there really are no significant red flags.” 

The Study

The researchers seek to assess the safety and tolerability of emtricitabine (Emtriva) in patients with early Alzheimer’s disease. Secondarily, team will assess if the drug can have a positive effect on inflammation, memory and daily function.

Participants must have early Alzheimer’s disease to qualify for this double-blind study led by Brown University. Of the 35 Phase I study participants, 25 will receive the active emtricitabine drug and 10 will be given a placebo.

Study partners include Rami Kantor, professor of medicine at Brown and HIV physician-scientist and co-director of Providence/Boston Center for AIDS Research Basic Science Core who declared, “My role is to follow the (study participants) clinically to make…sure (the medications) are safe.”

The study has been attracting attention and the local press report people are eager to participate. Dr. Sedivy was quoted by The Brown Daily Herald saying, “There is the big hope and expectation, which I think everybody shares, that this will possibly be a cure for Alzheimer’s.” He continued, “But the phase one clinical trial that the researchers are undertaking is the very first step in that direction.”

Lead Research/Investigator

Stephen Salloway, director of neurology and the memory and aging program at Butler Hospital, Martin M. Zucker professor of psychiatry and human behavior, professor of neurology

John Sedivy, Hermon C. Bumpus professor of biology and professor of medical science and co-principal investigator

Rami Kantor, professor of medicine, division of infectious diseases, HIV physician-scientist and co-director of Providence/Boston Center for AIDS Research Basic Science Core

Call to Action: Brown University and the Brown Center on the Biology of Aging have already demonstrated that emtricitabine has potential to reduce a type of age-related cellular inflammation associated with Alzheimer’s disease. This new trial represents an initial step toward determining if the drug might benefit patients. TrialSite News will monitor the progress of this 2.5-year study.

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