GAP partner, Genetech, is working with us on our Bio-Hermes study to increase diversity in Alzheimer’s clinical trials.

Missing a trial goal in Alzheimer’s disease is a pretty common occurrence—see crenezumab, for the latest. But Genentech’s latest reported miss was something different.

The Roche unit wanted to build a clinical trial program for its lead candidate gantenerumab that reflected the people who actually get the disease. That means—according to the Alzheimer’s Association—Black Americans and Hispanic people, who are much more likely to have the devastating neurodegenerative disease than white Americans. And yet they’ve historically been left out of trials for promising candidates.

Genentech wanted to change that with learnings that span 20 years of drug development in Alzheimer’s, but unfortunately, it wasn’t meant to be. In the phase 3 Graduate program, Genentech was unable to recruit the kind of population that would truly reflect the predominance of Alzheimer’s in non-white communities, according to Greg Rippon, M.D., vice president and chief medical partner of neurology, ophthalmology and internal medicine.

In Graduate 1 and 2, Genentech has enrolled 985 and 981 participants, respectively, across 30 countries. Despite including three pilot study locations and education campaigns that specifically tried to target more diverse communities, study referrals remained low. Across the two studies, about 10% of patients identified as Hispanic or Latino on ethnicity. Just 3% identified as Black or African American and 0.7% as Asian on race demographics. Otherwise, 96% of patients identified as white. 

A recent report on shortcomings in U.S. clinical research cited a phase 2 trial for Genentech’s crenezumab for a lack of diversity. One mid-stage trial had 360 participants in 83 sites and six countries, but still had 97.5% white patients and only 2.8% Hispanic.

Recruitment for the Graduate program, which is expected to read out by the end of the year, initiated back in 2018, just as Genentech was internally forming its organizational approach to increasing enrollment for underserved populations for all of its clinical programs.

“We did take the opportunity with Graduate to pilot some efforts to reach out to the community in an educational capacity and to try to increase enrollment and unfortunately, those didn’t end up being successful,” Rippon said. “But you learn from those experiences.”

Genentech has since applied the learnings to studies for the approved multiple sclerosis med Ocrevus, and they’re ready to give it a try in Alzheimer’s again. At the Alzheimer’s Association International Conference, Genentech announced a dedicated study in its Graduation program for gantenerumab that will aim to enroll a more diverse population.

The company moved in 2008 to develop a subcutaneous formulation of gantenerumab to make dosing easier—even perhaps, in the home by a qualified healthcare provider. That would mean easy access for patients who won’t have to travel as often to a clinical trial site. That’s one of the key challenges that has been cited in increasing diversity in clinical trials. Genentech is also studying administration by a non-healthcare provider caregiver in the phase 3 Graduation program, which will include the dedicated study enrolling diverse populations.

The Skyline program, which will include some of the new diversity initiatives, is a secondary prevention study. To help find a wider population, Genentech has engaged the Global Alzheimer’s Platform Foundation Network, or GAP-Net, to develop site-based efficiencies and trial effectiveness interventions. This will include community engagement events, social media campaigns and outreach in primary care facilities. Genentech will also implement a site optimization program. Skyline will allow patients to self-dose at home and other flexibilities that could mean patients only have to travel for on-site visits twice a year.

“There’s a lot that we tried in Graduate and then there’s a lot that we’re trying to introduce in the context of Skyline and in the new dedicated study to enhance underrepresented patient enrollment,” Rippon said.

Genentech is also participating in GAP-Net’s Bio-Hermes research study to help identify blood or digital tests that could predict the presence of amyloid plaques in the brain, which is a hallmark of the disease. The study is going to stay open until at least 20% of the population is made up of African American, Black, Hispanic or Latino participants.

And then Genentech is bringing the trials right to the patients. Multiple sites for Graduate will have Spanish language capabilities and at least two sites are being set up in Puerto Rico, even though Rippon said the overall effort to boost enrollment in underserved populations for this program was unsuccessful.

Further work is being done with Us Against Alzheimer’s, the Alzheimer’s Foundation of America and the Alzheimer’s Association as part of a disparities engagement network to try and find new solutions for addressing equity and access issues, according to Rippon. 

And then there’s a new auto-injector device in development, which could take ease of dosing a step further. Rippon said that device has been developed solely to provide a better experience for patients and caregivers.

All of this could mean that patients get to stay home—which is great for efforts to boost diversity, but also in general for Alzheimer’s care. Rippon said that travel is logistically difficult for Alzheimer’s patients. They may need to travel with a caregiver, who has to take time off work, once or twice a month for an infusion.

“We believe that we’re at the forefront of these efforts,” Rippon said of Genentech’s diversity initiatives. He noted that Roche has done this in other therapeutic areas including ophthalmology and COVID-19, in addition to MS. “We’ve organized ourselves internally so that we can apply learnings across areas and draw from the expertise—both internal expertise but importantly, expert external expertise—in how to best move this forward and do what we can to enroll this population. So it’s a very high priority for us as an organization.”

Going forward, Rippon said that all of these measures should be included in future Alzheimer’s trials from the beginning of clinical development. But now, Genentech is ensuring that therapies get this treatment in mid-stage development, whereas later-stage drugs will require a more “dedicated effort” to boost diversity. That could mean future trials post-approval, he noted.

Rippon said, of course, that the most important feedback they’ve heard from patients is that they have access to “an effective treatment, safe treatment”—and on that, the jury is quite literally still out on gantenerumab. Genentech is expecting a critical readout in the fourth quarter that could provide some clarity on whether it works or not to improve the cognitive symptoms of Alzheimer’s.

It’s been a tough haul in the clinic for Genentech and its peers. The company most recently suffered a failure of another in its pipeline, crenezumab, which was unsuccessful in patients with early disease and a specific genetic form of Alzheimer’s.

On that therapy’s future, Genentech has not made any decisions. But Rippon said that “the crenezumab experience” underscores the need to persevere in Alzheimer’s.

Dr. Richard Holub from GAP-Net site Neurological Associates of Albany talks about his commitment to finding a cure for Alzheimer’s disease and says he won’t be retiring anytime soon.

Dr. Richard Holub has spent the past 40 years dedicated to Alzheimer’s research.

He has treated thousands of Alzheimer’s patients and completed more than 125 clinical trials.

At 74, the president of Neurological Associates of Albany is one of the longest-tenured Alzheimer’s researchers in America.

Think of him as the marathon man of Alzheimer’s research.

Instead of a depressing interview about the heartbreaking and unstoppable scourge of Alzheimer’s that I anticipated, the afternoon I spent with Holub at his office on Madison Avenue near Washington Park left me feeling optimistic.

“A sense that hope is on the horizon is pervasive among Alzheimer’s researchers,” Holub told me. “With all the advances in the last few years, I feel certain that we will see an end to this disease.”

I asked, before he retires?

“I will continue working until this disease is just a bad memory,” said Holub, who employs a staff of 12 with 60 people currently enrolled in 10 clinical trials and dozens of patients in treatment.

Holub will travel to San Diego at the end of July to attend the Alzheimer’s Association International Conference. It draws thousands of researchers from more than 120 countries, who make presentations on emerging research and innovative practice techniques. A key area will be presentations on biomarkers, which is where Holub is focusing his energies.

Using advanced medical technology, for the past couple years Holub uses biomarkers to help diagnose Alzheimer’s in younger people before they begin displaying common symptoms such as memory loss that disrupts daily life and difficulty completing familiar tasks.

“It is a very complicated disease. We’re applying the lessons of our research and we’re getting better at targeting the links in how the disease progresses,” Holub said.

He uses highly specialized blood tests and positron emission tomography, or PET, scans with a trace of a radioactive substance in the brain to reveal abnormal deposits of beta-amyloid proteins, known as plaques, as well as abnormal accumulation of the tau protein. Tau forms threads that stick together to create tangles inside neurons. Both proteins block communications between brain synapses as Alzheimer’s disease advances.

“The biomarkers help us detect Alzheimer’s early on in patients before symptoms emerge,” Holub said. “We discovered that we were treating people too late. The key is to diagnose the disease while everything is normal and to begin treatment early to slow or halt the progression.”

Holub was involved in clinical trials for all five drugs that are FDA-approved to treat memory loss caused by Alzheimer’s disease, including the leading drug, Aricept.

Holub scoffs at over-the-counter dietary supplements such as Prevagen and Neuriva that claim to combat memory loss.

“Snake oil,” he said. “There is zero evidence that any of them work.” The same goes for the herbal remedy ginkgo biloba, a passing fad Alzheimer’s treatment in decades past. “It had no effect,” he said.

Holub’s is the only research facility in the region that tests patients for a late-onset Alzheimer’s risk gene called apolipoprotein E, or APOE. He has a National Institutes of Health, or NIH, grant for that study. The clinical trials are funded by pharmaceutical companies, including Eli Lilly, Eisai, Janssen Pharmaceuticals, Cassava Sciences and others.

New studies are also focusing on inflammation in the brain as a potential cause of Alzheimer’s and risk factors associated with diabetes and obesity. 

Six of Holub’s 10 clinical trials are still accepting new patients. There is no charge to the patient and no health insurance is required. Patients are screened and must sign consent forms. If an experimental drug is approved, participants in the clinical trials are first in line to receive it.

All Holub’s trials are conducted as double-blind placebo trials, so neither the participants nor the researchers know which treatment or intervention participants are receiving until the clinical trial is completed. Holub’s participants come from throughout upstate New York and parts of Vermont, Massachusetts and Pennsylvania. Clinical trials typically last 18 months and participants visit Holub’s office every two weeks or monthly, depending on the trial. The average age of participants is mid- to late-60s. Most are referred by a primary care physician. Some find Holub’s website (https://www.neurologicalassociatesofalbany.com) or call the office at 518-426-0575.

“They tell us this is a place they can speak freely and share their concerns and fears about Alzheimer’s,” said Mary Ellen Torrisi, senior research coordinator for the past eight years. “The trial participants want to contribute to advancing science and finding new treatments. Our patients really love Dr. Holub.”

Holub is in it for the long haul. He works out of a chalet-style building he purchased in 1979, with the ground floor for seeing patients and the basement level for conducting clinical trials. He is mild-mannered, soft-spoken and methodical. His pace is unhurried.

“This work is not a sprint,” said Holub, who grew up in Amityville on Long Island. He earned his medical degree at Georgetown University School of Medicine and came to Albany Medical Center for a residency in neurology in 1973. He never left.

His first brush with Alzheimer’s came as a youngster when he noticed that his maternal grandfather, William DeMarco, who helped raise him, struggled to find common words and had short-term memory loss. He died in 1960 at 69 after a rapid acceleration of symptoms, with arteriosclerosis listed as the cause of death. This was well before Alzheimer’s was widely recognized and commonly diagnosed in the U.S. beginning in the mid-1970s.

German physician Alois Alzheimer first described “a peculiar disease” in 1906 in a 51-year-old female patient who soon died. During an autopsy, Alzheimer saw abnormal deposits in and around nerve cells. He classified it as “presenile dementia” and considered the woman’s disease exceptionally rare. In 1910, German psychiatrist Emil Kraepelin, an associate of Alzheimer, first coined the term “Alzheimer’s disease” in a medical text.

“And there it pretty much sat as a one-off in a textbook for the next 70 years,” Holub explained.

By 1976, Alzheimer’s was recognized as the most common form of dementia. The Alzheimer’s Association was founded in 1980. Four years later, researchers identified beta-amyloid, a protein that collects between neurons and clumps together to form plaques. These plaques evolve from glue-like to an almost concrete consistency that leads to brain atrophy – the final stage of Alzheimer’s before death.

“I’m not going anywhere until we solve this problem,” Holub said. “That time is coming.”

Originally posted by the Times Union on July 20, 2022

Individuals who are usually at risk of developing Alzheimer’s can take part in pre-screening visits at every mobile site stop.

Global Alzheimer’s Platform Foundation (GAP) has introduced a new mobile health site to lower barriers to the participation of underrepresented communities in Alzheimer’s clinical trials.

Around 1% of the African Americans and Hispanics with Alzheimer’s take part in trials where therapies may be available for them.

This mobile research site is intended to address this disparity and from 19 July, the mobile site will make stops in the Orlando, Florida metropolitan area, US.

GAP president John Dwyer, Jr said: “Increasing diversity in Alzheimer’s clinical trials is the first best step we can take towards advancing the drug development pipeline to better treat — or eventually cure — this terrible disease. 

“By bringing clinical trials to people in their communities, we can help reduce the barriers that may inhibit people from participating in Alzheimer’s research studies.”

These problems could comprise transportation expenses and language barriers, among others.

Individuals who are usually at risk of developing Alzheimer’s can take part in pre-screening visits at every GAP mobile site stop, which requires only 15 to 20 minutes compared to standard ones needing several hours. 

The screenings will aid in determining if an individual can take part in an Alzheimer’s prevention study, which is the first GAP-facilitated fully supported prevention trial.

Free memory screenings, brain health education and information from other regional partners on community resources are the other resources provided by the mobile site at each stop.

GAP Recruitment and Strategic Initiatives associate director Tamiko Magee-Rodgers said: “Helping connect traditionally underrepresented people with educational resources, as well as building trust in communities where Alzheimer’s is so prevalent, is something that we’re excited to do.”

A patient-centric non-profit organisation, GAP focuses on expediting the delivery of new treatments for neurological disorders by lowering trial cost and duration. 

Currently, over 100 research centres across the globe are part of its network.

Originally posted by Clinical Trials Arena on July 15, 2022.

GAP President John Dwyer was quoted in the Wall Street Journal speaking about how the Centers for Medicare and Medicaid Services coverage decision limits Alzheimer’s patients.

The commercial failure of Biogen Inc.’s drug Aduhelm is putting new focus on the state of research into the causes of Alzheimer’s disease.

More than six million people in the U.S. are living with the progressive type of dementia, according to the Alzheimer’s Association, an advocacy group.

Aduhelm was hailed as a potential blockbuster that targeted a root cause of the disease by clearing a sticky protein known as amyloid from the brain. Abnormal accumulations of amyloid called plaque and tangles of another protein known as tau are characteristic features of the brains of people with Alzheimer’s.

“If you cut the brain open and amyloid plaque is absent, Alzheimer’s was not the cause of disease,” said Jeffrey Cummings, director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas.

But research into the benefits of targeting amyloid in Alzheimer’s patients has been mixed. There are more questions than answers about the role amyloid plays in the development of the disease, neurologists say.

“Alzheimer’s is a complex disease. It’s unlikely that a single mechanism is contributing to it,” said Maria Carillo, the Alzheimer’s Association’s chief science officer.

Other potential causes and risk pathways that Alzheimer’s researchers are probing include dysfunctional tau metabolism and the possibility that tau buildup can spread among cells like an infection. There are also theories that Alzheimer’s could be a form of diabetes or the result of a viral infection. Exposure to toxic substances, head trauma and lifestyle factors like diet and exercise have also been identified as possible risks. The Centers for Disease Control and Prevention said Friday that getting more aerobic exercise and managing high blood pressure could reduce the impact of some risk factors for Alzheimer’s.

The amyloid hypothesis, posited in the 1990s, proposes that amyloid-plaque formation leads to a cascade of negative effects including the accumulation of tau, inflammation, cell death and the loss of synapses, the junctions through which nerve cells known as neurons communicate with each other.

“It was so compelling that it triggered the pharmaceutical industry to act,” said Scott Small, director of the Alzheimer’s Disease Research Center at Columbia University.Advertisement – Scroll to Continue

But new data has poked holes in the hypothesis. A 2020 meta-analysis of 14 clinical trials involving drugs that target amyloid found the medications largely effective at clearing at least some plaque, but the drugs mostly had no or a small effect on cognition among Alzheimer’s patients.

Two clinical trials involving Aduhelm were included in the analysis. One showed no cognitive benefit to patients, while the other suggested some benefit. Biogen halted the trials after an independent data-monitoring committee concluded the drug wasn’t helping patients.

Amyloid is secreted by neurons in brains both healthy and diseased. Excessive buildup of the protein or the inability to sufficiently clear it can lead to problems, according to researchers. But amyloid plaque has also been found in the brains of healthy people. Some research has suggested that a small amount of amyloid inside neurons could be necessary for brain health, Dr. Small said.

For patients with a rare, inherited form of Alzheimer’s, research has linked certain genetic mutations to amyloid-plaque formation. For most Alzheimer’s patients, however, it is less clear what might trigger amyloid buildup.

Dr. Small and others think clues could be found inside neurons, in a system known as the endosomal-recycling pathway. Dr. Small compared a neuron to the New York subway system, where endosomes, a type of specialized structures inside cells, are a major junction.

“Proteins are flowing in and out, lines are converging at Grand Central Station,” he said. “If you have a defect there, you get traffic jams.”

Enlarged endosomes have been found in the brains of many Alzheimer’s patients, Dr. Small said. The pileups appear to promote amyloid buildup as well as synaptic loss. Causes of the jams could include rare genetic mutations as well as diabetes and obesity, Dr. Small said. Head injury and the gut microbiome—microorganisms that populate the gastrointestinal tract—could also play a role. Dr. Small is involved in Retromer Therapeutics Corp.’s work on a drug targeting a part of the endosomal recycling pathway.

Another theory is that a dysfunctional immune response involving cells called microglia could contribute to Alzheimer’s. Microglia account for about 10% of the cells found in the brain. They remove debris, pathogens and toxic proteins including amyloid plaque. When microglia aren’t functioning properly, possibly because of a genetic mutation or other age-related factors, their ability to clear plaque diminishes, said Beth Stevens, a neuroscientist at the Broad Institute of MIT and Harvard. Microglia are key players in neuroinflammation too, which can contribute to synaptic loss and cell death. They might also play a direct role in clearing synapses, which can lead to synaptic dysfunction and loss, Dr. Stevens said.

The buildup of amyloid might also impact microglia function, research has shown. “Amyloid can make these cells misbehave,” said Dr. Stevens. Future therapies for Alzheimer’s could involve enhancing the protective qualities of microglia and reducing their detrimental effects, she said.

More than 140 drugs are in the pipeline as potential Alzheimer’s treatments, including drugs that target tau and microglia function, according to a survey of registered clinical trials in the U.S. Three other amyloid-targeting monoclonal antibodies, which are in the same class as Aduhelm, are in development. One, called lecanemab, was submitted this month by co-developers Biogen and Japan-based Eisai Co. to the Food and Drug Administration for potential approval.

When the Centers for Medicare and Medicaid Services in April said it would limit coverage of Aduhelm to patients in clinical trials, it also said it would limit coverage of all monoclonal antibodies directed against amyloid. The public insurer said it could reconsider that decision if better data were presented.

Some neurologists say the risks of amyloid-targeting monoclonal antibody treatments, including brain swelling, outweigh potential therapeutic benefits. Others say the drugs could have some positive effect, particularly if administered early in the disease’s progression. Researchers are attempting to identify potential biomarkers in the blood and cerebrospinal fluid that could be used to detect Alzheimer’s early. They say it could be a game-changer in Alzheimer’s treatment.

Even a small positive effect could benefit some patients given the dearth of other options, some neurologists say. No other therapy is expected on the market for at least five years, according to the Global Alzheimer’s Platform Foundation, which funds Alzheimer’s research.

“If you’re a patient with mild cognitive impairment, your only hope is one of these four drugs,” said John Dwyer, president of the foundation.

Originally posted by the Wall Street Journal on May 22, 2022.

GAP-Net Site, Neurological Associates of Albany, was featured in the news about a new trial they are participating in.

Over the last five years, Jim Manuel says he slowly started to lose bits and pieces of his life. Pieces so small, it was easy for his wife and kids to think he was imagining it.

“There are just parts that I don’t remember as clear, and I don’t trust my memory as much. Also names, where it used to be like that, now it may take me a second or two — or maybe a couple — to be able to come up with it,” he explains to NEWS10’s Mikhaela Singleton.

“Initially, I put it off. For six months to a year I would say, I was scared. It was like if I acknowledged it, it makes it real,” he goes on to say.

However, Manuel, 62, says it was hard to ignore with his family history. He lost both his parents and grandparents to dementia, with his mother passing just a little more than one year ago.

“[It’s] terrifying, you know? I feel like I know what’s gonna happen if I do nothing, so therefore it is so critically important that I do something,” he says through emotion.

Manuel is now a patient at Neurological Associates of Albany — a local Alzheimer’s research and treatment center. Dr. Richard Holub says his office will be one of only 46 in the nation participating in a new Phase 3 clinical trial for LIFT-AD. The therapy by Athira Pharma is able to penetrate the wall protecting the brain called the “blood brain barrier”.

“They developed a small molecule which can be delivered by an insulin-like syringe. Once a day, and it’s very well received,” Dr. Holub explains.

LIFT-AD is designed for those with mild to moderate Alzheimer’s symptoms and aids by activating one of the brain’s naturally occurring regenerative systems, the HGF/MET pathway. Holub says this treatment option represents a new wave of Alzheimer’s research targeting the small, early contributors to the disease to hopefully prevent cognitive decline before it starts.

“In the brain and in neurodegenerative disease, there are forces that are promoting degeneration and there are counter forces focusing on regeneration. In Alzheimer’s disease, the degenerative forces gradually win over a long period of time, but what we call ‘neurotrophic factors’ push from the positive side against the progression of the disease to stabilize, slow down the disease, and potentially improve patients,” Dr. Holub explains.

“[LIFT-AD] initiates a cascade of events that are positive. So it’s neuroprotective, it’s neurorestorative, it reduces inflammation by one way. By another way, it improves blood flow,” he says. “If the trial goes well, as I hope it does, I could expect to see a measurable improvement in patients.”

He says the drug also stimulates the P300 system of the brain, which is critical to measuring the progression of Alzheimer’s. He says a successful treatment can lead to better cognitive processing and working memory.

Until 2021, the FDA had not approved a new Alzheimer’s treatment in more than 15 years. With only five approved methods on the market, the more than five million Americans suffering the disease had little to choose from.

Dr. Holub says the LIFT-AD trial is one of many now surfacing thanks to new understanding of the brain.

“There’s this explosion of understanding, and we realize that it’s in our grasp. It’s a hopefulness I can say we haven’t had in the 30-something years I’ve been doing this research,” Holub says. “Just in the last year or two, there’s a certain optimism, a certain sense, that we’re going to get there.”

“The first patient to be cured of Alzheimer’s is out there right now. So I mean, whether it’s me or someone else, that is energizing,” says Manuel.

Although he’s not currently enrolled in the LIFT-AD trial, Manuel says he came to Neurological Associates of Albany for just such opportunities.

“I could not be more enthusiastic. If I had to hitchhike to get here, I would do it. What really appealed to me is that they’re looking for people that are like me, pretty much asymptomatic or in the early stages. That drive like we’re going to get ahead of it, that’s obviously a lot more desirable than getting to the day where I don’t remember my wife’s name. I feel like even if we don’t succeed, at least I contributed something,” he says.

Neurological Associates of Albany is currently looking for eligible participants in the LIFT-AD trial. Visit the research center’s website here or call 518-426-0575.

Originally posted by News10 on May 3, 2022.