Clinical Trial Results at AAIC 2019 Focus on New Ideas and New Targets

LOS ANGELES, JULY 17, 2019 — New Alzheimer’s disease clinical trials, and a government-driven public/private initiative to speed them up, were highlighted at the Alzheimer’s Association International Conference (AAIC) 2019 in Los Angeles.

“It is clear, and has been for some years, that the (Alzheimer's) field needs to explore other options, and diversify the portfolio of targets. A renewed energy has been brought about by a five-fold increase in Alzheimer’s research funding at the federal level. These gains will propel already-established efforts by the National Institute on Aging, Alzheimer’s Association and others to diversify (therapeutic) targets,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer.

The Accelerating Medicine Partnership-Alzheimer’s Disease (AMP-AD) is a partnership among government, industry, and nonprofit organizations (including the Alzheimer’s Association) that focuses on discovering, validating and accelerating new drug targets. The $225 million initiative is made possible through the highest-ever levels of U.S. federal funding for research on Alzheimer’s and other dementias, approved and allocated in the last five years.

A record number of scientific abstracts - more than 3,400 - were submitted to AAIC this year, including 229 abstracts with results from or descriptions of Alzheimer’s clinical trials. AAIC 2019 also spotlighted three clinical trials using innovative methods and targets.

• One study reports, for the first time, 18-month results from an open-label extension of inhaled insulin in MCI and Alzheimer’s including significant benefits for memory and thinking, day to day functioning, and biological markers of Alzheimer’s.
• A second report describes a newly-initiated 48-week Phase 2/3 clinical trial of a drug targeting toxic proteins released in the brain by the bacterium, P. gingivalis, generally associated with degenerative gum disease. Previous research identified the bacterium in brains of more than 90% of people with Alzheimer’s across multiple studies and demonstrated that infection may trigger Alzheimer’s pathology in the brain. New human Phase 1b biomarker and cognitive data will be presented.
• An update on the U.S. POINTER study, now up and running in multiple locations. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk is a two-year clinical trial to evaluate whether intensive lifestyle interventions that target many risk factors for cognitive decline and dementia can protect cognitive function in older adults at increased risk for cognitive impairment and dementia.

“It is clear, and has been for some years, that the field needs to explore other options, other avenues, and diversify the portfolio of targets. A renewed energy has been brought about by a five-fold increase in Alzheimer’s research funding at the federal level, achieved largely due to efforts by the Alzheimer’s Association, the Alzheimer’s Impact Movement and our ferocious advocates. These gains will propel already-established efforts by the National Institute on Aging, Alzheimer’s Association and others to diversify the portfolio of drug targets for the scientific community,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer.

“Anti-amyloid drugs, though possibly helpful in the earliest stages of Alzheimer’s, have not yet proven effective in mild to moderate stages of the disease, even when they clear the brain of amyloid plaques,” said Carrillo. “However, amyloid research, especially in Alzheimer’s prevention trials like the A4 Study and the DIAN trial, may still prove fruitful. We look forward to hearing those results in coming years.”

The Accelerating Medicine Partnership-Alzheimer’s Disease (AMP-AD)
AMP-AD is a partnership among government, industry, and nonprofit organizations aiming to identify and characterize new, disease-relevant drug targets and accelerate the process of bringing new medicines to patients and families. This multisector partnership, led by the National Institute on Aging, is managed by the Foundation for the National Institutes of Health (FNIH). The combined funding and in-kind support for the first five years of this endeavor is $225 million dollars. The Alzheimer’s Association is the only non-profit organization that is a member of the AMP-AD Steering Committee.

"AMP-AD is an effort to bring the best and brightest minds from the public and the private sector together to find answers and ultimately a cure for this condition that so many people are worried about, and affected by, and where we really need those answers," said Francis S. Collins, MD, PhD, Director, U.S. National Institutes of Health, in this recent video: http://bit.ly/2XpY0b7.

The AMP-AD program operates in two domains:

• Biomarkers in Clinical Trials Project — This component of the program is testing the utility of PET Tau imaging for tracking disease progression and responsiveness to anti-amyloid treatment by incorporating longitudinal PET Tau imaging in two NIA-supported Phase II/III Alzheimer’s secondary prevention trials (the A4 study and the DIAN trial). The screening/pre-randomization data as well as the trial data and biosamples will be made available via the Global Alzheimer’s Association Interactive Network (GAAIN) platform.
• Target Discovery and Preclinical Validation Project — This component seeks to discover and characterize the next generation of therapeutic targets for AD by integrating the analyses of large-scale molecular data from human biosamples with network modeling approaches and experimental validation, and by enabling rapid and broad sharing of data and analytical results via the AMP-AD Knowledge Portal, a centralized data sharing platform. This project brings together six multi-institutional academic teams and a team of data scientists at Sage Bionetworks, a non-profit research organization enabling open science practices.

The achievements of the AMP-AD Target Discovery Project were highlighted in a series of presentations by the leading AMP-AD investigators at the pre-AAIC two-day symposium “Enabling Precision Medicine for Alzheimer’s Disease through Open Science” organized by the NIA and the Alzheimer’s Association. The symposium marked the release of more than 500 new candidate targets discovered by the AMP-AD teams, made available through the web-based interactive platform Agora, along with detailed information about how each target was derived and its druggability features.

To ensure seamless transition to the next phase of the AMP-AD Target Discovery Project, in September of 2018, NIA issued a new set of research grants; this $60M investment over the next five years will enhance the capabilities of the AMP-AD Knowledge Portal and Agora platform, expand the target discovery efforts and enable discovery of molecular signatures that can be used as biomarkers for patient stratification. The FNIH is coordinating efforts to renew and expand this transformative public private partnership by leveraging the NIA investment. One key area for strategic partnering is to extend the deep molecular profiling to brain and peripheral fluids samples collected in diverse populations, to better understand the heterogeneity of the disease and to enable a precision medicine approach to target and biomarker discovery.

“I am more optimistic today than I have ever been before about the future for treatment and early detection in Alzheimer’s disease and related dementias,” Carrillo said. “We can build on the knowledge that we have accumulated in the last 20 to 30 years but do it at an accelerated pace because we have additional dollars propelling us towards those discoveries, and initiatives like AMP-AD.”

In addition to the forward looking work of AMP-AD, AAIC 2019 highlighted three early phase clinical trials that are examples of “out of the box” thinking.

18-Month Results (Open Label Extension) of a Phase 2/3 Trial of Inhaled Insulin in People With MCI or Mild Alzheimer’s
In a Phase 2/3 clinical trial led by Suzanne Craft, PhD, Professor of Gerontology and Geriatric Medicine at Wake Forest School of Medicine, in collaboration with the Alzheimer’s Therapeutic Research Institute led by Paul Aisen, MD, 26 study sites enrolled 289 participants with MCI or Alzheimer’s. Participants received either 40-IU of placebo or insulin (Humulin-RU100, Eli Lilly) daily for 12 months, followed by a 6-month open-label extension (OLE). Outcomes included the cognitive test Alzheimer’s Disease Assessment Scale for Cognition-12 (ADASCog-12) at months 15 and 18, the functional measure Activities of Daily Living Scale for MCI (ADL-MCI), and Alzheimer’s biomarkers in cerebrospinal fluid (CSF). Results from the OLE were reported for the first time at AAIC 2019.

For the first 49 study participants, the intranasal device that delivered the insulin (Kurve Technology/Device 1) had inconsistent reliability. A new device (Impel NeuroPharma/Device 2) was used for the remaining 240 participants. The Device 2 population was pre-specified for the primary intent-to-treat (ITT) analyses, while secondary analyses examined the Device 1 ITT cohort. At the end of the initial study (12 months), the researchers found no benefits of insulin for the Device 2 population, but the Device 1 group showed a trend for better performance for the insulin group (p=0.091).

Of the 289 participants in the study, 203 Device 2 participants and 44 Device 1 participants entered the OLE. The Device 1 group treated with insulin throughout the trial had better ADASCog-12 scores at months 15 and 18 (-5.70 and -5.78 points, nominal p=0.004 and 0.018), than did participants originally assigned to placebo, and better ADL-MCI scores at month 18 (4.85 points, nominal p=0.047). For the Device 2 participants, the insulin group did not differ from the placebo group on the ADASCog-12 or other outcomes. Compliance and adverse events were similar for both treatment groups and both cohorts.

“This is a large effect in the Device 1 group, particularly as it is on top of background treatment,” Craft said. Participants in the clinical trials were able to continue to take other approved medicines for Alzheimer’s. “At 18 months, the results show a prolonged, statistically significant benefit for the insulin-treated group who used the Device 1 that strengthens over time, with a pattern consistent with a disease modifying effect.”

Reported for the first time at AAIC 2019, biomarker data for the Device 1 group showed the Abeta42/40 ratio (p=0.01) and Abeta42/tau ratio (p=0.03) significantly improved for the insulin treated group. These ratios provide integrated measures of Alzheimer’s-related pathology in the brain and, according to Craft, favorable changes support a possible disease modifying effect of the intervention. Amyloid beta 42 (Abeta42) is the primary component of the amyloid plaques that are one of the hallmark brain lesions of Alzheimer’s.

“While our Device 1 study population is small, the new data make a compelling case that there may be long-lasting beneficial effects of intranasal insulin for cognition, behavior and biomarkers that increase over time, as long as the device is getting insulin into the central nervous system,” said Craft. “These new results provide sufficient evidence for a larger study to be conducted.”

“It is very important to note that we are seeing what may prove to be an effective treatment for people who already are showing dementia symptoms,” Craft added. “It is crucial that we amplify efforts to treat people living with Alzheimer’s and other dementias today, and those who will get it in the coming years.”

Randomized Clinical Trial Targets Toxic Bacterial Proteins in Alzheimer’s
According to the Alzheimer’s Association, the idea that bacteria, viruses or other microbes may play a part in brain disease, including Alzheimer’s, is not new, but has recently been gaining strength and scientific evidence. Recently, evidence based on multiple, large data sets has lent support and credibility to the idea; but much more research is needed to confirm this work. To advance the discussion, AAIC 2019 hosted a “debate” on Tuesday, July 16 between five scientists with varying ideas and viewpoints on this emerging topic.

Also at AAIC 2019, as part of the Developing Topics poster session, Cortexyme (South San Francisco, CA) described their Phase 2/3 study of COR388, known as the GAIN Trial (GingipAIN inhibitor for treatment of Alzheimer’s disease). The company says it is “the first large, randomized, international study to test whether targeting P. gingivalis bacteria can slow or halt the progression of Alzheimer’s.”

The drug targets toxic virulence factors, called gingipains, secreted by Porphyromonas gingivalis, which is known primarily as the cause of chronic progressive degenerative gum disease. This Phase 2/3 trial (NCT03823404), which was initiated in April 2019, plans to recruit up to 570 people with mild to moderate Alzheimer’s at about 100 locations in the U.S. and Europe. Participants will be randomized to one of two doses of COR388 (40mg or 80mg twice daily) or placebo for 48 weeks. The primary endpoint is change in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11); secondary endpoints include ADCS-ADL and CDR-SB, which are well-established measures of daily functioning and dementia severity, respectively. Top-line results from the GAIN trial are expected by the end of 2021.

Previously, researchers identified P. gingivalis in the brains of greater than 90% of people with Alzheimer’s across multiple studies. In animal models assessed at several different independent laboratories, oral P. gingivalis infection invaded the brain and was associated with Alzheimer’s-type brain changes, including amyloid plaques, inflammation and the death of neurons in the hippocampus, a key region of the brain for memory. In tests on these animal models conducted by Cortexyme, the disease-related effects were blocked by COR388. In Phase 1b studies in people, the drug was well tolerated.

In new biomarker data reported for the first time at AAIC 2019, in the Phase 1b trial, people taking COR388 had roughly 30% lower levels of inflammation as measured by the inflammatory biomarker RANTES over the 28 days of treatment (p<.01). Study participants also had about 30% lower levels of fragmented proteins in the cerebrospinal fluid (p<.05).

“We are encouraged by the positive response from both investigators and patients in participating in the GAIN trial,” said Michael Detke, MD, PhD, Chief Medical Officer of Cortexyme. “With the GAIN trial, we believe we have designed a very robust study to assess the efficacy of COR388 in symptomatic Alzheimer’s patients who could benefit from treatment.”

U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk
With the aging of the population and the explosion of news cases of Alzheimer’s and other dementias worldwide there is an urgent need to find effective treatment and prevention approaches that can arrest or reverse the disease at its earliest stages.

Laura Baker, Ph.D., associate professor of gerontology and geriatric medicine at Wake Forest School of Medicine, and one of the principal investigators of the U.S. POINTER study, said, “Lifestyle interventions focused on combining healthy diet, physical activity and social and intellectual challenges represent a promising therapeutic strategy to protect brain health.”

The Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will compare the effects of two lifestyle interventions on brain health in older adults at risk for memory loss in the future. U.S. POINTER is the first such study to be conducted in a large group of Americans across the United States.

“We envision a future where we can treat and even prevent Alzheimer’s through a combination of brain-healthy lifestyle and targeted medicines, as we do now with heart disease,” Carrillo said. “We hope to prevent millions from dying with Alzheimer’s and reduce the terrible impact this disease has on families.”

Approximately 2,000 volunteers at five U.S. sites will be enrolled and followed for two years in the study. The study’s vanguard site and coordinating center is Wake Forest School of Medicine, Winston-Salem, NC, (PIs: J. Williamson, J. Cleveland) in partnership with the Western Carolina Chapter of the Alzheimer’s Association (Lead: K. Lambert), which already has begun enrolling participants. The second site led by the University of California-Davis, Davis, CA (PIs: R. Whitmer, S. Farias) in partnership with the Northern California and Northern Nevada Chapter of the Alzheimer’s Association (Lead: C. Day), is now recruiting.

At AAIC 2019, two additional U.S. POINTER sites were announced:

• The Chicago area will include a partnership between Rush University Medical Center (Site PI: M.C. Morris), Advocate Health Care (Advocate PI: D. Gitelman), and the Illinois Chapter of the Alzheimer’s Association (Leads: M. Chavin, T. Reynolds).
• The Houston area that includes a partnership between Baylor College of Medicine (PIs: V. Pavlik, M. Yu), Kelsey Research Foundation (Lead: A. Alexander), and the Houston and Southeast Chapter of the Alzheimer’s Association (Lead: R. Elbein).

According to Baker, at the North Carolina site more than 100 adults with a first degree family history of a memory impairment are currently screening for the study, and another 100 are completing their baseline assessments at the clinic and initiating the interventions. A fifth site will be added soon.

People age 60 to 79 will be randomly assigned to one of two lifestyle interventions. Both groups will be encouraged to include more physical and cognitive activity and a healthier diet into their lives and will receive regular monitoring of blood pressure and other health measurements. Participants in one intervention group will design a lifestyle program that best fits their own needs and schedules. Participants in the other intervention group will follow a specific program that includes weekly healthy lifestyle activities.

“U.S. POINTER provides an unprecedented opportunity to test whether intensive lifestyle modification can protect cognitive function in older Americans who are at increased risk of cognitive decline and dementia,” Baker added.

About the Alzheimer's Association International Conference^® (AAIC^®)
The Alzheimer’s Association International Conference (AAIC) is the world’s largest gathering of researchers from around the world focused on Alzheimer’s and other dementias. As a part of the Alzheimer’s Association’s research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
AAIC 2019 home page: aaic.alz.org
AAIC 2019 newsroom: aaic.alz.org/pressroom.asp

About the Alzheimer's Association^®
The Alzheimer’s Association is the leading voluntary health organization in Alzheimer's care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. Visit alz.org or call +1 800.272.3900.

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• Suzanne Craft, PhD, et al. Open Label Extension Results from a Phase II/III Trial of Intranasal Insulin. (Funders: U.S. National Institute on Aging, Eli Lilly (donated insulin and placebo))
• Mike Detke, MD, PhD, et al. Initiation of the Phase 2/3 GAIN trial of COR388, a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease (AD) based on Phase I a/b safety, PK, biomarker and efficacy data. (Funder: Cortexyme)
• Laura Baker, PhD, et al. U.S. POINTER: Study Design and Launch. (Funder: Alzheimer’s Association)

Media Contacts: 
Alzheimer’s Association Media Line, +1 312.335.4078, media@alz.org
AAIC 2019 Press Office, aaicmedia@alz.org

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