Research Highlights by Padmaja Genesh November 2021
Nasal vaccine for Alzheimer's enters phase 1 trial
Scientists from the Brigham and Women’s Hospital, in Boston, have launched a phase 1 clinical trial to see whether a nasal vaccine against Alzheimer’s Disease could be safe for humans.
The vaccine uses the adjuvant Protollin to activate white blood cells located in lymph nodes in the neck, to clear beta amyloid plaques. As a part of other treatments, this has been shown to be safe in humans.
While the beginning of the phase 1 trial is an exciting development, there are still many hurdles in proving that the vaccine is a safe and effective treatment. There is a significant gap between mouse models and human participants. In Alzheimer’s disease, we have a poor track record of translating from mice to humans.
This trial involves only 16 people, and it is looking primarily at safety. They are recruiting people who are older and actually have symptomatic Alzheimer’s disease and using tiny amounts of this vaccine to make sure it’s safe for people with Alzheimer’s disease.
If it proves to be safe for the participants, they would go on to another stage of the trial, where they would start to look at whether it’s effective. The take-home from this is that it’s exciting that things are moving forward, but it’s very early days, and we’re not sure if it’s going to be even safe, much less effective.
The most important take-home message of any study like this is that, right now, we estimate that about 40% of all-cause dementia, of which Alzheimer’s is about 60%, could be prevented by lifestyle, modifiable risk factors.
Trial Testing ALZ-101 Alzheimer’s Vaccine Recruits First Patient
ALZ-101 was developed using a proprietary AβCC technology, in which researchers create amyloid-beta oligomers (small fragments) that can no longer form neurotoxic fibers, known as fibrils.
The ALZ-101 vaccine is based on these changed amyloid-beta-42 oligomers — called amyloid-beta-42CC. These oligomers trigger the body to produce antibodies that can recognize amyloid-beta forms that can develop into neurotoxic fibrils.
Preclinical studies of ALZ-101 demonstrated that the therapy works specifically against those oligomeric forms that are found in the brain and spinal cord, and there seem to be no toxicity or inflammation concerns associated with the treatment.
The new Phase 1b clinical trial for ALZ-101 is a placebo-controlled, double-blind study, meaning that neither the researchers nor the participants will know which individuals are receiving the medication and which the placebo. It will be carried out in Finland by Alzinova’s partner, Clinical Research Services Turku (CRST).
The trial plans to enroll 26 patients with early Alzheimer’s disease, and its primary goal is to assess the ALZ-101 vaccine’s safety and tolerability.
Other goals, or endpoints, are to evaluate the body’s immune response to the vaccine after multiple doses, as well as to assess a number of biomarkers associated with Alzheimer’s.
Top-line results from the trial are expected in the second half of 2023.
Atuzaginstat Shows Potential in GAIN Trial Patients With Severe Gum Disease
Atuzaginstat is an orally administered small molecule that works to block the activity of gingipains — the toxic enzymes released by Porphyromonas gingivalis (P. gingivalis), a bacteria responsible for gum disease, that has been linked with Alzheimer’s Disease.
Treatment with Atuzaginstat (COR388) appeared to slow cognitive decline In a subset of patients with mild to moderate Alzheimer’s and evidence of severe gum disease due to P. gingivalis infection, according to results from the Phase 2/3 GAIN clinical trial.
While all patients in the GAIN study showed evidence of P. gingivalis infection in their cerebrospinal fluid, this patient subgroup had evidence in their saliva as well, indicating a more severe infection.
Across all treated study patients, however, Atuzaginstat’s use for over one year failed to meet this primary trial goal, or its other main goal, that of improving daily life activities.
The GAIN trial (NCT03823404) followed 643 adults, ages 55 to 80, with mild to moderate Alzheimer’s. Participants were randomized to either 40 or 80 mg of Atuzaginstat as an oral capsule, or to a placebo, twice daily for 48 weeks (about a year).
In the 242 patients with detectable levels of P.gingivalis DNA in their saliva at the study’s beginning, there was 57% slowing of cognitive decline in the 80 mg group and a 42% slowing in the 40 mg group, compared with those on placebo. Results also showed a trend toward benefit on gingival pocket depth in the 242 patients with P. gingivalis DNA detectable in saliva. Adverse events were reported to be mild.
No significant benefits in terms of daily life function, as assessed by the ADCS-ADL scale, was seen in this patient subgroup.
2 Trials Testing Oral Varoglutamstat Now Enrolling in US, Europe
Vivoryon Therapeutics is looking to enroll patients at different stages of Alzheimer’s disease for two ongoing, Phase 2 trials evaluating the safety and efficacy of its investigational oral treatment Varoglutamstat.
Varoglutamstat has shown evidence, in earlier trials, of improving cognition, memory, and attention in Alzheimer’s patients, with “encouraging results after only 12 weeks of weeks of treatment,” the company said in a press release.
Varoglutamstat (PQ912), a small molecule taken as an oral pill, is able to block the activity of an enzyme called glutaminyl cyclase. This enzyme is present at abnormally high levels in the brains of Alzheimer’s patients and is known to play a role in the formation of a particularly toxic form of amyloid-beta, called the N3pE amyloid.
N3pE amyloid acts as a seeding factor, promoting the clumping of amyloid-beta to form amyloid plaques- one of the hallmark features of Alzheimer’s Disease.
Glutaminyl cyclase is also important for the stability and activity of the pro-inflammatory CCL2 protein, which promotes tau protein clustering —causing tangles. Varoglutamstat holds the potential to lessen neuroinflammation and cognitive decline.
The first trial, a Phase 2b study called VIVIAD (NCT04498650), is currently underway at a dozen clinical sites in Denmark, Germany, and the Netherlands. It is aiming to recruit 250 patients with mild cognitive impairment and mild dementia due to Alzheimer’s. Information on enrollment is available here.
A complementary study — the first in the U.S. testing Varoglutamstat — is underway at the University of California San Diego (UCSD) School of Medicine. That Phase 2a/b study is called VIVA-MIND (NCT03919162).
Its initial enrollment target is 180 patients, with early stages of Alzheimer’s disease. More information is available on the trial page.
Massachusetts Center Will Use AI to Help Improve In-home Care
The MassAITC project was recently launched to focus on using artificial intelligence (AI) to improve in-home care for older adults and others with Alzheimer’s disease, with the help of a five-year, $20-million grant from the National Institute on Aging, a part of the National Institutes of Health.
MassAITC, which stands for Massachusetts AI and Technology Center for Connected Care in Aging and Alzheimer’s Disease, will find ways artificial intelligence can be used to support patients at home with devices such as wearable and contactless sensors.
More than 90% of older Americans would prefer to age at home, according to the release, but without support, this goal is often out of reach for most. At-home devices hold significant promise, but they have not been specifically developed for older adults or Alzheimer’s patients, nor are they capable of being delivered and managed remotely and adapted to a patient’s needs.
“Artificial intelligence has the potential to transform important areas of science and medicine, but there is a critical need to bring the power of AI to the patients, caregivers and clinicians who need it most,” said Paul Anderson, MD, PhD, senior vice president of research and education at Brigham and Women’s Hospital, which is collaborating with UMass Amherst.
The grant would allow experts from across the state to come together to help address gaps in homecare.
Other collaborators in the center, which will be housed at UMass Amherst, include Massachusetts General Hospital, Brandeis University, and Northeastern University.
By bringing together these interdisciplinary institutions, the combined expertise at MassAITC can help to speed up how fast technologies and programs are brought to the public. The goal is to allow AI technologies and machine learning to provide better at-home healthcare for patients and their caregivers, according to the release.
Lower Levels of Tau Marker Seen With Aduhelm in Phase 3 Trials
Aduhelm is an antibody-based therapy designed to target and eliminate amyloid-beta plaques from the brain, potentially slowing neurodegeneration and disease progression.
Treatment with Aduhelm (aducanumab) showed a significant correlation with lower blood levels of p-tau181, a disease biomarker, and with lesser cognitive and functional decline in Alzheimer’s patients, according to a recent data analysis of two Phase 3 clinical trials.
The data, analyzed from around 7,000 blood samples collected from more than 1,800 patients who participated in the EMERGE (NCT02484547) and ENGAGE (NCT02477800) trials, were presented at the Clinical Trials on Alzheimer’s Disease Conference (CTAD), held Nov. 9–12.
The two hallmarks of Alzheimer’s disease — amyloid-beta plaques and neurofibrillary tangles of the tau protein — disrupt communication between nerve cells, which leads to a loss of brain function, as well as cognitive and functional decline.
In this new pre-specified analysis of EMERGE and EMERGE data, Aduhelm significantly lowered blood plasma levels of p-tau181 — associated with neurofibrillary tangles of tau in the brain — in a dose- and time-dependent manner compared with placebo in both Phase 3 trials.
In the high-dose group from EMERGE, p-tau levels decreased by 13% from before treatment, whereas it rose by 8% among those on placebo. In the ENGAGE high-dose group, p-tau dropped by 16% compared to a 9% increase in the placebo group.
A greater reduction in p-tau significantly correlated with slower cognitive and functional decline in all four clinical outcome assessments used in both trials, which included the Clinical Dementia Rating Sum of Boxes Score, Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale–Cognitive Subscale, and Alzheimer’s Disease Cooperative Study/Activities of Daily Living scale.
Lower levels of p-tau181 in the bloodstream were also significantly related with changes in amyloid-beta plaques, as measured by positron emission tomography (PET) scans.
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