Safety and Efficacy of Amyloid-Beta Directed Antibody Therapy in MCI, LB and Amyloid-Beta Pathology

The number one goal of the National Alzheimer’s Project Act (NAPA) is to prevent and effectively treat Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD). The development of anti-amyloid immunotherapies is perhaps the most notable advance in the ADRD treatment arsenal in recent years, but much remains to be learned about the safety and efficacy of amyloid beta focused immunotherapies. To date two such treatments, aducanumab and lecanemab, have been approved for clinical use from the U.S. Food and Drug Administration (FDA). In April 2022, the Centers for Medicare & Medicaid Services (CMS) announced a National Coverage Determination (NCD) to cover FDA-approved monoclonal antibodies that target amyloid for the treatment of AD through Coverage with Evidence Development (CED), meaning that FDA-approved drugs in this class would only be covered for people with Medicare if they are enrolled in qualifying clinical trials (including NIH sponsored trials).  In July 2023, after lecanemab converted from accelerated to traditional approval, CMS expanded coverage of lecanemab (and as applicable, other drugs in this class that receive traditional approval), to include eligible patients whose physician participates in a qualifying registry. More detailed information regarding CMS coverage of monoclonal antibody therapies directed against amyloid, including the NCD CED decision memorandum, may be found on the CMS website.

The purpose of this NOFO is to seek applications proposing randomized placebo-controlled phase 2 clinical trials to determine the safety and efficacy of monoclonal amyloid-beta antibody therapies compared to placebo in mixed-etiology dementia (MED) populations with a focus on Lewy Body Dementias (LBD). In this NOFO the mixed-etiology dementias (MED) that are of interest and in scope are mild cognitive impairment and dementia cases with both 1) evidence of Alzheimer pathology biomarkers, such as amyloid positron emission tomography and/or low cerebrospinal fluid amyloid beta 42 combined with elevated phosphorylated tau; and 2) a clinical diagnosis of LBD, including either Parkinson’s disease dementia (PDD) and/or dementia with Lewy bodies (DLB).

DLB is a relatively common cause of dementia, affecting up to 5% of the population and thought to account for up to 30% of dementia patients. It is estimated that up to 80% of DLB patients will also have evidence of AD neuropathology.  Although PDD is less common, given the prevalence of AD in the general population, many individuals with PD and cognitive impairment or dementia diagnoses may also have evidence of AD neuropathology. Thus, MED with evidence of both AD and LBD likely affects a number of Medicare-eligible individuals presenting with symptoms of cognitive impairment or dementia. However, little is known about the efficacy and safety of amyloid immunotherapy in this population. Pre-market trials of anti-amyloid agents generally excluded individuals with clinically significant symptoms or neuropathology that could indicate a dementia diagnosis other than AD.

It is important to study amyloid-beta monoclonal antibody therapies in MED populations that include LBD both to learn whether there is a clinically meaningful benefit of the intervention and to understand the risks associated with these therapies.  Of particular concern is the association of amyloid-beta antibody therapy with amyloid-related imaging abnormalities (ARIA). ARIA may be characterized by focal vasogenic edema (ARIA-E) or microhemorrhage and/or superficial siderosis (ARIA-H).  ARIA may be asymptomatic or associated with fatigue, headache, confusion, dizziness, falls, vision change or nausea. In most patients, symptoms and signs of ARIA-E resolve over time, but recurrence may occur, particularly with dose escalation, and one fatality has been reported.  Microhemorrhage (ARIA-H) is a permanent imaging finding, and in rare cases, more severe bleeds have occurred in individuals receiving amyloid-beta immunotherapy, resulting in at least two deaths.  Risk of ARIA-E appears to be associated with the ApoE4 allele, the presence of > 4 microhemorrhages on baseline MRI, and treatment initiation and dose escalation. Risk of ARIA-H appears to increase with age and cerebrovascular disease burden.

Clinical trials enrolling individuals with LBD must carefully consider the risks associated with treatment. More information is needed regarding risk in individuals with LBD, as well as which individuals may be most at risk or most likely to benefit. Bayesian approaches with response adaptive randomization to examine specific subgroups and examinations of potential biomarkers may be helpful in this regard.  NINDS seeks applications that include diverse populations representative of the distribution of disease in the United States by sex, race/ethnicity, and geographic area. In addition, NINDS believes that input from people who are experiencing mild cognitive impairment or mild dementia of mixed etiology, who can ascribe value to potential benefits and weigh against potential risks is critically important. Accordingly, NINDS seeks applications that include community engagement cores incorporated across all stages of program development and levels of the organizational structure.

Community engagement (CE) is the process of working collaboratively with groups of people affiliated by geographic proximity, identity, special interest, or similar circumstances to address issues affecting the wellbeing of those people. CE is a strategy that can be used to promote health and health research by addressing barriers to and identifying ways to facilitate research participation across NIH-designated populations that experience health disparities (HDPs). CE should include practices that incorporate genuine bidirectional communication and education about culture, beliefs, motives, health, and clinical research. Continued respectful, equitable, and bidirectional knowledge transfer during community engagement can improve HDP community research participation, retention and adherence to the study protocol, and health empowerment. CE can help build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust. Many core principles (trust, inclusivity, culturally-centered, etc.) are outlined in the National Academy of Medicine’s Advancing Health Equity and Systems Transformation through Community Engagement strategy for assessing meaningful community engagement.  Additionally, domains of assessment include strengthened partnerships & alliances, expanded knowledge, improved health, health care programs and policies, and thriving communities.

While community engagement is a strategy, Community-Engaged research (CEr) is a research process that broadly implements CE principles and strategies to incorporate perspectives and meaningfully involve patients, caregivers, and other community and healthcare stakeholders throughout the entire research process—from planning the study, to conducting the study, and disseminating study results.  Engaging the community in research contributes to successful health equity study design that is inclusive of diverse participants and perspectives across the research continuum and provides infrastructure to ensure culturally appropriate research strategies, tools, and communication are implemented. Partnering with the community helps with development of sustainable interventions and the translation of study results into practice, potentially improving health outcomes.

In addition, NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes and provides supplemental guidance to NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, e.g., by minimizing the risk of bias and transparently reporting methods and results as described at https://www.ninds.nih.gov/Funding/grant_policy. As stated in the NIH application guidelines, if previously published or preliminary studies do not meet these rigor standards to an acceptable degree, applicants should address how the current study design addresses the deficiencies. The proposed clinical trial must be based on robust and rigorous supporting data, e.g., from non-clinical in vivo and/or in vitro studies or preliminary clinical studies that demonstrate that there is an adequate scientific foundation to justify the proposed trial. The proposed trial design must likewise demonstrate a rigorous and transparent approach.

Research Project Objectives

The objective of the proposed research is to determine the safety and better understand the potential efficacy of amyloid-beta monoclonal amyloid antibody therapies in diverse mixed etiology dementia (MED) populations with a focus on LBD via the conduct of a randomized placebo-controlled phase 2 clinical trial.  In this NOFO the mixed-etiology dementias (MED) that are of interest and that are in scope are dementia cases with evidence of 1) Alzheimer brain pathology based on biomarkers such as amyloid positron emission tomography and/or low cerebrospinal fluid amyloid beta 42 combined with elevated phosphorylated tau; and 2) a clinical diagnosis of LBD, including either Parkinson’s disease dementia (PDD) and/or dementia with Lewy bodies (DLB). Participants should meet McKeith criteria for the diagnosis of DLB (McKeith, etal, 2017) or Movement Disorder Society criteria for PDD (Emre, etal, 2007). The inclusion of other emerging blood-based or imaging biomarkers that may be markers of AD or LBD severity or serve as potential indicators of treatment response or risk is encouraged but established brain-based markers should be used to determine the eligible study population.  Trials proposing the study of FDA approved monoclonal antibodies are encouraged, but trials of amyloid-beta monoclonal antibody therapies that have not yet received FDA approval will also be considered, particularly if there is evidence to suggest a strong safety profile. The study of individuals eligible to be treated with anti-amyloid therapy under either the CMS National Coverage Determination to cover FDA-approved monoclonal antibodies that target amyloid for the treatment of AD through Coverage with Evidence Development (CED) or under the CMS plan to cover amyloid-beta antibody therapies that have received traditional approval when coupled with clinical team participation in a qualifying registry is of particular interest.

The NINDS is committed to reducing the disproportionate burden of neurological disease borne by underserved groups of society, including racial and ethnic minority, rural, and socioeconomically disadvantaged populations.  In keeping with this commitment, NINDS encourages applicants to consider differences among diverse populations representative of the distribution of disease in the United States by sex, race/ethnicity, and geographic distribution when planning their project.  Bayesian approaches with response adaptive randomization to examine specific subgroups are also encouraged.

Applications Not Responsive to this NOFO

Applications not responsive to this NOFO will be administratively withdrawn prior to review.

• This NOFO is only for studies related to humans; animal or other disease model studies are not responsive to this NOFO.
• Applications that include patient populations that do not have evidence of mild cognitive impairment or dementia with evidence of both AD and LBD (DLB or PDD) are not responsive to this NOFO.
• Applications that do not focus on determining the safety and potential efficacy of amyloid-beta monoclonal antibody therapies in diverse MED populations with LBD via the conduct of a randomized placebo-controlled phase 2 clinical trial are not responsive to this NOFO.
• Applications that propose mechanistic clinical trials or BESH clinical trials are not responsive to this NOFO.

See Section VIII. Other Information for award authorities and regulations.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.