Evaluating GLP-1 Receptor Agonist Semaglutide in Phase 3 Settings for Alzheimer Disease: The EVOKE Trials – NeurologyLive

Report on the EVOKE and EVOKE+ Clinical Trials for Alzheimer’s Disease

Introduction: Aligning Neurological Research with Sustainable Development Goal 3

In alignment with Sustainable Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote well-being for all at all ages, research into non-communicable diseases such as Alzheimer’s disease (AD) is of paramount importance. The EVOKE (NCT04777396) and EVOKE+ (NCT04777409) phase 3 clinical trials represent a significant effort to address the global health challenge of AD, directly contributing to SDG Target 3.4 concerning the reduction of premature mortality from non-communicable diseases and the promotion of mental health. These trials investigated the potential of oral semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, as a disease-modifying therapy to slow cognitive decline in patients with early-stage AD. The development of an effective oral therapy could substantially advance SDG Target 3.8 by improving access to quality and affordable essential medicines.

Trial Design and Methodology

Study Objectives and Population

The primary objective of the EVOKE and EVOKE+ trials was to evaluate the efficacy and safety of oral semaglutide in slowing the progression of AD. This goal supports the broader mission of SDG 3 to develop effective treatments for major global health issues. The studies were designed as multicenter, randomized, double-blind, placebo-controlled trials.

• Target Population: The trials enrolled a total of 1840 participants each.
• Enrollment Criteria:
  • Age: 55 to 85 years.
  • Diagnosis: Mild cognitive impairment or mild dementia confirmed to be due to AD through amyloid positivity.

Intervention and Endpoints

The methodology was structured to provide robust data on the therapeutic potential of semaglutide, contributing valuable knowledge to the global research community as encouraged by SDG Target 3.b (Support for R&D).

1. Randomization: Participants were randomized on a 1:1 basis.
2. Treatment Arm: Once-daily oral semaglutide (14 mg).
3. Control Arm: Placebo.
4. Treatment Duration: A 104-week treatment period following an 8-week titration, with a planned 52-week extension.

Primary and Secondary Endpoints

The endpoints were selected to measure clinically meaningful outcomes in health and well-being.

• Primary Endpoint: The primary measure of efficacy was the change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score at week 104.
• Secondary Endpoints: A comprehensive set of secondary measures included:
  • Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL).
  • Mini-Mental State Exam (MMSE).
  • Neuropsychiatry Inventory.
• Biomarker Analysis: To understand the underlying biological mechanisms, the trials included extensive biomarker collection through MRI/CT scans, amyloid PET, and a cerebrospinal fluid (CSF) substudy assessing AD pathology, neuroinflammation, neurodegeneration, and vascular health.

Analysis of Trial Outcomes and Implications for SDG 3

Topline Results

The topline results from the EVOKE trials indicated that the primary endpoint was not met. Oral semaglutide did not demonstrate a statistically significant superiority over placebo in reducing the rate of disease progression in patients with early AD. However, the trials did yield important findings relevant to future research aligned with SDG 3.

• Clinical Efficacy: No significant reduction in cognitive decline was observed in the overall study population.
• Biomarker Improvements: Despite the clinical outcome, improvements in AD-related biomarkers were noted.
• Safety Profile: Semaglutide was reported to be well-tolerated, with a safety profile consistent with previous data.
• Study Discontinuation: Based on the efficacy results, the planned one-year extension period was discontinued.

Expert Commentary and Future Outlook

Expert analysis suggests that while the outcome is disappointing, the trials contribute to the long-term goal of combating AD. Howard Fillit, MD, noted that the research signifies a crucial expansion beyond amyloid-focused treatments to target the complete pathobiology of the disease. The observed biomarker improvements may indicate a path forward for semaglutide as part of a combination therapy approach, a strategy vital for managing complex NCDs. This aligns with the continuous improvement and innovation required to achieve SDG 3. The data on biomarkers is anticipated to inform future prevention studies, a key component of promoting long-term health and well-being.

Contextual Framework: Supporting Evidence

Rationale for Phase 3 Development

The decision to advance semaglutide to phase 3 trials was based on a foundation of supportive data, underscoring the importance of a systematic R&D process in addressing global health priorities.

• Preclinical Models: Initial data from preclinical studies suggested a potential neuroprotective effect.
• Real-World Evidence: A target trial emulation using electronic health records of over one million patients with type 2 diabetes found that semaglutide treatment was associated with a significantly reduced risk of a first-time AD diagnosis compared to other antidiabetic medications.
• Cardiovascular Outcomes Trials: Post-hoc analyses from large cardiovascular studies also provided supportive evidence.

This body of evidence highlights how research into one NCD (diabetes) can inform strategies for another (Alzheimer’s), reflecting an integrated approach to achieving good health for all under SDG 3.

1. SDGs Addressed in the Article

SDG 3: Good Health and Well-being

• The article’s entire focus is on a major global health issue, Alzheimer’s disease (AD), which is a non-communicable neurological disorder. It discusses the EVOKE and EVOKE+ clinical trials, which are investigating a new treatment (semaglutide) to “slow cognitive decline in patients with early Alzheimer disease.” This directly relates to ensuring healthy lives and promoting well-being for all at all ages, particularly for the aging population affected by dementia.

2. Specific SDG Targets Identified

Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.

• Alzheimer’s disease is a progressive non-communicable disease (NCD). The clinical trials discussed in the article are explicitly aimed at treatment, focusing on a “disease-modifying approach rather than only symptom management.” The goal to “slow disease progression” directly contributes to the treatment of NCDs and the promotion of mental well-being for affected individuals, which is the core of this target.

Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases…

• This target emphasizes the importance of research and development (R&D) for new medicines. The article provides a detailed account of the “large-scale, double-blind, placebo-controlled, phase 3 studies” for semaglutide. This entire initiative, from its design to the analysis of its outcomes, represents a significant investment and effort in the R&D of a novel therapy for a major NCD, directly aligning with the objective of this target.

3. Indicators Mentioned or Implied in the Article

Indicators for Target 3.4

• Clinical Endpoints for Disease Progression: The article explicitly mentions the metrics used to measure the effectiveness of the treatment in slowing cognitive decline and preserving daily function. These are direct indicators of patient health and well-being.
  • Primary Endpoint: The article identifies the primary measure as the “change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) at week 104.”
  • Secondary Endpoints: Other measures mentioned include the “Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Mini-Mental State Exam, and Neuropsychiatry Inventory.”
• Biological Markers (Biomarkers): The article states that the trials collect objective biological data to measure the treatment’s impact on the underlying disease pathology. It mentions that investigators “collect data on MRI/CT scans, amyloid PET, and cerebrospinal fluid (CSF) biomarkers,” as well as markers for “neuroinflammation, neurodegeneration and synaptic injury.” These serve as scientific indicators of progress in treating the disease.

Indicators for Target 3.b

• Execution of Phase 3 Clinical Trials: The existence and detailed description of the EVOKE and EVOKE+ trials are a primary indicator of active R&D. The article highlights that these are “multicenter, randomized, double-blind, placebo-controlled trials” that have “enrolled 1840 participants,” signifying a major, late-stage R&D effort to develop a new medicine.
• Exploration of Novel Therapeutic Approaches: The investigation of a glucagon-like peptide-1 (GLP-1) receptor agonist for AD represents progress in R&D. The article notes this shows a “fundamental shift in how we approach the development of new Alzheimer treatments, expanding beyond amyloid to target the complete pathobiology of the disease.” This diversification of research pathways is an indicator of a robust R&D ecosystem.

4. Table of SDGs, Targets, and Indicators

Source: neurologylive.com