A Phase 3, 26-Week, Double-blind, Randomised, Placebo-controlled, Parallel-group Study to Investigate the Efficacy and Safety of Daily Administration of Tricaprilin as AC-OLE-01-VA in Participants With Mild to Moderate Alzheimer's Disease Dementia
The ALTER-AD (Alternative-Alzheimer Disease) study represents a pivotal Phase 3 clinical trial investigating Tricaprilin (also known as AC-OLE-01-VA), a novel ketogenic compound designed to address the fundamental energy hypometabolism that underlies Alzheimer's disease pathology. This trial is being conducted by Cerecin and represents one of the most advanced programs targeting brain energy metabolism in Alzheimer's disease currently in clinical development.
Alzheimer's disease affects over 55 million people worldwide, with this number projected to exceed 130 million by 2050. Despite decades of research and numerous clinical trials targeting amyloid-beta and tau pathology, disease-modifying therapies remain an unmet need. The ALTER-AD study takes a fundamentally different approach by targeting cerebral glucose hypometabolism, a core feature of Alzheimer's disease that precedes clinical symptoms by decades[1].
Alzheimer's disease is characterized by a profound decline in cerebral glucose metabolism, with brain regions critical for memory and cognition showing reductions of 20-45% in glucose uptake compared to healthy age-matched controls. This hypometabolism is not merely a consequence of neuronal loss but represents an early and progressive feature of the disease process that contributes to synaptic dysfunction, cognitive decline, and disease progression[1:1][2].
The mechanisms underlying cerebral glucose hypometabolism in Alzheimer's disease are multifactorial and include:
These defects create a self-perpetuating cycle where energy deficiency promotes amyloid aggregation, which further impairs energy metabolism, ultimately leading to synaptic failure and neuronal death[3][4].
Tricaprilin is a medium-chain triglyceride (MCT) compound that provides an alternative fuel source for the brain by promoting ketogenesis. Unlike glucose, ketone bodies (beta-hydroxybutyrate and acetoacetate) can enter the brain independently of insulin-mediated transport and are metabolized efficiently even in the presence of significant insulin resistance[5][6].
The therapeutic rationale for using ketone bodies in Alzheimer's disease includes:
Beta-hydroxybutyrate has been shown to protect against amyloid-beta-induced synaptic toxicity, reduce neuroinflammation, and enhance mitochondrial function in preclinical models[5:1][7].
Tricaprilin is metabolized in the liver to produce ketone bodies (primarily beta-hydroxybutyrate) that cross the blood-brain barrier and provide an alternative energy substrate for neuronal metabolism. The compound is designed to produce sustained elevation of circulating ketone bodies, addressing the cerebral energy deficit characteristic of Alzheimer's disease[7:1].
The mechanism of action encompasses several therapeutic pathways:
Preclinical studies demonstrated that tricaprilin administration resulted in elevated blood ketone levels, improved cognitive performance in Alzheimer's disease models, and reduced amyloid pathology[7:2][6:1].
The ALTER-AD study enrolls participants with mild to moderate Alzheimer's disease dementia, defined by:
The inclusion of both mild and moderate AD patients allows assessment of efficacy across the disease spectrum, while amyloid confirmation ensures enrollment of patients with underlying Alzheimer's pathology rather than other dementia subtypes.
Key exclusion criteria include:
Participants are randomly assigned in a 1:1 ratio to receive either tricaprilin or placebo. The double-blind design ensures that neither participants nor investigators know the treatment assignment. A double-dummy design maintains blinding by providing both active treatment and matching placebo.
Participants receive daily administration of tricaprilin (AC-OLE-01-VA) or placebo for 26 weeks. The dosing regimen is titrated to achieve target ketone levels while minimizing gastrointestinal tolerability issues, which are the most common adverse effects of MCT-based compounds.
Comprehensive assessments are conducted at baseline, week 13, and week 26 (end of treatment). Additional safety monitoring occurs throughout the study period.
The ALTER-AD study uses two co-primary endpoints to assess efficacy:
1. Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)
The ADAS-Cog is the gold standard cognitive outcome measure in Alzheimer's disease clinical trials. It assesses multiple cognitive domains including[8]:
The scale ranges from 0-70, with higher scores indicating greater impairment. A 4-point change is considered clinically meaningful in mild-to-moderate AD.
2. Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC)
The ADCS-CGIC provides a clinician's assessment of global change from baseline, integrating cognitive, functional, and behavioral domains[9]. The 7-point scale ranges from "marked worsening" to "marked improvement."
Key secondary endpoints include:
The ALTER-AD trial addresses a critical gap in Alzheimer's disease therapeutics. While amyloid-targeting therapies have shown success in clearing amyloid pathology, their clinical benefits have been modest, highlighting the need for multi-target approaches that address the complex pathophysiology of Alzheimer's disease[10].
By targeting cerebral energy metabolism, tricaprilin represents a fundamentally different therapeutic approach that may:
If successful, tricaprilin would represent the first approved therapy targeting cerebral energy metabolism in Alzheimer's disease. This would:
The ALTER-AD study includes comprehensive biomarker assessments that will validate:
Several other ketogenic approaches are being investigated for Alzheimer's disease, including:
Tricaprilin distinguishes itself through:
While amyloid-targeting therapies (lecanemab, donanemab) have demonstrated disease modification through amyloid clearance, their effects on clinical outcomes have been modest. Tricaprilin addresses a different pathological pathway, potentially providing complementary benefits:
| Feature | Amyloid Therapies | Tricaprilin |
|---|---|---|
| Target | Amyloid-beta plaques | Cerebral hypometabolism |
| Mechanism | Immunotherapy | Metabolic therapy |
| Disease stage | Early AD | Mild-to-moderate AD |
| Primary outcome | Cognitive decline | Cognition and global function |
Based on Phase 1 and 2 studies, tricaprilin has demonstrated an acceptable safety profile with the most common adverse events being:
Participants undergo regular monitoring of:
The biochemical pathway for ketogenesis from tricaprilin involves several enzymatic steps:
| Step | Enzyme | Location | Product |
|---|---|---|---|
| 1 | Lipase | Intestine | Glycerol + fatty acids |
| 2 | β-oxidation | Mitochondria | Acetyl-CoA |
| 3 | HMG-CoA synthase | Mitochondria | HMG-CoA |
| 4 | HMG-CoA lyase | Mitochondria | Acetoacetate |
| 5 | β-HBDH | Mitochondria | β-hydroxybutyrate |
| 6 | Thiolase | Mitochondria | Acetoacetyl-CoA |
Medium-chain triglycerides (MCTs) are metabolized differently from long-chain triglycerides (LCTs):
| Property | MCT | LCT |
|---|---|---|
| Chain length | C6-C12 | C14-C24 |
| Absorption | Direct to portal | Via chylomicrons |
| Transport | Portal vein | Lymphatic |
| Carnitine requirement | No | Yes |
| Ketone production | High | Low |
Tricaprilin (caprylin, C8) is optimized for maximal ketogenesis.
Ketone bodies enter the brain through specialized transporters:
| Transporter | Expression | Affinity | Notes |
|---|---|---|---|
| MCT1 | BBB endothelium | High | Rate-limiting |
| MCT2 | Neurons | Very high | Main neuronal transporter |
| MCT4 | Astrocytes | Moderate | Astrocyte-specific |
Tricaprilin is absorbed through the gastrointestinal tract:
Following absorption and hepatic metabolism:
Primary metabolic pathway:
The sample size of 535 participants is based on:
Primary efficacy analyses will use:
Tricaprilin may complement existing approaches:
| Combined Approach | Rationale |
|---|---|
| Tricaprilin + Lecanemab | Parallel mechanism support |
| Tricaprilin + Donanemab | Energy + amyloid clearance |
| Tricaprilin + standard care | Metabolic enhancement |
The combination rationale:
Point-of-care ketone monitoring:
Standardized uptake value ratio (SUVR):
Emerging biomarker panels:
| Marker | Matrix | Application |
|---|---|---|
| NfL | Plasma | Neurodegeneration |
| p-tau181/217 | Plasma | Tau pathology |
| Aβ42/40 | Plasma | Amyloid |
| YKL-40 | Plasma | Neuroinflammation |
Tricaprilin represents a therapeutic approach that addresses the fundamental energy crisis in Alzheimer's disease. The recognition that cerebral glucose hypometabolism is an early and progressive feature of AD has driven interest in metabolic therapies.
| Aspect | Traditional Approaches | Tricaprilin |
|---|---|---|
| Target | Amyloid/tau pathology | Energy metabolism |
| Mechanism | Remove/modify pathology | Support neuronal function |
| Disease stage | Early disease | Mild-to-moderate |
| Approach | Disease-modifying | Metabolic rescue |
| Primary effect | Slow pathology progression | Improve cellular energetics |
The metabolic rescue approach offers several theoretical advantages:
Tricaprilin may complement existing amyloid-targeting approaches:
| Combined Approach | Rationale |
|---|---|
| Tricaprilin + Lecanemab | Parallel mechanism support while amyloid cleared |
| Tricaprilin + Donanemab | Energy + amyloid clearance combination |
| Tricaprilin + standard care | Metabolic enhancement alongside symptomatic treatments |
If ALTER-AD is successful, combination trials with approved amyloid antibodies may be warranted to assess:
Point-of-care ketone monitoring enables therapeutic drug management:
| Parameter | Value |
|---|---|
| Device | Blood β-hydroxybutyrate meter |
| Sample | Capillary blood |
| Frequency | Weekly home monitoring during titration |
| Target range | 0.5-2.0 mM (ketogenic range) |
| Clinical correlation | Higher levels correlated with cognitive benefits in Phase 2 |
Standardized uptake value ratio (SUVR) measurements:
| Parameter | Value |
|---|---|
| Target regions | Posterior cingulate, precuneus, inferior parietal |
| Reference region | Cerebellar gray matter |
| Longitudinal assessments | Baseline, week 13, week 26 |
| Analysis method | Centiloid scaling for cross-study comparison |
| Expected change | Reduced glucose metabolism decline vs. placebo |
Emerging biomarker panels for patient selection and monitoring:
| Marker | Matrix | Application | Status |
|---|---|---|---|
| Neurofilament light (NfL) | Plasma | Neurodegeneration | Clinical |
| Phosphorylated tau 181/217 | Plasma | Tau pathology | Validated |
| Amyloid beta 42/40 ratio | Plasma | Amyloid | Validated |
| YKL-40 | Plasma | Neuroinflammation | Research |
| GFAP | Plasma | Astrogliosis | Research |
Absorption:
Distribution:
Metabolism:
Primary metabolic pathway:
Excretion:
Anticipated interactions:
No significant interactions expected:
Successful metabolic therapy may:
Metabolic therapy benefits:
Research ongoing on:
Areas under investigation:
Potential future trials:
Current AD therapies inadequately address energy metabolism:
| Current Therapy | Primary Effect |
|---|---|
| Cholinesterase inhibitors | Symptomatic enhancement |
| Memantine | Symptomatic protection |
| Anti-amyloid | Remove pathology |
| Anti-tau | Remove pathology |
Metabolic therapies address the energy crisis directly and may provide symptomatic benefit.
Positive results would enable:
Cerebral glucose hypometabolism in Alzheimer's disease: From mechanisms to therapy. 2023. ↩︎ ↩︎
Brain energy metabolism in Alzheimer's disease: Role of mitochondrial dysfunction. 2024. ↩︎
Mitochondrial dysfunction and cognitive decline in Alzheimer's disease. 2024. ↩︎
Synaptic energy failure in Alzheimer's disease: A therapeutic target. 2023. ↩︎
Ketone bodies as therapeutic agents in neurodegenerative diseases. 2023. ↩︎ ↩︎
Ketogenic diet and metabolic therapy for Alzheimer's disease: mechanisms and evidence. 2024. ↩︎ ↩︎
Tricaprilin: A novel ketogenic compound for Alzheimer's disease therapy. 2023. ↩︎ ↩︎ ↩︎
ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale. 2023. ↩︎
Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. 2023. ↩︎
Phase 3 clinical trials in Alzheimer's disease: Design and challenges. 2024. ↩︎