BMS-986368 Phase 2 - Agitation in Alzheimer's Disease

Trial ID: [NCT06808984](https://clinicaltrials.gov/study/NCT06808984) Sponsor: Celgene (Bristol Myers Squibb) Status: Recruiting Phase: Phase 2 Participants: 120

Overview

BMS-986368 is a Phase 2 clinical trial conducted by Celgene (Bristol Myers Squibb) investigating a novel therapeutic approach for agitation in Alzheimer's disease. The trial is currently recruiting participants, representing Celgene/BMS's continued investment in neuropsychiatric symptoms of dementia.

Trial ID: [NCT06808984](https://clinicaltrials.gov/study/NCT06808984) Sponsor: Celgene (Bristol Myers Squibb) Status: Recruiting Phase: Phase 2 Participants: 120

Overview

BMS-986368 is a Phase 2 clinical trial conducted by Celgene (Bristol Myers Squibb) investigating a novel therapeutic approach for agitation in Alzheimer's disease. The trial is currently recruiting participants, representing Celgene/BMS's continued investment in neuropsychiatric symptoms of dementia.

Agitation is one of the most common and challenging behavioral and psychological symptoms of dementia (BPSD), affecting up to 70% of patients during the disease course["@cerejeira2012"]. It encompasses a spectrum of behaviors including restlessness, aggression, disinhibition, and pacing that significantly impact quality of life for both patients and caregivers.

Trial Design

| Parameter | Value |
|-----------|-------|
| Phase | Phase 2 |
| Status | Recruiting |
| Enrollment | 120 participants |
| Sponsor | Celgene (Bristol Myers Squibb) |
| Condition | Agitation in Alzheimer's Disease |
| Study Type | Interventional |
| Allocation | Randomized |

Mechanism of Action

While the specific molecular mechanism of BMS-986368 has not been publicly disclosed, the therapeutic approach likely targets one or more of the key pathways implicated in Alzheimer's-related agitation:

Neuroinflammation Hypothesis

Neuroinflammation is increasingly recognized as a central contributor to behavioral symptoms in Alzheimer's disease. Key mechanisms include:

• Microglial activation: Chronic microglial activation produces pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) that can alter neuronal function and contribute to behavioral changes
• Cytokine effects on neurotransmission: Inflammatory cytokines can modulate dopamine, serotonin, and glutamate signaling in brain regions involved in emotional regulation
• Blood-brain barrier permeability: Neuroinflammation may increase BBB permeability, allowing peripheral inflammatory signals to affect CNS function

Neurotransmitter Modulation

Agitation in AD involves dysregulation of multiple neurotransmitter systems:

• Dopamine: Involved in motivational behavior and response to environmental stimuli. Dopaminergic dysfunction may contribute to apathy and agitation
• Serotonin: Critical for mood regulation and impulse control. Serotonergic deficits are associated with irritability and aggression
• GABA: The primary inhibitory neurotransmitter. GABAergic dysfunction may lead to disinhibition and excess motor activity
• Noradrenaline: Involved in arousal and attention. Locus coeruleus degeneration in AD may contribute to attentional deficits and agitation

Novel CNS Targets

Celgene/BMS has historically focused on innovative approaches to CNS disorders:

• Epigenetic modifiers: Histone deacetylase (HDAC) inhibitors and other chromatin-modifying enzymes
• Cell cycle regulators: Compounds targeting aberrant cell cycle re-entry in neurons
• RNA splicing modulators: Agents targeting alternative splicing events implicated in neurodegeneration
• Immunomodulatory approaches: Novel anti-inflammatory strategies for neuroprotection

Background

Burden of Agitation in Alzheimer's Disease

Agitation represents one of the most significant unmet needs in Alzheimer's disease management[@lyketsos2011]:

• Prevalence: Affects 40-70% of Alzheimer's patients during the disease course
• Impact on caregivers: Agitation is the primary driver of caregiver burnout and institutionalization
• Economic burden: Associated with $10,000-15,000 annually in excess healthcare costs per patient
• Treatment challenges: Current pharmacoptions have limited efficacy and significant side effect profiles

Current Treatment Landscape

| Treatment | Limitations |
|-----------|-------------|
| Atypical antipsychotics | Increased mortality, stroke, cognitive decline |
| Typical antipsychotics | Extrapyramidal symptoms, TD risk |
| Benzodiazepines | Falls, cognitive worsening, dependence |
| Mood stabilizers | Variable efficacy, toxicity concerns |
| Non-pharmacological | Limited efficacy in moderate-severe agitation |

This therapeutic gap underscores the need for novel agents like BMS-986368 that target underlying disease mechanisms rather than simply suppressing symptoms[@geda2013].

Clinical Development

Celgene/BMS Neuroscience Program

Celgene (acquired by Bristol Myers Squibb in 2019) has a robust neuroscience research program focusing on:

• Neurodegenerative diseases: Alzheimer's, Parkinson's, ALS, multiple sclerosis
• Neuropsychiatric disorders: Depression, anxiety, schizophrenia
• Pain: Chronic pain conditions including neuropathic pain

• Inflammatory and immune mechanisms in CNS disorders
• Novel small molecule approaches to modulate neural function
• Cell-based therapies for neurological conditions

Drug Development Pipeline

BMS-986368 represents one of several CNS candidates in the Celgene/BMS pipeline:

| Compound | Target | Indication | Stage |
|----------|--------|------------|-------|
| BMS-986368 | undisclosed | AD Agitation | Phase 2 |
| Various | HDAC | Neurodegeneration | Preclinical |
| Multiple | Immune modulators | MS, ALS | Various |

Study Endpoints

While specific endpoints are detailed on ClinicalTrials.gov, Phase 2 trials typically evaluate:

Primary Endpoints

• Safety and tolerability
• Dose-limiting toxicities
• Maximum tolerated dose

Secondary Endpoints

• Preliminary efficacy signals using validated agitation scales
• Pharmacokinetic parameters
• Target engagement biomarkers

Assessment Instruments

• Cohen-Mansfield Agitation Inventory (CMAI): Gold standard for agitation measurement
• Neuropsychiatric Inventory (NPI): Assesses behavioral symptoms including agitation
• ADAS-Cog: Cognitive function assessment
• CGI-C: Clinical Global Impression of Change

Safety Considerations

Given the patient population, special safety considerations include:

• Cardiovascular monitoring: Elderly patients with AD are at increased CV risk
• Cognitive effects: Assessment of any worsening of cognition
• Fall risk: Monitor for increased sedation or orthostatic changes
• Drug interactions: Many AD patients take multiple concomitant medications
• Mortality surveillance: Increased awareness following FDA black box warnings for antipsychotics in dementia

Clinical Significance

The development of BMS-986368 is significant for several reasons:

Related Pages

• [Agitation in Alzheimer's Disease](/diseases/alzheimers-disease)
• [Behavioral and Psychological Symptoms of Dementia](/mechanisms/bpsd-neurobiology)
• [Neuroinflammation in Alzheimer's Disease](/mechanisms/neuroinflammation-alzheimers)
• [Other Agitation Trials](/clinical-trials/?tag=agitation)
• [Celgene/BMS Pipeline](/clinical-trials/drug-pipeline)

External Links

• [ClinicalTrials.gov: NCT06808984](https://clinicaltrials.gov/study/NCT06808984)
• [BMS Research & Development Pipeline](https://www.bms.com/research-and-development/pipeline.html)
• [Celgene (BMS) Neuroscience](https://www.bms.com/research-and-development.html)

References