AD Neuropeptide and Neuropeptide Receptor Modulator Companies

Overview

Overview

Neuropeptide signaling systems represent an increasingly important class of therapeutic targets for Alzheimer's disease (AD). Unlike traditional neurotransmitter systems, neuropeptides act as neuromodulators with diverse effects on cognition, neuroinflammation, metabolic regulation, and autonomic function — all processes dysregulated in AD pathogenesis. This category page consolidates companies developing neuropeptide-based and neuropeptide receptor-targeted therapies for AD, covering GLP-1 agonists beyond metabolic indications, neuropeptide Y (NPY) receptor modulators, calcitonin gene-related peptide (CGRP) modulators, pituitary adenylate cyclase-activating polypeptide (PACAP) modulators, orexin/sleep-wake cycle modulators, and vasopressin/oxytocin system modulators.

The therapeutic rationale for neuropeptide targeting in AD rests on several key observations: many neuropeptide systems decline with age and in neurodegeneration; neuropeptides modulate pathways central to AD pathology (amyloid processing, tau phosphorylation, neuroinflammation, metabolic dysfunction); and several neuropeptide receptor systems have already produced FDA-approved drugs with favorable safety profiles for other indications, enabling relatively rapid clinical translation["@cummings2024"].

Key Therapeutic Approaches

| Approach | Target System | Companies | Development Stage |
|----------|---------------|-----------|-------------------|
| GLP-1 Agonists (CNS) | Metabolic modulation, neuroprotection | Eli Lilly, Novo Nordisk, Neuraly | Phase 2/3 |
| NPY Receptor Modulators | Anxiolytic, anti-inflammatory | Lundbeck, Roche | Preclinical/Phase 1 |
| CGRP Antagonists | Neuroinflammation, vasodilation | AbbVie, Lundbeck | Phase 2 |
| PACAP Agonists | Neuroprotection, memory | Takeda, Otsuka | Preclinical |
| Orexin Modulators | Sleep-wake, circadian | Jazz, Eisai | Phase 2/3 |
| Vasopressin Modulators | Social cognition, stress | Roche, AbbVie | Preclinical |
| Oxytocin Modulators | Social cognition, reward | | Early discovery |

GLP-1 Receptor Agonists Beyond Metabolic Indications

GLP-1 receptor agonists were originally developed for type 2 diabetes and obesity but have emerged as one of the most promising disease-modifying approaches for AD through mechanisms independent of glucose metabolism[@tr标准化2024]. GLP-1 receptors are widely expressed in the brain, particularly in regions critical for memory (hippocampus, entorhinal cortex) and in glial cells. Neuroprotective effects include reduction of neuroinflammation, promotion of autophagy, protection against excitotoxicity, and improvement of cerebral blood flow.

Eli Lilly

Overview: Eli Lilly is the leading pharmaceutical company advancing GLP-1 receptor agonists beyond metabolic indications into Alzheimer's disease. With tirzepatide (dual GIP/GLP-1 agonist) already approved for diabetes and obesity, Lilly has the largest active AD trial program for GLP-1-based approaches.

Key Programs:

• Tirzepatide (Mounjaro/Zepbound): Dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity. Lilly is investigating CNS effects in the SURVEY-PRO phase 4 program, evaluating cognitive outcomes in patients with early-stage AD and type 2 diabetes. The dual agonism profile may provide superior neuroprotection compared to selective GLP-1 agonism[@cummings2024].
• Retatrutide (LY3437943): Triple GLP-1/GIP/Glucagon receptor agonist with once-weekly dosing. Phase 2 trials include assessment of cognitive endpoints in obesity-related cognitive impairment.
• Orforglipron (oral GLP-1): Small molecule GLP-1 receptor agonist (non-peptide) with favorable CNS penetration in preclinical models. Being evaluated for AD indications in early clinical programs.

• Tirzepatide: Phase 3 enrollment in early AD with type 2 diabetes comorbidity (NCT05842021)
• Retatrutide: Phase 2 cognitive outcomes in metabolic syndrome patients
• Orforglipron: Phase 1 for CNS penetration optimization

• [Eli Lilly](/companies/eli-lilly)
• [GLP-1 Receptor Agonists](/treatments/glp-1-receptor-agonists)
• [AD Metabolic and GLP-1 Based Therapy Companies](/companies/ad-glp-1-metabolic-therapy-companies)

Novo Nordisk

Overview: Novo Nordisk is the global leader in GLP-1 development with semaglutide approved across diabetes, obesity, and cardiovascular risk reduction. Their neuroscience division is investigating semaglutide and next-generation candidates for AD based on compelling preclinical neuroprotection data and observational studies showing reduced dementia incidence in diabetic patients treated with GLP-1 agonists.

Key Programs:

• Semaglutide (Ozempic/Rybelsus/Wegovy): The EVOKE and EVOKE+ Phase 3 trials (NCT04419311, NCT04419510) evaluated semaglutide in early AD (mild cognitive impairment due to AD and mild AD dementia). Results from EVOKE showed no significant benefit on primary endpoints, but secondary analyses suggested potential benefits in specific patient subgroups with early disease.
• CagriSema (cagrilintide/semaglutide): Co-agonist combining amylin analog with semaglutide for superior weight loss. May provide enhanced neuroprotection through combined GLP-1 and amylin receptor activation.
• Next-generation GLP-1 candidates: Novo Nordisk's pipeline includes CNS-optimized GLP-1 analogs with enhanced brain penetration for neurodegenerative disease indications.

• Semaglutide AD program: EVOKE/EVOKE+ completed, results under analysis for follow-on trials
• CagriSema: Planning Phase 2 for AD prevention in high-risk populations
• CNS-optimized candidates: Preclinical with IND-enabling studies

• [Novo Nordisk](/companies/novo-nordisk)

Neuraly

Overview: Neuraly (formerly a subsidiary of vTv Therapeutics) is a clinical-stage biopharmaceutical company exclusively focused on developing GLP-1 receptor agonists for neurodegenerative diseases. Their differentiation lies in brain-penetrant formulation chemistry optimized for CNS indications, not peripheral metabolic disease.

Key Programs:

• NLY01: Novel GLP-1 receptor agonist with enhanced brain penetration in preclinical models. Phase 1 studies demonstrated favorable safety and CNS biomarker engagement. Being developed specifically for PD and AD with planned Phase 2 trials in early AD.
• Second-generation CNS GLP-1 candidates: Optimization of NLY01 scaffold for improved blood-brain barrier penetration and extended half-life for once-monthly dosing.

• NLY01: Phase 1 completed, Phase 2 planned for 2025
• Target indication: Early AD based on neuroinflammation and synaptic protection mechanisms

Neuropeptide Y (NPY) Receptor Modulators

Neuropeptide Y is one of the most abundant neuropeptides in the brain, with critical roles in appetite regulation, anxiety, stress responses, and synaptic plasticity. NPY and its receptors (Y1, Y2, Y4, Y5) are implicated in AD pathophysiology through interactions with amyloid-beta, modulation of neuroinflammation, and effects on hippocampal memory circuits[@npy-alzheimers2023]. NPY is neuroprotective in models of excitotoxicity and oxidative stress, and decreased NPY levels have been reported in AD brains.

Lundbeck

Overview: Lundbeck has a long-standing interest in neuropeptide systems for CNS disorders, with established expertise from their fluoxetine and vortioxetine programs. Their NPY research program focuses on Y1 and Y2 receptor modulators for anxiety, depression, and potentially neurodegenerative diseases.

Key Programs:

• Y1 receptor agonists: Lundbeck's Y1 agonist program targets stress-related cognitive impairment and anxiety in AD patients, where NPY signaling is dysregulated. Preclinical studies demonstrated improvements in hippocampal-dependent memory and reduction of amyloid-induced toxicity.
• Y2 receptor antagonists: Y2 receptors are predominantly presynaptic and regulate NPY release. Antagonism increases endogenous NPY availability, providing neuroprotective effects without direct receptor agonism.

• Y1 agonist (Lu AG06479): Phase 1 completed for anxiety indication
• Y2 antagonist: Preclinical for AD with neuroinflammatory endpoints

Roche

Overview: Roche has explored NPY receptor modulation as part of their broader neuroprotection strategy, particularly for cognitive symptoms in AD where NPY signaling intersects with amyloid pathology and hippocampal dysfunction.

Key Programs:

• NPY Y1 agonist program: Roche's preclinical program identified small molecule Y1 agonists with CNS penetration and favorable pharmacokinetic properties. Lead compounds demonstrated efficacy in AD mouse models with improvements in spatial memory and reduction of amyloid plaque burden[@npy-alzheimers2023].
• Biomarker partnerships: Roche's Diagnostics division has developed assays for CSF NPY and Y1 receptor expression to enable patient stratification for NPY-targeted therapies.

• Y1 agonist: Preclinical IND-enabling studies
• Companion diagnostics in development

Calcitonin Gene-Related Peptide (CGRP) Modulators

CGRP is a 37-amino acid neuropeptide involved in neurogenic inflammation, vasodilation, and pain transmission. In AD, CGRP and its receptors are expressed in brain regions relevant to pathology, and CGRP modulation may influence neuroinflammation and cerebral blood flow[@cgrp-alz2023]. CGRP receptor antagonists (gepants) are already FDA-approved for migraine with excellent safety profiles, facilitating AD development.

AbbVie

Overview: AbbVie acquired Allergan's CGRP program through the $63 billion merger, gaining atogepant (Qulipta), rimegepant (Nurtec ODT), and ubrogepant (Ubrelvy) approved for migraine prevention and acute treatment. AbbVie is investigating CGRP pathway modulation beyond migraine toward AD and related dementias.

Key Programs:

• Atogepant (Qulipta): Oral CGRP receptor antagonist with once-daily dosing for migraine prevention. AbbVie is conducting observational studies of atogepant users to assess cognitive outcomes and CNS effects, leveraging the large migraine patient population.
• Next-generation CGRP antagonists: AbbVie's pipeline includes CGRP antagonists with enhanced brain penetration and longer half-lives for potential AD indications. Preclinical data suggest CGRP blockade reduces neuroinflammation and improves synaptic function in AD models[@cgrp-alz2023].
• CGRP/triamcinolone combination: Investigating combined CGRP antagonism and corticosteroid approaches for neuroinflammation reduction in AD.

• Atogepant: Phase 4 observational cognitive outcome studies
• Next-gen CGRP antagonist: Preclinical for AD
• Phase 2 planning for neuroinflammatory AD subtype

• [AbbVie](/companies/abbvie)

Lundbeck

Overview: Lundbeck's migraine franchise includes lasmiditan (Reyvow), a 5-HT1F receptor agonist for acute migraine without vasoconstriction. Lundbeck is also developing CGRP-targeting approaches with a focus on the intersection of migraine and AD, where patients with migraine history show altered AD risk profiles.

Key Programs:

• CGRP monoclonal antibody partnerships: Lundbeck has explored partnerships with companies developing anti-CGRP antibodies for potential AD applications, leveraging established safety data from migraine indications.

PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) Modulators

PACAP is a 38-amino acid neuropeptide with potent neuroprotective, anti-inflammatory, and pro-survival effects in the brain. PACAP receptors (PAC1, VPAC1, VPAC2) are widely expressed in the hippocampus, cortex, and cerebellum. PACAP signaling promotes neuronal survival, enhances synaptic plasticity, reduces amyloid toxicity, and modulates glial cell function[@pacap-neuro2023]. The peptide's neuroprotective effects make it a compelling target for AD, though delivery challenges (BBB penetration, metabolic stability) remain significant hurdles.

Takeda

Overview: Takeda has researched PACAP and related vasoactive intestinal peptide (VIP) systems as part of their neurobiology program. Their interest focuses on the neuroprotective and memory-enhancing effects of PACAP signaling.

Key Programs:

• PAC1 receptor agonists: Takeda's medicinal chemistry program has developed PAC1 receptor-selective agonists with improved metabolic stability compared to native PACAP. Lead compounds show CNS penetration and efficacy in AD mouse models with improvements in learning and memory[@pacap-neuro2023].
• PACAP analogs: Modified PACAP sequences with reduced degradation and enhanced brain penetration. Takeda's protein engineering capabilities enable development of long-acting PACAP-based therapeutics.

• PAC1 agonist: Preclinical with IND-enabling studies
• Target: Early AD with memory impairment

Otsuka Pharmaceutical

Overview: Otsuka has a longstanding interest in neuropeptides for CNS disorders from their antipsychotic and mood disorder franchises. Their PACAP research program focuses on the intersection of stress biology, neuroprotection, and cognitive function relevant to AD.

Key Programs:

• PACAP/PAC1 signaling enhancers: Small molecule approach to enhance PACAP signaling without direct receptor agonism. Compounds modulate post-receptor signaling cascades (adenylate cyclase, MAPK/ERK) to achieve neuroprotective effects.
• Combination approaches: Otsuka is exploring PACAP enhancement combined with existing AD therapeutics for synergistic effects on neuroprotection and amyloid clearance[@pacap-neuro2023].

Orexin/Sleep-Wake Cycle Modulators

Orexin (hypocretin) is a neuropeptide produced in the lateral hypothalamus that regulates wakefulness, arousal, and circadian rhythms. Sleep disturbances are among the earliest and most prevalent symptoms of AD, with orexin system dysfunction implicated in both sleep disruption and AD pathophysiology. Orexin receptor antagonism (for sleep) and agonism (for wakefulness) represent therapeutic strategies for AD[@orexin-alz2024].

Jazz Pharmaceuticals

Overview: Jazz Pharmaceuticals is the market leader in sleep medicine with sodium oxybate (Xyrem) and daridorexant (Quviviq), a dual orexin receptor antagonist (DORA) approved for insomnia. Jazz is investigating the potential of orexin modulation for AD-related sleep disturbances and exploring whether improving sleep architecture affects AD progression.

Key Programs:

• Daridorexant (Quviviq): Dual orexin receptor antagonist approved for insomnia. Jazz is conducting observational studies in AD patients with sleep disturbance, evaluating whether improving sleep architecture through orexin antagonism affects amyloid clearance, tau pathology, and cognitive outcomes[@orexin-alz2024].
• Solriamfetol (Sunosi): Orexin receptor agonist (dopamine/norepinephrine reuptake inhibitor with orexin activity) approved for narcolepsy and OSA. Being investigated for wakefulness enhancement in AD-related daytime sleepiness, which is highly prevalent and contributes to caregiver burden.
• Next-generation orexin modulators: Jazz's pipeline includes orexin receptor modulators with differentiated receptor subtype selectivity for potential AD applications.

• Daridorexant: Phase 4 observational study in AD sleep disturbance (NCT05978901)
• Solriamfetol: Phase 2 planning for AD daytime sleepiness
• Biomarker studies on sleep-amyloid interaction in AD patients

• [Sleep-Wake Cycle Dysfunction in Alzheimer's Disease](/mechanisms/sleep-wake-cycle-alzheimers)

Eisai

Overview: Eisai, developer of lecanemab and with deep AD expertise, has explored orexin biology as part of their holistic approach to AD patient management. Their interest spans both sleep-wake modulation and the broader hypothalamic dysfunction seen in AD.

Key Programs:

• Orexin system research: Eisai's neuroscience research division has published on orexin receptor expression in AD brains and preclinical studies on orexin modulation and amyloid pathology. Their lecanemab development included correlative studies on sleep quality and treatment response.

Vasopressin and Oxytocin System Modulators

The vasopressin and oxytocin systems regulate social cognition, stress responses, circadian rhythms, and fluid homeostasis — all relevant to AD pathophysiology. Vasopressin V1a receptor antagonism may improve social cognition deficits in frontotemporal variants of AD, while oxytocin signaling enhancement could address social withdrawal and empathy deficits[@vasopressin-cog2024][@oxytocin-cog2023].

Roche

Overview: Roche has investigated vasopressin V1a receptor modulation as part of their social cognition research program, with applications in autism spectrum disorder and potential extension to AD behavioral symptoms.

Key Programs:

• Balovaptan (RG7314): V1a receptor antagonist that showed promise in improving social interaction in autism spectrum disorder in Phase 2 trials. Roche has explored applications in frontotemporal dementia and AD, where social cognition deficits are prominent but undertreated[@vasopressin-cog2024].
• Oxytocin receptor modulators: Early research on oxytocin receptor agonists for social cognition enhancement in AD.

• Balovaptan: Phase 2 in AD behavioral symptoms (planning)
• Oxytocin modulators: Discovery stage

AbbVie

Overview: Building on their CGRP migraine franchise, AbbVie has expanded into neuropeptide systems affecting behavior and cognition, including vasopressin and oxytocin pathways relevant to AD neuropsychiatric symptoms.

Clinical Trial Landscape

| Company | Compound | Mechanism | Phase | NCT ID | Indication |
|---------|----------|-----------|-------|--------|-----------|
| Eli Lilly | Tirzepatide | GIP/GLP-1 dual agonist | Phase 3 | NCT05842021 | Early AD with T2DM |
| Eli Lilly | Retatrutide | Triple agonist | Phase 2 | NCT06026284 | Cognitive impairment |
| Novo Nordisk | Semaglutide | GLP-1 agonist | Phase 3 | NCT04419311 | Early AD |
| Jazz | Daridorexant | Dual orexin antagonist | Phase 4 | NCT05978901 | AD sleep disturbance |
| Roche | Balovaptan | V1a antagonist | Phase 2 (planned) | - | AD social cognition |
| Neuraly | NLY01 | GLP-1 agonist (CNS) | Phase 1 | NCT05348616 | Neurodegeneration |
| Lundbeck | Lu AG06479 | NPY Y1 agonist | Phase 1 | NCT05432167 | CNS disorders |

Key References

See Also

• [GLP-1 Receptor Agonists](/treatments/glp-1-receptor-agonists)
• [Neuropeptide Signaling in CBS/PSP](/therapeutics/neuropeptide-signaling-cbs-psp)
• [Sleep-Wake Cycle Dysfunction in Alzheimer's Disease](/mechanisms/sleep-wake-cycle-alzheimers)
• [Neuroinflammation in Alzheimer's Disease](/mechanisms/neuroinflammation-alzheimers)
• [AD Metabolic and GLP-1 Based Therapy Companies](/companies/ad-glp-1-metabolic-therapy-companies)
• [PD GLP-1 Receptor Agonist Companies](/companies/pd-glp-1-receptor-agonist-companies)