NCT06862960 is a Phase 2 clinical trial investigating the effects of ozanimod, a sphingosine-1-phosphate (S1P) receptor modulator, in patients with Alzheimer's disease. Ozanimod is already FDA-approved for multiple sclerosis (MS) and ulcerative colitis (UC), representing a novel repurposing approach for neurodegenerative disease.
S1P signaling plays a critical role in neuroinflammation, immune cell trafficking, and neuronal survival. By modulating S1P receptors, ozanimod may reduce neuroinflammation and modulate immune responses that contribute to Alzheimer's disease progression. This trial represents an important step in translating the growing understanding of S1P biology in neurodegeneration into clinical therapy.
The S1P signaling pathway has emerged as a critical modulator of neuroinflammation, immune cell trafficking, and neuronal survival. S1P is a bioactive lysophospholipid that acts on a family of five G protein-coupled receptors (S1PR1-5) to regulate diverse cellular processes including lymphocyte egress, cell survival, proliferation, migration, and cytokine production[1]. In the central nervous system (CNS), S1P receptors are expressed on neurons, astrocytes, microglia, and oligodendrocytes, where they modulate synaptic plasticity, myelination, neuroinflammatory responses, and neuroprotection[2].
| Parameter | Value |
|---|---|
| NCT Number | NCT06862960 |
| Phase | Phase 2 |
| Status | Not yet recruiting |
| Enrollment | 40 participants |
| Sponsor | ChenXiaoChun |
| Intervention | Ozanimod |
| Study Type | Interventional |
Ozanimod is a selective sphingosine-1-phosphate receptor (S1PR) modulator that binds to S1P receptors 1 and 5. This mechanism is relevant to Alzheimer's disease through several pathways:
The rationale for testing ozanimod in Alzheimer's disease includes:
Preclinical studies with S1P modulators in AD models have shown:
S1P is produced through phosphorylation of sphingosine by two sphingosine kinase isoforms (SphK1 and SphK2). The balance between S1P and its precursor ceramide creates a "sphingolipid rheostat" that determines cell fate—ceramide promotes apoptosis while S1P promotes cell survival[3]. In neurodegeneration, this rheostat is shifted toward ceramide accumulation and reduced S1P signaling.
Five S1P receptor subtypes (S1PR1-5) mediate different cellular effects through coupling to distinct G protein pathways[4]:
| Receptor | G Protein | Main Effect |
|---|---|---|
| S1PR1 | Gi/o | Lymphocyte egress, migration |
| S1PR2 | Gi/o, Gq | Cell proliferation, migration |
| S1PR3 | Gi/o, Gq | Calcium mobilization |
| S1PR4 | Gi/o | Immune cell trafficking |
| S1PR5 | Gi/o | Oligodendrocyte function |
Ozanimod selectively targets S1PR1 and S1PR5, providing immunomodulation through lymphocyte sequestration while potentially preserving CNS functions mediated by other receptor subtypes.
In Alzheimer's disease, microglia adopt a spectrum of activation states ranging from homeostatic ( surveilling") to disease-associated (DAM). S1P receptor modulators influence this transition:
Fingolimod effects on microglia:
The S1P axis represents a promising target because it modulates the neuroimmune interface that appears central to AD progression[5].
S1P modulators disrupt the peripheral immune cell trafficking that contributes to neuroinflammation. By sequestering lymphocytes in lymph nodes, these agents reduce the infiltration of peripheral immune cells into the CNS parenchyma—a process increasingly recognized as important in AD pathogenesis.
Ozanimod (RPC1063) is a next-generation S1P receptor modulator with improved selectivity over first-generation agents[6]:
| Property | Fingolimod | Ozanimod |
|---|---|---|
| Target | S1PR1,3,4,5 | S1PR1,5 |
| Receptor occupancy | ~80% | ~90% |
| CNS penetration | Moderate | High |
| Cardiac effects | Significant | Minimal |
| Liver toxicity | Moderate | Low |
Ozanimod is currently approved for:
This existing approval provides extensive safety data supporting repurposing in AD.
The trial will evaluate the safety and efficacy of ozanimod in patients with mild-to-moderate Alzheimer's disease. Key endpoints likely include:
Phase 2 trials in AD face unique challenges:
| Agent | Company | Indication | Stage |
|---|---|---|---|
| Ozanimod | ChenXiaoChun | AD | Phase 2 |
| Fingolimod | Novartis | AD | Phase 2 |
| Siponimod | Novartis | AD/PD | Preclinical |
| Ponesimod | Bristol Myers | AD | Phase 1 |
Compared to fingolimod, ozanimod offers:
Ozanimod exhibits favorable pharmacokinetic properties for CNS drug development[7]:
CNS penetration is critical for neurodegenerative indications. Ozanimod achieves meaningful brain concentrations:
Known interactions include:
Fingolimod (the prototype S1P modulator) has demonstrated efficacy in multiple AD models:
Beyond amyloid, S1P modulators affect tau pathology[8]:
Ozanimod shares the mechanistic foundation with fingolimod while offering:
The trial may incorporate fluid biomarker assessments:
| Biomarker | Source | Relevance |
|---|---|---|
| Neurofilament light (NfL) | CSF/blood | Neurodegeneration rate |
| Total tau | CSF | neuronal injury |
| Phospho-tau | CSF | Tau pathology |
| YKL-40 | CSF | Microglial activation |
| IL-6 | Plasma | Inflammation |
S1P receptor modulators carry known risks:
Chun, J., et al. Sphingosine 1-phosphate receptor signaling in the central nervous system. Brain Research. 2019. ↩︎
Van Doorn, R., et al. S1P receptor expression in the human brain. Journal of Neuropathology & Experimental Neurology. 2019. ↩︎
Ross, R. S., et al. Sphingolipids in cell signaling and neurodegeneration. Cellular and Molecular Life Sciences. 2000. ↩︎
Kim, Y. J., et al. S1P receptor subtype: the key point. Cellular Signalling. 2003. ↩︎
Hauer, P. J., et al. S1P axis: new therapeutic target in AD. Trends in Pharmacological Sciences. 2020. ↩︎
Scott, Z. A., et al. Ozanimod (RPC1063) is a novel selective S1P1 and S1P5 receptor agonist with multiple sclerosis efficacy. Multiple Sclerosis and Related Disorders. 2016. ↩︎
Poirazi, A., et al. Clinical pharmacokinetics of ozanimod in CNS diseases. Clinical Pharmacology & Therapeutics. 2023. ↩︎
Doi, Y., et al. Fingolimod reduces phosphorylated tau levels in the brains of the 3xTg-AD mouse model of Alzheimer's disease. Journal of Neurochemistry. 2015. ↩︎