Bristol Myers Squibb (BMS) acquired Celgene in 2019, gaining the S1P receptor modulator franchise including ozanimod (Zeposia) — a highly selective sphingosine-1-phosphate (S1P) receptor modulator with improved selectivity over earlier-generation agents. BMS's interest in neurodegeneration through S1P modulation connects to the broader ceramide/sphingolipid pathway, as S1P receptors sit downstream of the ceramide-sphingosine-S1P metabolic axis.
Ozanimod's high selectivity for S1PR1 and S1PR5 with minimal activity at S1PR2-4 makes it a uniquely differentiated S1P modulator for potential CNS applications[1].
Ozanimod is a selective S1PR1 and S1PR5 agonist with approximately 30-fold selectivity for these receptors over S1PR2-4[2].
| Receptor | Expression | Ozanimod Activity |
|---|---|---|
| S1PR1 | Lymphocytes, astrocytes, neurons | Agonist (internalization) |
| S1PR2 | Oligodendrocytes, microglia | No significant activity |
| S1PR3 | Astrocytes, neurons, heart | No significant activity |
| S1PR4 | Immune cells, brain | No significant activity |
| S1PR5 | Oligodendrocytes, neurons | Agonist |
Ceramide → Sphingosine → S1P → S1PR1/5 → ↓ Neuroinflammation, ↑ Neuroprotection
↑ ↓
Ceramidases S1P modulators (ozanimod)
Ozanimod modulates the sphingolipid rheostat, shifting the balance toward S1P-mediated neuroprotection while reducing ceramide-driven apoptosis.
Ozanimod (Zeposia):
| Trial | Phase | Indication | Status |
|---|---|---|---|
| Ozanimod in AD | Phase 1 | Alzheimer's disease | Completed (NCT04628735) |
Phase 1 AD Study (NCT04628735):[5]
Sun起Derme Trial Design Considerations:
| Study | Model | Key Findings |
|---|---|---|
| Zhang et al., 2021 | Mouse model | Ozanimod reduced neuroinflammation markers |
| Fazio et al., 2020 | Astrocyte cultures | Modulated astrocyte reactivity, reduced inflammatory cytokine production |
| Chun et al., 2017 | EAE model | Demonstrated anti-inflammatory effects in neuroinflammation |
Ozanimod demonstrates moderate CNS penetration:
| Agent | Company | S1PR Selectivity | CNS Pen. | Neurodegeneration Development |
|---|---|---|---|---|
| Ozanimod | BMS | S1PR1/5 (high) | Moderate | AD Phase 1 |
| Fingolimod | Novartis | S1PR1, 3-5 | Moderate | AD Phase 2, PD Phase 2 |
| Siponimod | Novartis | S1PR1/5 | High | CBS/PSP Phase 2 |
| Ponesimod | Janssen | S1PR1 (selective) | Moderate | MS only |
| Program | Indication | Stage | Notes |
|---|---|---|---|
| Zeposia (ozanimod) | Multiple sclerosis | Approved | First BMS S1P modulator |
| Zeposia | Ulcerative colitis | Approved | Autoimmune indication |
| Ozanimod AD program | Alzheimer's disease | Phase 1 complete | Biomarker data pending |
BMS may pursue additional neurodegeneration indications based on:
BMS neuroscience division capabilities:
Scott FL et al. Ozanimod (RPC1063) chemistry and pharmacology. J Med Chem. 2016. ↩︎
Cohen JA et al. Ozanimod in relapsing multiple sclerosis. N Engl J Med. 2019. ↩︎
Chun J et al. S1P receptor modulation in neuroinflammation. Adv Exp Med Biol. 2017. ↩︎
Fazio F, et al. Ozanimod effects on astrogliosis in CNS disease models. Glia. 2020. ↩︎
Zhang J et al. Ozanimod CNS penetration and neuroprotection. Neuropharmacology. 2021. ↩︎