P2, N=105, Not yet recruiting, St. Joseph's Hospital and Medical Center, Phoenix

Our findings show that BAF312 has significant anticancer effects in EOC cells by inhibiting the ERK and AKT pathways, and might potentially be used to treat EOCs.

P=N/A, N=210, Completed, Novartis

P1, N=24, Completed, Idorsia Pharmaceuticals Ltd. | Recruiting --> Completed | Trial completion date: Mar 2024 --> Aug 2024 | Trial primary completion date: Mar 2024 --> Aug 2024

Here, we unveil the clinical relevance of SPHK1 in bladder cancer progression and the driver role in bladder cancer metastasis. Moreover, we demonstrated the inhibitory effect of FDA-approved SPHK1 inhibitor FTY720 on bladder cancer metastasis from both in vitro and in vivo models.

Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF‑κB signaling pathway.

P3, N=680, Enrolling by invitation, Idorsia Pharmaceuticals Ltd. | Not yet recruiting --> Enrolling by invitation

Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.

P=N/A, N=30, Completed, Hikma Pharmaceuticals LLC | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Nov 2023

Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke...In the future, a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells, along with the activation of M2-type microglia. These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.

P1, N=28, Completed, Wake Forest University Health Sciences | Active, not recruiting --> Completed

P3, N=680, Not yet recruiting, Idorsia Pharmaceuticals Ltd.

SET inhibition by shRNA and FTY720 also decreased cell proliferation and colony formation in MCPyV(+) MCC cells. Overall, these results pave a path for use of drugs targeting SET protein for the treatment of MCC.

P3, N=120, Recruiting, Novartis Pharmaceuticals | N=180 --> 120

Adoptively transferred antigen-specific CX3CR1- CD8+ T cells differentiated into the CX3CR1+ subset in mice treated with FTY720, which inhibits lymphocyte egress from secondary lymphoid tissues, suggesting the intratumoral generation of CX3CR1+ CD8+ T cells rather than their trafficking from secondary lymphoid organs. Furthermore, analysis of adoptively transferred antigen-specific CD8+ T cells, in which the Cx3cr1 gene was replaced with a marker gene confirmed that CX3CR1+ CD8+ T cells could directly differentiate from the intratumoral CX3CR1- subset. These findings highlight that tumor antigen-specific CX3CR1- CD8+ T cells can fully differentiate outside the secondary lymphoid organs, and generate CX3CR1+ CD8+ T cells in the tumor microenvironment, which are distinct from CD8+ T cells that express markers of exhaustion.

(1) Background: OSU-2S is a derivative of FTY720 and exhibits significant inhibitory effects on various cancer cells...OSU-2S significantly inhibited tumour growth in A549 cells and xenografted animal models. (4) Our study confirms the inhibitory effect of OSU-2S on NSCLC, screens and demonstrates its potential targets AURKA(p-AURKA) and S1PR1, and provides a research basis for treating NSCLC with OSU-2S.

P4, N=30, Recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2025 --> Jan 2026 | Trial primary completion date: Feb 2025 --> Jan 2026

P2, N=38, Not yet recruiting, Medical University of South Carolina

P3, N=420, Recruiting, Idorsia Pharmaceuticals Ltd. | Trial completion date: Jun 2026 --> May 2027 | Trial primary completion date: Dec 2025 --> Oct 2026

P=N/A, N=113, Completed, Novartis

P3, N=420, Recruiting, Idorsia Pharmaceuticals Ltd. | Trial completion date: Jul 2026 --> May 2027 | Trial primary completion date: Jan 2026 --> Oct 2026

P3, N=180, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2029 --> Dec 2031 | Trial primary completion date: Aug 2026 --> Mar 2027

Our data suggest that the neuroprotection of siponimod/BAF312 likely involves the relief of oxidative stress in neuronal cells. Further studies are needed to explore the molecular mechanisms of such interactions to determine the relationship between mitochondrial dysfunction and neuroinflammation/neurodegeneration.

P=N/A, N=30, Active, not recruiting, Hikma Pharmaceuticals LLC | Trial completion date: Oct 2023 --> May 2024

P=N/A, N=451, Completed, Novartis Pharmaceuticals | Recruiting --> Completed | N=330 --> 451 | Trial completion date: Feb 2025 --> Aug 2023 | Trial primary completion date: Feb 2025 --> Aug 2023

Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.

At present, a series of FTY720 derivatives, which have pharmacological effects such as anti-tumor and alleviating airway hyperresponsiveness, have been developed through structural modification. This article reviews the pharmacological effects of FTY720 and its derivatives.

P3, N=420, Recruiting, Idorsia Pharmaceuticals Ltd.

P3, N=420, Recruiting, Idorsia Pharmaceuticals Ltd.

Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(β-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS.

P1, N=28, Active, not recruiting, Wake Forest University Health Sciences | Recruiting --> Active, not recruiting | N=10 --> 28 | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2023

FTY720 sensitizes cisplatin-resistant oral squamous cell carcinoma cells for paclitaxel.

Sponsored by Bristol Myers Squibb

P1, N=24, Recruiting, Idorsia Pharmaceuticals Ltd. | Trial completion date: Sep 2023 --> Mar 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

Direct effects of sipo on MG were Supported By cell culture analyses. Our findings suggest that sipo has both direct and indirect modulatory properties on microglia in in vitro and in vivo models for MS with implications for putative neuroprotection during progression.

Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

P3, N=1651, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Mar 2023

These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.