Tavalisse (fostamatinib)

P1, N=20, Not yet recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial primary completion date: Mar 2024 --> Aug 2024

P=N/A, N=16, Terminated, Rigel Pharmaceuticals | N=45 --> 16 | Active, not recruiting --> Terminated; met minimum enrollment goal, however, enrollment was slow due to the pandemic, therefore, the study was terminated

Drug-gene association analysis revealed that both upregulated and downregulated DEGs were associated with fostamatinib...CMap analysis unveiled SA-83851 as a potential candidate to counteract the effects of DEGs, specifically in cells harbouring mutant TP53. Further research, including in vitro and in vivo validations, is warranted to develop drugs targeting BCSCs.

P1, N=30, Not yet recruiting, Stefanie Sarantopoulos, MD, PhD.

P2/3, N=871, Completed, Sean Collins | Active, not recruiting --> Completed

P3, N=34, Completed, Kissei Pharmaceutical Co., Ltd. | Active, not recruiting --> Completed | N=24 --> 34

The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.

For patients who previously received corticosteroids and a TPO-RA, the choice of subsequent therapy (eg a different TPO-RA, rituximab, fostamatinib, mycophenolate mofetil, splenectomy) is not well defined. VAYHIT3 will evaluate the ability of a short therapeutic course of ianalumab to induce durable responses in patients who have received 2 or more prior lines of therapy, including at least 1 corticosteroid and 1 TPO-RA, for whom significant unmet needs exist. Current status: VAYHIT3 is recruiting. Ianalumab is also being investigated in 2 ongoing, randomized, double-blind, Phase III ITP trials: VAYHIT1 (NCT05653349) is assessing ianalumab versus placebo in addition to first-line corticosteroids, and VAYHIT2 (NCT05653219) is assessing ianalumab versus placebo in addition to eltrombopag in patients who failed first-line corticosteroid treatment.

Patients with ITP lasting for ≥3 months (persistent or chronic primary ITP), and who do not respond adequately or maintain a response to initial therapy, are usually treated with advanced therapies such as thrombopoietin receptor agonists (TPO-RAs [avatrombopag/romiplostim/eltrombopag]), rituximab, and fostamatinib. All-cause hospitalization was high in this population. Further studies are needed to understand long-term clinical and economic outcomes among ITP patients.

Patients who fail to respond or maintain a response to initial therapy (e.g., corticosteroids, intravenous immunoglobulins), move to advanced therapies with robust evidence such as thrombopoietin receptor agonists (TPO-RAs [eltrombopag/ romiplostim/ avatrombopag]), rituximab, and fostamatinib, as per the international consensus guidelines. Approximately 5% of patients underwent splenectomy (incidence rate: 27 per 1000 person-years [95% CI: 15–40]) with mean (SD) time of 245 (186) days post initiation of advanced ITP therapy (Table 2). Conclusion This study demonstrated high clinical burden and need for subsequent additional therapies among patients with primary ITP lasting ≥3 months, which is evident from high rates of switching between advanced therapies, bleeding events requiring medical attention, TEs, and ITP-related hospitalizations.

Corticosteroids are the standard first-line treatment for ITP, while thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib are recommended for later lines; however, these treatments have limited sustained efficacy and may be associated with short- and long-term side effects that impact QoL. Pts with ITP are dissatisfied with current treatment options because of a perceived lack of efficacy, the burden of short- and long-term side effects, and the need for daily, life-long administration. Additionally, some commonly prescribed treatments for ITP are associated with fatigue. Pts and MDs would like new ITP treatments to offer a sustained period of remission or cure, and pts wish to be able to discontinue them without fear of relapse.

Our multi-omics analysis offers deeper perspectives on ESCC invasiveness and unveils new phosphorylated hub proteins with their regulatory kinase. This study also suggests that fostamatinib may be a potential agent for treating ESCC.

A subset of these patients with del(5q) may do better with lenalidomide. Recently, in randomized trials, luspatercept has shown better responses compared with ESAs in treatment-naive patients and imetelstat in patients refractory to ESAs. Other evaluated novel compounds (fostamatinib, H3B-880, roxadustat, pyruvate kinase receptor activator) have not yet shown meaningful efficacy...While lower-risk myelodysplastic syndromes/neoplasms tend to have an indolent course, a subset of them has a dismal prognosis. Improving prognostication and serial monitoring will help in identifying high-risk patients for appropriate management.

In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, "re-educated" pro-tumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the anti-tumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC.

The kinase inhibitor fostamatinib significantly inhibited the proliferative, invasive, and migratory capabilities of GC cells by inhibiting TLK2 activity. Altogether, this study reveals a novel functional relationship between TLK2 and the mTORC1/ASNS axis in GC. Therefore, TLK2 may serve as a potential therapeutic target for GC.

In conclusion, Fostamatinib shows promise as a potential drug for the treatment of breast cancer by regulating the cell cycle and inhibiting the proliferation of breast cancer cells.

Collectively, our findings demonstrate the central role of macrophage Syk in NB progression and demonstrate that Syk blockade can "reeducate" TAMs towards immunostimulatory phenotype, leading to enhanced T cell responses. These findings further support the clinical evaluation of fostamatinib alone or with radiation and ICB, as a novel therapeutic intervention in neuroblastoma.

The clinical use of the most advanced SYK inhibitor, Fostamatinib, has been limited due to its unwanted side effects...The identified compounds might have the potential to be developed into promising SYK inhibitors for the treatment of various diseases, including autoimmune disorders, cancer, and inflammatory diseases. This work aims to identify potential phytochemicals to develop a new protein kinase inhibitor for treating advanced malignancies by providing an updated understanding of the role of SYK.Communicated by Ramaswamy H. Sarma.

These results, paired with numerous published preclinical data, provide additional evidence that inhibition of the IRE1-mediated UPR may have therapeutic potential in treating GBM. We propose a possible drug repurposing strategy to simultaneously target IRE1 and the spleen tyrosine kinase (SYK) in patients with GBM.

The RP2D of Fos will be 200 mg orally BID when combined with wPac. AE profile of the combination was as expected and the combination demonstrated promising efficacy in pts with recurrent PROC. Clinical trial information: NCT03246074.

Moreover, combining Syk inhibitor, R788 along with anti-PDL1 mAb and radiation provided a synergistic effect leading to complete tumor regression and durable anti-tumor immunity in aggressive MYCN-and non-MYCN-driven murine neuroblastoma tumor models. Collectively, our findings demonstrate the importance of Syk inhibitor, R788, in enhancing the anti-tumor immune responses in NB and support the clinical evaluation of R788 either alone or together with radiation and immune check point inhibitors as a potential treatment strategy for NB.

Other second-line options that can be good alternatives depending on the clinical context include rituximab, dapsone, fostamatinib or immunosuppressive drugs. The aim of this review is to describe the particularities of the diagnosis and treatment of ITP in older people, including the response and tolerance to the currently available drugs. We also discuss some situations related to co-morbidities that can frequently lead to adapt the management strategy in older patients.

PRC1 may have a prognostic value for patients with LUAD, and be correlated with the mutation count, aneuploidy, hypoxia and tumor-infiltrating immune cells. Fostamatinib was found to be a potential drug targeting PRC1 in LUAD.

In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment.

Patients with MDS with del(5q) must have received prior therapy with lenalidomide and those with MDS with ring sideroblasts must have received luspatercept. Preliminary data suggests that treatment with fostamatinib at doses of up to 200mg po bid can be safely administered in patients with lower-risk MDS who have failed available therapies. Enrollment is ongoing to determine the potential efficacy of doses of up to 200mg bid. Additional correlative studies to determine predictors of response are underway.

No abstract available

Moreover, high expression of PAK2 is associated with worse survival outcome of ccRCC patients. These master kinases are targetable by inhibitory FDA-approved drugs such as fostamatinib, minocycline, tamoxifen and bosutinib which can serve as novel therapeutic agents for ccRCC treatment.

Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

In contrast, the pharmacokinetic/pharmacodynamic analysis for exposure safety revealed that R406 exposure significantly correlated with the incidence of hypertension. Even though the influence of elevated exposure on other toxicities, including diarrhea and neutropenia, is still unclear, careful management is required with dose escalation to avoid toxicity-related discontinuation.

It was found that compounds such as amiloride, imatinib, omeprazole, troglitazone, pantoprazole, and fostamatinib might be effective in gastric cancer treatment. Fostamatinib seems a potential therapeutic drug in gastric cancer due to its inhibitory effect on two survival genes. However, these findings should be confirmed through experimental investigations.

The selective, orally bioavailable SYK inhibitor entospletinib (ENTO) has demonstrated clinical activity and tolerability in HOXA9/MEIS1- driven AML...Lanraplenib (LANRA) is a next-generation SYK inhibitor with similar potency and selectivity to ENTO but with more favorable pharmacologic properties that is currently being evaluated in combination with gilteritinib in patients with relapsed or refractory (R/R) FLT3 -mutated AML (NCT05028751)...Results Kinase selectivity profiling found >10-fold higher selectivity of ENTO and LANRA for SYK vs other kinases with improved potency and selectivity compared with the approved first-generation agent, fostamatinib...Combinations with AML standard-of-care and investigational agents, including azacytidine, showed at least additive effects. Strong synergy with the JAK inhibitor ruxolitinib was consistent mechanistically with a reporter model that demonstrated the ability of LANRA to block activation of STAT5 in response to proleukemic paracrine signaling. Finally, robust synergy across a range of LANRA concentrations was found when paired with venetoclax and gilteritinib...The highly predictive response for SYK inhibition with concurrent NPM1 m/ FLT3 -ITD mutations and synergy with gilteritinib observed in patient derived models is supportive of its clinical evaluation in combination with a FLT3 inhibitor. Our work supports the rationale for an ongoing Phase 1b/2 study of LANRA in combination with gilteritinib in patients with R/R FLT3 -mutated AML.

The drug screening revealed that bortezomib, fostamatinib, gemcitabine, homoharringtonine and vinorelbine had anti-proliferative effects, which have not been previously reported for DMM. It was concluded that NCC-DMM1-C1 cells may be a useful tool for the study of DMM.

Finally, to investigate whether leukemic cells with mutated NFKBIE remain sensitive to other BCR inhibitors, we tested their growth in the presence of the PI3K inhibitor idelalisib or SYK inhibitor fostamatinib (Figure 1B). In contrast to IBR, both drugs inhibited the proliferation of NFKBIE-mutated cells in vitro , with a greater effect observed with idelalisib. Collectively, these data demonstrate that NFKBIE mutations can reduce the response to IBR treatment and suggest that such cases may benefit more from treatment with a PI3K inhibitor.

"We showed that fostamatinib (which can target PLK1 and other over-expressed serine/threonine kinases such as AURKA, MELK, NEK2, and TTK) is more active against cancer lines with more pronounced signatures of invasion (e.g., extracellular matrix organization/degradation). Furthermore, we identified surface-bound (e.g., ADAM15, CD276, ABCC5, CD36, NRP1, SCARB1) and likely secreted proteins (e.g., APLN, ANGPT2, CTHRC1, ADAM12) that are potential mPrCa diagnostic markers. Overall, we demonstrated that comprehensive analyses of public genomics data could reveal potentially clinically relevant information regarding mPrCa."

In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.

Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line...Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches.

Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively...In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.

To determine whether the spontaneous in vitro proliferation is dependent on BCR signals, the TP53/CDKN2A/2B-deficient cells were transfected with Cas9 ribonucleoprotein complexes targeting the IgM heavy chain constant region (IGHM) gene or were treated with the BCR inhibitors ibrutinib, idelalisib and fostamatinib...Finally, we tested the activity of combined treatment with a BCR inhibitor and the CDK4/6 inhibitor palbociclib against the murine and human TP53/CDKN2A/2B-deficient Richter syndrome models. Combined treatment showed synergistic activity in vitro and significantly prolonged mouse survival in vivo compared to single agent treatment (n = 10 mice/group, P<0.001). In conclusion, these data provide evidence that BCR signals are directly involved in regulating CLL cell proliferation and suggest that frequently co-occurring genetic lesions in TP53 and CDKN2A/2B contribute to Richter transformation by allowing for BCR dependent/costimulatory signal independent proliferation, which can be therapeutically targeted with a BCR and CDK4/6 inhibitor combination.

Rituximab was administered in 51.8% (7 in first, 22 in second, and 26 in subsequent lines), immunosuppressors in 49% (mycophenolate mofetil N=15, azathioprine N=14, cyclophosphamide N=12, and cyclosporine N=11), and splenectomy was performed in 20% of patients. Notably, thrombopoietin receptor analogues (TPO-RA) were given in 38% of cases, namely eltrombopag (N=24), romiplostim (N=16) or both (N=4). Additional therapies included plasma exchange (N=4), recombinant erythropoietin (EPO, N=3), GCSF (N=2), bortezomib (N=2), fostamatinib (N=1), and parsaclisib (N=1)...In conclusion, these data highlight the clinical severity and the unmet need for therapy in adult Evans’ syndrome. Moreover, the great frequency of relapses and burden of complications underline the poor clinical outcome of this condition.