This is a 4-visit, multi-center, randomized, double-masked, parallel group study evaluating the safety and efficacy of CSF-1 in the treatment of presbyopia.

Start Date26 Feb 2019

Sponsor / Collaborator

Orasis Pharmaceuticals Ltd.Startup

100 Clinical Results associated with Cilmostim

100 Translational Medicine associated with Cilmostim

100 Patents (Medical) associated with Cilmostim

1,719

Literatures (Medical) associated with Cilmostim

01 May 2025·MICROBIAL PATHOGENESIS

TLR-4Ab and IFNγAb with exogenous IL-10 treated LPS induced mice shown differential inflammatory response upon RANKL-M-CSF stimulation in resident bone marrow cells

Article

Author: Samanta, Sharmistha ; Bishayi, Biswadev ; Mukherjee, Gopinath

The inflammatory response in bone tissue often triggered by LPS is a complex process. Since LPS through TLR4 and in presence of IFNγ activates osteoclast differentiation and bone resorption, therefore, suppression of osteoclastogenesis through inhibition of TLR4 vs IFNγ mediated inflammation could be a reasonable strategy for the treatment of inflammatory bone loss. Administration of anti-TLR4 (30 mg/kg) and anti-IFNγ antibodies (6.6 mg/kg) were utilized before LPS (5 mg/kg) challenge and subsequently mice were treated with mouse IL-10 (0.02 mg/kg). Then RBMCs were isolated from different groups of mice and stimulated (in vitro) with M-CSF (10 ng/ml) and RANKL (10 ng/ml) to induce bone marrow cell differentiation in presence of LPS (100 ng/ml). The involvement of RANKL and M-CSF in the regulation of bone inflammation underlines the intricate signaling pathways. Furthermore, the study sheds light on the potential therapeutic effects of exogenous IL-10 possibly through STAT3 signaling in the RBMCs. The use of antibodies against TLR4 and IFNγ, in conjugation with IL-10in LPS bone damage model, appears to downregulate the activation of NF-κB, and reduction of many pro-inflammatory cytokines regulating the inflammatory cascade in RBMC. This suggests a promising avenue for the development of treatments aimed at mitigating bone inflammation associated with bacterial infections. Therefore, inhibition of TLR4 and IFNγ could be explored as potential therapeutic agents against LPS induced bone loss.

01 Mar 2025·CLINICAL RHEUMATOLOGY

Molecular mechanism of osteoclast differentiation of PBMC in patients with rheumatoid arthritis

Article

Author: Huang, Ying ; An, Yang ; Ma, Wukai ; Li, Long ; Zeng, Ping ; Lu, Daomin ; Li, Taiheng ; Lan, Weiya

OBJECTIVE:

Rheumatoid arthritis (RA) is an autoimmune condition that causes severe joint deformities and impaired functionality, affecting the well-being and daily life of individuals. Consequently, there is a pressing demand for identifying viable therapeutic targets for treating RA. This study aimed to explore the molecular mechanisms of osteoclast differentiation in PBMC from patients with RA through transcriptome sequencing and bioinformatics analysis.

METHODS:

Blood samples were collected from 20 patients with RA, including 15 females and 5 males. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Osteoclast differentiation was induced using a medium containing RANKL and M-CSF for 14 days, with medium changes every 2 days. After 14 days, osteoclasts were identified by TRAP staining, and multinucleated TRAP-positive cells were counted as osteoclasts. Subsequently, transcriptome sequencing was performed using the Illumina Novaseq 6000 platform, and differential expression analysis was conducted using the DESeq2 package in R. Differentially expressed genes were selected with a significance threshold of p < 0.05 and a fold change ≥ 2 (|Log2FC|≥ 1). Bioinformatics analysis was performed using R, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.

RESULTS:

TRAP staining showed successful induction of PBMCs into osteoclasts. Transcriptome sequencing revealed a significant number of differentially expressed genes (DEGs) in the induced groups compared with the control group. GO analysis showed that these DEGs were predominantly associated with biological processes related to the transmission of chemokine signals, reactions to living organisms, and bolstering neutrophil-driven defense mechanisms. KEGG analysis showed that these DEGs were enriched by primary signaling pathways, including interactions between cytokines and their receptors, chemokine signaling pathway, cell cycle regulation, neutrophil extracellular trap formation, and TNF signaling pathway.

CONCLUSIONS:

Osteoclast differentiation of PBMC from patients with RA involves various gene alterations, multiple biological processes, and signaling pathways, providing insight into the potential mechanism of PBMC osteoclast differentiation in RA. Key Points • A total of 1841 DEGs were obtained between the induced group and the normal group. • These DEGs were involved in multiple biological processes and signaling pathways.

01 Feb 2025·ANNALS OF THE RHEUMATIC DISEASES

GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica

Article

Author: Reitsema, Rosanne D ; Alegria, Guillermo Carvajal ; Quéré, Baptiste ; Brouwer, Elisabeth ; Boukhlal, Sara ; van Sleen, Yannick ; Devauchelle-Pensec, Valérie ; Abdulahad, Wayel H ; Zhang, Anqi ; Diepstra, Arjan ; Heeringa, Peter ; Cornec, Divi ; Dasgupta, Bhaskar ; Hemon, Patrice ; Roozendaal, Caroline ; Jiemy, William F ; Kwee, Thomas Christian ; van der Geest, Kornelis S M ; Sandovici, Maria

OBJECTIVES:

Insight into the immunopathology of polymyalgia rheumatica (PMR) is scarce and mainly derived from peripheral blood studies. The limited data available point towards macrophages as potential key players in PMR. This study aimed to identify the factors driving proinflammatory macrophage development and their functions in the immunopathology of PMR.

METHODS:

Monocyte phenotypes were investigated by flow cytometry in peripheral blood (PMR, n = 22; healthy controls, n = 20) and paired subacromial-subdeltoid (SASD) bursal fluid (PMR, n = 9). Macrophages in SASD bursa were characterised by immunohistochemistry and immunofluorescence (PMR, n = 12; controls undergoing shoulder replacement surgery, n = 10). The functions of cytokines expressed in PMR-affected tissue were examined using macrophage differentiation cultures (PMR, n = 7; healthy controls, n = 7).

RESULTS:

Monocytes (CD14^highCD16^- and CD14^highCD16⁺) were increased in blood of PMR patients and activated in bursal fluid. Macrophages dominated immune infiltrates in PMR-affected tissue, expressing various proinflammatory cytokines. While interleukin (IL)-6 and interferon-gamma (IFN-γ) expression was abundant in both PMR and control tissue, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were significantly increased in PMR tissue. Macrophages in PMR-affected tissue showed an elevated CD206/folate receptor β ratio, reflecting a GM-CSF skewed signature. A combination of GM-CSF/M-CSF/IFN-γ significantly boosted IL-6 production in vitro, while limited IL-6 production was observed without GM-CSF.

CONCLUSIONS:

The monocyte compartment is expanded and activated in PMR. Macrophages in PMR-affected tissue produce abundant proinflammatory cytokines such as IL-6. A network of locally expressed cytokines, including GM-CSF, M-CSF, and IFN-γ, may drive the proinflammatory functions of these macrophages. Overall, macrophages may constitute key therapeutic targets for PMR.

News (Medical) associated with Cilmostim

17 Oct 2023

·www.sciencedaily.com

Boosting weak immune system: Scientists find an unusual weapon against virus

Infections with cytomegalovirus (CMV) are extremely common and often pose no major threat to the vast majority of people. They can however be deadly for people whose immune system is weakened, e.g., after bone marrow transplantation. Current treatments against CMV infections are very limited and can have severe side effects. Researchers now propose a new way to protect against CMV. Instead of targeting the virus, their approach boosts the weak immune system and lets it fight the virus on its own. Infections with cytomegalovirus (CMV) are extremely common and often pose no major threat to the vast majority of people. They can however be deadly for people whose immune system is weakened, e.g., after bone marrow transplantation. Current treatments against CMV infections are very limited and can have severe side effects. Researchers led by Prof. Michael Sieweke at the Center for Regenerative Therapies Dresden (CRTD) at TUD Dresden University of Technology and the Center of Immunology of Marseille Luminy (CIML) propose a new way to protect against CMV. Instead of targeting the virus, their approach boosts the weak immune system and lets it fight the virus on its own. The results were published in the journal EMBO Molecular Medicine. Some viruses can be dormant throughout a person's life and cause no harm but become dangerous when the immune system is weakened. One of such viruses is human cytomegalovirus (CMV). Harmless to the general public but life-threatening to patients with a supressed immune system. "Patients undergoing bone marrow transplantations have their blood and immune system fully replaced by that of the donor. In the first months after transplantation they are defenseless. They can either catch CMV or have virus reactivated that was dormant in the patient. At the moment, there is no ideal treatment. The available ones work in a limited way or can cause severe side effects such as kidney failure, liver failure, deafness, sepsis, and others," explains Dr. Julien Subburayalu, a clinical scientist in the Sieweke group at the Center for Regenerative Therapies Dresden (CRTD), one of the leading authors of the study. The Unusual Approach: Boosting Immune System Teaming up with Dr. Marc Dalod, an expert on CMV immunity, the researchers led by Prof. Sieweke took an unusual approach. Instead of targeting the virus with antiviral treatments, they focused on strengthening the immune system to fight the virus on its own. "So far, antiviral treatments focused on targeting specific viruses, either through vaccination or by drugs that work on viral molecular machinery," mentions Dr. Marc Dalod, group leader at the Centre d'Immunologie de Marseille-Luminy (CIML) and author of the study. "Our method intervenes at the level of patient's blood stem cells to boosts general antiviral defenses. It's ideal as a prophylactic or a general intervention strategy in immunosuppressed individuals," says Prof. Michael Sieweke, Alexander von Humboldt Professor and research group leader at the CRTD and CIML. Cytokine: Small but Mighty Molecule The new approach focuses on the cytokine known as macrophage colony-stimulating factor (M-CSF, CSF1). It's a small signaling molecule that works as a messenger and activator for the immune system. "The cytokine boosts the production of specific white blood cells, mainly monocytes and macrophages," says Dr. Prashanth Kumar Kandalla, one of the leading authors of the study. Although normally monocytes and macrophages were not known as the primary defense force against viruses, the authors found that they activated other immune cells, so-called natural killer cells, that help fight the virus. "In case of immunocompromised patients, the number of white blood cells is very low. This is why their body is defenseless against infections. M-CSF treatment would boost the immune system by triggering the production of new white blood cells and restore the patient's ability to fight the pathogen," explains Dr. Kandalla. The team could show that M-CSF boosted production of white blood cells in immunocompromised mice and in such a way protected them from an otherwise lethal CMV infection without affecting bone marrow transplantation. Clinical Trials Are Needed The study showed that the concept worked in mice and in human cells in a culture dish. "We are keen to expand our findings and support them with data derived from patients in the clinic. For example, we would like to test our cytokine approach as a prophylactic intervention following bone marrow transplantation to prevent CMV reactivation. For this, clinical trials are necessary. We are now looking for partners who could help us finance such trials," concludes Prof. Sieweke. Because of its unique ability to boost the immune defence, the new approach is not limited to CMV or bone marrow transplantation patients. The authors expect that it could also be useful to treat other viral infections, and help other patients with a weakened immune system, for example after sepsis or chemotherapy.

Immunotherapy

23 Apr 2022

·www.prnewswire.com

Orasis Pharmaceuticals Announces Phase 2b Trial Efficacy and Safety Results of Novel Presbyopia Eye Drop Candidate, CSF-1, at the 2022 American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting

Orasis Pharmaceuticals, an emerging ophthalmic pharmaceutical company focused on developing a unique eye drop to improve near vision for people with presbyopia, today announced Phase 2b data demonstrating the efficacy and safety of its novel eye drop candidate, CSF-1, for the treatment of presbyopia at the 2022 American Society for Cataract and Refractive Surgery (ASCRS) Annual Meeting being held April 22-26 in Washington, D.C. The Phase 2b trial served as the foundation for the design and conduct of the Phase 3 NEAR-1 and NEAR-2 clinical trials of CSF-1, for which topline results were recently announced. In the first Paper Session, which will be presented on Monday, April 25, the Phase 2b trial results showed that CSF-1 (pilocarpine hydrochloride 0.4%) preservative-free ophthalmic solution formulated in a proprietary vehicle met its primary endpoint, with 47% of participants in the CSF-1 group achieving a 3-line or more gain in DCNVA 1-hour post-treatment on Day 15 compared to 16% in the vehicle group (P=0.0002). Additionally, the trial met its secondary endpoint, with 80% of participants in the CSF-1 group achieving a 2-line or more gain in DCNVA compared to 43% in the vehicle group (P=0.0001). CSF-1 demonstrated tolerability with a favorable safety profile. The most reported treatment-related adverse events experienced by over 5% of trial participants included instillation site pain (5.5%), headache (9.1%) and vision blur (10.9%) with all adverse events in the study reported as mild, transient and self-resolving. "In addition to meeting the primary endpoint, achieving the secondary endpoint of a 2-line or more gain is clinically meaningful, especially for early presbyopes whose near vision is not yet severely impacted," said Marjan Farid, M.D., presenting author. "We're also encouraged that there was no negative impact on distance or night vision, which is critical when looking at the potential benefit of an investigative treatment like CSF-1 could bring to patients to help them manage in their day-to-day lives." Additionally, a post hoc analysis of the Phase 2b trial of CSF-1 will be presented in the second Paper Session on Monday, April 25. The analysis met its primary endpoint of sustained improvement, with 47% of participants showing an improvement of 20/40 visual acuity (VA) level or better consistently over an 8-hour period on Day 15 following one dose of CSF-1. In both monocular and binocular measurements, the proportion of participants who achieved sustained DCNVA improvements was higher in the CSF-1 group vs. vehicle for participants assessed for sustained 20/40 vision across all time points (P<0.05). "These results, which showed that a greater proportion of participants receiving CSF-1 achieved sustained functional near vision of 20/40 or better compared to vehicle when tested binocularly, demonstrate clinically meaningful improvement that may allow individuals treated with CSF-1 to more easily conduct day-to-day activities requiring near vision," said Preeya K. Gupta, M.D., presenting author. Binocular summation, or the superiority of binocular performance over monocular performance, is acutely involved with improved visual acuity. As binocular suppression is observed in a majority of patients with presbyopia, achieving binocular summation is an important marker for evaluating efficacy of potential treatments for this age-related condition. "We are pleased with the favorable safety and efficacy results from this study, as well as the rapid onset and sustained duration of action," said Elad Kedar, Chief Executive Officer of Orasis Pharmaceuticals. "The Phase 2b trial provided robust data and critical direction to inform the Phase 3 NEAR-1 and NEAR-2 clinical trials, for which we recently reported similar positive, topline efficacy and safety results. The consistency of these results, which had nearly identical designs, reinforces CSF-1's efficacy, safety and comfort, and its potential to provide a first-line treatment option for people living with presbyopia." *ASCRS Disclaimer: All educational content of the ASCRS Annual Meeting is planned by its program committee, and ASCRS does not endorse, promote, approve, or recommend the use of any products, devices, or services.

Orasis Pharmaceuticals Ltd.PresbyopiaCilmostim

21 Apr 2022

·www.biospace.com

Orasis Pharmaceuticals Announces Positive Phase 3 Topline Results of Novel Eye Drop Candidate, CSF-1, for the Treatment of Presbyopia

Orasis Pharmaceuticals, an emerging ophthalmic pharmaceutical company focused on developing a unique eye drop to improve near vision for people with presbyopia, today announced that the Phase 3 NEAR-1 and NEAR-2 clinical trials, which evaluated the efficacy and safety of CSF-1, its novel eye drop candidate, met their primary and key secondary endpoints. Additional details of these trials will be presented at future medical meetings and will serve as the basis for the New Drug Application submission to the U.S. Food and Drug Administration (FDA) in the second half of 2022. In both trials, CSF-1 met its primary and key secondary endpoints on Day 8, achieving statistically significant 3-line or more gain in distance-corrected near visual acuity (DCNVA), and no loss of 1-line or more in distance visual acuity. Pooled across the two studies, 40% and 50% of participants demonstrated these gains 1-hour post-dose 1 and 1-hour post-dose 2 respectively (P<0.0001). CSF-1 also achieved statistically significant 3-line improvement at all measured time points on Days 1 and 15. On Day 15, participants achieved statistically significant 3-line or more improvement in DCNVA as early as 20 minutes and up to 8 hours post-dose 1. In addition, CSF-1 demonstrated an excellent tolerability and safety profile, with comparable redness and comfort versus vehicle, validating the preservative-free presentation and proprietary formulation of CSF-1. The most common treatment-related adverse events of headache and instillation sight pain occurred in only 6.8% and 5.8% of participants, respectively. Of all CSF-1 participants, only 2.6% reported moderate treatment-related adverse events. All other adverse events were mild. These results were achieved with a minimum effective dose of pilocarpine hydrochloride at 0.4%, which is less than one-third the concentration of the commercially available treatment. With a proprietary vehicle, CSF-1 is formulated preservative-free and provides for dosing flexibility with a comfort and safety pro does not compromise distance or night vision. "Currently, optometry delivers 85% of all comprehensive eye care exams, making a difference in the vision of so many patients," said Paul Karpecki, O.D., FAAO. "New and existing presbyopia patients will come into an optometry practice that now offers presbyopia drops, as well as contact lenses and spectacles – all playing a role in the management of the patients looking for options." "These statistically significant and clinically meaningful results are promising as eye care providers are eager to find alternate treatment options to improve quality-of-life for their patients with presbyopia, many of whom rely solely on reading glasses, which can be cumbersome," said Edward Holland, M.D., Professor of Ophthalmology, University of Cincinnati and Director of Cornea, Cincinnati Eye Institute. "Based on the efficacy and excellent tolerability demonstrated with such a minimum effective dose, I would see CSF-1 as a clear place to start many presbyopia patients." "We are extremely pleased with these positive results, which mark a significant milestone for CSF-1 and Orasis, and they position us well to be the next product to launch in this exciting category," said Elad Kedar, Chief Executive Officer of Orasis Pharmaceuticals. "The potential of CSF-1 to provide a first-line treatment option for people living with presbyopia is promising and we look forward to working with regulatory authorities to advance CSF-1 toward commercialization." To provide strategic options for CSF-1, Orasis plans to initiate a safety study with the option to extend long-term.

Orasis Pharmaceuticals Ltd.PresbyopiaCilmostim

100 Deals associated with Cilmostim

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03885011 (CTgov)	Phase 2	Presbyopia	166	pilocarpine HCl+diclofenac Na (CSF-1-FDC)	yzdflqleqq = lccxxytwfv ypcohgcgkb (wwgfcwncgf, gjjufgdlfn - nvhmwgtsqs) View more	-	26 Jan 2023
				pilocarpine HCl+pilocarpine (Pilo)	yzdflqleqq = xnfbcepzkh ypcohgcgkb (wwgfcwncgf, pzdjtvxwqs - oinprjltec) View more

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