Evaluation of the Safety and Efficacy of Silmitasertib (CX-4945) in Combination With Standard of Care (SOC) for Treating Patients With Community-Acquired Pneumonia (CAP) Associated With SARS-CoV-2 and Influenza Viral Infections

This is a Phase II, multi-center, double-blind, randomized, interventional study in approximately 120 subjects to evaluate clinical benefit of CX-4945 in adult outpatients with SARS-CoV-2 and influenza viral infection-associated pneumonia. The subjects will be recruited into two domains, including SARS-CoV-2 and influenza virus domains. The study will compare the efficacy of Standard of Care (SOC) combined with CX-4945 against SOC paired with a placebo, utilizing a 1:1 allocation ratio in each domain.

Start Date01 Mar 2024

Sponsor / Collaborator

Senhwa Biosciences, Inc.

NCT05817708 / CompletedPhase 1

A Dose Selection Phase 1 Study Evaluating the Safety and Tolerability of Silmitasertib

This is a Phase I single center, open-label, parallel design in 30 subjects to evaluate safety and tolerability of CX-4945 200mg QD, 200 mg BID and 400mg BID doses (10 subjects in each regimen) for continuously 5 days in healthy subjects for dose selection.

Start Date07 Nov 2022

Sponsor / Collaborator

Senhwa Biosciences, Inc.

NCT04668209 / TerminatedPhase 2IIT

Phase II, Randomized, Investigator Initiated Trial to Evaluate Safety and to Explore Clinical Benefit of Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19)

This multi-center, open-label, 2 arm parallel-group, randomized, interventional prospective exploratory study in 40 patients aimed to evaluate safety and explore putative clinical benefits of Silmitasertib 1000 mg BID dose in patients with severe illness caused be SARS-COV-2. This will be a two-arm trial comparing the SOC/best supportive care alone to the SOC/best supportive care with addition of Silmitasertib (allocation ratio 1:1).

Start Date21 Jan 2021

Sponsor / Collaborator

University of Arizona

[+1]

100 Clinical Results associated with Silmitasertib

100 Translational Medicine associated with Silmitasertib

100 Patents (Medical) associated with Silmitasertib

219

Literatures (Medical) associated with Silmitasertib

01 Mar 2024·Cancer letters

CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy

Article

Author: Wang, Xi-Yu ; Huang, Xi-Tai ; Zhao, Guang-Yin ; Ma, Ming-Jian ; Xu, Xiang ; Li, Fu-Xi ; Yin, Xiao-Yu ; Zhu, Ying-Qin ; Zhao, Wei ; Shi, Yin-Hao ; Ye, Jing-Yuan ; Liu, Zhi-De ; Xu, Qiong-Cong ; Wang, Jie-Qin

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.

01 Dec 2023·European journal of medicinal chemistry

Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors

Article

Author: Li, Zhewen ; Xu, Yechun ; Zou, Yi ; Liu, Jiayuan ; Zhang, Xianglei ; Shao, Qiang ; Su, Haixia ; Chen, Guofeng ; Li, Minjun

Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC₅₀ values ranging from 0.41 to 2.46 μM. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein.

01 Nov 2023·Molecular biology reports

CK2 inhibitor CX4945 inhibits collagen degradation of HaCaT human keratinocyte cells via attenuation of MMP-1 secretion

Article

Author: Lee, Sang Yeol ; Jeon, Jusu

INTRODUCTION:

During skin aging, the extracellular matrix (ECM) concomitantly breaks down. Out of the various protein components that comprise ECM, collagen is the most abundant one. Matrix metalloproteinase-1 (MMP-1) is a major collagenase that can degrade collagen. Therefore, the inhibition of MMP-1 may be critical for skin aging prevention. CX4945 is an inhibitor of casein kinase 2 and shows anticancer effects on various types of cancer cells.

METHODS AND RESULTS:

In this report, we investigated the MMP-1-inhibiting effect of CX4945 in HaCaT human keratinocyte cells. We performed zymography assays, Western blot analysis and immunoprecipitation assay to investigate the anti-MMP-1 effects of CX4945. CX4945 was found to inhibit collagen degradation via attenuation of the MMP-1 secretion out of HaCaT cells. This activity of CX4945 may be mediated by the induction of MMP-1 ubiquitylation via c-Jun N-terminal kinase (JNK) signaling. In wound healing cell migration assay, CX4945 also showed suppressive effect on the migration of HaCaT cells. This finding was closely related to the attenuation of CREB transcription factor via the downregulation of ERK mitogen-activated protein kinase as observed in Western blot analysis.

CONCLUSION:

Our report suggests that the inhibitory effects of CX4945 on MMP-1 in epidermal cells may offer a basis for further studying its therapeutic potential as an anti-wrinkle agent.

News (Medical) associated with Silmitasertib

03 Apr 2024

·www.prnewswire.com

AACR 2024 Annual Meeting-Visit Senhwa Biosciences Exhibit Booth

TAIPEI and SAN DIEGO, April 3, 2024 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, announces it will be exhibiting at the American Association for Cancer Research (AACR) Annual Meeting, 2024, held in San Diego, California, at the San Diego Convention Center from April 5 to 10. The AACR Annual is one of the biggest and most important events in cancer research, and brings together clinicians, researchers, industry, policymakers, and patient organizations. Senhwa will display a booth for the first time at the conference (Booths: Ground Level #1454, open from April 7-10), showcasing the innovative mechanisms and clinical results of the company's two new drugs, Pidnarulex (CX-5461) and Silmitasertib (CX-4945) in treating various cancers and the combination with PARP inhibitors and IO therapeutics. The team is very excited to meet its research and medical partners, make new connections, and get updated with the latest advancements in cancer research. Aside from the booth, the Company will host a dinner reception at the Hilton San Diego Bayfront. Those partner physicians who have worked closely on clinical trials in the United States, Canada, Australia, Taiwan are invited and this event aims to explore more potential collaboration opportunities. a At the same time, the Senhwa AACR team is led by CEO, Jin-Ding Huang Ph. D and also includes Ms. Joanne Lo, director of business development, Ms. Mermay Chen, director of strategy and Tzu-I Chao, director of drug development and other managers from the US subsidiary. The company's major focus is engaging with academic and industry researchers as well as with clinicians in person, and explore more opportunities, which may include cooperation in clinical trials, licensing agreements, introducing late-stage or marketed novel drugs to expand the company's current product line. If you are attending this year's AACR and wish to learn more about how we can support your research or enroll in our clinical network program, visit us at Booth #1454 or get in touch with our team to schedule your meeting. See you in San Diego! About Silmitasertib Silmitasertib is a first-in-class small molecule drug that targets the CK2 protein and acts as a CK2 inhibitor. Clinical studies thus far have shown Silmitasertib to be safe and well-tolerated in humans and is easily administered with its oral formulation. Silmitasertib is currently under development through several oncology programs in adults and children with recurrent/advanced or metastatic cancer. To date, three Phase I and one Phase I/II study of Silmitasertib in oncology, as well as two Phase II trials in infectious diseases, have been completed. The US FDA has granted Silmitasertib Orphan Drug Designation for the treatment of Cholangiocarcinoma in December 2016, Rare Pediatric Disease Designation and Orphan Drug Designation for the treatment of Medulloblastoma in July 2020 and December 2021, respectively. Fast Track Designation was granted in August 2021 for the treatment of recurrent Sonic Hedgehog driven Medulloblastoma. About Senhwa Biosciences Senhwa Biosciences, Inc. is a leading clinical-stage company focused on developing first-in-class, next-generation DNA Damage Response therapeutics and seeks to address unmet medical needs in oncology and infectious diseases. Headquartered in Taiwan, with an operational base in San Diego, California, Senhwa is well-positioned to oversee the development of its compounds. Silmitasertib (CX-4945) and Pidnarulex (CX-5461), both with novel mechanisms of action as anti-cancer drugs for the treatment of multiple indications, are the core products in Senhwa Bioscience's pipeline. Clinical trials are currently ongoing in Australia, Canada, United States and Taiwan. Visit Senhwa Biosciences' website for more details: SOURCE Senhwa Biosciences, Inc.

Orphan DrugFast TrackPhase 2AACR

20 Mar 2024

·www.prnewswire.com

Senhwa Biosciences Announces First Patient Dosed in the Phase II Study of Silmitasertib in Patients with Community-Acquired Pneumonia Associated with Viral Infection in Taiwan

TAIPEI and SAN DIEGO, March 20, 2024 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, announced today that their first patient has been successfully dosed in the phase II study of Silmitasertib (CX-4945) in patients with community-acquired pneumonia (CAP) associated with viral infection in Taiwan. This trial is to investigate whether early medical intervention of Silmitasertib restrains the progression of CAP by inhibiting the elevated cytokine release associated with SARS-CoV-2 and Influenza viruses. This phase II trial is led by an inter-hospital team specializing in infectious diseases, with extensive experiences in carrying out large-scale international clinical trials for various anti-viral new drugs. The study team consists of five well-known hospitals including National Taiwan University Hospital, National Taiwan University Cancer Center, Far Eastern Memorial Hospital, Tri-Service General Hospital and Taoyuan General Hospital, Ministry of Health and Welfare. According to the latest warning issued by the World Health Organization (WHO) that the globe may face another wave of pandemic of Disease X, possibly caused by the evolution of influenza, novel coronavirus strains, or a new pathogen unknown to humans. In addition, the reported case of the first human infection with avian flu and subsequent death in mainland China earlier this year promoted the WHO to conduct a risk assessment for transmission. Silmitasertib (CX-4945) developed by Senhwa Biosciences possesses a novel mechanism that targets human host cells, making it less susceptible to the effects of viral mutations. The purpose of this trial is to give early medical intervention in the course of the disease with Silmitasertib (CX-4945) as to prevent the progression of CAP, to avoid hospitalization and enhance the subject's clinical condition, while reducing the risks associated with elevated cytokine release related to infections of new coronaviruses or influenza viruses. Furthermore, compared to Silmitasertib (CX-4945), the next-generation drug CX-8184 exhibits higher activity and better neutralizing and inhibiting abilities against viruses. It is currently being developed to be administered directly to the lungs, aiming to become a novel treatment with convenient usage and broad-spectrum antiviral potential, if successful. About Silmitasertib Silmitasertib is a first-in-class small molecule drug that targets the CK2 protein and acts as a CK2 inhibitor. Clinical studies thus far have shown Silmitasertib to be safe and well-tolerated in humans and is easily administered with its oral formulation. Silmitasertib is currently under development through several oncology programs in adults and children with recurrent/advanced or metastatic cancer. To date, three Phase I and one Phase I/II study of Silmitasertib in oncology, as well as two Phase II trials in infectious diseases, have been completed. The US FDA has granted Silmitasertib Orphan Drug Designation for the treatment of Cholangiocarcinoma in December 2016, Rare Pediatric Disease Designation and Orphan Drug Designation for the treatment of Medulloblastoma in July 2020 and December 2021, respectively. Fast Track Designation was granted in August 2021 for the treatment of recurrent Sonic Hedgehog driven Medulloblastoma. About Senhwa Biosciences Senhwa Biosciences, Inc. is a leading clinical-stage company focused on developing first-in-class, next-generation DNA Damage Response therapeutics and seeks to address unmet medical needs in oncology and infectious diseases. Headquartered in Taiwan, with an operational base in San Diego, California, Senhwa is well-positioned to oversee the development of its compounds. Silmitasertib (CX-4945) and Pidnarulex (CX-5461), both with novel mechanisms of action as anti-cancer drugs for the treatment of multiple indications, are the core products in Senhwa Bioscience's pipeline. Clinical trials are currently ongoing in Australia, Canada, United States and Taiwan. Visit Senhwa Biosciences' website for more details: SOURCE Senhwa Biosciences, Inc.

Orphan DrugFast TrackPhase 2Qualified Infectious Disease Product

26 Dec 2023

·www.prnewswire.com

Senhwa Biosciences Received Taiwan FDA IND Approval for Phase II Study of Silmitasertib in Patients with Community-Acquired Pneumonia (CAP) Associated with Viral Infection

TAIPEI and SAN DIEGO, Dec. 26, 2023 /PRNewswire/ -- Senhwa Biosciences, Inc. (TPEx: 6492), a drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, announced today that Taiwan Food and Drug Administration has approved its Phase II IND application of Silmitasertib (CX-4945) to treat patients with community-acquired pneumonia (CAP) caused by viral infection. The trial is a phase II multi-center, randomized-controlled interventional prospective study, and the purpose of this trial is to investigate whether early intervention of Silmitasertib restrains the progression of CAP by inhibiting the elevated cytokine release associated with SARS-CoV-2 and Influenza viruses. This trial will be led by an inter-hospital team, which is specialized in infectious diseases and possesses extensive experiences in carrying out large-scale international clinical trials for various anti-viral new drugs, across five well-known hospitals including National Taiwan University Hospital, National Taiwan University Cancer Center, Far Eastern Memorial Hospital, Tri-Service General Hospital and Taoyuan General Hospital, Ministry of Health and Welfare. Silmitasertib works by inhibiting CK2 protein kinase, which have implicated in regulation of several signaling pathways that are important for innate immune responses. CK2 modulates inflammatory pathways, including NF-κB, PI3K–Akt–mTOR, and JAK–STAT. Inhibition of CK2 by Silmitasertib diminishes the secretion of IL-6 and MCP-1 (Rosenberger et al.). Silmitasertib treatment also reduces the expression of TNF-α and CCL4 in NiSO4-stimulated MoDCs (Bourayne et al.). "Senhwa regards this phase II as the proof-of-concept study to demonstrate Silmitasertib can be a therapeutic strategy that are not restricted to only a specific viral infection, but applicable to various viruses," said Jin-Ding Huang, CEO of Senhwa Biosciences, Inc. The global market for related therapeutic drugs has exceeded a value of over $120.6 billion USD in 2020 and it's projected to grow at a CAGR of 7.88% and reach more than $339 billion USD by 2030 according to market research. About Silmitasertib Silmitasertib is a first-in-class small molecule drug that targets the CK2 protein and acts as a CK2 inhibitor. Clinical studies thus far have shown Silmitasertib is safe and well-tolerated in humans and is easily administered with its oral formulation. Silmitasertib is currently under development through several oncology programs in adults and children with recurrent/advanced or metastatic cancer. To date, three Phase I trials and one Phase II trial of Silmitasertib in cancer patients have been completed while two other Phase I and II studies of Silmitasertib are still ongoing. The US FDA has granted Silmitasertib Orphan Drug Designation for the treatment of Cholangiocarcinoma in December 2016, Rare Pediatric Disease Designation and Orphan Drug Designation for the treatment of Medulloblastoma in July 2020 and December 2021, respectively. Fast Track Designation was granted in August 2021 for the treatment of recurrent Sonic Hedgehog driven Medulloblastoma. About Senhwa Biosciences Senhwa Biosciences, Inc. is a leading clinical-stage company focused on developing first-in-class, next-generation DNA Damage Response therapeutics and seeks to address unmet medical needs in oncology and infectious diseases. Headquartered in Taiwan, with an operational base in San Diego, California, Senhwa is well-positioned to oversee the development of its compounds. Silmitasertib (CX-4945) and Pidnarulex (CX-5461), both with novel mechanisms of action as anti-cancer drugs for the treatment of multiple indications, are the core products in Senhwa Bioscience's pipeline. Clinical trials are currently ongoing in Australia, Canada, United States and Taiwan. Visit Senhwa Biosciences' website for more details: SOURCE Senhwa Biosciences, Inc.

Orphan DrugPhase 2Fast TrackINDPhase 1

100 Deals associated with Silmitasertib

External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Influenza, Human	Phase 2	TW	Senhwa Biosciences, Inc.	01 Mar 2024
Community Acquired Pneumonia	Phase 2	TW	Senhwa Biosciences, Inc.	01 Mar 2024
COVID-19	Phase 2	US	Senhwa Biosciences, Inc.	03 Dec 2020
Medulloblastoma	Phase 2	US	Stanford University School of Medicine	14 Mar 2019
Cholangiocarcinoma	Phase 2	US	Senhwa Biosciences, Inc.	01 Jun 2014
Cholangiocarcinoma	Phase 2	KR	Senhwa Biosciences, Inc.	01 Jun 2014
Cholangiocarcinoma	Phase 2	TW	Senhwa Biosciences, Inc.	01 Jun 2014
Basal Cell Carcinoma	Phase 1	US	Senhwa Biosciences, Inc.	01 Apr 2019
Plasma cell myeloma refractory	Phase 1	US	Cylene Pharmaceuticals, Inc.	01 Sep 2010
Relapse multiple myeloma	Phase 1	US	Cylene Pharmaceuticals, Inc.	01 Sep 2010

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02128282 (S4-13-001, Pubmed) Manual	Phase 1/2	Cholangiocarcinoma First line	84	Gemcitabine+Cisplatin+Silmitasertib	uegbrfaksw(btlibpqgps) = rkqxrazaed jcfdxundfc (tblryqprmq, 7.6 ~ 14.7) View more	Positive	24 Sep 2022
NCT02128282 (S4-13-001, Pubmed) Manual	Phase 1/2	Cholangiocarcinoma First line	84	Gemcitabine+Cisplatin	uegbrfaksw(btlibpqgps) = eqwxcoetzi jcfdxundfc (tblryqprmq, 3.1 ~ NE) View more	Positive	24 Sep 2022
NCT04663737 (Biospace) Manual	Phase 2	COVID-19	20	CX-4945	erlsqvobeb(lyxghriegw) = uiaasjfgyl umiekwcjkb (gzkfxivult ) View more	Positive	20 Oct 2021
NCT04663737 (Biospace) Manual	Phase 2	COVID-19	20	Standard of Care	pqzmiaavms(chmlkrbjgv) = cwucwabpsz jrinxzqiwe (qepqzzsxbr ) View more	Positive	20 Oct 2021
NCT02128282 (S4-13-001, ASCO_GI2021) Manual	Phase 1/2	Metastatic Cholangiocarcinoma First line	87	gemcitabine+cisplatin+Silmitasertib	sxmumkcghd(xrlggkjyay) = ojzcknlgrr xxjeepmpgd (hsjmminsmg, 7.6 - 14.7) View more	Positive	22 Jan 2021
NCT02128282 (ASCO_GI2017)	Phase 1/2	Advanced Cholangiocarcinoma	127	CX-4945	zvnmzhgdzr(empkjwzclt) = fympomxjfe nkkvsmitvj (ldnjefilei ) View more	-	21 Mar 2017

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