Delving into the Latest Updates on Linsitinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Linsitinib (USAN/INN)

+ [1]

Target

IGF-1R x INSR

Mechanism

IGF-1R antagonists(Insulin-like growth factor I receptor antagonists), INSR inhibitors(Insulin receptor inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersEndocrinology and Metabolic Disease+ [4]

Active Indication

Graves OphthalmopathyHashimoto DiseaseEsophageal Squamous Cell Carcinoma

Inactive Indication

Adrenocortical CarcinomaAdvanced Hepatocellular CarcinomaAdvanced Malignant Solid Neoplasm+ [9]

Originator Organization

Astellas Pharma, Inc.

Active Organization

Sling Therapeutics, Inc.Startup

Tongji University

Inactive Organization

Astellas Pharma, Inc.

OSI Pharmaceuticals, Inc.

Novartis Pharmaceuticals Corp.

+ [1]

Drug Highest PhasePhase 2/3

First Approval Date-

RegulationSpecial Review Project (CN), Orphan Drug (US)

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Structure

Molecular FormulaC26H23N5O

InChIKeyPKCDDUHJAFVJJB-VLZXCDOPSA-N

CAS Registry867160-71-2

The overall study objective is to continue to assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of linsitinib in subjects who were enrolled in the prior VGN-TED-301 through Week 24. These subjects include VGN-TED-301 Week 24 proptosis non-responders or subjects who relapse during the Follow-Up Period of VGN-TED-301.

Start Date11 Oct 2023

Sponsor / Collaborator

Sling Therapeutics, Inc.Startup

NCT05276063 / Active, not recruitingPhase 2/3

A Phase 2b, Randomized, Double-Mask, Placebo-Controlled, Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)

The overall objective is to study the safety, pharmacokinetics and efficacy of linsitinib (a small molecule IGF-1R inhibitor) administered orally twice daily (BID) vs. placebo, at 24 weeks in the treatment of subjects with active, moderate to severe thyroid eye disease (TED).

Start Date01 Jul 2022

Sponsor / Collaborator

Sling Therapeutics, Inc.Startup

100 Clinical Results associated with Linsitinib

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100 Translational Medicine associated with Linsitinib

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100 Patents (Medical) associated with Linsitinib

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162

Literatures (Medical) associated with Linsitinib

01 Dec 2024·European Journal of Pharmaceutical Sciences

In vitro assessment of inhibitory effects of kinase inhibitors on CYP2C9, 3A and 1A2: Prediction of drug-drug interaction risk with warfarin and direct oral anticoagulants

Article

Author: Kahma, Helinä ; Neuvonen, Mikko ; Cai, Weimin ; Paludetto, Marie-Noëlle ; Kurkela, Mika ; Jin, Shasha ; Backman, Janne T. ; Backman, Janne T ; Xiang, Xiaoqiang

OBJECTIVEThis study aimed to evaluate the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of kinase inhibitors with warfarin and direct oral anticoagulants (DOACs).METHODSAn in vitro CYP probe substrate cocktail assay was used to study the inhibitory effects of fifteen kinase inhibitors on CYP2C9, 3A, and 1A2. Then, DDI predictions were performed using both mechanistic static and physiologically-based pharmacokinetic (PBPK) models.RESULTSLinsitinib, masitinib, regorafenib, tozasertib, trametinib, and vatalanib were identified as competitive CYP2C9 inhibitors (K_i = 1.4, 1.0, 1.1, 3.8, 0.5, and 0.1 μM, respectively). Masitinib and vatalanib were competitive CYP3A inhibitors (K_i = 1.3 and 0.2 μM), and vatalanib noncompetitively inhibited CYP1A2 (K_i = 2.0 μM). Moreover, linsitinib and tozasertib were CYP3A time-dependent inhibitors (K_I = 26.5 and 400.3 μM, k_inact = 0.060 and 0.026 min^-1, respectively). Only linsitinib showed time-dependent inhibition of CYP1A2 (K_I = 13.9 μM, k_inact = 0.018 min^-1). Mechanistic static models identified possible DDI risks for linsitinib and vatalanib with (S)-/(R)-warfarin, and for masitinib with (S)-warfarin. PBPK simulations further confirmed that vatalanib may increase (S)- and (R)-warfarin exposure by 4.37- and 1.80-fold, respectively, and that linsitinib may increase (R)-warfarin exposure by 3.10-fold. Mechanistic static models predicted a smaller risk of DDIs between kinase inhibitors and apixaban or rivaroxaban. The greatest AUC increases (1.50-1.74) were predicted for erlotinib in combination with apixaban and rivaroxaban. Linsitinib, masitinib, and vatalanib were predicted to have a smaller effect on apixaban and rivaroxaban AUCs (AUCR 1.22-1.53). No kinase inhibitor was predicted to increase edoxaban exposure.CONCLUSIONSOur results suggest that several kinase inhibitors, including vatalanib and linsitinib, can cause CYP-mediated drug-drug interactions with warfarin and, to a lesser extent, with apixaban and rivaroxaban. The work provides mechanistic insights into the risk of DDIs between kinase inhibitors and anticoagulants, which can be used to avoid preventable DDIs in the clinic.

01 Nov 2023·Redox Biology

Accumulation of endogenous adenosine improves cardiomyocyte metabolism via epigenetic reprogramming in an ischemia-reperfusion model

Article

Author: Qian, Sanli ; Wang, Peng ; Sun, Xiaolei ; Li, Bingyu ; Sun, Aijun ; Wu, Tingting ; Wang, Cong ; Chen, Yingjie ; Huo, Yuqing ; Ge, Junbo ; Gao, Rifeng ; Zou, Yunzeng ; Zhang, Jinyan ; Fan, Fan ; Fassett, John

Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.

24 Apr 2023·Scientific reports

The combined signatures of the tumour microenvironment and nucleotide metabolism-related genes provide a prognostic and therapeutic biomarker for gastric cancer.

Article

Author: Zhong, Lei ; Deng, Dawei ; Zhang, Yunshu ; Yuan, Qihang ; Liu, Jifeng ; Shang, Dong

The tumour microenvironment (TME) is vital to tumour development and influences the immunotherapy response. Abnormal nucleotide metabolism (NM) not only promotes tumour cell proliferation but also inhibits immune responses in the TME. Therefore, this study aimed to determine whether the combined signatures of NM and the TME could better predict the prognosis and treatment response in gastric cancer (GC). 97 NM-related genes and 22 TME cells were evaluated in TCGA-STAD samples, and predictive NM and TME characteristics were determined. Subsequent correlation analysis and single-cell data analysis illustrated a link between NM scores and TME cells. Thereafter, NM and TME characteristics were combined to construct an NM-TME classifier. Patients in the NMlow/TMEhigh group exhibited better clinical outcomes and treatment responses, which could be attributed to the differences in immune cell infiltration, immune checkpoint genes, tumour somatic mutations, immunophenoscore, immunotherapy response rate and proteomap. Additionally, the NMhigh/TMElow group benefited more from Imatinib, Midostaurin and Linsitinib, while patients in the NMlow/TMEhigh group benefited more from Paclitaxel, Methotrexate and Camptothecin. Finally, a highly reliable nomogram was developed. In conclusion, the NM-TME classifier demonstrated a pretreatment predictive value for prognosis and therapeutic responses, which may offer novel strategies for strategizing patients with optimal therapies.

11

News (Medical) associated with Linsitinib

08 Nov 2023

·www.prnewswire.com

Sling Therapeutics to Participate in Upcoming Investor Conferences

ANN ARBOR, Mich., Nov. 8, 2023 /PRNewswire/ -- Sling Therapeutics, Inc., a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED), will be participating in three upcoming investor conferences in November 2023. Details of the presentations can be found below. Stifel 2023 Healthcare Conference Chief Executive Officer, Ryan Zeidan, Ph.D., will present a company presentation and host 1x1 investor meetings on Tuesday, November 14, at 9:45 a.m. ET. BTIG 3rd Annual Ophthalmology Day Chief Executive Officer, Ryan Zeidan, Ph.D., will present a company presentation and host 1x1 investor meetings on Monday, November 27, at 3:30 p.m. ET. Piper Sandler Healthcare Conference Chief Executive Officer, Ryan Zeidan, Ph.D., will present a company presentation and host 1x1 investor meetings on Wednesday, November 29, at 9:50 a.m. ET. About Sling Therapeutics Sling Therapeutics, Inc., is a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED). The company is advancing the evaluation of its lead product candidate, linsitinib, in a Phase 2b clinical trial based on extensive preclinical and clinical data. Linsitinib offers the potential of a convenient oral small molecule that could significantly reduce the treatment burden for people living with TED. For more information visit . Investor Contact Jessica Vo Gilmartin Group, LLC [email protected] Media Contact Adam Daley Berry & Company Public Relations 212.253.8881 [email protected] SOURCE Sling Therapeutics

Phase 2

25 Sep 2023

·www.prnewswire.com

Sling Therapeutics Announces Publication Demonstrating Attenuation of Pathologic Bone Marrow Activity with Linsitinib in a Mouse Model of Thyroid Eye Disease

- Linsitinib inhibited the formation of CD4+ T-cells in bone marrow, which are upregulated and clinically relevant in Thyroid Eye Disease (TED) - - Ongoing global Phase 2b LIDS clinical trial evaluating linsitinib for treatment of active, moderate to severe TED will provide clinical context and relevance - ANN ARBOR, Mich., Sept. 25, 2023 /PRNewswire/ -- Sling Therapeutics, Inc., a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED), today announced the publication of new preclinical data demonstrating linsitinib reduced pathologic bone marrow activity in a mouse model of TED. The data have been published in the peer-review journal Frontiers in Endocrinology. "As TED develops in patients, autoreactive CD4+ T-cells migrate into the bone marrow, inducing activation of the bone marrow and consecutive myelopoiesis. These latest preclinical data showed treatment with linsitinib significantly inhibited the activation pathway by blocking myeloid cells traveling to the thyroid and orbit, and directly induced arginase-1 in the bone marrow, leading to a depletion of arginine," said Anja Eckstein, M.D., professor and head of the Department of Orthoptics, Oculoplastic and Reconstructive Surgery and Orbital Center at the University Eye Hospital Essen, Germany. "Given that T-cells require arginine to activate and proliferate properly, the number of CD4+ T-cells in the bone marrow significantly decreased following treatment with linsitinib, resulting in reduced inflammation and tissue damage." "This recent dataset reinforces Sling's deep commitment to preclinical work designed to better elucidate the role of linsitinib as a potential first-line oral drug to treat all stages of TED," said Jeffrey Kent, M.D., Chief Medical Officer of Sling Therapeutics. "Abnormal bone marrow activity has been implicated in multiple autoimmune diseases, where the role of cytokine production via increased hematogenesis exacerbates clinical disease. We are pleased to be among first to demonstrate the effect of IGF-1R inhibition on this process and we are even more delighted to demonstrate that linsitinib markedly reduces pro-inflammatory cytokines which are released due to upregulated activity of hematopoietic stem and progenitor cells (HSPC). We look forward to translating these preclinical results in our ongoing global Phase 2b LIDS trial." The preclinical study investigated the effect of linsitinib on bone marrow activity in mice immunized with a plasmid encoding the A-subunit of thyroid stimulating hormone receptor (TSHR). Analyses of treated bone marrow showed downregulation of multiple cytokines associated with TED and upregulation of arginase-1. For more information about the Phase 2b LIDS trial, visit . About Thyroid Eye Disease (TED) TED is a debilitating autoimmune disease that affects about 20,000 people in the U.S. per year and has a similar prevalence in Europe. Dysfunction in the IGF-1R signaling pathway leads to a prevalence of thyroid-stimulating hormone receptor autoantibodies (TSHR-Abs) that drive excess fibrous tissue growth behind the eyes. The inflammation can push the eyes forward or cause the eyes and eyelids to become red and swollen. As the disease progresses it can lead to pain, eye bulging, and double vision. TED predominantly affects women, and most frequently affects people with hyperthyroidism due to Graves' disease. About Sling Therapeutics Sling Therapeutics, Inc., is a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED). The company is advancing the evaluation of its lead product candidate, linsitinib, in a Phase 2b clinical trial based on extensive preclinical and clinical data. Linsitinib offers the potential of a convenient oral small molecule that could significantly reduce the treatment burden for people living with TED. For more information visit . Investor Contact Jessica Vo Gilmartin Group, LLC [email protected] Media Contact Adam Daley Berry & Company Public Relations 212.253.8881 [email protected] SOURCE Sling Therapeutics

Phase 2Clinical Result

13 Sep 2023

·www.biospace.com

Sling Therapeutics to Participate in the Stifel Virtual I&I Summit

ANN ARBOR, Mich., Sept. 13, 2023 /PRNewswire/ -- Sling Therapeutics, Inc., a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED), will be participating at the Stifel I&I summit, held virtually, from September 19 - 20, 2023. Ryan Zeidan, Ph.D., Chief Executive Officer of Sling Therapeutics, will present a company presentation on September 19, at 12:45 p.m. ET. About Sling Therapeutics Sling Therapeutics, Inc., is a biopharmaceutical company focused on late-stage development of an oral small molecule for the treatment of thyroid eye disease (TED). The company is advancing the evaluation of its lead product candidate, linsitinib, in a Phase 2b clinical trial based on extensive preclinical and clinical data. Linsitinib offers the potential of a convenient oral small molecule that could significantly reduce the treatment burden for people living with TED. For more information visit . Investor Contact Jessica Vo Gilmartin Group, LLC jessi@gilmartinir.com

Phase 2

100 Deals associated with Linsitinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D09925	Linsitinib	-	DB06075

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adrenocortical Carcinoma	Preclinical	NL	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	NL	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	DE	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	DE	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	AU	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	AU	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	IT	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	CA	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	CA	Astellas Pharma, Inc.	01 Dec 2009
Adrenocortical Carcinoma	Preclinical	IT	Astellas Pharma, Inc.	01 Dec 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01560260 (SARC, Pubmed \| Clin Cancer Res) Manual	Phase 2	Gastrointestinal Stromal Tumors	20	Linsitinib	(zzkmqyymvj) = kglpgnihuk wyapihnjie (wlkowxvkek ) View more	Positive	15 Apr 2020
NCT01186861 (Pubmed \| Med J Aust) Manual	Phase 2	Non-Small Cell Lung Cancer Maintenance	205	erlotinib+linsitinib	(wcodxjuwgn): P-Value = 0.601 View more	Negative	05 Sep 2017
				erlotinib+Placebo
NCT01560260 (SARC, CTgov)	Phase 2	Paraganglioma \| Chondrosarcoma \| Gastrointestinal Stromal Tumors \| Carney Complex	20	Pharmacological Study+Linsitinib	mrfuvvulyr(tubfyfhuer) = eygcoooznn iwnewukrau (ybwylxqlpg, bgivxlqguz - zyznpxfnrw) View more	-	19 Jan 2017
NCT01221077 (Pubmed \| Clin Lung Cancer) Manual	Phase 2	Non-Small Cell Lung Cancer	88	erlotinib+Linsitinib	(cvovlpjofm) = vhvejyojui sgffpzmgto (emzucxoihp ) View more	Negative	01 Jan 2017
				erlotinib+Placebo	(cvovlpjofm) = kfacfltote sgffpzmgto (emzucxoihp ) View more
NCT00739453 (Pubmed \| Clin Cancer Res) Manual	Phase 1	Advanced Malignant Solid Neoplasm	95	Linsitinib+Erlotinib (Advanced Solid Tumors)	(ejfgcstosn) = On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. tsdxflvljd (ubvjahabgo ) View more	Positive	15 Jun 2016
				Linsitinib+Erlotinib (non-small cell lung cancer (NSCLC))
NCT01533181 (CTgov)	Phase 2	Small cell lung cancer recurrent	44	Topotecan (Arm A: Topotecan)	(rgdmhfhuwk) = xbvreacqes qlzgqkugwr (dankramgdv, zzsocpncxb - opxotjcrjp) View more	-	14 Jan 2016
				OS-906 (Arm B: OS-906)	(rgdmhfhuwk) = xslshkcucx qlzgqkugwr (dankramgdv, wofwqegfto - wvkxusafch) View more
NCT00924989 (Pubmed \| Lancet Oncol) Manual	Phase 3	Adrenocortical Carcinoma	139	Linsitinib	(comxbpccqo) = aqolbcijtc eplerurikt (qpfdpzkkpo )	Negative	01 Apr 2015
				Placebo	(comxbpccqo) = rbxyuybgrt eplerurikt (qpfdpzkkpo ) View more
NCT01533246 (CTgov)	Phase 2	Recurrent Prostate Carcinoma \| Metastatic Prostate Carcinoma \| Metastatic castration-resistant prostate cancer \| Adenocarcinoma of prostate	17	laboratory biomarker analysis+linsitinib	meuevphhbp(ggdxzehdgn) = pbffgrfnnf wsasaojjjf (iiwhbkkysp, mdvcqbccma - zznhscduxw) View more	-	13 Mar 2015
NCT00514007 (Pubmed \| Clin Cancer Res) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	95	OSI-906	(muufvqxjmb) = 400 mg once daily and 150 mg twice daily mrueeqxxjf (ljfuzioppq ) View more	Positive	15 Feb 2015
NCT00514306 (Pubmed \| Clin Cancer Res) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	79	OSI-906	(nhrobaiynh) = 600 mg for both S1 and S3 schedules aftbzedywb (fjbddhkjry ) View more	Positive	15 Feb 2015