A Phase 1/2 Multiple Ascending Dose Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of BMS-911543 in Subjects With Myelofibrosis

The purpose of this first in human study is to determine if BMS-911543 is safe and tolerable in subjects with symptomatic intermediate-1, intermediate-2 or high risk myelofibrosis to permit clinical testing at the Maximum Tolerated Dose or at a Clinically Active Dose, and to determine if BMS-911543 will demonstrate efficacy in symptomatic myelofibrosis.

Start Date07 Apr 2011

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with BMS-911543

100 Translational Medicine associated with BMS-911543

100 Patents (Medical) associated with BMS-911543

Literatures (Medical) associated with BMS-911543

03 Oct 2023·Expert Opinion on Investigational Drugs

Novel Janus-kinase (JAK) Inhibitors in Myelofibrosis

Review

Author: Eskazan, Ahmet Emre ; Ipek, Yildiz ; Kilic, Berkay ; Gunay, Ulgar Boran

INTRODUCTIONJAK inhibitors (JAKis), used in the treatment of myelofibrosis, have entered standard treatment, providing significant improvements in spleen size and symptom burden. Although splenomegaly provides a reduction and some improvement in cytopenia, there is still a way to go. Novel JAKis are being investigated to overcome barriers to treatment access, such as therapeutic challenges, intolerance, and unresponsiveness.AREAS COVEREDThis review includes the current status of JAKi treatment for myelofibrosis, mainly focusing on investigational JAKis; jaktinib, lestaurtinib, itacitinib, gandotinib, BMS-911543, ilginatinib, TQ05105, and flonoltinib maleate. MEDLINE and clinicaltrials.gov were screened to identify all completed or active studies on this topic. The outcomes of the preclinical studies and clinical trials are presented and discussed for each drug.EXPERT OPINIONIn patients with myelofibrosis, momelotinib was effective in treating anemia, whereas jaktinib was effective in both anemia and Total Symptom Score (TSS). More phase 3 studies are needed to provide more precise evidence. The increasing variety of JAKis will allow for more personalized treatment options for myelofibrosis in the future. The potential impact on disease progression, molecular responses, and the duration of this response will become important parameters for future evaluations of these drugs.

01 Jun 2021·Journal of Allergy and Clinical ImmunologyQ1 · MEDICINE

JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis

Q1 · MEDICINE

Article

Author: Thomas Bieber ; Nadine Herrmann ; Takashi Sakai ; Laura Maintz ; Anna Sophie Klaeschen ; Joerg Wenzel ; Nicole Leib ; Tim Joachim Nümm

BACKGROUNDJanus kinase (JAK) inhibitors are a new class of therapeutic compounds for dermatological diseases. In atopic dermatitis (AD), data of clinical phase III trials show rapid improvement of pruritus and significant reduction of inflammation within the first weeks with a favorable safety profile. However, their mode of action in AD is not fully understood.OBJECTIVESIn our study, we investigate the effect of different JAK inhibitors on cell differentiation, phenotype, and function of inflammatory dendritic epidermal cells (IDECs).METHODSWe analyzed the JAK expression in IDEC from ex vivo skin and in vitro generated IDECs using flow cytometry and PCR. Further, we studied in vitro the effect of different JAK inhibitors on IDEC cell differentiation, phenotype, and maturation.RESULTSIDECs express JAK1 and JAK2 ex vivo and in vitro. We found that JAK1 and JAK2 were upregulated during the differentiation from monocytes to IDECs. Conversely, JAK2 inhibition by ruxolitinib (JAK1/2 inhibitor) or BMS-911543 (JAK2 inhibitor) abrogated the differentiation from monocytes into IDECs. Differentiated IDECs can redifferentiate into a more monocyte-like phenotype in the presence of ruxolitinib or BMS-911543. Furthermore, we showed that concomitant inhibition of JAK1/2 rather than blocking JAK1 or JAK2 alone, impaired maturation and the release of proinflammatory cytokines on lipopolysaccharide stimulation.CONCLUSIONSOur results suggest that inhibition of JAK1/2 impairs IDEC differentiation and function. We provide new insight into the mode of action of JAK inhibitors in AD and highlight the role of JAK1/2 inhibitors for the treatment of patients with AD.

19 Apr 2019·The Journal of Organic ChemistryQ2 · CHEMISTRY

C–H Arylation in the Formation of a Complex Pyrrolopyridine, the Commercial Synthesis of the Potent JAK2 Inhibitor, BMS-911543

Q2 · CHEMISTRY

Article

Author: Cohen, Benjamin ; Beutner, Gregory L. ; Markwalter, Chester E. ; Fox, Richard J. ; Fanfair, Dayne ; Hay, Michael ; Zhu, Keming ; Lawler, Michael ; Eastgate, Martin D. ; Lobben, Paul ; Tran, Kristy ; Wei, Carolyn ; Regens, Christopher ; Skliar, Dimitri ; Hsiao, Yi ; Cuniere, Nicolas L. ; Bakrania, Lopa ; Strotman, Neil A. ; Rosner, Thorsten ; Soumeillant, Maxime C.

The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.

100 Deals associated with BMS-911543

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Primary Myelofibrosis	Phase 2	-	Bristol Myers Squibb Co.	-
Neoplasms	Preclinical	AU	Bristol Myers Squibb Co.	07 Apr 2011
Neoplasms	Preclinical	US	Bristol Myers Squibb Co.	07 Apr 2011

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