A Phase 1b/2 Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib (LANRA) in Combination With the FLT3 Inhibitor Gilteritinib, in Patients With FLT3-mutated Relapsed or Refractory AML

The primary objective of this study is to evaluate the safety of lanraplenib (LANRA) in combination with the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib, in participants with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML).

开始日期2022-08-05

申办/合作机构

Kronos Bio, Inc.

NCT03285711 / Completed临床2期

A Phase 2, Randomized, Double-Blind, Multicenter Study Evaluating the Safety and Efficacy of Filgotinib and GS-9876 in Subjects With Lupus Membranous Nephropathy (LMN)

The primary objective of this study is to evaluate the efficacy of filgotinib and lanraplenib (previously GS-9876) in adults with lupus membranous nephropathy (LMN).

开始日期2017-10-06

申办/合作机构

Gilead Sciences, Inc.

NCT03134222 / Completed临床2期

A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of Filgotinib and GS-9876 in Female Subjects With Moderately-to-Severely Active Cutaneous Lupus Erythematosus (CLE)

The primary objective of this study is to evaluate the efficacy of filgotinib and lanraplenib (formerly GS-9876) in females with moderately-to-severely active cutaneous lupus erythematosus (CLE).

开始日期2017-05-24

申办/合作机构

Gilead Sciences, Inc.

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100 项与 Lanraplenib 相关的临床结果

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100 项与 Lanraplenib 相关的转化医学

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100 项与 Lanraplenib 相关的专利（医药）

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项与 Lanraplenib 相关的文献（医药）

2023-07-01·The Journal of investigative dermatology

Neutrophil-Specific Syk Expression Is Crucial for Skin Disease in Experimental Epidermolysis Bullosa Acquisita

Article

作者: Szilveszter, Kata P ; Balogh, Lili ; Németh, Tamás ; Káposztás, Eszter ; Mócsai, Attila

Autoantibodies against the dermal-epidermal junction component type VII collagen (C7) trigger skin disease in the inflammatory form of epidermolysis bullosa acquisita. We have previously identified the Syk tyrosine kinase as a crucial participant in anti-C7 antibody-induced experimental epidermolysis bullosa acquisita. However, it is still unclear which cellular lineage needs to express Syk during the disease process. In this study, we show that the loss of Syk, specifically from neutrophils, results in complete protection from the anti-C7 antibody-initiated skin disease both macroscopically and microscopically. Mice with a neutrophil-specific Syk deletion had decreased neutrophil accumulation and abrogated CXCL2 and IL-1β levels in the skin upon anti-C7 treatment, whereas isolated Syk-deficient neutrophils had decreased superoxide release, cell spreading, and cytokine release on C7-anti-C7 immune complex surfaces. Entospletinib and lanraplenib, two second-generation Syk-specific inhibitors, effectively abrogated immune complex-induced responses of human neutrophils and decreased the anti-C7 antibody-initiated, neutrophil-mediated ex vivo dermal-epidermal separation in human skin samples. Taken together, these results point to a crucial role for Syk in neutrophils in the development and progression of epidermolysis bullosa acquisita and suggest Syk inhibition as a potential therapeutic strategy.

2022-11-28·Rheumatology2区 · 医学

Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren’s syndrome: a randomized, phase 2, double-blind, placebo-controlled study

2区 · 医学

Article

作者: Mozaffarian, Neelufar ; Gurtovaya, Oksana ; Bombardieri, Michele ; Mathur, Anubhav ; Mozaffarian, Afsaneh ; Pechonkina, Alena ; Price, Elizabeth ; Matzkies, Franziska ; Jiang, Wendy ; Downie, Bryan ; Kivitz, Alan ; Gottenberg, J Eric

Abstract:

Objective:

The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS.

Methods:

This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton’s tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes.

Results:

The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2.

Conclusion:

Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings.

Trial registration:

ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942.

2022-05-30·Rheumatology2区 · 医学

Filgotinib or lanraplenib in moderate to severe cutaneous lupus erythematosus: a phase 2, randomized, double-blind, placebo-controlled study

2区 · 医学

Article

作者: Matzkies, Franziska ; Mozaffarian, Afsaneh ; Fleischmann, Roy ; Gurtovaya, Oksana ; Touma, Zahi ; Werth, Victoria P ; Wallace, Daniel ; Pechonkina, Alena ; Downie, Bryan ; Robern, Michael ; Tiamiyu, Iyabode

Abstract:

Objectives:

To explore the safety and efficacy of filgotinib (FIL), a Janus kinase 1 inhibitor, and lanraplenib (LANRA), a spleen kinase inhibitor, in cutaneous lupus erythematosus (CLE).

Methods:

This was a phase 2, randomized, double-blind, placebo-controlled, exploratory, proof-of-concept study of LANRA (30 mg), FIL (200 mg) or placebo (PBO) once daily for 12 weeks in patients with active CLE. At week 12, PBO patients were rerandomized 1:1 to receive LANRA or FIL for up to 36 additional weeks.

Results:

Of 47 randomized patients, 45 were treated (PBO, n = 9; LANRA, n = 19; FIL, n = 17). The primary endpoint [change from baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) score at week 12] was not met. The least squares mean CLASI-A score change from baseline was −5.5 (s.e. 2.56) with PBO, −4.5 (1.91) with LANRA and −8.7 (1.85) with FIL. Numerical differences between FIL and PBO were greater in select subgroups. A ≥5-point improvement in the CLASI-A score at week 12 was achieved by 50.0%, 56.3% and 68.8% in the PBO, LANRA and FIL arms, respectively. A numerically greater proportion of patients in the FIL arm (50%) also achieved ≥50% improvement in the CLASI-A score at week 12 (37.5% PBO, 31.3% LANRA). Most adverse events (AEs) were mild or moderate in severity. Two serious AEs were reported with LANRA and one with FIL.

Conclusion:

The primary endpoint was not met. Select subgroups displayed a numerically greater treatment response to FIL relative to PBO. LANRA and FIL were generally well tolerated.

Trial registration:

ClinicalTrials.gov identifier NCT03134222

项与 Lanraplenib 相关的新闻（医药）

2024-03-21

·BioSpace

Kronos Bio Reports Recent Business Progress and Fourth-Quarter and Full-Year 2023 Financial Results

Phase 1/2 study of KB-0742 is on track to clear 80mg four-days-on, three-days-off schedule in the third quarter of 2024; topline data from expansion cohort at this schedule expected in the first half of 2025 IND-enabling studies for KB-9558 expected to complete in 2024 with first-in-human study anticipated to commence in the first half of 2025 $175.0 million in cash, cash equivalents and investments as of December 31, 2023, providing expected cash runway into the second half of 2026 SAN MATEO, Calif. and CAMBRIDGE, Mass., March 21, 2024 (GLOBE NEWSWIRE) -- Kronos Bio Inc (Nasdaq: KRON), a company dedicated to transforming the lives of those affected by cancer, today reported recent business progress and fourth-quarter and full-year 2023 financial results. “In 2023, we made great progress across our portfolio and business. We demonstrated that KB-0742 has a safety pro is clearly differentiated from all other CDK9 inhibitors, and we believe our extended dosing schedule will show increased efficacy signals while maintaining a favorable safety profile,” said Nobert Bischofberger, Ph.D., president and chief executive officer of Kronos Bio. “We also announced our second development candidate, KB-9558, which is designed to target the KAT domain of p300 and downregulate IRF4 transcription in multiple myeloma. We are looking forward to completing the IND-enabling studies in 2024 and expect to dose our first patients in the first half of 2025.” Clinical Program and Recent Company Updates KB-0742 At the 2023 AACR-NCI-EORTC International Conference, the Company reported target engagement, tumor regressions, and an acceptable safety pro KB-0742 dosed at 60mg three-days-on, four-days-off in heavily pre-treated patients with transcriptionally addicted solid tumors. Out of fourteen “all-comer” patients, two patients with myxoid liposarcoma exhibited tumor regressions: one (7th line) had a partial response (per RECIST v1.1) lasting 113 days and the second achieved a 26% reduction in tumor diameters with stable disease. KB-0742 also cleared the 80mg three-days-on, four-days-off schedule in dose escalation and is currently enrolling patients in the KB-0742 60mg four-days-on, three-days-off dose escalation cohort of the Phase 1/2 trial. At a medical conference in mid-2024, the Company intends to share an update on the clinical data to date from patients with transcriptionally addicted tumors who were dosed with 60mg three-days-on, four-days-off, and from “all-comer” patients in the dose-escalation cohort who received 80mg three-days-on, four-days-off. In the third quarter of 2024, the Company expects to clear the 80mg four-days-on, three-days-off dose escalation cohort, and begin enrolling patients in an expansion cohort including one or more of the following: non-small cell lung cancer, small cell lung cancer, ovarian cancer, and triple negative breast cancer. The Company expects to announce topline data from the expansion cohort at the 80mg four-days-on, three-days-off dose in the first half of 2025. KB-9558 In December 2023, the Company announced the nomination of KB-9558, a p300 KAT inhibitor, as a development candidate. KB-9558 is the second development candidate to emerge from Kronos Bio’s product engine, where the Company identified that inhibition of the lysine acetyltransferase (KAT) domain on p300 inhibits expression of interferon regulatory factor 4 (IRF4) and thus collapses the transcription regulatory network that is required for the survival of multiple myeloma cells. The Company plans to present data on KB-9558 at the American Association for Cancer Research (AACR) annual meeting, being held from April 5-10, 2024 in San Diego, California, including how targeting p300’s enzymatic KAT domain can selectively downregulate IRF4. Pending completion of IND-enabling studies in 2024, the Company intends to initiate a first-in-human trial in relapsed or refractory multiple myeloma in the first half of 2025. Lanraplenib In December 2023, after a review of data from the Phase 1b portion of its Phase 1b/2 trial of lanraplenib in combination with gilteritinib in FLT3-mutated relapsed/refractory acute myeloid leukemia (AML), the Company decided not to proceed to Phase 2. Company Update Kronos Bio extended its expected cash runway by a year, into the second half of 2026, through restructurings and resource optimization. Fourth-Quarter and Full-Year 2023 Financial Highlights Cash, Cash Equivalents and Investments: With its ongoing and currently planned clinical programs and $175.0 million in cash, cash equivalents and investments as of December 31, 2023, the Company anticipates sufficient resources to fund its planned operations into the second half of 2026. R&D Expenses: Research and development expenses were $18.7 million for the fourth quarter of 2023, which includes non-cash stock-based compensation expense of $2.5 million. For the full year of 2023, research and development expenses were $86.4 million, which includes non-cash stock-based compensation expense of $12.0 million. G&A Expenses: General and administrative expenses were $10.9 million for the fourth quarter of 2023, which includes non-cash stock-based compensation expense of $2.7 million. For the full year of 2023, general and administrative expenses were $41.7 million, which includes non-cash stock-based compensation expense of $13.0 million. Net Loss: Net loss for the fourth quarter of 2023 was $25.3 million, or $0.43 per share, including non-cash stock-based compensation expense of $5.2 million. Net loss for the full-year 2023 was $112.7 million, or $1.95 per share, including non-cash stock-based compensation expense of $25.0 million. About Kronos Bio, Inc. Kronos Bio is a biopharmaceutical company that is advancing an investigational CDK9 inhibitor compound, KB-0742, in a Phase 1/2 clinical trial as a treatment for MYC-amplified solid tumors and other transcriptionally addicted solid tumors as well as a preclinical development candidate, KB-9558, targeting the KAT domain of p300 for multiple myeloma. The Company’s scientific focus is on developing medicines that target deregulated transcription, the hallmark of cancer and other serious diseases. Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass. For more information, visit or follow the Company on LinkedIn. Forward-Looking Statements Statements in this press release that are not statements of historical fact are forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The press release, in some cases, uses terms such as “anticipate,” “believe,” “could,” “expect,” “on track,” “plan,” “potential,” “promising,” “will,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements include statements regarding Kronos Bio’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the Phase 1/2 study of KB-0742 being on track to clear 80mg four-days-on, three-days-off schedule in Q3 2024; expected clinical results from the KB-0742 study; the expected timing for additional clinical data from the Phase 1/2 KB-0742 study; the potential completion of IND-enabling studies and the initial of a clinical trial for KB-9558 and the timing thereof; future pipeline development activities or outcomes; the potential of Kronos Bio’s product candidates; Kronos Bio’s expected cash runway; and other statements that are not historical fact. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: risks associated with changes to the assumptions underlying estimated expenses and savings; changes in the macroeconomic environment or competitive landscape that impact Kronos Bio’s business; whether Kronos Bio will be able to progress its clinical trials on the timelines anticipated, including due to risks inherent in the clinical development of novel therapeutics; risks related to Kronos Bio’s limited experience as a company in conducting clinical trials; the risk that results of preclinical studies and early clinical trials (including preliminary results) are not necessarily predictive of future results; and risks associated with the sufficiency of Kronos Bio’s cash resources and need for additional capital. These and other risks are described in greater detail in Kronos Bio’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in its Quarterly Report on Form 10-Q for the quarter ended September 30, 2023, filed with the SEC on November 13, 2023, and in its Annual Report on Form 10-K for the year ended December 31, 2023, being filed with the SEC today. Any forward-looking statements that are made in this press release speak only as of the date of this press release and are based on management’s assumptions and estimates as of such date. Except as required by law, Kronos Bio assumes no obligation to update the forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. Kronos Bio, Inc. Statements of Operations and Comprehensive Loss (in thousands, except per share data) (Unaudited) Three Months Ended December 31, Year Ended December 31, 2023 2022 2023 2022 Revenue $ 2,286 $ — $ 6,288 $ — Operating expenses: Research and development 18,704 23,168 86,379 93,715 General and administrative 10,926 10,514 41,739 43,400 Total operating expenses 29,630 33,682 128,118 137,115 Loss from operations (27,344 ) (33,682 ) (121,830 ) (137,115 ) Other income (expense), net: Interest and other income, net 2,024 1,900 9,157 3,911 Total other income (expense), net 2,024 1,900 9,157 3,911 Net loss (25,320 ) (31,782 ) (112,673 ) (133,204 ) Other comprehensive income (loss): Net unrealized gain (loss) on available-for-sale securities 274 258 811 (753 ) Net comprehensive loss $ (25,046 ) $ (31,524 ) $ (111,862 ) $ (133,957 ) Net loss per share, basic and diluted $ (0.43 ) $ (0.56 ) $ (1.95 ) $ (2.37 ) Weighted-average number of shares used to compute net loss per share, basic and diluted 58,268 56,523 57,744 56,201 Kronos Bio, Inc. Selected Balance Sheet Data (in thousands) (Unaudited) December 31, 2023 December 31, 2022 Cash, cash equivalents and investments $ 174,986 $ 247,947 Total assets $ 213,279 $ 294,938 Total liabilities $ 54,201 $ 50,439 Total stockholders’ equity $ 159,078 $ 244,499 Investor & Media Contact: Margaux Bennett Vice President, Corporate Development and Investor Relations, Kronos Bio 650-781-5026 mbennett@kronosbio.com

临床1期财报AACR会议高管变更临床结果

2024-03-20

·精准药物

氧杂环丁烷在药物发现中的应用

1背景当前药物化学项目集中于更多更具挑战性的生物靶点，候选药物的分子复杂性大大增加。为此，药物研究者们不断寻找创新的功能分子基团以应对这一挑战。今天我们要分享的是伦敦帝国理工学院化学系分子科学研究中心发表在Journal of Medicinal Chemistry上的文章：Oxetanes in Drug Discovery Campaigns。文章介绍了氧杂环丁烷在药物发现中的应用以及应用中的一些优缺点。四元杂环因其具有低分子量，高极性和特异的三维属性而深受研究者们的欢迎，其中氧杂环丁烷基团被报道的更多（图1）。图1. (a) 具有生物活性的四元杂环的例子；（b）文献中报道四元杂环的数量变化氧杂环丁烷基团在天然产物中常有出现，最著名的有FDA批准的紫杉醇（图2a），虽然氧杂环丁烷被证明不是紫杉醇生物活性的必要结构，但含氧杂环丁烷基团的类似物的亲和力和细胞毒性低于紫杉醇的母体结构。图2. (a) 紫杉醇；(b) gem-二甲基和羰基衍生物的等排体 3,3-二取代的氧杂环丁烷可以作为gem-二甲基和羰基的等排体（图2b），Carreira 团队和罗氏公司合作证明氧杂环丁烷可以作为gem-二甲基的等排体来阻断候选药物中C-H活性位点的代谢 [1]；氧杂环丁烷还可以作为羰基的等排体用来改善药物分子的代谢稳定性及提高药物分子的水溶性等性质。2应用举例氧杂环丁烷在专利和学术期刊中广泛出现，目前有七种包含氧杂环丁烷的候选药物正在进行临床试验（图3a-3g）。七种候选药物中有超过50%的结构是氨基-氧杂环丁烷，其中氧杂环丁烷基团可以减弱氨基的碱度。此外，七种化合物中有6种化合物的氧杂环丁烷是3位取代，因为3位取代的稳定性和可合成性更高。通常在药物设计的后期引入氧杂环丁烷来改善先导化合物的PK性质（logD、溶解度、清除率或碱度等）。图3a. Crenolanib[2] 图3b. Fenebrutinib[3]图3b Fenebrutinib中氧杂环丁烷的引入降低了化合物4的pKaH，对化合物的溶解度和药代动力学特性也有一定的益处。图3c. Ziresovir[4]图3c 中Ziresovir，在研发后期通过引入氧杂环丁烷来降低化合物5中氨基的碱度，氧杂环丁烷小体积的特性也有助于降低分布体积，避免药物在组织中堆积，降低了毒性风险。图3d. Lanraplenib[5]图3d 中Entospletinib 由于其不充分的溶解度，与质子泵抑制剂不良的相互作用以及吗啉环氧化导致的高代谢清除率退出了临床开发。在后期优化阶段引入4-乙基哌嗪替换吗啉改善了化合物的代谢稳定性，随后引入氧杂环丁烷替代乙基，降低了化合物的碱度，提高了在 pH 2 和 Caco-2 渗透性下的溶解度。图3e. Danuglipron[6]图3e Danuglipron 中氧杂环丁烷作为一个小的极性头被引入，它增加了化合物的活性，没有对 LogD 和其他物理化学性质（如清除率和毒性）产生负面影响。图3f. GDC-0349[7]图3f 化合物7有较差的游离血浆清除率和避免由细胞色素P450酶类（CYP酶）时间依赖性抑制（TDl），这可能导致药物存在潜在的毒性问题。将嘧啶环换成烷基确实将CYP抑制降低了10倍以上，但心脏毒性增高（hERG：IC50= 8.5 μM），这与叔烷基胺碱度增加有关（pKaH= 7.6）。GDC-0349 在氮上引入氧杂环丁烷取代基降低了pKaH，同时降低了hERG毒性，与化合物7相比，游离血浆清除率也降低了10倍。图3g. PF-06821497[8]图3g中先导化合物8是一种有效的EZH2抑制剂，但代谢稳定性差且溶解度不足。可通过降低LogD和增加立体性来改善这两种特性。最后化合物9引入了甲氧基和氧杂环丁烷，显著改善了代谢和溶解度特性，并使化合物更适合蛋白口袋。图4. 化合物PF-06821497与EZH2的共晶体结构新引入的氧杂环丁烷立体中心对结合很重要，化合物PF-06821497与 EZH2 复合物的共晶结构表明（图4），氧杂环丁烷取代基在蛋白空腔中占据了一个确定的空间，氧杂环丁烷中的CH 基团和两个酪氨酸侧链之间存在两个潜在的 CH−π相互作用。3小结氧杂环丁烷基团在药物发现中有非常重要的应用，研究表明，氧杂环丁烷的稳定性与其取代模式密切相关，其中3,3-二取代最稳定。研究者们揭示了氧杂环丁烷在药物研发中的许多潜在优势，但也发现了很多的挑战。氧杂环丁烷的潜在优势1.氧杂环丁烷的诱导吸电子效应可以降低相邻基团的pKaH （α位降低约2.7、β位降低约1.9、γ位降低约0.7、δ位降低约0.3），可通过引入氧杂环丁烷来减少或消除药物化合物的碱性。2.氧杂环丁烷中sp3杂化的碳原子增加了化合物的立体性，这种构象效应可以增加化合物的水溶性。3.氧杂环丁烷的体积小，极性大，可用于阻断代谢不稳定的位点，并且不会显著增加化合物的分子量和亲脂性。4.氧杂环丁烷可以作为羰基官能团的生物等排体，这可能有助于规避羰基特异性酶降解，提高水溶性，获得新的IP空间。5.氧杂环丁烷适度的环应变可以引导通过活性药物成分（APIs）代谢而被微粒体环氧化物水解酶（mEH）降解，从而避免由CYP酶清除导致的肝毒性。氧杂环丁烷的潜在劣势，面临的挑战及未来的方向1.氧杂环丁烷的合成仍然具有挑战性。2.氧杂环丁烷构建模块的选择是有限的，这种约束影响了药物化合物中氧杂环丁烷结构的取代模式。3.氧杂环丁烷在酸性条件或高温条件下是不稳定的，所以预测给定的氧杂环丁烷取代模式的稳定性是具有挑战性的。4.氧杂环丁烷在严苛条件下的潜在不稳定性可能成为多步大规模合成的问题，所以通常氧杂环丁烷仅在药物开发的最后阶段引入，以补救一些有问题的物理化学性质，如溶解度或代谢稳定性。5.氧杂环丁烷化合物相关性质的数据集有限，限制了基于数据的预测。参考文献（上下滑动可查看更多）本文：Rojas, J. Oxetanes in Drug Discovery Campaigns. J. Med. Chem. 2023, 66, 12697–12709.[1]. Wuitschik, G.; etal. Oxetanes as Promising Modules in Drug Discovery. Angew. Chem., Int. Ed. 2006, 45, 7736−7739.[2]. Smith, C. C.; etal. Crenolanib Is a Selective Type I Pan-FLT3 Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 5319−5324.[3]. Crawford, J. J.; Zhang, H. In ACS Symposium Series; American Chemical Society, 2019; Vol. 1332, pp 239−266.[4]. Zheng, X.; etal. Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors. J. Med. Chem. 2018, 61, 10228−10241.[5]. Blomgren, P.; etal. Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases. ACS Med. Chem. Lett. 2020, 11, 506−513.[6]. Griffith, D. A.; etal. A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. J. Med. Chem. 2022, 65, 8208−8226.[7]. Pei, Z.; etal. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349. ACS Med. Chem. Lett. 2013, 4, 103−107.[8]. Kung, P.-P.; etal. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(Methoxy(Oxetan-3-yl)Methyl)-2-((4- Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihy-droisoquinolin-1(2H)-one (PF-06821497). J. Med. Chem. 2018, 61, 650−665.声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

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2024-01-25

·FierceBiotech

Kronos calls time on CMO, CSO roles as part of C-suite shakeup

Replacing the three jettisoned C-suite roles will be four SPV positions overseeing: R&D; clinical development; corporate strategy and portfolio management; and corporate operations and legal. Kronos Bio had already trimmed back its headcount and pipeline in the wake of a mid-stage cancer flop. Now, it’s the company’s C-suite who are heading to the exits. The biotech has “eliminated three executive officer roles”—meaning Chief Medical Officer Jorge DiMartino, M.D., Chief Scientific Officer Christopher Dinsmore, Ph.D., and Chief Operating Officer and General Counsel Barbara Kosacz will all be out of a job. The company explained the changes were needed to ensure a “streamlined leadership structure designed to focus on pipeline advancement and align with Kronos Bio’s current operating needs.” The three executives will leave the company on Feb.16, although they will remain as strategic advisors for the business, according to a Jan. 25 press release. The leadership shakeup follows a headcount reduction of 19% in November in order to fund KB-0742, a CDK9 inhibitor currently in a phase 1/2 trial for solid tumors and non-Hodgkin lymphoma. A month after the layoffs, Kronos said it was discontinuing a cancer trial for lanraplenib and seeking a partner for the SYK inhibitor in the wake of a mid-stage trial flop. “This new leadership structure is designed to streamline our operations and reflects our ongoing effort to advance our pipeline, optimize our resources, and efficiently deliver on our business objectives,” CEO Norbert Bischofberger, Ph.D., said in the release. “I would like to thank Jorge, Chris, and Barbara for their leadership and dedication, and I wish them well in their future endeavors,” Bischofberger added. “They each built and managed strong teams, laying the groundwork for this new structure and preparing our future leaders for success.” Replacing the three jettisoned C-suite roles will be four SPV positions overseeing R&D; clinical development; corporate strategy and portfolio management; and corporate operations and legal. Those positions are filled by Charles Lin, Ph.D., Elizabeth Olek, Rocio Martin Hoyos and Allison Frisbee, respectively. Kronos said it expects to make savings from the changes, even after termination costs are accounted for. Besides KB-0742, Kronos has a partnership with Roche’s Genentech for several undisclosed discovery programs. Inked a year ago, the Genentech partnership is crucial for Kronos, coming right after the biotech kicked a late-stage AML asset called entospletinib to the curb. The Roche unit jumped in to save the day for the struggling biotech with a $20 million upfront payment plus milestones that could top $177 million for the first program and $100 million for the first licensed product. Kronos also recently revealed a new development candidate, dubbed KB-9558. The preclinical asset is designed to modulate the IRF4 transcription regulatory network—a key driver in multiple myeloma.

高管变更

100 项与 Lanraplenib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11596	-	-	DB14770

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
难治性急性髓细胞白血病	临床2期	美国	Kronos Bio, Inc.	2022-08-05
难治性急性髓细胞白血病	临床2期	西班牙	Kronos Bio, Inc.	2022-08-05
复发性急性髓细胞白血病	临床2期	美国	Kronos Bio, Inc.	2022-08-05
复发性急性髓细胞白血病	临床2期	西班牙	Kronos Bio, Inc.	2022-08-05
膜性肾小球肾炎	临床2期	美国	Gilead Sciences, Inc.	2017-10-06
皮肤红斑狼疮	临床2期	美国	Gilead Sciences, Inc.	2017-05-24
皮肤红斑狼疮	临床2期	加拿大	Gilead Sciences, Inc.	2017-05-24
干燥综合征	临床2期	美国	Gilead Sciences, Inc.	2017-05-01
干燥综合征	临床2期	波兰	Gilead Sciences, Inc.	2017-05-01
干燥综合征	临床2期	西班牙	Gilead Sciences, Inc.	2017-05-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03285711 (CTgov)	临床2期	膜性肾小球肾炎	9	Filgotinib placebo+Lanraplenib (Lanraplenib 30 mg)	淵鑰齋鬱獵築廠鹹築廠(壓遞齋衊顧範衊鏇糧製) = 蓋積餘簾糧選願艱鹽鏇蓋淵壓憲鑰廠壓壓淵鬱 (窪窪壓遞齋積壓壓糧構, 膚鏇淵願廠蓋獵餘窪範 ~ 範網簾觸餘鹹憲獵壓鹽) 更多	-	2020-05-18
				Lanraplenib placebo+Filgotinib (Filgotinib 200 mg)	淵鑰齋鬱獵築廠鹹築廠(壓遞齋衊顧範衊鏇糧製) = 製鏇顧窪膚鹽簾築鏇願蓋淵壓憲鑰廠壓壓淵鬱 (窪窪壓遞齋積壓壓糧構, 築膚鬱鹹顧淵築蓋網獵 ~ 衊醖襯夢選膚襯廠願膚) 更多
NCT03134222 (CTgov)	临床2期	皮肤红斑狼疮	47	Filgotinib placebo+Lanraplenib (Lanraplenib 30 mg)	繭選製製憲憲願繭鬱網(網蓋憲鹹膚艱範遞憲積) = 鹹簾鏇繭窪鏇蓋築鹽簾築鹽鬱願積醖憲鏇壓衊 (積夢繭糧鬱蓋壓齋顧憲, 餘艱遞簾夢繭醖選襯壓 ~ 餘壓築醖鹽壓築繭獵獵) 更多	-	2020-04-08
				Lanraplenib placebo+Filgotinib (Filgotinib 200 mg)	繭選製製憲憲願繭鬱網(網蓋憲鹹膚艱範遞憲積) = 鹽繭糧憲製願醖餘鹹遞築鹽鬱願積醖憲鏇壓衊 (積夢繭糧鬱蓋壓齋顧憲, 鹹淵積積膚糧餘窪淵衊 ~ 齋淵糧鑰選遞襯構鏇鏇) 更多
NCT03100942 (CTgov)	临床2期	干燥综合征	152	Filgotinib placebo+Lanraplenib (Lanraplenib)	衊蓋願獵願簾遞鏇鬱遞(鬱鬱築遞憲觸衊遞遞鹹) = 繭餘廠鏇鑰獵鹽繭膚襯膚願壓鹽網選築遞積鹹 (遞製鹽遞糧餘鏇鬱鹽繭, 鬱糧繭範鬱觸餘遞鑰簾 ~ 廠膚觸醖餘獵廠範製憲) 更多	-	2020-01-22
				Tirabrutinib placebo+Filgotinib (Filgotinib)	衊蓋願獵願簾遞鏇鬱遞(鬱鬱築遞憲觸衊遞遞鹹) = 選網糧糧餘窪夢網艱衊膚願壓鹽網選築遞積鹹 (遞製鹽遞糧餘鏇鬱鹽繭, 選獵簾窪廠構憲觸齋簾 ~ 襯製壓範網繭廠選觸艱) 更多
NCT02959138 (CTgov)	临床1期	炎症 \| 白内障	36	lanraplenib (Cohort 1: Moderate Renal Impairment)	糧繭製積蓋願顧艱齋遞(醖顧鹽壓餘襯鏇鹹蓋顧) = 遞糧築簾鹹鹹夢膚獵鬱積範觸齋築淵醖築窪窪 (遞艱構築網鬱簾襯網遞, 願餘顧積積選簾構衊衊 ~ 製餘願廠鹹網窪網鑰夢) 更多	-	2019-10-25
				lanraplenib (Cohort 1: Healthy Control)	糧繭製積蓋願顧艱齋遞(醖顧鹽壓餘襯鏇鹹蓋顧) = 簾鏇遞鏇構構簾簾築鑰積範觸齋築淵醖築窪窪 (遞艱構築網鬱簾襯網遞, 壓醖醖遞繭鬱範網糧構 ~ 鹹繭鑰獵衊顧鹽繭獵廠) 更多
EULAR2019	临床2期	类风湿关节炎 DAS28(CRP) \| ACR20/50/70 \| HAQ-DI	83	GS-9876 10 mg	醖簾淵遞淵獵願窪範構(鹽淵襯獵鬱獵繭鬱觸鹹) = 築衊築願憲鏇鏇夢觸壓襯齋憲鹽築願淵積糧壓 (鹽衊構襯蓋選觸範構願 )	-	2019-06-12
				GS-9876 30 mg	醖簾淵遞淵獵願窪範構(鹽淵襯獵鬱獵繭鬱觸鹹) = 鬱鑰鑰糧餘顧鏇製夢繭襯齋憲鹽築願淵積糧壓 (鹽衊構襯蓋選觸範構願 )
NCT02885181 (CTgov)	临床2期	类风湿关节炎	83	GS-9876 placebo+Filgotinib+Methotrexate (Filgotinib)	積遞選願積餘鑰壓憲蓋(鏇製繭壓觸構構鬱鏇鏇) = 鹹鑰構鹽築糧鬱鹽齋簾觸繭艱醖製蓋糧糧淵憲 (獵構構獵觸簾顧壓衊齋, 觸積鏇鏇鏇鬱鏇願膚構 ~ 顧鹽醖積鑰醖蓋觸鏇獵) 更多	-	2018-09-19
				Filgotinib placebo+Methotrexate (Placebo)	積遞選願積餘鑰壓憲蓋(鏇製繭壓觸構構鬱鏇鏇) = 觸醖鬱網範鹹窪製廠範觸繭艱醖製蓋糧糧淵憲 (獵構構獵觸簾顧壓衊齋, 網壓夢獵鑰顧繭膚構夢 ~ 選範糧構遞淵製壓憲膚) 更多