Beyond Midostaurin Which Are the Most Promising FLT3 Inhibitors In
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A Human Multi-Lineage Hepatic Organoid Model for Liver Fibrosis
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.01.278473; this version posted September 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A Human Multi-Lineage Hepatic Organoid Model for Liver Fibrosis Yuan Guan1, Annika Enejder2, Meiyue Wang1, Zhuoqing Fang1, Lu Cui3, Shih-Yu Chen4, Jingxiao Wang1, Yalun Tan1, Manhong Wu1, Xinyu Chen1, Patrik K. Johansson2, Issra Osman1, Koshi Kunimoto3, Pierre Russo5, Sarah C. Heilshorn2 and Gary Peltz1* 1Department of Anesthesia, Stanford University School of Medicine, Stanford CA, 94305; 2Department of Materials Science and Engineering, Stanford University, Stanford CA, 94305; 3Department of Pathology, Institute of Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University School of Medicine, Stanford, 94305, CA, USA; 4Shih-Yu Chen, Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan; 5Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 The authors have declared that no conflict of interest exists. *Address Correspondence to: [email protected] 300 Pasteur Dr. Room L232 Stanford, CA 94305. bioRxiv preprint doi: https://doi.org/10.1101/2020.09.01.278473; this version posted September 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Summary Despite its devastating consequences, liver fibrosis has no treatments. Genome engineering and a hepatic organoid system was used to produce the first in vitro model for human liver fibrosis. Hepatic organoids engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD) developed the key features of ARPKD liver pathology (abnormal bile ducts and hepatic fibrosis) in only 21 days. -
FLT3 Inhibitors in Acute Myeloid Leukemia Mei Wu1, Chuntuan Li2 and Xiongpeng Zhu2*
Wu et al. Journal of Hematology & Oncology (2018) 11:133 https://doi.org/10.1186/s13045-018-0675-4 REVIEW Open Access FLT3 inhibitors in acute myeloid leukemia Mei Wu1, Chuntuan Li2 and Xiongpeng Zhu2* Abstract FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents. Keywords: FMS-like tyrosine kinase 3 inhibitors, Acute myeloid leukemia, Midostaurin, FLT3 Introduction RAS, MEK, and PI3K/AKT pathways [10], and ultim- Acute myeloid leukemia (AML) remains a highly resist- ately causes suppression of apoptosis and differentiation ant disease to conventional chemotherapy, with a me- of leukemic cells, including dysregulation of leukemic dian survival of only 4 months for relapsed and/or cell proliferation [11]. refractory disease [1]. Molecular profiling by PCR and Multiple FLT3 inhibitors are in clinical trials for treat- next-generation sequencing has revealed a variety of re- ing patients with FLT3/ITD-mutated AML. In this re- current gene mutations [2–4]. New agents are rapidly view, we summarized the preclinical and clinical studies emerging as targeted therapy for high-risk AML [5, 6]. on new FLT3 inhibitors, including sorafenib, lestaurtinib, In 1996, FMS-like tyrosine kinase 3/internal tandem du- sunitinib, tandutinib, quizartinib, midostaurin, gilteriti- plication (FLT3/ITD) was first recognized as a frequently nib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG mutated gene in AML [7]. -
Federal Register Notice 5-1-2020 Pdf Icon[PDF – 358
Federal Register / Vol. 85, No. 85 / Friday, May 1, 2020 / Notices 25439 confidential by the respondent (5 U.S.C. schedules. Other than examination DEPARTMENT OF HEALTH AND 552(b)(4)). reports, it provides the only financial HUMAN SERVICES Current actions: The Board has data available for these corporations. temporarily revised the instructions to The Federal Reserve is solely Centers for Disease Control and the FR Y–9C report to accurately reflect responsible for authorizing, supervising, Prevention the revised definition of ‘‘savings and assigning ratings to Edges. The [CDC–2020–0046; NIOSH–233–C] deposits’’ in accordance with the Federal Reserve uses the data collected amendments to Regulation D in the on the FR 2886b to identify present and Hazardous Drugs: Draft NIOSH List of interim final rule published on April 28, potential problems and monitor and Hazardous Drugs in Healthcare 2020 (85 FR 23445). Specifically, the develop a better understanding of Settings, 2020; Procedures; and Risk Board has temporarily revised the activities within the industry. Management Information instructions on the FR Y–9C, Schedule HC–E, items 1(b), 1(c), 2(c) and glossary Legal authorization and AGENCY: Centers for Disease Control and content to remove the transfer or confidentiality: Sections 25 and 25A of Prevention, HHS. withdrawal limit. As a result of the the Federal Reserve Act authorize the ACTION: Notice and request for comment. revision, if a depository institution Federal Reserve to collect the FR 2886b chooses to suspend enforcement of the (12 U.S.C. 602, 625). The obligation to SUMMARY: The National Institute for six transfer limit on a ‘‘savings deposit,’’ report this information is mandatory. -
Efficacy and Safety of Midostaurin-Based Induction and Maintenance Therapy for Newly Diagnosed AML
POST-ASH Issue 4, 2016 Efficacy and Safety of Midostaurin-Based Induction and Maintenance Therapy for Newly Diagnosed AML For more visit ResearchToPractice.com/5MJCASH2016 CME INFORMATION OVERVIEW OF ACTIVITY Each year, thousands of clinicians, basic scientists and other industry professionals sojourn to major international oncology conferences, like the American Society of Hematology (ASH) annual meeting, to hone their skills, network with colleagues and learn about recent advances altering state-of-the-art management in hematologic oncology. These events have become global stages where exciting science, cutting-edge concepts and practice-changing data emerge on a truly grand scale. This massive outpouring of information has enormous benefits for the hematologic oncology community, but the truth is it also creates a major challenge for practicing oncologists and hematologists. Although original data are consistently being presented and published, the flood of information unveiled during a major academic conference is unmatched and leaves in its wake an enormous volume of new knowledge that practicing oncologists must try to sift through, evaluate and consider applying. Unfortunately and quite commonly, time constraints and an inability to access these data sets leave many oncologists struggling to ensure that they’re aware of crucial practice-altering findings. This creates an almost insurmountable obstacle for clinicians in community practice because they are not only confronted almost overnight with thousands of new presentations and -
Disruption of CSF-1R Signaling Inhibits Growth of AML with Inv(16)
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2021 Disruption of CSF-1R signaling inhibits growth of AML with inv(16) Simonis, Alexander ; Russkamp, Norman F ; Mueller, Jan ; Wilk, C Matthias ; Wildschut, Mattheus H E ; Myburgh, Renier ; Wildner-Verhey van Wijk, Nicole ; Mueller, Rouven ; Balabanov, Stefan ; Valk, Peter J M ; Theocharides, Alexandre P A ; Manz, Markus G DOI: https://doi.org/10.1182/bloodadvances.2020003125 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-202789 Journal Article Published Version The following work is licensed under a Publisher License. Originally published at: Simonis, Alexander; Russkamp, Norman F; Mueller, Jan; Wilk, C Matthias; Wildschut, Mattheus H E; Myburgh, Renier; Wildner-Verhey van Wijk, Nicole; Mueller, Rouven; Balabanov, Stefan; Valk, Peter J M; Theocharides, Alexandre P A; Manz, Markus G (2021). Disruption of CSF-1R signaling inhibits growth of AML with inv(16). Blood advances, 5(5):1273-1277. DOI: https://doi.org/10.1182/bloodadvances.2020003125 STIMULUS REPORT Disruption of CSF-1R signaling inhibits growth of AML with inv(16) Alexander Simonis,1,* Norman F. Russkamp,1,* Jan Mueller,1 C. Matthias Wilk,1 Mattheus H. E. Wildschut,1,2 Renier Myburgh,1 Nicole Wildner-Verhey van Wijk,1 Rouven Mueller,1 Stefan Balabanov,1 Peter J. M. Valk,3 Alexandre P. A. Theocharides,1 and Markus G. Manz1 1Department of Medical Oncology and Hematology, University Hospital -
Precision Medicine in Pediatric Neurooncology: a Review
UCLA UCLA Previously Published Works Title Precision Medicine in Pediatric Neurooncology: A Review. Permalink https://escholarship.org/uc/item/6tv2b43d Journal ACS chemical neuroscience, 9(1) ISSN 1948-7193 Authors Mochizuki, Aaron Y Frost, Isaura M Mastrodimos, Melina B et al. Publication Date 2018 DOI 10.1021/acschemneuro.7b00388 Peer reviewed eScholarship.org Powered by the California Digital Library University of California HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author ACS Chem Manuscript Author Neurosci. Author Manuscript Author manuscript; available in PMC 2019 July 24. Published in final edited form as: ACS Chem Neurosci. 2018 January 17; 9(1): 11–28. doi:10.1021/acschemneuro.7b00388. Precision Medicine in Pediatric Neurooncology: A Review Aaron Y. Mochizuki∥, Isaura M. Frost∥, Melina B. Mastrodimos∥, Ashley S. Plant┴, Anthony C. Wang#, Theodore B. Moore∥, Robert M. Prins#,∇,○, Paul S. Weiss*,†,‡,§,∇, Steven J. Jonas*,†,∥,◆,¶ †California NanoSystems Institute, University of California, Los Angeles, Los Angeles, California 90095, United States ‡Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States §Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California 90095, United States ∥Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, United States ┴Division of Pediatric Oncology, Children’s Hospital of Orange -
Recommendations from York and Scarborough Medicines
Recommendations from York and Scarborough Medicines Commissioning Committee July 2018 Drug name Indication Recommendation, rationale and place in RAG status Potential full year cost impact therapy CCG commissioned Technology Appraisals 1. Nil NHSE commissioned Technology Appraisals – for noting 2. TA520: Atezolizumab for Atezolizumab is recommended as an option for Red No cost impact to CCGs as NHS England treating locally advanced or treating locally advanced or metastatic non- commissioned. metastatic non-small-cell lung small-cell lung cancer (NSCLC) in adults who cancer after chemotherapy have had chemotherapy (and targeted treatment if they have an EGFR- or ALK‑ positive tumour), only if: atezolizumab is stopped at 2 years of uninterrupted treatment or earlier if the disease progresses and the company provides atezolizumab with the discount agreed in the patient access scheme. 3. TA522: Pembrolizumab for Pembrolizumab is recommended for use within Red No cost impact to CCGs as NHS England untreated locally advanced or the Cancer Drugs Fund as an option for commissioned. metastatic urothelial cancer untreated locally advanced or metastatic when cisplatin is unsuitable urothelial carcinoma in adults when cisplatin- containing chemotherapy is unsuitable, only if: pembrolizumab is stopped at 2 years of uninterrupted treatment or earlier if the disease progresses and the conditions of the managed access agreement for pembrolizumab are followed TA523: Midostaurin for Midostaurin is recommended, within its Red No cost impact to CCGs as NHS England untreated acute myeloid marketing authorisation, as an option in adults commissioned. leukaemia for treating newly diagnosed acute FLT3- mutation-positive myeloid leukaemia with standard daunorubicin and cytarabine as induction therapy, with high-dose cytarabine as consolidation therapy, and alone after complete response as maintenance therapy. -
Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG . -
Crenolanib Is a Selective Type I Pan-FLT3 Inhibitor
Crenolanib is a selective type I pan-FLT3 inhibitor Catherine Choy Smitha,b,1, Elisabeth A. Lasatera,1, Kimberly C. Lina, Qi Wangc, Melissa Quino McCreeryd, Whitney K. Stewarta, Lauren E. Damona, Alexander E. Perle, Grace R. Jeschkee, Mayumi Sugitae, Martin Carrolle, Scott C. Koganb,d, John Kuriyanc, and Neil P. Shaha,b,2 aDivision of Hematology/Oncology, bHelen Diller Family Comprehensive Cancer Center, and dDivision of Laboratory Medicine, University of California, San Francisco, CA 94143; cDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; and eDivision of Hematology/Oncology, Perelman School of Medicine and the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104 Edited* by Charles L. Sawyers, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved February 13, 2014 (received for review November 4, 2013) Tyrosine kinase inhibitors (TKIs) represent transformative thera- inhibitor and holds significant promise for achieving prolonged pies for several malignancies. Two critical features necessary for remissions. However, ponatinib potently inhibits a number of maximizing TKI tolerability and response duration are kinase selec- kinases, which may be responsible for unanticipated serious tivity and invulnerability to resistance-conferring kinase domain (KD) cardiovascular toxicities that have emerged with this agent. mutations in the intended target. No prior TKI has demonstrated The ability to selectively suppress resistance-conferring muta- both of these properties. -
Pdgfra) D842v Mutant Gastrointestinal Stromal Tumor (Gist
PRELIMINARY REPORT OF CRENOLANIB IN THE TREATMENT OF ADVANCED PLATELET DERIVED GROWTH FACTOR A (PDGFRA) D842V MUTANT GASTROINTESTINAL STROMAL TUMOR (GIST) M. von Mehren1, M. Heinrich2, E. Tetzlaff1, K. Padavic-Shaller1, M. Yu1, C. Muralidhara3, A.Ramachandran3, H. Shah3 1Fox Chase Cancer Center, Philadelphia, PA; 2Oregon Health and Science University, Portland, OR; 3AROG Pharmaceuticals, Dallas, TX. BACKGROUND PATIENT CHARACTERISTICS PHARMACOKINETICS PARTIAL METABOLIC RESPONSE Many patients with advanced GIST treated with • To date, 7 patients (4 F, 3 M) have been accrued. • Serum pharmacokinetics samples were obtained pre dose approved tyrosine kinase therapies have prolonged • All had metastatic disease in liver and/or and at 30 (± 10), 60 (± 15), 120 (± 15) minutes and at 4 (±1), disease control with a median survival of 5 years. Rare mesentery/retroperitoneum. 8 (±2), and 24 (±4) hours after crenolanib administration subsets of GIST do not derive the same benefit from • Best response to prior therapy was stable disease. • Analysis was performed by an isocratic high performance treatment. One such subset is GIST that carries a • Safety data is available in 6 patients and efficacy in 6 patients. liquid chromatography assay with tandem mass mutation in PDGFRA exon 18, D842V. In vitro, approved spectrometry therapies do not cause a decrease in cell proliferation or • Crenolanib was rapidly absorbed, with a tmax of ~2 hours loss of PDGFRA phosphorylation1. In clinical trials, • Serum trough concentrations of crenolanib (at 24hrs) were available data suggests no response to standard ~12% the peak concentration. 2 therapies . 2000.00 1800.00 3 Crenolanib is a benzimidazole compound being 1600.00 • 2 patients had metabolically active disease (SUV ≥ developed for the treatment of GIST patients with 1400.00 D842V Pt-001 10 in baseline PET scan) upon study entry. -
Samaritan Fund
Items supported by the Samaritan Fund (a) Non-drug Items supported by the Fund (b) Other items supported by the Samaritan Fund Mechanism (c) Self-financed Drugs supported by the Samaritan Fund (SF) and Community Care Fund (CCF) Medical Assistance Programme (First Phase Programme) (for specified self- financed cancer drugs) (a) Non-drug Items supported by the Fund 1. Percutaneous Transluminal Coronary Angioplasty (PTCA) and other consumables for interventional cardiology 2. Cardiac Pacemakers 3. Myoelectric Prosthesis 4. Custom-made Prosthesis 5. Appliances for prosthetic and orthotic services, physiotherapy and occupational therapy services (e.g. prosthesis) 6. Home use equipment and appliances (e.g. wheelchair, replacement of external speech processor for patients done with cochlear implant) 7. Gamma knife surgery 8. Harvesting of marrow in a foreign country for marrow transplant The Fund will only support the model which can meet the basic medical needs of the patients. (b) Other items supported by the Samaritan Fund Mechanism 1. Positron Emission Tomography (PET) service (c) Drugs supported by the Samaritan Fund The following specific self-financed drugs are supported by the Samaritan Fund: Item Drug Types of Clinical indications diseases 1 Abatacept Rheumatology Rheumatoid arthritis 2a Adalimumab Dermatology Severe psoriasis 2b Ophthalmology Non-infectious intermediate, posterior and panuveitis 2c Paediatric chronic non-infectious anterior uveitis 2d Rheumatology Ankylosing spondylitis 2e Juvenile idiopathic arthritis 2f Psoriatic -
PRAC Draft Agenda of Meeting 11-14 May 2020
11 May 2020 EMA/PRAC/257460/2020 Human Division Pharmacovigilance Risk Assessment Committee (PRAC) Draft agenda for the meeting on 11-14 May 2020 Chair: Sabine Straus – Vice-Chair: Martin Huber 11 May 2020, 10:30 – 19:30, via teleconference 12 May 2020, 08:30 – 19:30, via teleconference 13 May 2020, 08:30 – 19:30, via teleconference 14 May 2020, 08:30 – 16:00, via teleconference Organisational, regulatory and methodological matters (ORGAM) 28 May 2020, 09:00-12:00, via teleconference Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also change during the course of the review. Additional details on some of these procedures will be published in the PRAC meeting highlights once the procedures are finalised. Of note, this agenda is a working document primarily designed for PRAC members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on-going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006, Rev. 1). Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020.