TEC

[04-December-2023] A dual JAK3/TEC inhibitor, LITFULO™ (ritlecitinib) is approved for adults and adolescents over 12 years of age for treatment of severe alopecia areata. KIRKLAND, QC, Dec. 4, 2023 /CNW/ - Today, Pfizer Canada announced that Health Canada has granted a Notice of Compliance (NOC) for LITFULO™ (ritlecitinib). A once-daily oral treatment, LITFULO is the first and only treatment approved by Health Canada for individuals 12 years of age and older with severe alopecia areata.i Approximately two per cent of the global population are affected by alopecia areata which is an autoimmune disease where the immune system attacks the body's hair follicles causing patchy to complete hair loss on the scalp, face and/or body. ii,iii,iv "For patients with substantial hair loss, alopecia areata can be difficult to manage physically and emotionally, especially for younger people," said Dr. Melinda Gooderham, dermatologist at the SKiN Centre for Dermatology in Peterborough, Ontario. "As a physician, it has been frustrating to have so little to offer patients. I'm pleased to have a new option available." An estimated 775,000 Canadians are affected by alopecia areata at some point in their lifetime, with most people starting to show signs in their teens through to their 30s. However, patients can start to develop symptoms at any age with nearly 20 per cent of people being diagnosed before the age of 18.v,vi,vii "Alopecia areata has a devastating impact on a person's mental health and quality of life," said Carolynne Harrison, President of the Canadian Alopecia Areata Foundation (CANAAF). "Until now, there have been no approved medical treatment options to help patients and their families living with this condition. The alopecia community across Canada is looking forward to access to a new treatment option for both adolescents and adults with the severe form of alopecia areata." About Alopecia Areata Alopecia areata is a T cell-mediated autoimmune disease affecting the hair follicles. Inflammation in the hair follicles causes hair loss and the loss of the ability to regrow hair until the response is suppressed.viii This hair loss often occurs on the scalp, but it can also affect eyebrows, eyelashes, facial hair, and other areas of the body.ix,x Alopecia areata can affect people of any age, gender, race, or ethnicity and can cause considerable burden beyond hair loss.xi,xii,xiii,xiv "The approval of LITFULO marks an important milestone for Canadians, including those as young as 12, living with severe hair loss from alopecia areata," said Frédéric Lavoie, Inflammation and Immunology Lead for Pfizer Canada. "This approval represents the first treatment option approved by Health Canada for severe alopecia areata. As a leader in inflammation and immunology, we at Pfizer Canada are immensely proud to be bringing this new option for Canadians living with this challenging autoimmune disease." Pfizer Canada is currently assessing the timeline for the availability of LITFULO in Canada and is committed to bringing supply of this medicine to Canadians as quickly as possible. About LITFULO™ LITFULO is used to treat severe alopecia areata in people 12 years of age and older.xv LITFULO is an inhibitor of JAK3 and the TEC family kinases.xvi Inhibition of JAK3 and TEC kinase family members by LITFULO may block signaling of cytokines and cytolytic activity of T cells, which is implicated in the pathogenesis of alopecia areata.xvii About Pfizer Canada Pfizer Canada ULC is the Canadian operation of Pfizer Inc., one of the world's leading biopharmaceutical companies. Our diversified health care portfolio includes some of the world's best known and most prescribed medicines and vaccines. We apply science and our global resources to improve the health and well-being of Canadians at every stage of life. Our commitment is reflected in everything we do, from our disease awareness initiatives to our community partnerships. To learn more about Pfizer Canada, visit pfizer.ca or you can follow us on LinkedIn, Facebook, Twitter or YouTube. ____________________________________ SOURCE Pfizer Canada

HONG KONG and SHANGHAI, China and FLORHAM PARK, N.J., April 11, 2023 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM: HCM, HKEX: 13) today announces that new and updated clinical and non-clinical data related to five HUTCHMED investigational drug candidates will be presented during the American Association for Cancer Research Annual Meeting 2023 (AACR 2023), which will take place from April 14 to 19, 2023 in Orlando, Florida. Savolitinib Title: A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophageal junction adenocarcinomas or gastric cancerLead Author: Lin Shen, MD, Peking University Cancer Hospital & InstituteType: Poster presentationSession Number: PO.CT02.01 – Phase II Clinical Trials 1Abstract Link: https://www.abstractsonline.com/pp8/#!/10828/presentation/10376 Title: Baseline and on-treatment plasma-based genomics as a predictor of outcome in SAVANNAH: Savolitinib + osimertinib in EGFRm MET overexpressed/​amplified NSCLC post-osimertinibLead Author: Ryan J Hartmaier, Ph.D, AstraZenecaType: Poster presentationSession Number: LB294/7Abstract Link: https://www.abstractsonline.com/pp8/#!/10828/presentation/9996 Mesenchymal epithelial transition factor (“MET”) gene amplification is associated with poor prognosis in gastric cancer (“GC”) and gastroesophageal junction adenocarcinomas (“GEJ”). Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor. Here we reported the preliminary efficacy and safety data from a Phase II trial of savolitinib monotherapy in patients with MET-amplified advanced or metastatic GC/GEJ (NCT04923932). Additionally, utility of plasma-based genomics was investigated in the SAVANNAH Phase II trial of savolitinib in addition to osimertinib in epidermal growth factor receptor (EGFR) mutated, MET overexpressed/amplified non-small cell lung cancer (“NSCLC”) post osimertinib. First presentation of the SAVANNAH results occurred at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) in August 2022. Surufatinib Title: Surufatinib plus toripalimab for first-line treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 positive expression: A multicenter, single-arm phase 2 studyLead Author: Ying Cheng, MD, Jilin Cancer HospitalType: Poster presentationSession Number: PO.CT02.02 – Phase II Clinical Trials 2Abstract Link: https://www.abstractsonline.com/pp8/#!/10828/presentation/10405 Surufatinib (a small-molecule inhibitor of vascular endothelial growth factor receptor (“VEGFR”) 1-3, fibroblast growth factor receptor (“FGFR”) 1 and colony-stimulating factor 1 receptor (“CSF-1R”)) plus toripalimab (an anti-programmed cell death protein-1 (“PD-1”) antibody) showed encouraging antitumor activity in solid tumors. Programmed death ligand 1 (“PD-L1”) expression is the established biomarker for first-line immune checkpoint inhibitors therapy in advanced NSCLC. We conducted an open-label, multi-cohort, single-arm Phase II study to evaluate the safety and efficacy of surufatinib plus toripalimab in patients with advanced solid tumors. Here, we reported the results of advanced NSCLC with PD-L1 positive expression cohort (NCT04169672). HMPL-760 Title: HMPL-760 is a highly potent and selective reversible BTK inhibitor, targeting BTK and BTKC481S in B-cell malignanciesLead Author: Linfang Wang, HUTCHMEDType: Poster presentationSession Number: PO.ET09.07 – Tyrosine Kinase and Phosphatase Inhibitors 1Abstract Link: https://www.abstractsonline.com/pp8/#!/10828/presentation/6728 Bruton’s tyrosine kinase (“BTK”), a member of the Tec family, plays a crucial role in signaling through B-cell receptor (“BCR”). BTK inhibition blocks BCR signals and prevents B-cell activation and growth. First-generation BTK inhibitors such as ibrutinib covalently binds to a cysteine residue (“C481”) of BTK. Their most frequent acquired resistance is the development of a serine mutation in the binding site (“C481S”). Next generation BTK inhibitors such as HMPL-760 aim to overcome this resistance to first-generation inhibitors. The poster outlined preclinical data showing HMPL-760 is a reversible, selective, highly potent BTK inhibitor targeting both BTKWT and BTKC481S. The first-in-human Phase I clinical trials of HMPL-760 are under way in patients with relapsed/refractory B-Cell Non-Hodgkin’s Lymphoma (NCT05190068). HMPL-306 Title: Preclinical characteristic of HMPL-306, a CNS-penetrable dual inhibitor of mutant IDH1 and IDH2Lead Author: Na Yang, HUTCHMEDType: Poster presentationSession Number: PO.ET01.01 – Oncogenes and Tumor Suppressor Genes as Targets for Therapy 1Abstract Link: https://www.abstractsonline.com/pp8/#!/10828/presentation/8579 Mutations in isocitrate dehydrogenase (“IDH”) 1/2 are frequently identified in various cancers, such as acute myeloid leukemia (“AML”), cholangiocarcinoma, chondrosarcoma and glioma. Mutant IDHs (“mIDHs”) cause accumulated 2-hydroxyglutarate, leading to blockage of cell differentiation, thereby inducing malignant transformation. Rare cases were identified carrying co-existing mutations in IDH1 and IDH2. mIDH isoform switching, from mutant IDH1 to mutant IDH2 and vice versa, have been reported as a mechanism of acquired resistance to IDH inhibition in AML and cholangiocarcinoma. Thus, simultaneous inhibition on both mIDH1 and mIDH2 may be a promising strategy to overcome resistance and improve clinical efficacy. HMPL-306, a dual inhibitor of mIDH1/mIDH2, developed by HUTCHMED, is being evaluated in clinical trials (NCT04272957, NCT04762602, NCT04764474). The poster outlines preclinical data that shows that HMPL-306 is a potent, durable, dual inhibitor of IDH1/2 mutation that crosses the blood brain barrier and demonstrated effect on pharmacodynamic markers that lead to the differentiation of immature malignant cells to mature normal cells. The strong activity and favorable pharmacokinetics profiles support further clinical evaluation. HMPL-453 Title: HMPL-453, a highly selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays potent activity in FGFR-altered tumor modelsLead Author: Jia Hu, HUTCHMEDType: Poster presentationSession Number: PO.ET01.07 – Growth Factor Receptors as Therapeutic TargetsAbstract Link: https://www.abstractsonline.com/pp8/#!/10828/presentation/8706 Fibroblast growth factors (“FGFs”) and their receptors (“FGFRs”) regulate numerous cellular processes. Dysregulation of FGFR signaling due to receptor fusion, mutation or amplification is observed across multiple cancer types, making activated FGFRs an important therapeutic target. Herein, we presented the preclinical characterization of HMPL-453, a highly potent and selective inhibitor of FGFR1, 2, and 3, discovered and being currently developed in Phase II clinical trial (NCT04353375) by HUTCHMED. The presentation outlines preclinical data that shows that HMPL-453 is a highly potent and selective inhibitor of FGFR 1, 2, and 3 with strong activity against FGFR-deregulated tumors in preclinical models, supporting continued investigation in patients with FGFR alterations (such as fusion and mutation) either as a single agent or in combination with PD-1 blockade. About Savolitinib (ORPATHYS® in China) Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. Іt blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression. Іn 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca. About Surufatinib (SULANDA® in China) Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with VEGFR and FGFR, which both inhibit angiogenesis, and CSF-1R, which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects. HUTCHMED currently retains all rights to surufatinib worldwide. About HMPL-760 HMPL-760 is an investigational, non-covalent, third-generation BTK inhibitor. It is a highly potent, selective, and reversible inhibitor against both wild-type and C481S-mutated BTK. HUTCHMED currently retains all rights to HMPL-760 worldwide. About HMPL-306 HMPL-306 is a novel dual-inhibitor of ꞮDH1 and ꞮDH2 enzymes. ꞮDH1 and ꞮDH2 mutations have been implicated as drivers of certain hematological malignancies, gliomas and solid tumors, particularly among acute myeloid leukemia patients. HUTCHMED currently retains all rights to HMPL-306 worldwide. About HMPL-453 HMPL-453 is a novel, highly selective and potent inhibitor targeting FGFR 1, 2 and 3. Aberrant FGFR signaling has been found to be a driving force in tumor growth (through tissue growth and repair), promotion of angiogenesis and resistance to anti-tumor therapies. Abnormal FGFR gene alterations are believed to be the drivers of tumor cell proliferation in several solid tumor settings. HUTCHMED currently retains all rights to HMPL-453 worldwide. About HUTCHMED HUTCHMED (Nasdaq/AIM: HCM; HKEX:13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery and global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has more than 5,000 personnel across all its companies, at the center of which is a team of about 1,800 in oncology/immunology. Since inception it has focused on bringing cancer drug candidates from in-house discovery to patients around the world, with its first three oncology drugs now approved and marketed in China. For more information, please visit: www.hutch-med.com or follow us on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including its expectations regarding the therapeutic potential of savolitinib, surufatinib, HMPL-760, HMPL-306 and HMPL-453, the further clinical development for savolitinib, surufatinib, HMPL-760, HMPL-306 and HMPL-453, its expectations as to whether any studies on savolitinib and HMPL-453 would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates and the timing and availability of subjects meeting a study’s inclusion and exclusion criteria; changes to clinical protocols or regulatory requirements; unexpected adverse events or safety issues; the ability of savolitinib, surufatinib, HMPL-760, HMPL-306 and HMPL-453, including as a combination therapy, to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions and to gain commercial acceptance after obtaining regulatory approval; the potential market of savolitinib, surufatinib, HMPL-760, HMPL-306 and HMPL-453 for a targeted indication; the sufficiency of funding; and the impact of the COVID-19 pandemic on general economic, regulatory and political conditions. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the U.S. Securities and Exchange Commission, The Stock Exchange of Hong Kong Limited and on AIM. HUTCHMED undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. CONTACTS Investor Enquiries Mark Lee, Senior Vice President+852 2121 8200Annie Cheng, Vice President+1 (973) 306 4490 Media Enquiries Americas – Brad Miles, Solebury Strategic Communications+1 (917) 570 7340 (Mobile) bmiles@soleburystrat.comEurope – Ben Atwell / Alex Shaw, FTI Consulting+44 20 3727 1030 / +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile) HUTCHMED@fticonsulting.comAsia – Zhou Yi, Brunswick+852 9783 6894 (Mobile) HUTCHMED@brunswickgroup.com Nominated Advisor Atholl Tweedie / Freddy Crossley, Panmure Gordon+44 (20) 7886 2500

SAN DIEGO and TORONTO, May 02, 2022 (GLOBE NEWSWIRE) -- Aptose Biosciences Inc. (“Aptose” or the “Company”) (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral kinase inhibitors to treat hematologic malignancies, today highlighted recent publications of preclinical data for luxeptinib (CG-806) in three peer-reviewed scientific journals. Luxeptinib, Aptose’s oral, dual lymphoid and myeloid kinome inhibitor, is an investigational drug currently in two Phase 1 a/b trials: one in patients with relapsed or refractory B cell malignancies, and separately in patients with relapsed or refractory acute myeloid leukemias (AML) or high-risk myelodysplastic syndromes (MDS). Recent Journal Articles: Luxeptinib disables NLRP3 inflammasome-mediated IL-1β release and pathways required for secretion of inflammatory cytokines IL-6 and TNFα Biochemical Pharmacology (2022)195 114861 Luxeptinib is an orally bioavailable kinase inhibitor with potency against select kinases including BTK. Aberrant activation of inflammasomes act as drivers of pathological complications observed during autoimmune and inflammatory disorders, metabolic syndromes, and cancer; and inhibiting the inflammasome-induced activation of pro-inflammatory cytokines has shown beneficial effects in human disease models. BTK and certain other kinases serve as an integral components or influence functions of the NLRP3 inflammasome complex. The aim of this study was to determine if luxeptinib interferes with the release of IL-1β, IL-6 and TNFα from THP-1 monocytes and bone marrow-derived macrophages following endotoxin exposure and priming of the NLRP3 inflammasome. Key findings: Luxeptinib inhibits NLRP3 inflammasome function in THP-1 monocytes and bone marrow-derived macrophages. Mechanistically, luxeptinib prevents the release of cleaved IL-1β from THP-1 cells by inhibiting the ability of the NLRP3 inflammasome to proteolytically cleave caspase-1 to its active form. Luxeptinib does not impede the assembly of the NLRP3-ASC complex but does potently inhibit three kinases phosphorylated in response to endotoxin. Phosphorylation and nuclear translocation of transcription factor NF-κBp65 was inhibited by luxeptinib. Luxeptinib also inhibits the release of TNFα and IL-6 in response to activation of the TLR pathway without affecting the TLR/IRAK/MyD88 proteins. These studies provide novel insights into the mechanisms by which luxeptinib interferes with the NLRP3 inflammasome and endotoxin-induced inflammatory signaling pathways, along with its protective effects against inflammation-induced toxicity in murine models. The ability of luxeptinib to inhibit inflammatory pathways at concentrations which are well-tolerated in patients makes it a potential clinical candidate for the treatment of inflammatory diseases and inflammation-associated resistance in cancer. Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma Cell Death & Disease -Nature (2022)13:246. Small molecules BTK inhibitors like ibrutinib are approved for the treatment of mantle cell lymphoma, or MCL, a rare subtype of non-Hodgkin’s lymphoma (NHL). Nevertheless, median duration of response is less than two years, and MCL patients who develop therapeutic resistance have poor outcomes. Resistance to BTK inhibitors is not clearly understood and a number of alternative mechanisms have been implicated. Luxeptinib, previously known as CG-806, inhibits LYN, SYK, and BTK activation, potently inhibiting both wildtype and C481S mutant BTK, and is expected to have activity in settings where resistance to BTK inhibitors is driven by these mutations. In a Phase 1 trial in patient with chronic lymphocytic leukemia (CLL) and NHL, treatment with luxeptinib resulted in decreased phosphorylation of SYK and BTK in the circulating malignant cells within eight hours of administration. This current pre-clinical study investigates mechanism and efficacy of luxeptinib in MCL. Key findings: Luxeptinib induced apoptosis in ibrutinib-resistant MCL cell lines, and in primary MCL cells luxeptinib downmodulated anti-apoptotic proteins Mcl-1 and Bcl-xL and reversed stromal cell survival effects. Luxeptinib, but not ibrutinib, blocked SYK and BTK signaling and inhibited ERK phosphorylation in MCL cell lines and primary MCL cells. Dual suppression of BTK/SYK activation with luxeptinib demonstrated efficacy in a PDX MCL model, where efficacy was accompanied by downmodulation of Bcl-2 family proteins and NFκB. Luxeptinib induced metabolic reprogramming toward a glycolytic shift in MCL cells, accompanied by mitochondrial depolarization and induction of mitophagy that eliminates dysfunctional mitochondria and leads to cell death. Luxeptinib Inhibits BTK/SYK/ERK signaling and is a potentially promising new therapy in MCL and NHL. Luxeptinib (CG-806) targets FLT3 and clusters of kinases operative in acute myeloid leukemia Molecular Cancer Therapeutics (2022),Mol. Cancer Ther. molcanther.0832.2021. AML cells survive via dysregulation of multiple pathways, including FLT3 mutations that occur in approximately 30% of AML patients and are associated with increased risk of relapse and poor survival. Luxeptinib, currently in a Phase 1a/b clinical trial for the treatment of AML, potently inhibits both FLT3 and many of the kinases that participate in rescue pathways that contribute to relapsed and refractory disease. In this study, researchers investigated the range of kinases it inhibits, its antiproliferative landscape ex vivo with AML patient samples, and its in vivo efficacy in xenograft models. Key findings: Luxeptinib, an oral non-covalent kinase inhibitor, potently suppresses wild type and mutant forms of FLT3 and select clusters of kinases that can participate in rescue pathways. Oral luxeptinib demonstrated strong antitumor activity in preclinical in vivo AML xenograft models but no myelosuppression or evidence of tissue damage in acute toxicology studies. Importantly, luxeptinib does not inhibit the TEC, EGFR, or ERBB2 kinases that can be associated with cardiac, skin and bleeding adverse events. Ex vivo profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, IDH1/2, ASXL1, NPM1, SRSF2, TP53 or RAS. A combination of venetoclax and luxeptinib enhanced cell killing of the majority of AML samples relative to either drug alone. Luxeptinib retained activity against FLT3 mutants that render cells resistant to quizartinib, gilteritinib, and crenolanib FLT3 inhibitors. “These publications contribute to the wealth of preclinical data demonstrating luxeptinib’ s unique activity as a lymphoid and myeloid kinome inhibitor, and now as an inflammation kinome inhibitor, and support its continued clinical development in several therapeutic areas,” said William G. Rice, Ph.D., Chairman, President, and Chief Executive Officer. “Luxeptinib is a clinical-stage compound, currently in Phase 1 a/b studies in AML and B-cell malignancies. We look forward to reporting on our progress in the upcoming months.” About Aptose Aptose Biosciences is a clinical-stage biotechnology company committed to developing personalized therapies addressing unmet medical needs in oncology, with an initial focus on hematology. The Company's small molecule cancer therapeutics pipeline includes products designed to provide single agent efficacy and to enhance the efficacy of other anti-cancer therapies and regimens without overlapping toxicities. The Company has two clinical-stage investigational products under development for hematologic malignancies: HM43239, an oral, myeloid kinome inhibitor in an international Phase 1/2 trial in patients with relapsed or refractory acute myeloid leukemia (AML); and luxeptinib, an oral, dual lymphoid and myeloid kinome inhibitor in a Phase 1 a/b trial in patients with relapsed or refractory B-cell malignancies who have failed or are intolerant to standard therapies, and in a separate Phase 1 a/b trial in patients with relapsed or refractory AML or high risk myelodysplastic syndrome (MDS). For more information, please visit .