Mcl-1 x Bcl-xl x Bcl-2

DUBLIN, March 15, 2023 /PRNewswire/ -- Jazz Pharmaceuticals, Inc. (Nasdaq: JAZZ) today announced that the company, along with its partners, will present five new abstracts at the American Association for Cancer Research (AACR) Annual Meeting from April 14-19, 2023. Research findings to be presented include data from company-sponsored and collaborative trials studying Zepzelca® (lurbinectedin), zanidatamab and JZP898. "The data Jazz and our partners are presenting at AACR this year demonstrate our commitment to advancing the next generation of oncology care, including our ongoing research for lurbinectedin," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "Over the last year, Jazz has added promising new immuno-oncology and targeted therapy candidates to our pipeline – including zanidatamab, a novel late-stage HER2-targeted bispecific antibody – and progressed ongoing development programs with the goal of improving standards of care across multiple cancer types with significant unmet need and poor outcomes." Data highlights at the AACR Annual Meeting include: A poster presentation evaluating the role of SLFN11 expression in predicting response to lurbinectedin, a DNA damaging agent, in human small cell lung cancer (SCLC) cell lines and in vivo models. Results demonstrate that efficacy may be correlated to SLFN11 protein expression, consistent with the RNA level association.1 A poster presentation featuring data identifying MCL1 as a specific lurbinectedin target and demonstrating anti-tumor activity of lurbinectedin in combination with a specific BCL2 inhibitor and with a specific BCL2L1 inhibitor in in vivo and in vitro models.2 A poster presentation titled "ERBB2 amplification detected in ctDNA as a surrogate for tumor tissue FISH analysis of HER2 status in phase 1 study with zanidatamab for the treatment of locally advanced or metastatic HER2 expressing cancers." The AACR abstracts are available at: The full list of Jazz-supported presentations at the 2023 AACR Annual Meeting are: Zepzelca® (lurbinectedin) Presentations Zanidatamab Presentation* JZP898 Presentation About Zanidatamab Zanidatamab is an investigational bispecific antibody, based on Zymeworks' Azymetric™ platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks, along with collaborators Jazz and BeiGene, Ltd. (BeiGene), are developing zanidatamab in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for first-line GEA. Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China. About Zepzelca® (lurbinectedin) Zepzelca is an alkylating drug that binds guanine residues within DNA. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.3 The FDA approved Zepzelca under accelerated approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The approval is based on overall response rate (ORR) and duration of response demonstrated in an open-label, monotherapy clinical study. In December 2021, Jazz and PharmaMar announced the initiation of LAGOON, a confirmatory Phase 3 clinical trial of Zepzelca for the treatment of patients with relapsed small cell lung cancer. If successful, LAGOON will serve as the confirmatory trial for Zepzelca to support full approval in the U.S. Zepzelca is a prescription medicine used to treat adults with small cell lung cancer that has spread to other parts of the body (metastatic) and who have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working. Zepzelca is approved based on response rate and how long the response lasted. Additional studies will further evaluate the benefit of Zepzelca for this use. Zepzelca is not approved as part of a combination therapy or as a first-line maintenance treatment for patients with extensive-stage small cell lung cancer. Important Safety Information for Patients Before receiving ZEPZELCA, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems. are pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start treatment with ZEPZELCA. You should use effective birth control (contraception) during treatment with and for 6 months after your final dose of ZEPZELCA. Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA. Males with female partners who are able to become pregnant should use effective birth control during treatment with and for 4 months after your final dose of ZEPZELCA. Females who are breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for 2 weeks after your final dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ZEPZELCA works. What should I avoid while using ZEPZELCA? Avoid eating or drinking grapefruit, or products that contain grapefruit juice during treatment with ZEPZELCA. ZEPZELCA can cause serious side effects, including: Low blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts. Tell your healthcare provider right away if you develop: fever or any other signs of infection unusual bruising or bleeding tiredness pale colored skin Liver problems. Increased liver function tests are common with ZEPZELCA, and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA. Tell your healthcare provider right away if you develop symptoms of liver problems including: loss of appetite nausea or vomiting pain on the right side of your stomach area (abdomen) Your healthcare provider may temporarily stop treatment, lower your dose, or permanently stop ZEPZELCA if you develop low blood cell counts or liver problems during treatment with ZEPZELCA. The most common side effects of ZEPZELCA include: Tiredness low white and red blood cell counts increased kidney function blood test (creatinine) increased liver function blood tests increased blood sugar (glucose) nausea decreased appetite muscle and joint (musculoskeletal) pain low level of albumin in the blood constipation trouble breathing low levels of sodium and magnesium in the blood vomiting cough diarrhea These are not all of the possible side effects of ZEPZELCA. Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. You may also report side effects to Jazz Pharmaceuticals at 1-800-520-5568. More information about Zepzelca, including Full Prescribing Information and Patient Information, is available here. ZEPZELCA is a trademark of Pharma Mar, S.A. used by Jazz Pharmaceuticals under license. About JZP898 JZP898 (also known as WTX-613) is an investigational differentiated, conditionally-activated interferon alpha (IFNα) INDUKINE™ molecule. JZP898 is an engineered IFN⍺2b cytokine pro-drug that is activated specifically within the tumor microenvironment where it can stimulate IFNα receptors on cancer-fighting immune effector cells. JZP898 was created leveraging Werewolf Therapeutics' proprietary PREDATOR™ protein engineering technology, which integrates specialized protein design elements to enhance activity, stability and tumor selectivity within a single molecule, called INDUKINE molecules. About Jazz Pharmaceuticals plc Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseases—often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. Within these therapeutic areas, we are identifying new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science. Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. Please visit for more information. Caution Concerning Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to paving the way for next-generation precision therapies for patients and improving the standard of care for these serious and life-threatening cancers and other statements that are not historical facts. These forward-looking statements are based on Jazz Pharmaceuticals' current plans, objectives, estimates, expectations and intentions and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks and uncertainties associated with pharmaceutical product development, and other risks and uncertainties affecting Jazz Pharmaceuticals and its development programs, including those described from time to time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals plc's Securities and Exchange Commission filings and reports (Commission File No. 001-33500), including Jazz Pharmaceuticals' Annual Report on Form 10-K for the year ended December 31, 2022 and future filings and reports by Jazz Pharmaceuticals. Other risks and uncertainties of which Jazz Pharmaceuticals is not currently aware may also affect Jazz Pharmaceuticals' forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. The forward-looking statements herein are made only as of the date hereof or as of the dates indicated in the forward-looking statements, even if they are subsequently made available by Jazz Pharmaceuticals on its website or otherwise. Jazz Pharmaceuticals undertakes no obligation to update or supplement any forward-looking statements to reflect actual results, new information, future events, changes in its expectations or other circumstances that exist after the date as of which the forward-looking statements were made. Contacts: Jazz Media Contact: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc CorporateAffairsMediaInfo@jazzpharma.com Ireland +353 1 637 2141 U.S. +1 215 867 4948 Jazz Investor Contact: Andrea N. Flynn, Ph.D. Vice President, Head, Investor Relations Jazz Pharmaceuticals plc investorinfo@jazzpharma.com Ireland +353 1 634 3211 U.S. +1 650 496 2717 References: 1 2 3 ZEPZELCA (lurbinectedin) Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc. Company Codes: NASDAQ-NMS:JAZZ

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 .

BAKX Therapeutics emerged from stealth in a big way back in July, striking an $852 million deal with Ipsen for its lead cancer candidate, a small molecule designed to activate the body’s natural process for programmed cell death. And Ipsen’s putting a bit more cash in the company’s coffers to see that program into the clinic. CEO Sree Kant unveiled a $25 million Series A round on Thursday, led by AB Magnitude Ventures Group with a hand from Ipsen and Sherpa Healthcare Partners. The funds will be used to advance the company’s BAKX activator program, which traces back to pioneering work around apoptosis by the Dana-Farber Cancer Institute’s Loren Walensky and Albert Einstein College of Medicine’s Evripidis Gavathiotis. Apoptosis is a form of programmed cell death used by the body to get rid of unneeded or abnormal cells. But some cancer cells are able to evade this mechanism, multiplying out of control. Companies like BAKX are looking to restore that barrier, inducing cancer cell death while sparing healthy cells. Most other experimental therapies go after pro-survival proteins called Bcl-2, Bcl-xl and Mcl-1. This strategy, to “inhibit the inhibitor,” has been effective in certain types of leukemia, with one drug, AbbVie and Genentech’s Venclexta, securing approval back in 2016. But as is often the case with cancer therapies, the development of resistance poses a challenge. Instead, BAKX is targeting pro-apoptotic proteins, such as BAK and BAX, which are downstream of Bcl-2, Bcl-xl and Mcl-1. By directly activating these proteins, scientists believe they can drive apoptosis and destroy tumor cells. Kant compared the approach to Thelma and Louise at the edge of the cliff. You could drive the cancer cell off the cliff in one of two ways: You can let off the brakes, or press the accelerator. While pro-survival protein inhibitors take the brakes off, BAKX is pressing the accelerator. The biotech’s lead candidate, a small molecule activator of BAX called BKX-001, is expected to enter the clinic in 18 to 24 months, Kant said conservatively. “Hopefully we can do it much, much earlier,” he added. Ipsen put down $14.5 million upfront and $837.5 million in biobucks to collaborate on the candidate back in July. While the partners are hoping to go after leukemia, lymphoma and solid tumors, Kant says they’ll likely focus on hematology first. BAKX also has two discovery programs for undisclosed targets up its sleeve. “I wasn’t looking at science which would be a good story I can sell to the investors,” Kant said. “The only thing I’m thinking of is science that I can make a drug with. So if my daughter asks me what do you do for a living, I can tell her I make drugs.”