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NEW YORK--( BUSINESS WIRE )--Pfizer Inc. (NYSE: PFE) continues to showcase potential practice-changing research and next-generation candidates across its robust Oncology portfolio at the European Society for Medical Oncology (ESMO) Congress 2024, being held September 13-17 in Barcelona. Data from more than 50 company-sponsored, investigator-sponsored and collaborative research abstracts, including more than 10 oral and mini-oral presentations, will be presented across the company’s tumor areas and core scientific modalities, as well as a potential treatment for a cancer-related condition. “ At this year’s ESMO, we are looking forward to demonstrating our progress toward delivering next-generation biologics and novel combinations that have the potential to be new standards of care for patients,” said Chris Boshoff, Chief Oncology Officer and Executive Vice President, Pfizer. “ Our key data presentations highlight our scientific leadership in developing targeted therapies, including small molecules and antibody-drug conjugates, across our core tumor areas, including breast, bladder and thoracic cancers.” “ At ESMO, Pfizer will share important data highlighting our commitment to transforming outcomes for patients living with lung cancer, including longer-term follow-up results from the BRAFTOVI + MEKTOVI PHAROS study in BRAF V600E-mutated metastatic non-small cell lung cancer,” said Karin Tollefson, Chief Oncology Medical Officer, Pfizer. “ We are also looking forward to sharing progress on our industry-leading pipeline of new molecules, including encouraging early results for two novel, investigational antibody-drug conjugates and preliminary data on a novel combination of Pfizer’s next-generation CDK inhibitors.” Key research includes a late-breaking presentation of updated results from the pivotal Phase 2 PHAROS* study of BRAFTOVI (encorafenib) + MEKTOVI (binimetinib) in patients with BRAF V600E-mutant metastatic non-small cell lung cancer (mNSCLC). Longer-term efficacy and safety data will be presented, following the initial primary overall response results (ORR) that supported the FDA approval for BRAFTOVI + MEKTOVI in this indication in 2023 and the recent approval by the European Commission in August 2024. Further, Pfizer will share updated data from the safety lead-in of the ongoing Phase 3 BREAKWATER trial, showing antitumor activity of BRAFTOVI + cetuximab + FOLFIRI in patients with untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC) in a mini-oral presentation. Additionally, Pfizer will present a late-breaking Proffered Paper Presentation on the Phase 2 efficacy and safety results for its GDF-15 inhibitor, ponsegromab, in patients with cancer-associated cachexia, highlighting the company’s commitment to improving the treatment journey for people living with cancer. Cancer cachexia is a common, life-threatening wasting condition characterized by severe weight loss. The condition affects patients with advanced cancers and can greatly impact a patient’s ability to tolerate cancer treatment and quality of life. Despite its severity, there are no FDA-approved treatments for cachexia. i,ii Pfizer will also present early clinical-stage research for a number of priority pipeline areas, including encouraging Phase 1 results of the potential first-in-class antibody-drug conjugate (ADC) candidate SGN-PDL1V (PF-08046054) in NSCLC and head and neck squamous cell carcinoma (HNSCC); initial data for the investigational ADC disitamab vedotin in combination with KEYTRUDA ® (pembrolizumab) in human epidermal growth factor receptor 2 (HER2)-expressing locally advanced or metastatic urothelial cancer (la/mUC); and the first data combining atirmociclib, our highly-selective cyclin-dependent kinase 4 (CDK4) inhibitor (CDK4i), with a novel CDK2 inhibitor (CDK2i) in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) from a Phase 1 dose-escalation study. Key ESMO Presentations Genitourinary Cancer PADCEV + KEYTRUDA**: additional analysis from the pivotal EV-302 trial continues to support the combination as a new standard of care for patients with previously untreated la/mUC. An exploratory analysis shows PADCEV + KEYTRUDA ® showed consistent progression free survival (PFS), overall survival (OS), and ORR versus chemotherapy regardless of Nectin-4 or PD-L1 expression. Disitamab Vedotin: preliminary efficacy and safety data for disitamab vedotin in combination with KEYTRUDA highlights Pfizer’s continued commitment to developing novel therapeutics to meet the needs of patients with bladder cancer. Results from the safety run-in of the ongoing Phase 2 trial showed encouraging early efficacy and a safety profile consistent with previously presented data in treatment-naive patients with HER2-expressing la/mUC. Thoracic Cancer SGN-PDL1V (PF-08046054): encouraging Phase 1 results will be presented for PDL1V, a novel, investigational vedotin ADC directed to PD-L1-expressing solid tumors. Data from the dose-escalation and dose optimization cohorts of the ongoing Phase 1 study show PDL1V as monotherapy was generally well tolerated with no unexpected adverse events, and encouraging antitumor activity was observed in patients with heavily pretreated NSCLC and HNSCC. Breast Cancer Atirmociclib (PF-07220060) + PF-07104091 : initial data from a dose-escalation study evaluating the innovative combination of atirmociclib, a potential first-in-class CDK4-selective inhibitor, with PF-07104091, a novel CDK2-selective inhibitor, showed a manageable safety profile and encouraging efficacy in patients with heavily pretreated HR+/HER2- breast cancer. These early results highlight the potential of Pfizer's strategy to advance atirmociclib as a future CDK inhibitor backbone therapy that may address treatment resistance with first generation CDK4/6i, subject to clinical success and regulatory approval. The CDK4i+2i combination is continuing to be explored in an ongoing Phase 1b/2 dose escalation and dose expansion study (NCT05262400). Additional information on the Pfizer-sponsored abstracts, including date and time of presentation, follow in the chart below. Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented at ESMO, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries starting September 16, 2024. BREAST CANCER Mini Oral Presentation (Abstract 618MO) Saturday, September 14, 2:45 PM-4:15 PM CEST Phase 1b/2 first-in-class novel combination trial of next generation CDK4-selective inhibitor PF-07220060 and next generation CDK2-selective inhibitor PF-07104091 in HR+ HER2- metastatic breast cancer and advanced solid tumors Yap et al Poster Presentation (Abstract 413P) Monday, September 16, 9:00 AM-5:00 PM CEST Longitudinal circulating tumor DNA (ctDNA) dynamics in Phase 1/2a study of the first-in-class CDK4-selective inhibitor, PF-07220060, in combination with endocrine therapy in patients with HR+/HER2− metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors Yap et al Poster Presentation (Abstract 359P) Monday, September 16, 9:00 AM-5:00 PM CEST Overall survival of palbociclib (PAL) + endocrine therapy (ET) in Japanese patients with hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in the 1st line (1L) or 2nd line (2L) setting: A multicenter observational study Nakayama et al Poster Presentation (Abstract 354P) Monday, September 16, 9:00 AM-5:00 PM CEST Synergistic preclinical efficacy through combination of the CDK4 and CDK2 selective inhibitors, PF-07220060 and PF-07104091, respectively, in HR+ HER2- breast cancer Anders et al Poster Presentation (Abstract 356P) Monday, September 16, 9:00 AM-5:00 PM CEST Real-world effectiveness in subgroups of palbociclib + endocrine therapy in HR+/HER2- ABC patients: Interim Results of the PERFORM study Pfeiler et al EARLY PIPELINE Oral Presentation, Proffered Paper (Abstract 607O) Friday, September 13, 4:00 PM-5:30 PM CEST Interim results of a Phase 1 study of SGN-PDL1V (PF-08046054) in patients with PDL1-expressing solid tumors Oliva Bernal et al GASTROINTESTINAL CANCER Mini Oral Presentation (Abstract 515MO) Saturday, September 14, 2:45 PM-4:15 PM CEST Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): updated results from the BREAKWATER safety lead-in (SLI) Tabernero et al GENITOURINARY CANCER Mini Oral Presentation (Abstract 1966MO) Sunday, September 15, 8:30 AM-10:00 AM CEST EV-302: Exploratory analysis of nectin-4 expression and response to 1L enfortumab vedotin (EV) + pembrolizumab (P) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC) Powles et al Poster Presentation (Abstract 1968P) Sunday, September 15, 9:00 AM-5:00 PM CEST Study EV-103 dose escalation/cohort A (DE/A): 5y follow-up of first-line (1L) enfortumab vedotin (EV) + pembrolizumab (P) in cisplatin (cis)-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) Rosenberg et al Poster Presentation (Abstract 2001P) Sunday, September 15, 9:00 AM-5:00 PM CEST Epidemiology and treatment patterns of patients with locally advanced or metastatic urothelial cancer in France: a non-interventional database study Joly et al Poster Presentation (Abstract 1638P) Sunday, September 15, 9:00 AM-5:00 PM CEST Enzalutamide (ENZA) with or without leuprolide in patients (pts) with high-risk biochemically recurrent (hrBCR) prostate cancer (PC): EMBARK post hoc analysis by age Shore et al Poster Presentation (Abstract 1626P) Sunday, September 15, 9:00 AM-5:00 PM CEST Incidence of hematologic toxicities in the homologous recombination repair (HRR)-deficient population of the TALAPRO-2 trial and their potential association with germline vs somatic origin of HRR gene alterations Azad et al Poster Presentation (Abstract 1637P) Sunday, September 15, 9:00 AM-5:00 PM CEST Efficacy of talazoparib and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with androgen receptor pathway inhibitors (ARPI) or docetaxel – post hoc analysis from both cohorts in TALAPRO-2 study Agarwal et al Poster Presentation (Abstract 1633P) Sunday, September 15, 9:00 AM-5:00 PM CEST Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): TALAPRO-2 (TP-2) China cohort Zeng et al Mini Oral Presentation (Abstract 1967MO) Sunday, September 15, 8:30 AM-10:00 AM CEST Preliminary efficacy and safety of disitamab vedotin (DV) with pembrolizumab (P) in treatment (Tx)-naive HER2-expressing, locally advanced or metastatic urothelial carcinoma (la/mUC): RC48G001 Cohort C Galsky et al MELANOMA Poster Presentation (Abstract 1071TiP) Saturday, September 14, 9:00 AM-5:00 PM CEST Phase 1 study of the investigational CD228 x 4-1BB costimulatory antibody Anticalin bispecific SGN-BB228 (PF-08046049) in advanced melanoma and other solid tumors Dummer et al SUPPORTIVE AND PALLIATIVE CARE Oral Presentation, Proffered Paper (Abstract LBA82) Saturday, September 14, 2:45 PM-4:25 PM CEST Efficacy and safety of ponsegromab, a first-in-class, monoclonal antibody inhibitor of growth differentiation factor-15, in patients with cancer cachexia: A randomized, placebo-controlled, Phase 2 study Crawford et al THORACIC CANCER Mini Oral Presentation (Abstract LBA56) Saturday, September 14, 10:15 AM-11:45 AM CEST Updated efficacy and safety from the Phase 2 PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC) Riely et al Poster Presentation (Abstract 1398TiP) Saturday, September 14, 9:00 AM-5:00 PM CEST Be6A Lung-01, a Phase 3 study of sigvotatug vedotin (SV), an investigational antibody-drug conjugate (ADC) versus docetaxel in patients (pts) with previously treated non-small cell lung cancer (NSCLC) Peters et al Poster Presentation (Abstract 1279P) Saturday, September 14, 9:00 AM-5:00 PM CEST First-line lorlatinib vs crizotinib in Asian patients with ALK+ non-small cell lung cancer (NSCLC): 5-year outcomes from the CROWN study Wu et al *The PHAROS trial is conducted with support from Pierre Fabre. **Pfizer and Astellas have a clinical collaboration agreement with Merck to evaluate the combination of PADCEV ® and KEYTRUDA ® in patients with previously untreated metastatic urothelial cancer. Prescribing Information for Pfizer Medicines Please see full Prescribing Information for PADCEV. Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI. About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including antibody-drug conjugates (ADCs), small molecules, bispecific antibodies and other immunotherapy biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs that help people with cancer globally live better and longer lives. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com . In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . DISCLOSURE NOTICE: The information contained in this release is as of September 11, 2024. The Company assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about Pfizer Oncology, Pfizer’s Oncology portfolio of marketed and investigational therapies, including combinations, and an investigational therapy for a cancer-related condition; expectations for our product pipeline, in-line products and product candidates, including their potential benefits, clinical trial results and other developing data; potential breakthrough, best- or first-in-class or blockbuster status or expected market entry of our medicines; and other statements about our business, operations and financial results that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risk and uncertainties include, among other things, uncertainties regarding the commercial success of Pfizer’s oncology portfolio; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; risks associated with interim and preliminary data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when any drug applications, biologics license applications and/or emergency use authorization applications may be filed in any jurisdictions for any potential indication for Pfizer’s product candidates; whether and when any such applications that may be pending or filed for any of Pfizer’s product candidates may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether any such product candidates will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of Pfizer’s products or product candidates, including development of products or therapies by other companies; manufacturing capabilities or capacity; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “ Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov and www.pfizer.com . i Cleveland Clinic. Cachexia (Wasting Syndrome). Cachexia (Wasting Syndrome): Symptoms & Treatment (clevelandclinic.org) . Accessed September 3, 2024. ii Lisa Martin, Michael B. Sawyer, Cancer Cachexia: Emerging Preclinical Evidence and the Pathway Forward to Clinical Trials, JNCI: Journal of the National Cancer Institute , Volume 107, Issue 12, December 2015, djv322, https://doi.org/10.1093/jnci/djv322 Category: Pipeline

Analysis conducted among 3,743 patients with history of heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction (HFpEF) from four clinical trials1 Obesity considered key driver in the development of HFpEF,2 with approximately 80% of people with HFpEF living with overweight or obesity3 Semaglutide is not approved in the US to reduce heart failure outcomes PLAINSBORO, N.J., Aug. 30, 2024 /PRNewswire/ -- Today, The Lancet published a new pooled, participant-level analysis of patients with heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction (HFpEF) from the SELECT, FLOW, STEP-HFpEF and STEP-HFpEF DM randomized, placebo-controlled trials.1 According to the analysis, semaglutide led to a 31% reduced risk of combined cardiovascular (CV) death or worsening heart failure (HF) events, based on an incidence of 5.4% in patients assigned to semaglutide versus 7.5% in those assigned to placebo (HR 0.69; 95% CI 0.53-0.89; P=0.0045).1 Semaglutide also led to a 41% lower risk of worsening HF (2.8% versus 4.7% with placebo; HR 0.59 (95% CI 0.41-0.82), P=0.0019).1 There was no significant effect on the incidence of CV death (3.1% with semaglutide versus 3.7% with placebo); HR 0.82 (95% CI 0.57-1.16), P=0.25).1 Statistical analyses were not adjusted for multiplicity and hazard ratios should not be used to infer definitive treatment effects.1 Semaglutide is not approved in the US to reduce heart failure outcomes. The study was a pooled, post hoc participant-level analysis of 3,743 patients with a history of HFpEF from four randomized trials to examine the effects of once-weekly semaglutide (2.4 mg in SELECT, STEP-HFpEF, STEP-HFpEF DM; 1.0 mg in FLOW) on HF events.1 The STEP-HFpEF Program enrolled participants with obesity-related HFpEF; in SELECT (participants with atherosclerotic cardiovascular (CV) disease and overweight/obesity) and FLOW (participants with type 2 diabetes and chronic kidney disease), HFpEF classification was investigator-reported.1 The main endpoint for this pooled analysis was a composite of time to first CV death or worsening HF event (hospitalizations or urgent visits due to HF). Additional endpoints included components of the composite: time to first HF event and time to CV death.1 Obesity is considered a key driver in the development of HFpEF,2 with approximately 80% of people with HFpEF living with overweight or obesity.3 In addition, type 2 diabetes is also highly prevalent in people with HFpEF and is associated with greater symptom burden, worse functional capacity, and more severely impaired quality of life.2,4 "Due in part to the obesity epidemic, HFpEF has emerged as the most common type of heart failure. Patients with obesity-related HFpEF are at high risk for serious complications including hospitalizations and death, and have limited treatment options," said Dr. Mikhail Kosiborod, lead study author and cardiologist at Saint Luke's Mid America Heart Institute. "Collectively, this new analysis is the most comprehensive evaluation of semaglutide to date that assesses clinically relevant HF events, such as CV death and hospitalization." Adverse events leading to treatment discontinuation occurred in 21% of patients in the semaglutide group and 13.9% of patients in the placebo group.1 Gastrointestinal disorders leading to treatment discontinuation occurred in 11.1% of patients in the semaglutide group and 2.7% of patients in the placebo group.1 Fewer semaglutide versus placebo-treated patients experienced serious adverse events across the four trial populations.1 "Combining the HFpEF participant populations across the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials allowed us to take a closer look at how semaglutide impacted patients living with this debilitating and often progressive condition," said Michelle Skinner, PharmD, Vice President Medical Affairs, Novo Nordisk. "It is encouraging to have this additional analysis that examines the effect of semaglutide in this vulnerable patient population." About obesity, HFpEF, and type 2 diabetes When the heart is too stiff to fill properly but is capable of pumping out a normal percentage of blood, the condition is called HFpEF.5 This is the most common type of heart failure, comprising approximately 50% of all heart failure cases.6 Despite therapeutic advances in HFpEF, significant unmet needs persist.6,7 The prevalence of obesity is rapidly increasing.8,9 Obesity affects about 4 in 10 US adults and is considered a key driver of HFpEF.2,10 Approximately 80% of people with HFpEF live with overweight or obesity and 40-50% of people with HFpEF have diabetes.2,3 About the SELECT trial (semaglutide 2.4 mg) SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was a multicenter, randomized, double-blind, placebo-controlled, event-driven superiority trial designed to evaluate the efficacy of semaglutide 2.4 mg versus placebo as an adjunct to cardiovascular standard of care for reducing the risk of major adverse cardiovascular events in people with established CVD and overweight or obesity with no prior history of diabetes.11 The trial, initiated in 2018, enrolled 17,604 adults and was conducted in 41 countries at more than 800 investigator sites.11 About the STEP-HFpEF trial (semaglutide 2.4 mg) STEP-HFpEF was a 52-week, double-blind, randomized, placebo-controlled trial designed to investigate the effects of semaglutide 2.4 mg subcutaneous once-weekly on symptoms, physical function, and body weight compared with placebo, both added to standard of care, in patients with HFpEF and obesity. STEP-HFpEF included 529 adults with symptomatic HFpEF (ejection fraction ≥45%) and obesity (BMI ≥30 kg/m2). Dual primary endpoints were change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and percentage change in body weight; with key secondary endpoints of change in 6-minute-walk distance (6MWD), a hierarchical composite endpoint (all-cause death, heart failure events, difference in KCCQ-CSS change and difference of at least 30 meters in 6MWD change) and change in C-reactive protein.12 About the STEP-HFpEF DM trial (semaglutide 2.4 mg) STEP-HFpEF DM was a 52-week, double-blind, randomized, placebo-controlled trial designed to investigate the efficacy of semaglutide 2.4 mg subcutaneous once-weekly on symptoms, physical function, and body weight compared with placebo, both added to standard of care, in patients with HFpEF, obesity, and type 2 diabetes. STEP-HFpEF DM included 616 adults with symptomatic HFpEF (ejection fraction ≥45%), obesity (BMI ≥30 kg/m2) and type 2 diabetes. Dual primary endpoints were change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and percentage change in body weight; with key secondary endpoints of change in 6-minute-walk distance (6MWD), a hierarchical composite endpoint (all-cause death, heart failure events, difference in KCCQ-CSS change and difference of at least 30 meters in 6MWD change) and change in C-reactive protein.13 About the FLOW trial (semaglutide 1 mg) FLOW was a randomized, double-blind, parallel-group, placebo-controlled, event-driven superiority trial comparing injectable once-weekly semaglutide 1.0 mg with placebo as an adjunct to standard of care on kidney outcomes for delaying the progression of renal impairment and lowering the risk of renal and cardiovascular mortality in people with type 2 diabetes and CKD. 3,533 adults were enrolled in the trial which was conducted in 28 countries at around 400 investigator sites. The FLOW trial was initiated in June 2019.14 The primary objective of the FLOW trial was to demonstrate a delay in the progression of CKD and to lower the risk of onset of kidney failure (initiation of long-term dialysis, kidney transplantation, or a reduction in the eGFR to <15 ml per minute per 1.73 m2 sustained for ≥28 days), a sustained (for ≥28 days) 50% or greater reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes. Key secondary endpoints, assessed in a hierarchical order, included annual rate of change in eGFR (total eGFR slope), time to first occurrence of a composite MACE endpoint (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) and time to occurrence of an all-cause death.14 About Novo Nordisk Novo Nordisk is a leading global healthcare company that's been making innovative medicines to help people with diabetes lead longer, healthier lives for more than 100 years. This heritage has given us experience and capabilities that also enable us to drive change to help people defeat other serious chronic diseases such as obesity, rare blood, and endocrine disorders. We remain steadfast in our conviction that the formula for lasting success is to stay focused, think long-term, and do business in a financially, socially, and environmentally responsible way. With U.S. headquarters in New Jersey and commercial, production and research facilities in seven states plus Washington DC, Novo Nordisk employs approximately 8,000 people throughout the country. For more information, visit novonordisk-us.com, Facebook, Instagram, X, LinkedIn, and YouTube. References Kosiborod, MN, Deanfield J, Pratley R, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. The Lancet. Published online: August 30, 2024. Borlaug BA, Jensen MD, Kitzman DW, et al. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2022; 118:3434-3450. Gevaert AB, Kataria R, Zannad F, et al. Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms and management. Heart. 2022; 108:1342-1350. Yap J, Tay WT, Teng TK, et al. Association of diabetes mellitus on cardiac remodelling, quality of life, and clinical outcomes in heart failure with reduced and preserved ejection fraction. J Am Heart Assoc. 2019; 8:e013114. American Heart Association. Types of heart failure. Available at: . Last accessed: August 2024. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2023 May 9;81(18):1835-1878. doi: 10.1016/j.jacc.2023.03.393. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020 Sep;17(9):559-573. doi: 10.1038/s41569-020-0363-2. World Obesity Federation. World obesity atlas 2024. Available at: . Last accessed: August 2024. World Obesity Federation. Prevalence of obesity. Available at: . Last accessed: August 2024. Centers for Disease Control and Prevention. Adult obesity facts. Available at: . Last accessed: August 2024. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023; 389:2221-2232. Kosiborod MN, Abildstrom SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023; 389:1069-1084. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024;390:1394-1407. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391:109-121. © 2024 Novo Nordisk All rights reserved. US24SEMO01152 August 2024 SOURCE NOVO NORDISK INC.

Scientists developed a human pancreatic cancer fibrotic barrier 3D cell-culture model to assess treatments for pancreatic ductal adenocarcinoma. By targeting the ROCK2 pathway, they achieved a notable decrease in fibrosis and enhanced tissue permeability to drugs, offering promising avenues for overcoming treatment obstacles in pancreatic cancer. In a pioneering study, scientists at Okayama University developed a human pancreatic cancer fibrotic barrier 3D cell-culture model to assess treatments for pancreatic ductal adenocarcinoma. By targeting the ROCK2 pathway, they achieved a notable decrease in fibrosis and enhanced tissue permeability to drugs, offering promising avenues for overcoming treatment obstacles in pancreatic cancer. This innovative strategy has the potential to transform therapeutic interventions, representing a pivotal advancement in tackling this formidable disease. Pancreatic cancer, recognized as one of the deadliest cancers, poses a persistent challenge for medical professionals globally due to its aggressive behavior and resistance to conventional therapies. The dense fibrotic tissue surrounding pancreatic tumors acts as a significant barrier, hindering the delivery of macromolecular drugs such as antibodies and nanomedicines. Therefore, addressing fibrosis is crucial in enhancing therapeutic outcomes for patients with pancreatic cancer, whose prognosis remains bleak. Understanding the underlying mechanisms driving fibrosis is essential in advancing treatment strategies for this devastating illness. The conventional models used for studying pancreatic ductal adenocarcinoma (PDAC) fibrotic environment often fail to accurately mimic the complexity of the disease. Seeking a more clinically relevant approach, a team of researchers led by Professor Mitsunobu R. Kano from Okayama University, Japan in collaboration with The University of Tokyo and Tohoku University developed a realistic human pancreatic cancer fibrotic barrier model using patient-derived pancreatic stellate cells (PSCs). Their research, co-authored by Prof. Hiroyoshi Y. Tanaka from Okayama University, Prof. Horacio Cabral from The University of Tokyo, and Prof. Atsushi Masamune from Tohoku University, was made available online on 29 March 2024 and was formally published in the May 2024 issue of the Journal of Controlled Release. This innovative model offers a convenient, rapid, and highly reproducible experimental platform to assess pathogenetic mechanisms driving fibrosis as well as to test the efficacy of potential therapeutic interventions. Understanding the molecular mechanisms driving extracellular matrix (ECM) remodeling in PDAC fibrosis is crucial for overcoming treatment barriers. By dissecting these signaling pathways, researchers aimed to determine points of intervention that could be manipulated to enhance tissue permeability and develop more effective treatments for pancreatic cancer. "We used advanced cell culture techniques along with molecular and pharmacological interventions to examine the signaling pathways involved in PDAC fibrosis," explained Professor Kano. "Initially, we assessed the impact of blocking the transforming growth factor-β (TGFβ) and Rho-associated kinase (ROCK) pathways on ECM remodeling and tissue permeability within our 3D fibrotic tissue model. Additionally, we also investigated the involvement of YAP (Yes-associated protein), a key regulator of cell differentiation, in mediating the effects of ROCK inhibition on ECM remodeling and tissue permeability." The results shed light on promising avenues for enhancing drug delivery in PDAC by targeting specific signaling pathways involved in fibrosis. "Inhibition of the TGFβ pathway led to a reduction in ECM remodeling and improved tissue permeability of drugs in 3D-PDAC fibrotic model. Similarly, blocking the ROCK pathway, particularly through ROCK2 inhibition, resulted in decreased ECM remodeling and enhanced drug permeability. Knockdown experiments revealed the predominant role of ROCK2 in regulating these processes," shares Prof. Kano. "Additionally, targeting the YAP protein, a downstream effector of ROCK signaling, produced similar improvements in ECM remodeling and drug permeability." These findings highlight the potential of targeting the TGFβ/ROCK2/YAP signaling axis to mitigate fibrotic barriers and enhance drug delivery in pancreatic cancer, offering promising prospects for improving treatment outcomes in this challenging disease. Looking ahead, the implications of the study extend beyond pancreatic cancer alone. "Fibrosis is prevalent not only in pancreatic cancer but also in other cancers that are difficult to treat, such as those affecting the stomach, breast, and lung, as well as in some non-cancerous diseases. With effective medical treatments lacking for fibrotic conditions, our findings offer a glimmer of hope for enhancing treatment strategies and outcomes in a broader spectrum of fibrotic cancers as well as non-cancerous fibrotic conditions," concludes Prof. Kano.