Bundle-Branch Block

Engineers have developed a new nanoelectronic device that can perform accurate machine-learning classification tasks in the most energy-efficient manner yet. Using 100-fold less energy than current technologies, the device can crunch large amounts of data and perform artificial intelligence (AI) tasks in real time without beaming data to the cloud for analysis. With its tiny footprint, ultra-low power consumption and lack of lag time to receive analyses, the device is ideal for direct incorporation into wearable electronics for real-time data processing and near-instant diagnostics. Forget the cloud. Northwestern University engineers have developed a new nanoelectronic device that can perform accurate machine-learning classification tasks in the most energy-efficient manner yet. Using 100-fold less energy than current technologies, the device can crunch large amounts of data and perform artificial intelligence (AI) tasks in real time without beaming data to the cloud for analysis. With its tiny footprint, ultra-low power consumption and lack of lag time to receive analyses, the device is ideal for direct incorporation into wearable electronics (like smart watches and fitness trackers) for real-time data processing and near-instant diagnostics. To test the concept, engineers used the device to classify large amounts of information from publicly available electrocardiogram (ECG) datasets. Not only could the device efficiently and correctly identify an irregular heartbeat, it also was able to determine the arrhythmia subtype from among six different categories with near 95% accuracy. The research will be published on Oct. 12 in the journal Nature Electronics. "Today, most sensors collect data and then send it to the cloud, where the analysis occurs on energy-hungry servers before the results are finally sent back to the user," said Northwestern's Mark C. Hersam, the study's senior author. "This approach is incredibly expensive, consumes significant energy and adds a time delay. Our device is so energy efficient that it can be deployed directly in wearable electronics for real-time detection and data processing, enabling more rapid intervention for health emergencies." A nanotechnology expert, Hersam is Walter P. Murphy Professor of Materials Science and Engineering at Northwestern's McCormick School of Engineering. He also is chair of the Department of Materials Science and Engineering, director of the Materials Research Science and Engineering Center and member of the International Institute of Nanotechnology. Hersam co-led the research with Han Wang, a professor at the University of Southern California, and Vinod Sangwan, a research assistant professor at Northwestern. Before machine-learning tools can analyze new data, these tools must first accurately and reliably sort training data into various categories. For example, if a tool is sorting photos by color, then it needs to recognize which photos are red, yellow or blue in order to accurately classify them. An easy chore for a human, yes, but a complicated -- and energy-hungry -- job for a machine. For current silicon-based technologies to categorize data from large sets like ECGs, it takes more than 100 transistors -- each requiring its own energy to run. But Northwestern's nanoelectronic device can perform the same machine-learning classification with just two devices. By reducing the number of devices, the researchers drastically reduced power consumption and developed a much smaller device that can be integrated into a standard wearable gadget. The secret behind the novel device is its unprecedented tunability, which arises from a mix of materials. While traditional technologies use silicon, the researchers constructed the miniaturized transistors from two-dimensional molybdenum disulfide and one-dimensional carbon nanotubes. So instead of needing many silicon transistors -- one for each step of data processing -- the reconfigurable transistors are dynamic enough to switch among various steps. "The integration of two disparate materials into one device allows us to strongly modulate the current flow with applied voltages, enabling dynamic reconfigurability," Hersam said. "Having a high degree of tunability in a single device allows us to perform sophisticated classification algorithms with a small footprint and low energy consumption." To test the device, the researchers looked to publicly available medical datasets. They first trained the device to interpret data from ECGs, a task that typically requires significant time from trained health care workers. Then, they asked the device to classify six types of heart beats: normal, atrial premature beat, premature ventricular contraction, paced beat, left bundle branch block beat and right bundle branch block beat. The nanoelectronic device was able to identify accurately each arrhythmia type out of 10,000 ECG samples. By bypassing the need to send data to the cloud, the device not only saves critical time for a patient but also protects privacy. "Every time data are passed around, it increases the likelihood of the data being stolen," Hersam said. "If personal health data is processed locally -- such as on your wrist in your watch -- that presents a much lower security risk. In this manner, our device improves privacy and reduces the risk of a breach." Hersam imagines that, eventually, these nanoelectronic devices could be incorporated into everyday wearables, personalized to each user's health pro real-time applications. They would enable people to make the most of the data they already collect without sapping power. "Artificial intelligence tools are consuming an increasing fraction of the power grid," Hersam said. "It is an unsustainable path if we continue relying on conventional computer hardware."

– EXKIVITY is the First Category-1 Innovative Drug Approved for Takeda China Following a Phase 2 Global Pivotal Study – Approval Based on Data from the Phase 1/2 Clinical Trial Demonstrating EXKIVITY’s Clinical Benefit and Durable Responses in EGFR Exon20 Insertion+ NSCLC – Results Demonstrated a Confirmed Overall Response Rate (ORR) of 28% and Median Duration of Response (DoR) of 15.8 Months per Independent Review Committee (IRC) OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that EXKIVITY® (mobocertinib) has been approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. EXKIVITY has shown clinically meaningful and durable responses in patients with locally advanced or metastatic EGFR Exon20 insertion+ NSCLC and is now the first and only treatment available for this patient population in China. EXKIVITY, an oral tyrosine kinase inhibitor designed to target Exon20 insertions, was reviewed as part of the NMPA’s Breakthrough Therapy program. Full approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial. “The approval of EXKIVITY in China for patients with locally advanced or metastatic EGFR Exon20 insertion+ NSCLC was only possible through dedicated collaboration and support from the NMPA and the Chinese government,” said Awny Farajallah, Head, Global Medical Affairs Oncology, Takeda. “Lung cancer is a devastating disease, and we know the discovery and delivery of precision medicines like EXKIVITY to target cancer types that are hard-to-treat have the potential to improve patient outcomes. We are thrilled to introduce EXKIVITY in China as the second lung cancer therapy from Takeda and remain committed to research and development to meet the needs of this patient community.” Lung cancer is the most commonly diagnosed cancer in China, and NSCLC accounts for approximately 85% of all lung cancer cases in the country.1 Of those patients diagnosed with EGFR-mutated NSCLC in China, up to 10% harbor Exon20 insertions.2-7 Despite this prevalence, patients in China have lacked a targeted treatment option designed to address cancers driven by these mutations. “Since the discovery of EGFR mutations nearly twenty years ago, patients with Exon20 insertions have been waiting for a targeted therapy to treat their disease,” said Sean Shan, President of Takeda China. “The approval of EXKIVITY in China is a remarkable breakthrough, demonstrating the strong commitment of the Chinese government to encourage and accelerate the introduction of innovative therapies. EXKIVITY offers a targeted, oral therapy to a population that has been historically underserved, and this approval brings us one step closer to defeating this complex and heterogeneous disease for patients in this region.” This approval is based on the results from the platinum-pretreated population in the Phase 1/2 trial of EXKIVITY, which consisted of 114 patients with EGFR Exon20 insertion+ NSCLC who received prior platinum-based therapy and were treated at the 160 mg dose. Results demonstrated a confirmed ORR of 28% per IRC as well as a median DoR of 15.8 months per IRC, a median overall survival (OS) of 20.2 months and a median progression-free survival (PFS) of 7.3 months per IRC. The most common treatment-related adverse reactions (TRAEs) were diarrhea (92%), rash (46%), paronychia (38%) and decreased appetite (37%). About EXKIVITY (mobocertinib) EXKIVITY is a first-in-class, oral tyrosine kinase inhibitor (TKI) specifically designed to selectively target epidermal growth factor receptor (EGFR) Exon20 insertion mutations. EXKIVITY is currently approved in the United States, Great Britain, Switzerland, South Korea, Australia and China for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR Exon20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. For more information about EXKIVITY, visit . For the Prescribing Information, including the Boxed Warning, please visit . About EGFR Exon20 Insertion+ NSCLC Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.9, 10 Patients with epidermal growth factor receptor (EGFR) Exon20 insertion+ NSCLC make up approximately 1-2% of patients with NSCLC, and the disease is more common in Asian populations compared to Western populations.2-6 This disease carries a worse prognosis than other EGFR mutations, as EGFR TKIs – which do not specifically target EGFR Exon20 insertions – and chemotherapy provide limited benefit for these patients. Takeda is committed to continuing research and development to meet the needs of the lung cancer community through the discovery and delivery of transformative medicines. EXKIVITY IMPORTANT SAFETY INFORMATION QTc Interval Prolongation Heart rate-corrected QT (QTc) interval prolongation, including resultant life-threatening arrhythmias, such as Torsades de Pointes, occurred in patients treated with mobocertinib. A concentration-dependent QTc interval prolongation of approximately 12.7 msec (90% CI: 8.69, 16.8) was observed at the steady-state Cmax following 160 mg daily doses based on an analysis of data from 194 patients with advanced solid malignances. Clinical trials of mobocertinib did not enroll patients with baseline QTc greater than 470 msec. Assess QTc and electrolytes at baseline and correct abnormalities in sodium, potassium, calcium, and magnesium prior to initiating mobocertinib. Monitor QTc and electrolytes periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation, such as in patients with congenital long QTc syndrome, heart disease, electrolyte abnormalities, or those who are taking medicinal products known to prolong the QTc interval. Avoid concomitant use of medicinal products which are known to prolong the QTc interval. Avoid concomitant use of strong or moderate CYP3A inhibitors with mobocertinib, which may further prolong the QTc interval. Permanently discontinue mobocertinib in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis have occurred in patients treated with mobocertinib. Withhold mobocertinib for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation and diagnosis confirmation. Permanently discontinue mobocertinib if ILD/pneumonitis is confirmed. Cardiac Toxicity Cardiac failure (including congestive cardiac failure, decreased ejection fraction, and cardiomyopathy) has occurred in patients treated with mobocertinib. Mobocertinib can cause QTc prolongation resulting in Torsades de Pointes. Atrial fibrillation (1.3%), ventricular tachycardia (0.3%), first degree atrioventricular block (0.7%), second degree atrioventricular block (0.3%), left bundle branch block (0.3%), supraventricular extrasystoles (0.3%) and ventricular extrasystoles (0.3%) also occurred in patients receiving mobocertinib. The causality of these events to mobocertinib has not been established. Conduct cardiac monitoring, including assessment of left ventricular ejection fraction at baseline and during treatment. Patients who develop signs and symptoms consistent with cardiac failure should be treated as clinically indicated. Withhold, reduce the dose, or permanently discontinue mobocertinib based on the severity. Diarrhea In clinical studies, most patients experienced mild to moderate diarrhea. Diarrhea can be severe or life threatening. The median time to first onset of diarrhea was five days but could occur as soon as 24 hours after administration of mobocertinib. Diarrhea is usually transient and had a median time to resolution of three days. Prolonged diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Early and compliant diarrhea management such as prescribed anti-diarrheal medicinal products (e.g., loperamide), diet, adequate fluid intake (~2L clear liquids per day), and patient education is recommended. Instruct patients to have anti-diarrheal medicinal products (e.g., loperamide) readily available. Begin anti-diarrheal treatment at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. In mobocertinib clinical trials where loperamide was used as the antidiarrheal, the dosage regimen for loperamide was 4 mg at the first bout of diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours; daily dose of loperamide did not exceed 16 mg. If using loperamide as the antidiarrheal treatment, refer to loperamide product labeling for additional information. If diarrhea does not improve or additional signs or symptoms are reported, standard medical practice intervention, including other anti-diarrheal medications, are recommended. Antidiarrheal prophylaxis may be considered as needed. Monitor electrolytes and instruct patients to increase fluid and electrolyte intake as needed. No dose modification is necessary unless the patient does not tolerate mobocertinib or the symptoms recur, or the diarrhea doesn’t resolve with medical intervention. Interrupt mobocertinib and reduce subsequent doses if severe diarrhea occurs. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, mobocertinib can cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mobocertinib and for one month following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with mobocertinib and for one week following the final dose of mobocertinib. Takeda’s Commitment to Oncology At Takeda Oncology, we are united by our aspiration to cure cancer and motivated every day to work harder for patients with limited or ineffective treatment options. Our agile structure and deep in-house expertise are complemented by a network of partnerships that optimize our ability to research, develop and deliver transformative medicines to people living with cancer. Building on decades of leadership in oncology and a portfolio of approved medicines for hematologic cancers and solid tumors, we are advancing a cutting-edge pipeline focused on the power of innate immunity. With inspiration from patients and innovation from everywhere, our goal is to introduce new classes of immunotherapies that can lead to deep, durable responses so that more patients can benefit from – and have access to – innovative medicines. For more information, visit . About Takeda Pharmaceutical Company Limited Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE: TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries. For more information, visit . Important Notice For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. 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These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: or at . Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. Medical information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. Regulatory information This indication is approved in China under conditional approval. 1 Gan J, Fang W, Zhang L. Therapy of lung cancer in China: introducing the special collection. Therapeutic Advances in Medical Oncology. 2021;13. 2 Riess, Jonathan W. Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC. (18)30770-6/fulltext. Accessed September 28, 2022. 3 Fang, Wenfeng. BMC Cancer. EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer. . Accessed September 28, 2022. 4 Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 2016;107(9):1179-1186. doi:10.1111/cas.12996 5 Yatabe Y, Kerr KM, Utomo A, et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac Oncol. 2015;10(3):438-445. doi:10.1097/JTO.0000000000000422 6 Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006. doi:10.1001/jama.2014.3741 7 Yang, Guangjian et al. “EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.” Lung cancer (Amsterdam, Netherlands) vol. 145 (2020): 186-194. 8 Zhou C. Lung cancer molecular epidemiology in China: recent trends. Transl Lung Cancer Res. 2014 Oct;3(5):270-9. doi: 10.3978/j.issn.2218-6751.2014.09.01 9 Sung H. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. . Accessed September 28, 2022 10 American Cancer Society. What is Non-Small Cell Lung Cancer? . Accessed September 28, 2022.

New Case Report Reveals Opportunity to Become First-Line Therapy for Patients SUNNYVALE, Calif.--(BUSINESS WIRE)-- EBR Systems, Inc., developer of the world’s only wireless cardiac pacing system for heart failure, today announced the publication of a case report demonstrating the WiSE™ CRT System’s ability to successfully deliver leadless Left Bundle Branch Area Pacing (LBBAP). WiSE is the only leadless pacing technology able to achieve LBBAP, a novel form of conduction system pacing which can reverse left bundle branch block and deliver cardiac resynchronization therapy (CRT). Published last month in the European Heart Journal, the case report details the successful deployment of the WiSE Electrode implanted in the LV septum of an 82-year-old male with tachyarrhythmia-induced cardiomyopathy. The patient exhibited improved electrical resynchronization on ECG and reported significant symptomatic improvement at six-month follow-up. This is the first reported case of LBBAP delivered via the WiSE CRT system, and it is also the first reported case of permanent LBBAP from the LV aspect of the interventricular septum. “EBR continues to pursue the feasibility of leadless LBBAP and the hope that the WiSE CRT system can benefit even more patients,” said John McCutcheon, President and CEO at EBR Systems. “We are committed to supporting an upcoming physician-initiated study to further investigate WiSE’s potential to deliver first-line therapy for patients.” LBBAP pacing has been proposed as a strategy to achieve physiological pacing by utilizing the heart’s native conduction system, allowing faster left ventricular activation time.1 LBBAP has potential applications in both traditional bradycardia pacing and as an alternative approach to Cardiac Resynchronization Therapy (CRT).2 Until now, LBBAP has required use of a conventional pacing lead, driven deep into the ventricular septum, which can be technically challenging.3 “We are pleased to confirm WiSE’s ability to deliver leadless left bundle branch pacing in this new report,” said Professor Pascal Defaye, the Head of Rhythmology and Cardiac Stimulation Unit at CHU de Grenoble-Alpes, France, who performed the implant. “WiSE is the first and only leadless pacing system that can deliver physiologic, conduction system pacing without leads. Our initial case demonstrates the exciting potential of EBR’s technology.” EBR Systems’ WiSE Technology EBR Systems’ WiSE is the world’s only wireless, endocardial (inside the heart) pacing system in clinical use for stimulating the heart’s left ventricle. This has long been a goal of cardiac pacing companies since internal stimulation of the left ventricle is thought to be a potentially superior, more anatomically correct pacing location. WiSE Technology enables cardiac pacing of the left ventricle with a novel cardiac implant that is roughly the size of a large grain of rice. The need for a pacing wire on the outside of the heart’s left ventricle – and the attendant problems – are potentially eliminated. WiSE is an investigational device and is not currently available for sale in the United States. About EBR Systems Silicon Valley-based EBR Systems is dedicated to superior treatment of cardiac rhythm disease by providing more physiologically effective stimulation through wireless cardiac pacing. The company’s patented proprietary Wireless Stimulation Endocardially (WiSE) technology was developed to eliminate the need for cardiac pacing leads, historically the major source of complications and reliability issues in cardiac rhythm disease management. The company’s initial product is designed to eliminate the need for coronary sinus leads to stimulate the left ventricle in heart failure patients requiring CRT. Future products will address wireless endocardial stimulation for bradycardia and other non-cardiac indications. EBR Systems is backed by respected private equity investors including M.H. Carnegie & Co., Brandon Capital Partners, Split Rock Partners, Ascension Ventures and Emergent Medical Partners. 1 Zhang W, Huang J, Qi Y, et al. Cardiac Resynchronization Therapy by Left Bundle Branch Area Pacing in Patients with Heart Failure and Left Bundle Branch Block. Heart Rhythm. 2019; 16(12):1783-1790. 2 Padala SK and Ellenbogen KA. Left Bundle Branch Pacing is the Best Approach to Physiological Pacing. Heart Rhythm O2. 2020; 1(1):59-67. 3 Li X, Li H, Ma W, et al. Permanent Left Bundle Branch Area Pacing for Atrioventricular Block: Feasibility, Safety, and Acute Effect. Heart Rhythm. 2019;16:1766-1773.