Post Graduate Institute of Medical Education & Research

TUESDAY, Aug. 27, 2024 -- For salvage for biliary access in patients with benign biliary disease and difficult bile duct cannulation, the endoscopic ultrasound-guided rendezvous technique (EUS-RV) and precut sphincterotomy have similar success rates and comparable, acceptable complication rates, according to a study published online Aug. 27 in the Annals of Internal Medicine . Arup Choudhury, M.D., from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues compared EUS-RV and precut sphincterotomy as salvage techniques for difficult bile duct cannulation in benign biliary obstruction in a parallel-group, superiority, randomized controlled trial. Patients were randomly assigned to EUS-RV or precut sphincterotomy (50 patients to each group); those with failure in EUS-RV were crossed over to precut sphincterotomy and vice versa. The researchers found that the two groups had similar technical success rates (92 versus 90 percent; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.16), median procedure times (10.1 versus 9.75 minutes), and overall complication rates (12 versus 10 percent; relative risk, 1.20; 95 percent confidence interval, 0.39 to 3.68). Five patients in the EUS-RV and five in the precut sphincterotomy groups developed postendoscopic retrograde cholangiopancreatography pancreatitis. When crossed over to the other group, all failed cases in either salvage group could be successfully cannulated. "EUS-RV is not superior to precut sphincterotomy as a salvage technique for difficult bile duct cannulation in benign biliary diseases, and has a similar adverse event profile to precut sphincterotomy," the authors write.

Researchers have identified a new mechanism behind knee osteoarthritis, showing that increased stiffening in the extracellular matrix led to a decrease in the Klotho 'longevity protein,' which led to damage in healthy cartilage cells. The findings may inform better treatment targets and increase understanding of other conditions caused by aging tissues in the body. Researchers in the United States and Japan have discovered a new mechanism that links age-related cartilage tissue stiffening with the repression of a key protein associated with longevity. These findings enhance the understanding of mechanisms that lead to the deterioration of joints that causes osteoarthritis, according to the authors of a new study, published January 10th in Nature Communications. In the study, researchers showed that increased stiffening of the extracellular matrix -- a network of proteins and other molecules that surround and support tissues in the body -- led to a decrease in a so-called "longevity protein" called Klotho (?-Klotho) in knee cartilage brought about by epigenetic changes. This Klotho decrease then damaged the cells in healthy cartilage called chondrocytes. Conversely, exposing aged chondrocytes to a softer extracellular matrix restored the knee cartilage to a more youthful state. As stiffening of extracellular matrix is a defining feature of cartilage aging, these findings demonstrate the role Klotho plays in the formation of osteoarthritis and offers new potential treatment targets to restore cartilage health. The researchers also note that their results may be applicable to the toll that epigenetic factors caused by aging takes on other tissues throughout the body. "This research enhances our mechanistic understanding of why osteoarthritis happens in the first place, and it paves the way for the development of therapeutics to prevent these changes. Such therapeutics are important because there are currently no disease-modifying treatments for osteoarthritis; the best we can do for now is minimize pain and disability," said Fabrisia Ambrosio, PhD, MPT, inaugural director of the Atlantic Charter Discovery Center for Musculoskeletal Recovery of the Schoen Adams Research Institute at Spaulding Rehabilitation Network, and Member of the Faculty of Physical Medicine and Rehabilitation at Harvard Medical School. "Since matrix stiffening is a feature of aged tissues throughout the body, we anticipate that these findings may also have implications beyond cartilage repair for the field of aging research." Examining the root cause of irreversible cartilage damage Osteoarthritis occurs when cartilage in a joint stiffens and begins to break down which then damages the underlying bone, resulting in pain, swelling and feelings of stiffness. Osteoarthritis is the most common form of arthritis, affecting approximately 32.5 million individuals in the United States alone -- rates expected to rise with the aging population and trends in obesity. Osteoarthritis can significantly interfere with a person's ability to perform routine daily tasks; about half of adults with the condition are of working age, which impacts their ability to earn a living. There are currently no treatments to reverse this cartilage stiffening and resulting damage. Treatments such as exercise, weight loss, physical therapy, medications, injections and joint replacement surgery are aimed at reducing pain and improving mobility. Much has remained unknown about the molecular causes of this damage and how to treat it. These unknowns are especially germane to knee osteoarthritis, where no single event causes the cartilage damage, and the greatest predictive risk factor is aging. Increasingly, researchers have sought to better understand the role epigenetics, or how changes in behaviors and environment as people age alter how genes work, can impact tissues and disease processes throughout the body. Using advanced mass spectrometry technology, the researchers mapped out the trajectory of structural and protein changes in mice with knee osteoarthritis over the course of their lifetimes and according to sex. They then compared their findings to the current understanding of knee osteoarthritis in humans. The researchers found that Klotho was heavily involved in the molecular process that led to osteoarthritis. This work was an extension of previous studies showing that Klotho protects mitochondria within skeletal muscle and plays a key role in skeletal muscle regeneration following injury. As people age, their klotho levels go down, hence why it's referred to as a longevity protein. The new analysis revealed that when knee cartilage tissue became stiffer, the gene that codes for Klotho was repressed. They verified this in models of young and old chondrocyte cells responsible for cartilage formation, which were seeded in environments designed to mimic young and old tissue stiffness. Young chondrocyte cells looked old when put on a stiff surface due to the loss of Klotho, but when the researchers protected the cells from the stiffness in their environment, they observed chondrocyte health. "These results provide a compelling new paradigm that will be important for the field in terms of understanding the connection between age-related tissue stiffening and risk for osteoarthritis with aging," said Hirotaka Iijima, PhD, PT, assistant professor at Institute for Advanced Research and Graduate School of Medicine in Nagoya University. Interestingly, their analysis also revealed that incidence of osteoarthritis increased in male mice with age, while female mice showed no onset of the disease and their cartilage tissue was generally preserved. This unexpected finding differs from the response observed in people, where post-menopausal women are significantly more likely to develop severe knee osteoarthritis than men. These findings warrant further study, according to the authors, and a project is underway in Dr. Ambrosio's lab to examine the effects menopause has on knee osteoarthritis at the molecular level. Future research aims to address therapeutic gaps in age-related conditions With the latest findings, the researchers plan to study whether there are ways to intervene with the disease process that leads to osteoarthritis, such as by blocking the pathway that represses Klotho, even in the face of a stiff extracellular matrix environment. They hope their findings can be used to develop treatments for osteoarthritis and other conditions caused by aging. "We're interested in evaluating whether epigenetic regulation of Klotho and other longevity factors by the extracellular matrix may help explain functional decline of tissues throughout the system," said Dr. Ambrosio. In addition to Drs. Ambrosio and Iijima, co-authors of the study include Gabrielle Gilmer, BCE, Kai Wang, PhD, Allison C., Bean, MD, PhD, Yuchen He, Hang Lin, PhD, Wan-Yee Tang, PhD, Daniel Lamont, PhD, Chia Tai, MS, Akira Ito, PhD, PT, Jeffrey J Jones, PhD and Christopher Evans, PhD. This study was supported in part by Grant-in-Aid from the Japan Society for the Promotion of Science for Overseas Research Fellowships; research grants from the Uehara Memorial Foundation; National Institute on Aging grants R01AG052978, R01AG061005 and P2CHD086843; the National Institute of General Medical Sciences of the NIH under Award Number T32GM008208; JSPS KAKENHI Grant Number JP21H03302; Kyoto University Nano Technology Hub in "Nanotechnology Platform Project," sponsored by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; and the John and Posy Krehbiel Professorship in Orthopedics at Mayo Clinic.

Current Board Chairman Martin Edwards, M.D. to Retire in Planned Transition CAMBRIDGE, Mass. & SALISBURY, England--(BUSINESS WIRE)-- KalVista Pharmaceuticals, Inc. (NASDAQ: KALV), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of oral, small molecule protease inhibitors, today announced that the Board of Directors has appointed current member Brian J.G. Pereira, M.D., as Chairman, effective immediately. In conjunction, current Chairman Martin Edwards, M.D. has resigned from the Board in a planned transition concurrent with the Company’s annual meeting. “We are pleased that Brian has agreed to take the Chairman role at this critical time,” said Andrew Crockett, Chief Executive Officer of KalVista. “Brian’s long experience in late-stage drug development and commercialization will be particularly valuable in his new role as KalVista continues to grow into a pre-commercial company focused on advancing sebetralstat as the first oral on-demand therapy for treatment of HAE attacks. We also thank Martin, who was one of the founding investors in KalVista, for his years of loyal service and friendship to the company, and we wish him well in his future endeavors.” Dr. Pereira has been a member of the KalVista Board of Directors since 2019 and is currently President & CEO of Visterra, Inc., a subsidiary of Otsuka Pharmaceuticals focused on biologics research and clinical development of therapies for patients with immune-mediated and other hard-to-treat diseases. Dr. Pereira previously served as President & CEO of AMAG Pharmaceuticals where he raised four financing rounds at increasing valuations and built the clinical development, manufacturing, supply-chain and commercial infrastructure for Feraheme. Prior to AMAG Pharmaceuticals, he held senior roles at Tufts Medical Center, including President and CEO of a Tufts Medical Center Physician Organization and interim COO. He is an Adjunct Professor of Medicine at Tufts University School of Medicine and has authored over 200 published scientific articles. Dr. Pereira received his medical degree (MBBS) from St. John’s Medical College, MD (Medicine) and DM (Nephrology) from the Post Graduate Institute and MBA from Kellogg School of Management at Northwestern University. About KalVista Pharmaceuticals, Inc. KalVista Pharmaceuticals, Inc. is a pharmaceutical company focused on the discovery, development, and commercialization of oral, small molecule protease inhibitors for diseases with significant unmet need. KalVista has developed a proprietary portfolio of novel, small molecule plasma kallikrein inhibitors initially targeting hereditary angioedema (HAE) and diabetic macular edema (DME). KalVista is developing sebetralstat as an oral on-demand therapy for HAE attacks and is enrolling the Phase 3 KONFIDENT clinical trial. In addition, KalVista’s oral Factor XIIa inhibitor program represents a new generation of therapies that may further improve the treatment for people living with HAE. In DME, an intravitreally administered plasma kallikrein inhibitor, called KVD001, has completed a Phase 2 clinical trial. For more information about KalVista, please visit . For more information on the sebetralstat HAE on-demand Phase 3 KONFIDENT study, please visit . 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. Forward-looking statements can be identified by words such as: "anticipate," "intend," "plan," "goal," "seek," "believe," "project," "estimate," "expect," "strategy," "future," "likely," "may," "should," "will" and similar references to future periods. These statements are subject to numerous risks and uncertainties, including the potential impact of COVID-19, that could cause actual results to differ materially from what we expect. Examples of forward-looking statements include, among others, timing or outcomes of communications with the FDA, our expectations about safety and efficacy of our product candidates and timing of clinical trials and its results, our ability to commence clinical studies or complete ongoing clinical studies, including our Phase 3 KONFIDENT trial, and to obtain regulatory approvals for sebetralstat and other candidates in development, the ability of sebetralstat and other candidates in development to treat HAE or DME, and the future progress and potential success of our oral Factor XIIa program. Further information on potential risk factors that could affect our business and financial results are detailed in our filings with the Securities and Exchange Commission, including in our annual report on Form 10-K for the year ended April 30, 2022, our quarterly reports on Form 10-Q, and our other reports that we may make from time to time with the Securities and Exchange Commission. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise. View source version on businesswire.com: Contacts KalVista Pharmaceuticals, Inc. Jarrod Aldom Vice President, Corporate Communications (201) 705-0254 jarrod.aldom@kalvista.com Source: KalVista Pharmaceuticals, Inc. View this news release online at: