Bone Resorption

Nes-Ziona, Israel, April 29, 2024 (GLOBE NEWSWIRE) -- Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the “Company” or “Enlivex”), a clinical-stage macrophage reprogramming immunotherapy company, today issued the following update to shareholders from Chief Executive Officer, Oren Hershkovitz. Dear fellow shareholders, I have been serving as the Chief Executive Officer of Enlivex for the last four and a half years. During that period, we have been working diligently to develop our drug product candidate, AllocetraTM, as a first-in-kind modulator of a spectrum of negative immune reactions from low, chronic, debilitating inflammation to high-grade, life-threatening cytokine storms. To-date, we have completed numerous pre-clinical studies across multiple disease models, infused AllocetraTM in more than 100 patients and witnessed the encouraging safety profile and potential effect of AllocetraTM. We saw a patient with COVID-19 in critical condition saying goodbye to his loved ones via a video call, as the consensus in the ICU was that he would not last through the night, and that patient received an infusion of AllocetraTM and within hours had a complete reversal of his condition, resulting in his release from the hospital several days later. We also saw a patient with an ultra-rare condition, vanishing bone disease in the shoulder joint. In this case, not only was the joint cartilage completely eroded, but the shoulder bone itself had completely disintegrated. After four years of escalation and nine months of continued hospitalization, the patient received a compassionate treatment of injections of matched AllocetraTM to the shoulder joint. We witnessed the outstanding recovery of the inflammatory condition resulting in hospital discharge after five weeks and no re-hospitalization in the following three years. We have witnessed, first-hand, the potential effect of AllocetraTM as a life-changer, and all of us at Enlivex are committed to translate that first-hand experience into a global one. On April 11, 2024, we released the top-line data from a placebo-controlled, randomized, dose-finding, multi-country, multi-center Phase II trial, which evaluated frozen-formulation Allocetra™ in addition to standard of care in patients with sepsis associated with pneumonia, biliary, urinary tract, or peritoneal infections. The trial randomization resulted in a higher risk profile of the AllocetraTM group as compared to the control group, making some of the data challenging to interpret. In small clinical trials, these things happen from time to time. While we are not happy that this occurred, we are pleased that AllocetraTM demonstrated (i) a potential indication of effect not only stand-alone but also as compared to the control group in high-risk urinary tract infection (UTI) sepsis patients, and (ii) a favorable safety and tolerability profile. We believe that these results have increased the likelihood of AllocetraTM to eventually change the lives of millions of people around the world, whether in sepsis or osteoarthritis. We believe that each of these two market segments represents a potential multi-billion dollar commercial opportunity for Enlivex. The Phase II sepsis study also demonstrated the giant leap we made in transforming AllocetraTM into a completely off-the-shelf drug that can be easily shipped and stored in clinical sites globally and easily administered by physicians, including in complex environments, such as in intensive care units. As we continue to analyze the data from the sepsis study, we will also assess whether collaborators may seek to work with us on a larger sepsis study, which could be in high-risk UTI sepsis patients or across multiple patient populations. Some asked us recently what the link is between a potential indication of effect in sepsis and the treatment of osteoarthritis. We note that the basic mechanism of action of AllocetraTM is to positively modulate macrophages that are at the core of the particular inflammatory cause. We chose osteoarthritis after careful review of the scientific literature that showed high correlation between inflamed macrophages and osteoarthritis severity and clinical manifestation. Therefore, the potential indication of effect and the favorable safety and tolerability profile of AllocetraTM as demonstrated in the sepsis trial are very important, in our opinion, and we expect that these increase the probability of success in osteoarthritis. We announced earlier this week that the first two patients had been dosed in the Company’s multi-country, randomized, controlled Phase I/II trial evaluating AllocetraTM in up to 160 patients with moderate to severe knee osteoarthritis. We anticipate two significant milestones relating to osteoarthritis, the first of which being results from the ongoing clinical trial of AllocetraTM in patients with end-stage knee osteoarthritis, which we expect in Q3 2024. These patients have been suffering from knee osteoarthritis for many years, and, following various treatments, eventually have reached the stage requiring knee replacement surgery. We are offering them, as a last resort, a single injection of AllocetraTM to the knee. We started with the first patient approximately seven months ago, and we are continuing to enroll patients. Our second milestone, which we expect in Q3 2025, is top-line results from the Company’s multi-country, randomized, controlled Phase I/II trial evaluating AllocetraTM in up to 160 patients with moderate to severe knee osteoarthritis. We expect that our existing cash resources will provide adequate coverage, plus a safety margin, for obtaining the data from these two important trials. I am privileged to lead such an enthusiastic and dedicated team at Enlivex who accomplished and executed so much in the past four and a half years The team at Enlivex is genuinely excited about the prospect of AllocetraTM to be a game changer in the world of medicine. We appreciate your continued support. It takes time, courage and tenacity to change the world, and we hope to do just that. Sincerely, Oren Hershkovits, Ph.D., CEO ABOUT SEPSIS Sepsis is a life-threatening disease with no therapies approved by the U.S. Food and Drug Administration (“FDA”) and a high unmet medical need. According to the U.S. Centers for Disease Control and Prevention, each year, at least 1.7 million adults in the United States develop sepsis, with approximately 270,000 dying of the disease. About UTI Urinary tract infection is the second most common infectious disease affecting more than 150 million people globally annually. Up to 31% of sepsis cases start as UTIs, representing up to 9.8 million cases annually worldwide, leading to as many as 1.6 million deaths.1 ABOUT KNEE OSTEOARTHRITIS2 Osteoarthritis is by far the most common form of arthritis, affecting more than 32.5 million Americans and more than 300 million individuals worldwide. About half of knees with ACL injuries develop osteoarthritis within 5 to 15 years. 78 million Americans are projected to have osteoarthritis by the year 2040. Symptomatic knee osteoarthritis is particularly prevalent and disabling, with 40% of men and 47% of women developing knee osteoarthritis in their lifetimes. Osteoarthritis accounts for over one million hospitalizations annually in the United States, primarily for total joint replacement. The burden of osteoarthritis is enormous, and the need for treatments that reduce pain and attendant disability for persons with osteoarthritis is critical. There are currently no medications approved by either the FDA or the European Medicines Agency that have been demonstrated to arrest, slow or reverse progression of structural damage in the joint. ABOUT ALLOCETRA™ Allocetra™ is being developed as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, Allocetra™ has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as "unmet medical needs", as a stand-alone therapy or in combination with leading therapeutic agents. ABOUT ENLIVEX Enlivex is a clinical stage macrophage reprogramming immunotherapy company developing Allocetra™, a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Resetting non-homeostatic macrophages into their homeostatic state is critical for immune system rebalancing and resolution of life-threatening and life-debilitating conditions. For more information, visit http://www.enlivex.com. Safe Harbor Statement: This press release contains forward-looking statements, which may be identified by words such as “expects,” “plans,” “projects,” “will,” “may,” “anticipates,” “believes,” “should,” “would”, “could,” “intends,” “estimates,” “suggests,” “has the potential to” and other words of similar meaning, including statements regarding expected cash balances, market opportunities for the results of current clinical studies and preclinical experiments, the effectiveness of, and market opportunities for, ALLOCETRATM programs. All such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that forward-looking statements involve risks and uncertainties that may affect Enlivex’s business and prospects, including the risks that Enlivex may not succeed in generating any revenues or developing any commercial products; that the products in development may fail, may not achieve the expected results or effectiveness and/or may not generate data that would support the approval or marketing of these products for the indications being studied or for other indications; that ongoing studies may not continue to show substantial or any activity; and other risks and uncertainties that may cause results to differ materially from those set forth in the forward-looking statements. The results of clinical trials in humans may produce results that differ significantly from the results of clinical and other trials in animals. The results of early-stage trials may differ significantly from the results of more developed, later-stage trials. The development of any products using the ALLOCETRATM product line could also be affected by a number of other factors, including unexpected safety, efficacy or manufacturing issues, additional time requirements for data analyses and decision making, the impact of pharmaceutical industry regulation, the impact of competitive products and pricing and the impact of patents and other proprietary rights held by competitors and other third parties. In addition to the risk factors described above, investors should consider the economic, competitive, governmental, technological and other factors discussed in Enlivex’s filings with the Securities and Exchange Commission, including in the Company’s most recent Annual Report on Form 20-F filed with the Securities and Exchange Commission. The forward-looking statements contained in this press release speak only as of the date the statements were made, and we do not undertake any obligation to update forward-looking statements, except as required under applicable law. ENLIVEX CONTACT Shachar Shlosberger, CFO Enlivex Therapeutics, Ltd. shachar@enlivexpharm.com INVESTOR RELATIONS CONTACT Dave Gentry, CEO RedChip Companies Inc. 1-407-644-4256 ENLV@redchip.com 1 Management of Urosepsis in 2018, Bonkat et. al., European Urology Focus Volume 5, Issue 1, (2019) 2 Source: The Arthritis Foundation; Disease modification in osteoarthritis; pathways to drug approval, Katz et. Al., Osteoarthritis and Cartilage Open (2) (2020)

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 骨转移是乳腺癌患者发病率和死亡率的重要因素。之前已经证明，来自LSD1敲低(KD)乳腺癌细胞的外泌体miRNA抑制成骨细胞分化并促进破骨细胞分化。然而，LSD1如何调节外泌体miRNAs以及miRNAs是否通过形成转移前生态位促进骨转移仍不清楚。 3月6日，吉林大学胡鑫研究团队在期刊《Cell Death Discovery》上发表了题为“LSD1 modulates the bone metastasis of breast cancer cells through hnRNPA2B1-mediated sorting of exosomal miRNAs”的研究论文，本研究中， 体内实验表明，来自LSD1 KD乳腺癌细胞的外泌体显著促进骨转移。 研究表明，LSD1在调节miRNA的外泌体分选中起着至关重要的作用。 https://www.nature.com/articles/s41420-024-01897-5 研究背景 01 转移约占癌症相关死亡的90%，而骨是转移细胞最常见的目标之一。转移病灶的生长破坏组织稳态，从而促进癌细胞的存活和增殖。骨转移患者的骨骼相关事件包括高钙血症、骨溶解、骨折、脊髓压迫和骨髓发育不全，严重影响患者的生活质量。此外，骨转移患者的预期寿命和预后较差。乳腺癌是女性癌症相关死亡的主要原因，而乳腺癌的骨转移是无法治愈的。 外泌体是细胞分泌的细胞膜外囊泡，直径一般在30 ~ 150nm之间。它们通过包裹的生物分子如蛋白质、脂质、RNA和代谢物介导细胞间通讯。最近的证据表明，乳腺癌来源的外泌体mirna有助于骨转移。来自MDA-MB-231和SCP28外泌体的miR-21在乳腺癌骨转移患者的血清外泌体中被发现高表达，从而改变程序性细胞死亡4 (PDCD4)的蛋白水平，从而促进转移前生态位的产生，促进破骨细胞分化，增强骨转移。此外，从雌激素受体(ER)阳性乳腺癌细胞中获得的外泌体被观察到将miR-19a转移到破骨细胞前体，通过降低磷酸酶和紧张素同源物(PTEN)的表达促进破骨细胞分化，从而激活核因子-κB (NF-κB)和蛋白激酶B (AKT)信号通路。 研究进展 02 为研究LSD1 KD乳腺癌细胞释放的外泌体对骨结构的影响，研究人员采用micro-CT对小鼠胫骨进行扫描。所得图像三维重建显示，LSD1 KD组小鼠胫骨骨小梁发生明显损伤。根据micro-CT结果计算BMD, BV/TV, Tb.N和Tb.Sp。研究人员发现BMD、BV/TV、Tb.N减少，而Tb.Sp在LSD1 KD组中显著升高，表明LSD1 KD外泌体促进乳腺癌骨转移，导致骨丢失。此外，LSD1 KD组小鼠胫骨trap染色细胞明显多于控制组和LSD1 挽救组。相反，在LSD1 KD小鼠胫骨中，OCN的免疫组化染色减少。 总之，这些结果表明，LSD1 KD乳腺癌细胞来源的外泌体通过破坏胫骨小梁促进乳腺癌细胞的骨转移，并通过增加破骨细胞数量和减少成骨细胞数量诱导骨溶解。 LSD1敲低(KD)乳腺癌细胞外泌体诱导骨溶解 研究结论 03 近年来的研究表明，外泌体参与了肿瘤的发生和发展。LSD1 KD乳腺癌细胞来源的外泌体促进骨溶解，从而重塑骨转移微环境。这提示靶向肿瘤相关外泌体miRNA可能是抑制肿瘤转移的一种可行策略。已有研究表明，抑制外泌体释放可抑制肿瘤中外泌体引起的增殖、转移和化疗耐药。 因此，阻断靶细胞对肿瘤相关外泌体的摄取有望成为抑制肿瘤发生发展的策略。 参考资料： https://www.nature.com/articles/s41420-024-01897-5 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 北京｜9月20日-21日 ▶第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

The FDA is warning that Equinoxe devices sold until August 2021 were “packaged in defective bags” that omitted a layer of material that’s meant to protect plastic components of the implants from excessive air exposure that may lead to oxidation. The FDA this week published a safety notice alerting patients and healthcare providers to possible risks linked to certain shoulder joint replacement implants. The Equinoxe Shoulder System, which is sold by Exactech, is used to replace shoulder joints that are causing pain or have lost normal structure and function due to various forms of arthritis or injuries to the area. The implants have been sold in the U.S. since 2004. In its notice, the FDA warns that Equinoxe devices sold until August 2021 were “packaged in defective bags” that omitted a layer of material that’s meant to protect plastic components of the implants from excessive exposure to oxygen that may lead to oxidation. If oxidation did occur while the devices were in their packaging, the plastic pieces may have started to degrade, speeding up the expected timeline for device wear and failure and potentially causing the components to crack or fracture while implanted. In those instances, patients may need to undergo another surgery to repair or replace the damaged device. Because of those risks, the FDA is recommending that healthcare providers stop implanting any Equinoxe systems that were packaged in the defective bags and to monitor any patients who have already been implanted with devices sold between 2004 and 2021. Though the agency doesn’t recommend that currently well-functioning systems be preemptively removed or replaced, it is advising doctors to consider conducting revision surgery on patients who are experiencing worsening pain or joint weakness that may be linked to the implant. The FDA noted in the safety alert that Exactech has “declined to initiate a voluntary recall” for the affected Equinoxe shoulder implants, but added that it is still working with the company to review information about the devices’ safety and effectiveness and to evaluate the risks of all of its implants that may have been distributed in defective packaging—since the same issue has been identified in many of Exactech’s other joint replacement devices, including those for the knee, ankle and hip, leading to voluntary recalls in 2021 and 2022. The regulator also said it’s working with its international counterparts to dig into registry data concerning the affected shoulder implants to “explore potential causes of the higher failure rates.” Exactech, meanwhile, defended its decision to hold off on a formal recall of the Equinoxe implants in a “general advisory notice” published on its website. In it, the company described how revision surgeries are typically rarer among shoulder replacements than those for the hips, knees and ankles, since shoulders generally bear far less weight than the other joints, therefore putting less stress on the implants. Exactech also cited registry data collected in the U.K. and Australia showing that, across both countries and both anatomic total shoulder (aTSA) and reverse total shoulder (rTSA) cases, revision rates for the Equinoxe devices were largely consistent with all-cause revision rates for all shoulder joint replacement systems in both countries—except in aTSA cases in Australia, in which the Equinoxe devices were associated with a heightened risk of revision after 1.5 years. Additional post-market study data collected by Exactech claim that among more than 4,000 aTSA Equinoxe patients in the U.S. and Europe, only 18 experienced “some notation of polyethylene wear, osteolysis, or massive bone loss” between late 2004 and last July, adding up to an occurrence rate of 0.41%. Among more than 11,000 rTSA patients, meanwhile, the rate fell to 0.07%, with just eight reported occurrences. The company also tapped an independent lab to perform oxidation testing of the defective bags. The lab concluded that, after the devices’ listed five-year shelf life, those packaged in the bags registered a maximum oxidation index of 0.7, which is below the 1.0 threshold linked to negative mechanical impacts, per Exactech.