Recurrent respiratory tract infections

Joenja® is the first and only medicine specifically for APDS to be reimbursed within the NHS Recommended for adult and pediatric patients 12 years of age and older with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) April 23, 2025: Pharming Group N.V. (“Pharming” or “the Company”) (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) announces that the National Institute for Health and Care Excellence (NICE) has issued positive final guidance recommending Joenja® (leniolisib) for reimbursement and use within the National Health Service (NHS) in England and Wales for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. The NICE recommendation is based on the totality of the data, including the Phase III clinical trial evaluating leniolisib, an oral selective PI3Kδ inhibitor, in patients with APDS, a rare and progressive primary immunodeficiency. In the primary analysis, treatment with leniolisib led to significant improvements in immune deficiency and immune dysregulation compared to placebo. The Phase III trial demonstrated an improvement in clinical outcomes, which was maintained during longer-term treatment within the open-label extension trial. Fabrice Chouraqui, Chief Executive Officer of Pharming, said: “This positive recommendation for Joenja® from NICE is a significant milestone for patients living with APDS in England and Wales. It underscores Pharming’s commitment to work closely with regulatory and reimbursement authorities, the medical immunology community, and patient associations to bring this first targeted treatment to patients who may benefit.” Professor Sinisa Savic, Professor of Clinical Immunology at St James’s University Hospital, said: “Data from clinical trials demonstrate that leniolisib provides real benefits for patients with APDS, a rare primary immunodeficiency. APDS is a complex and progressive condition that leads to immune dysregulation and recurrent infections, significantly impacting patients' quality of life. The recommendation by NICE, which allows this targeted therapy to be prescribed on the NHS, marks an important step forward in improving treatment options for individuals with this condition.” Dr Susan Walsh, Chief Executive Officer at Immunodeficiency UK, said: “This is a hugely welcomed decision that will make a massive difference to the lives of people with APDS, and their families, by potentially allowing them to have a better quality of life. With leniolisib, we now have a targeted treatment available that addresses the fundamental cause of the immune system problems experienced in APDS. This is a huge leap forward. We are grateful to Pharming for working with NICE to make this drug available via the NHS. Together, they have shown a real commitment to providing people affected by ultra-rare, immune system conditions the treatments they need.” The final NICE recommendation aligns with the U.K. Medicines and Healthcare products Regulatory Authority (MHRA) approval and falls under NICE’s Highly Specialised Technologies (HST) pathway, which evaluates treatments for very rare and severe diseases. Leniolisib is now available for use and funded in England through the Innovative Medicines Fund, ensuring immediate patient access. In Wales, leniolisib is expected to be funded within the next three months through the NHS in specialist centers. APDS is a rare primary immunodeficiency that was first characterized in 2013. APDS is caused by variants in either one of two identified genes known as PIK3CD or PIK3R1, which are vital to the development and function of immune cells in the body. Variants of these genes lead to hyperactivity of the PI3Kδ (phosphoinositide 3-kinase delta) pathway, which causes immune cells to fail to mature and function properly, leading to immunodeficiency and dysregulation1,2,3 APDS is characterized by a variety of symptoms, including severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy.4,5 Because these symptoms can be associated with a variety of conditions, including other primary immunodeficiencies, it has been reported that people with APDS are frequently misdiagnosed and suffer a median 7-year diagnostic delay.6 As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.4-7 A definitive diagnosis can be made through genetic testing. APDS affects approximately 1 to 2 people per million worldwide. Joenja® (leniolisib) is an oral small molecule phosphoinositide 3-kinase delta (PI3Kẟ) inhibitor approved in the U.S., U.K., Australia and Israel as the first and only targeted treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. Joenja® inhibits the production of phosphatidylinositol-3-4-5-trisphosphate, which serves as an important cellular messenger and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Results from a randomized, placebo-controlled Phase III clinical trial demonstrated statistically significant improvement in the coprimary endpoints, reflecting a favorable impact on the immune dysregulation and deficiency seen in these patients, and interim open label extension data has supported the safety and tolerability of long-term leniolisib administration.8,9 Leniolisib is currently under regulatory review in the European Economic Area, Canada and several other countries for APDS, with plans to pursue regulatory approval in Japan. Leniolisib is also being evaluated in two Phase III clinical trials in children with APDS and in two Phase II clinical trials in primary immunodeficiencies (PIDs) with immune dysregulation. The safety and efficacy of leniolisib has not been established for PIDs with immune dysregulation beyond APDS. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. We are commercializing and developing a portfolio of innovative medicines, including small molecules and biologics. Pharming is headquartered in Leiden, the Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. References Lucas CL, et al. Nat Immunol. 2014;15(1):88-97. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218. Nunes-Santos C, Uzel G, Rosenzweig SD. J Allergy Clin Immunol. 2019;143(5):1676-1687. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606. Maccari ME, et al. Front Immunol. 2018;9:543. Jamee M, et al. Clin Rev Allergy Immunol. 2020 Dec;59(3):323-333. Condliffe AM, Chandra A. Front Immunol. 2018;9:338. Rao VK, et al Blood. 2023 Mar 2;141(9):971-983. Rao VK, et al. J Allergy Clin Immunol 2024;153:265-74. The content above comes from the network. if any infringement, please contact us to modify.

全文共2589字预计阅读时长7分钟“中国企业在基因编辑领域已具备与美国同行相当的竞争力，这种趋势只会持续增强。”在CRISPR MEDiCiNE 2025峰会上，参会的美国科学家马克·温伯格如是说。让温伯格有感而发的，是其眼前看到的来自中国生物技术公司辉大基因的两项最新研究结果：1）HG302（hfCas12Max治疗杜氏肌营养不良）：零严重不良反应，无剂量限制性毒性，患儿3个月内即呈现运动功能改善（北极星评估+1分，6分钟步行距离增加60米，4级爬梯时间缩短30秒）。2）全球首款RNA编辑疗法HG204（hfCas13Y治疗MECP2重复综合征）：患儿认知、运动与情绪显著改善，为这一毁灭性儿童神经发育疾病带来曙光。其中，这项针对MECP2重复综合征（一种致死性遗传病）的初步研究成果具有里程碑意义，因为这是首个在大脑内测试的CRISPR疗法！首个在大脑内测试的CRISPR疗法2024年底，医生们将一种实验性CRISPR疗法注入了一名患有MECP2重复综合征的9岁男孩大脑中。所谓MECP2重复综合征，指的是一种罕见的X染色体连锁神经发育障碍，由MECP2基因（甲基化CpG结合蛋白2基因）的额外拷贝（重复或倍增）引起。该基因位于Xq28区域，其过度表达会导致神经系统功能异常，主要影响男性（女性由于X染色体失活机制通常症状较轻）。具体到这位9岁的患者，虽其生理年龄已经达到9岁，但其智力水平相当于11个月大婴儿，临床上表现为智力障碍、运动障碍、语言发育迟缓和缺失、反复呼吸道感染等。辉大基因分享的视频显示，在治疗前，这个男孩需要有人双手搀扶才能勉强行走。他对抛球或堆叠积木等口头指令毫无反应。但四周后，他能够传递皮球；十二周后，他的步态明显改善，积木堆叠动作也更为灵巧。这项针对MECP2重复综合征（一种致死性遗传病）的初步研究成果具有里程碑意义：这不仅是首个在大脑内测试的CRISPR疗法。更值得注意的是，主导这项突破的是一家名不见经传的中国生物技术公司——辉大基因。据报道，辉大基因采用独特的Cas13Y酶技术，通过调控mRNA而非DNA来精准平衡MECP2基因表达——该基因过度表达会导致当前病症，而表达不足则引发雷特综合征。除此之外，辉大基因还在会议上公布了针对杜氏肌营养不良症（DMD）的两例CRISPR治疗初步数据。辉大基因公开资料显示，在HG302项目中，他们通过单个病毒载体将高保真Cas12（hfCas12Max）和靶向人DMD基因第51号外显子剪接供体（SD）位点的CRISPR RNA递送到肌肉中。该位点将被HG302破坏，从而允许第51号外显子跳跃，形成从第50到53号外显子的正确开放阅读框，恢复功能性肌营养不良蛋白的表达，进而改善肌肉功能。目前，虽然该疗法需要超高剂量（数万亿病毒颗粒），但已治疗的两名患儿暂时均未出现严重不良反应。首例患者治疗后6分钟步行测试距离增加55米，运动功能评估也有改善。且早在2024年初，美国FDA便已授予HG302孤儿药资格认定（ODD），用于治疗DMD。辉大基因：能否成为基因编辑领域新黑马？辉大基因此番崛起正值美国科学界面临研发经费削减、资本避险情绪升温之际。且与中国创新药目前高昂的发展势头高度一致。公开信息显示，辉大基因由杨辉、姚璇等人于2018年创立，致力于基因治疗药物的研发，长期目标是利用基因编辑技术治疗遗传病以及威胁人类健康的慢性疾病。该公司CEO陆英明（Alvin Luk）曾在拜耳、渤健等跨国药企担任高管，曾带领团队在神经、眼科和肌肉疾病领域持续突破。目前，辉大基因已累计融资1.32亿美元，正寻求2700-4000万美元C+轮融资用于渐冻症、阿尔茨海默病等新项目。外媒文章指出，与多数美国同行专注单一技术不同，辉大基因建立了包含Cas12、Cas13、碱基编辑和表观遗传编辑在内的全技术平台。“我们可以为不同疾病选择最佳工具。”陆英明表示，这正是他加入这家公司的关键原因。但就基因编辑疗法的研发而言，仍面临不少未解决的现实难题。一方面，很多基因编辑疗法的在研适应症多为罕见病，患者少，难以满足统计需求。另一方面，基因编辑疗法对DNA/RNA的编辑具有永久性，仍存在很多未知风险概率。陆英明坦言：“我们联系了至少10家医院，有的没听说过CRISPR，有的因2018年'基因编辑婴儿'事件心存顾虑。”基于重重困境，合作共赢是目前像辉大基因这样的公司最好的选择之一。采访中，陆英明透露，公司战略聚焦于技术授权或与大型药企合作。小结就在2月初，STAT News资深遗传学领域记者Jason Mast在采访了75位投资者、高管、分析师和科学家后得出一个结论：The CRISPR companies are not OK。后来，先是蓝鸟生物卖身，后又是福泰制药终止基因疗法相关合作、辉瑞停止相关管线等。一个个失败的案例似乎对这篇文章的结论做出了印证。不过，值得一提的是，从2024年CGT领域的融资事件来看，行情整体在回暖。2024年共28家聚焦细胞疗法的新锐企业获得共约12.1亿美元的早期融资，超越2023年（11.54亿美元）。而就2025年这几个月发生的事情来看，随着行业整体看好情绪上涨，或许类似辉大基因这样的公司仍有大施拳脚之地。点击预约，观看FDA近日大事件回放~参考资料：1.各公司官网2.China startup injects CRISPR therapy into the brain for the first time3.其他公开资料图片来源：AI版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn点击这里，查看更多精彩!

The first patient dosed was able to correctly identify words—such as mommy, cookies and airplane—at a conversational level without visual cues.\n Regeneron’s investigational gene therapy has been tied to notable hearing improvements in 10 of 11 children who were treated for a rare genetic condition that causes hearing loss.“You can see the efficacy very early on,” Regeneron’s senior vice president and co-head of genetic medicines, Christos Kyratsous, Ph.D., told Fierce Biotech in an interview. “We are actively talking to FDA and other agencies around the world to understand what the clinical data set [is] but also everything else that you need to put together for your package to eventually get a drug approved.”The findings come from a phase 1/2 trial, called CHORD, and build off earlier data demonstrating restored hearing for two patients who received the gene therapy. The latest data were shared Feb. 24 at the Association for Research in Otolaryngology’s 48th Annual MidWinter meeting in Orlando, Florida.Regeneron’s gene therapy, dubbed DB-OTO, is a cell-selective AAV gene therapy for children with hearing loss stemming from a mutation to the otoferlin gene. The company snapped up DB-OTO through its $109 million acquisition of Decibel Therapeutics in 2023.To date, 12 participants between the ages of 10 months and 16 years have received DB-OTO, with nine children receiving an intracochlear injection in one ear and three receiving the investigational treatment in both ears. The gene therapy is delivered via a surgical procedure that is similar to a cochlear implantation.Among 11 participants with at least one post-treatment assessment, 10 demonstrated a notable hearing improvement at various decibel levels, according to researchers. Furthermore, among five children with 24-week assessments, three experienced improvements that brought their hearing to “nearly normal” or “normal” levels.One participant has not experienced a change from baseline hearing at 24 weeks after dosing.  The updated data cut includes safety data from all 12 patients, with Regeneron finding both the surgical procedure and DB-OTO to be well tolerated.No adverse events caused by DB-OTO have occurred, according to Regeneron. Five of 12 patients experienced transient post-surgical vestibular AEs—such as uncontrollable eye movements, nausea, dizziness and vomiting—which resolved within six days of dosing.Two serious treatment-emergent AEs were reported, neither of which Regeneron believes are tied to DB-OTO.The TEAEs occurred in separate patients, with one child experiencing a grade 3 case of mastoiditis—inflammation or infection of the mastoid bone—in the cochlear implant ear, which cleared after a course of antibiotics. The patient also had a recurrent upper respiratory tract infection and chronic inflammation in both ears.A different patient experienced grade 3-level walking instability, which went away within 24 hours and was attributed to a varicella vaccine reaction.To date, 53 TEAEs were reported in 10 of 12 patients receiving DB-OTO.  When zooming in on the first patient dosed, new 72-week results show speech and development progress since receiving the therapy at 10 months of age. The child was able to correctly identify words—such as mommy, cookies and airplane—at a conversational level without visual cues, as measured by formal speech perception assessments.“She, at her baseline, could not hear at all,” Jonathon Whitton, Ph.D., Regeneron’s vice president and auditory global program head, told Fierce. “She received DB-OTO in one ear, and within a few weeks, she started responding to sounds.”Over the course of six months, the patient became able to hear certain whispers, according to Whitton, who said a 48-week assessment showed maintenance of “very good hearing sensitivity.”“We\'re entering a new era here,” Whitton, a pediatric audiologist, explained. “Previously, we usually didn\'t know what was causing the hearing loss when people came to the clinic. Now we can start to understand that.” Otoferlin-related hearing loss is an ultrarare condition that leads to a lack of a functional protein involved in the communication between the sensory cells of the inner ear and the auditory nerve. DB-OTO is designed to provide a payload of cDNA that expresses the protein in hair cells that are missing it, helping restore hearing.The FDA has recognized the gene therapy’s promise, granting DB-OTO orphan drug, rare pediatric disease, fast track and regenerative medicine advanced therapy designations.“This is the beginning of identifying ways to actually provide sort of elegant solutions to these individuals to potentially allow them to hear, and so I think that this is quite an exciting moment for the entire field,” Whitton said.While Regeneron isn’t sharing a specific time for a readout of the second part of the trial—an expansion in which participants receive simultaneous intracochlear injections of DB-OTO in both ears—Whitton said the company is in talks with regulatory agencies about whether CHORD could serve as a pivotal study.   When asked how DB-OTO compares to Eli Lilly’s investigational gene therapy being assessed in a phase 1/2 trial for OTOF-mediated hearing loss, Regeneron\'s Whitton detailed differences in the delivery process.At the start of 2024, Eli Lilly shared data that tied its investigational therapy, known as AK-OTOF, to restored hearing in one child who had experienced hearing loss since birth. The Akouos delivery device, which is being developed in parallel for intracochlear administration, is made to deliver AK-OTOF throughout the cochlea.“There\'s a big difference in how the therapy is delivered to the ear,” Whitton said about AK-OTOF compared to DB-OTO. “They both involve a surgical delivery of the gene therapy directly to the inner ear. The surgical approach that they\'re taking is to go through the ear canal, basically, and so this is at least for the very young children in the study—this is a new procedure to do.”For its part, Regeneron decided to use the same surgical approach that is already used for children with cochlear implants so the company could enroll very young participants.“Intervention with congenital deafness is urgent, so we try to provide intervention as early as possible to maximize outcomes in these patients,” Whitton explained.While the two gene therapies are also molecularly different, Kyratsous said it’s still too soon to see how those differences will play out in the clinic. Even though the gene therapy field has seen various setbacks lately, Kyratsous said Regeneron remains dedicated to its therapies.“We truly believe in the power of these technologies—we believe in what they can do for patients,” he explained. “So, we are trying to adopt the long-term view, as we do for most of the technologies we are working on.”“This is just the beginning,” Whitton added. “We\'re actively working on additional targets to try to address other types of childhood hearing loss. We\'re also thinking about age-related hearing loss, noise-induced hearing loss—these are big public health concerns, and we want to help.”