Condoliase(Seikagaku Corp.)

PARSIPPANY, N.J.--( BUSINESS WIRE )--Ferring Pharmaceuticals and its clinical development partner, Seikagaku Corporation (Seikagaku), today announced the presentation of data from two Phase 3 trials evaluating the efficacy and safety of SI-6603 (generic name: condoliase), an investigational product being studied for the treatment of radicular leg pain associated with lumbar disc herniation (LDH). The podium presentation at the North American Spine Society’s (NASS) Annual Meeting included results from one study conducted in the U.S. and one in Japan. In addition, The Spine Journal has published the results of the pivotal U.S. Phase 3 study. NASS Presentation In the double-blind, sham or placebo controlled Phase 3 studies, patients with LDH were randomized to receive either a single intradiscal injection of SI-6603 1.25 Units or control (sham injection for U.S. study; placebo injection for Japanese study) followed by 52 weeks of observation. The modified intention-to-treat population in the U.S. study included 341 participants (SI-6603 n=169; sham n=172), and the study population in Japan included 163 participants (SI-6603 n=82; placebo n=81). The studies met their primary endpoint, showing significantly greater change from baseline (CFB) in worst leg pain at Week 13 compared to sham (U.S.) / placebo (Japan) (least squares mean [LSM] difference: -7.5 [p=0.0263] for the U.S. study and -15.2 [p=0.001] for the Japan study). “ Treatment for radicular leg pain associated with lumbar disc herniation is currently limited to conservative pain management and physical therapy or surgery. The data from these two Phase 3 studies further support the potential of SI-6603 as a therapeutic option for the millions of Americans suffering from the debilitating impact of this condition, ” said Kee Kim, MD, University of California, Davis. The most common treatment-emergent adverse events (TEAEs) in the U.S. trial were spinal magnetic resonance imaging abnormalities (SI-6603 28.1%; sham 9.2%) and back pain (SI-6603 19.2%; sham 12.6%). In the Japan trial, the most common TEAEs were back pain (SI-6603 36.6%; placebo 33.3%) and leg pain (SI-6603 25.6%; placebo 35.8%). There were no treatment-related serious adverse events (SAEs) with SI-6603 in the U.S. study, and in the Japan study, one SAE (back pain) was considered potentially related to SI-6603. About the Phase 3 Trial in the U.S. In this randomized double-blind, sham-controlled, parallel Phase 3 study — known as the Discovery 6603 clinical trial (NCT03607838) — participants were randomized 1:1 to receive either SI-6603 (1.25 U) or sham injection followed by 52 weeks of observation. The primary endpoint was defined as the CFB to Week 13 in worst leg pain during the past 24 hours averaged over the previous seven days, as assessed by Visual Analogue Scale, a pain rating score from 0 – 100 with a higher score indicating greater pain intensity. Key secondary endpoints included the CFB in average worst leg pain at 52 weeks, percentage of participants with negative straight leg raise test, and 50% responder rates for worst leg pain and Oswestry Disability Index (ODI). Since the key secondary endpoint of change in average worst leg pain at Week 52 was not significant, the serial gatekeeping testing algorithm dictated that there were no significant group differences for Week 13 herniation volume or ODI score regardless of their p-values. Endpoints were assessed using a mixed model for repeated measures (MMRM) analysis of the modified intention-to-treat population (mITT). The trial included U.S. participants ages 30 to 70 years old who had contained posterolateral LDH with the chief complaint being unilateral radiculopathy/radicular leg pain and inadequate improvement in pain despite more than six weeks of conservative treatment. Among 352 randomized participants, 341 constituted the mITT population (SI-6603 n=169; sham injections n=172). About the Phase 3 Trial in Japan In this randomized, double-blind, placebo-controlled study, participants were randomized 1:1 to receive either a single injection of SI-6603 (1.25U) or placebo injection, followed by 52 weeks of observation. The primary endpoint was the CFB to Week 13 in average worst leg pain during the past 24 hours over the previous seven days, as assessed by Visual Analogue Scale, a pain rating score from 0 – 100 with a higher score indicating greater pain intensity. Secondary endpoints included CFB up to Week 52 in average worst leg pain, herniation volume and ODI score. Endpoints were assessed using an analysis of covariance model. About Lumbar Disc Herniation About 9 million adults in the U.S. suffer from lumbar disc herniation each year. A disc herniation is a displacement of the gel-like inner core of the intervertebral disc, called the nucleus pulposus, through its external membrane (annulus fibrosus) due to wear and tear, aging or sudden injury. As a result of this displacement, the disc presses on the spinal nerve, often producing pain. 1,2 About SI-6603 SI-6603, which contains condoliase as its active pharmaceutical ingredient, is an investigational product being studied for the treatment of radicular leg pain associated with lumbar disc herniation via a single, direct intradiscal injection. SI-6603 (condoliase) is designed to reduce nerve root compression and thereby the radicular leg pain. SI-6603 was developed by Seikagaku. Marketing approval for SI-6603 in Japan was obtained from the Japanese Ministry of Health, Labour and Welfare in March 2018 and SI-6603 has been marketed in Japan only as HERNICORE ® 1.25 units for intradiscal injection through Seikagaku's Japanese sales partner Kaken Pharmaceutical Co., Ltd. (Tokyo, Japan) since August 1, 2018. 3 Alliance with Seikagaku Seikagaku and Ferring entered into a license agreement for SI-6603 in August 2016. Ferring plans to commercialize the product in the United States upon FDA approval and has received further rights to develop, register and commercialize SI-6603 worldwide, excluding Japan. About Ferring Pharmaceuticals Ferring Pharmaceuticals is a privately-owned, research-driven, specialty biopharmaceutical group committed to building families and helping people live better lives. In the United States, Ferring is a leader in reproductive medicine and maternal health, and in areas of gastroenterology and orthopaedics. We are at the forefront of innovation in microbiome-based therapeutics and uro-oncology intravesical gene therapy. Our company was founded in 1950 and is headquartered in Saint-Prex, Switzerland. Ferring employs more than 7,000 people worldwide and markets its medicines in over 100 countries. Ferring USA is based in Parsippany, New Jersey, and employs more than 900 employees. For more information, please visit www.ferringusa.com , call 1-888-FERRING (1-888-337-7464), or connect with us on LinkedIn and X (Twitter) . References: Vialle LR, Vialle EN, Suárez Henao JE, Giraldo G. Lumbar Disc Herniation. Rev Bras Ortop . 2015 Nov 16;45(1):17-22. doi: 10.1016/S2255-4971(15)30211-1. PMID: 27019834; PMCID: PMC4799068. Herniated Disk in the Lower Back. OrthoInfo. American Academy of Orthopaedic Surgeons. Available at: https://orthoinfo.aaos.org/en/diseases–conditions/herniated-disk-in-the-lower-back/ . Accessed May 23, 2023. Press Release. Seikagaku and Kaken Announce the Launch of HERNICORE ® 1.25 Units for Intradiscal Injection in Japan. July 31,2018. Available at: https://www.seikagaku.co.jp/en/news/news-6617037418084939174/main/0/link/20180731-e.pdf . Accessed May 24, 2023.

*仅供医学专业人士阅读参考 大脑是人体的指挥中心，这不仅包括动作、思考，也包括各种代谢机能。 下丘脑弓状核（ARC）就是对调节代谢至关重要的一个大脑区域，它负责感知胰岛素水平、调节食物摄入、控制燃烧脂肪和消耗能量等相关生理进程。 在肥胖和2型糖尿病等代谢性疾病中，ARC会出现显著的胰岛素抵抗，此时我们就容易吃得更多、积累脂肪、出现代谢健康问题。 为什么ARC神经元会变得对胰岛素不敏感呢？ 今日，墨尔本大学科研团队在《自然》杂志发文，研究者们发现，在代谢性疾病状态下，ARC神经元周围的神经元周围基质网络（PNN）会出现异常的纤维化现象，浆糊一样在神经元外形成一道物理屏障，隔绝胰岛素与神经元的相互作用。 好家伙，原来我脑子里是真有浆糊。 使用相应药物来溶解这滩浆糊，就能有效改善ARC的胰岛素敏感性，帮小鼠减轻体重、控好血糖。 论文题图 本质上来说，这滩浆糊就是细胞外基质（ECM）。细胞外基质是多糖、蛋白等大分子组成的细胞外/间复杂的网架结构，对细胞功能有重要作用。细胞外基质的过度沉积就是我们所说的纤维化。 在胰岛素抵抗中，也可以观察到外周组织中的细胞外基质纤维化，这会损害胰岛素信号传导。虽然传统上认为，纤维化主要发生在外周组织中，不过近几年的研究在急性脑损伤和几种神经系统疾病中也观察到了大脑内的细胞外基质纤维化现象。 在大脑中，细胞外基质又有了新的名字。有研究发现，在ARC中表达AgRP的神经元周围，存在一种独特的细胞外基质亚型，也就是神经元周围基质网络（PNN）。AgRP神经元在饥饿期间高度活跃，我一说它的外号饥饿神经元，你们肯定有印象。 PNN与AgRP神经元的功能高度相关，因此研究者认为，或许是PNN的纤维化现象，干扰了AgRP神经元功能，加剧了代谢性疾病调控的恶性循环。 为了验证这一点，研究者在高脂高糖饮食（HFHS）喂养的小鼠中进行了实验。饲喂HFHS诱导小鼠肥胖（DIO），12周后，研究者观察到小鼠ARC中PNN组织染色的面积和强度显著增加，这一过程的发生与小鼠的代谢病关键病生理特征发展是同步的。 伴随饮食诱导的肥胖，小鼠PNN显著扩增 分析PNN成分可见，其中的硫酸软骨素糖胺聚糖（CS-GAG）丰度显著增加。看这几个字儿眼熟吧，其实神经细胞外基质的组成和软骨真也差不多啊。 从实验数据来看，在DIO小鼠中，PNN的周转率显著降低了，PNN每天降解速率约为0.1%，而正常小鼠中为2.6%。 DIO小鼠的PNN降解速度显著降低 PNN的纤维化对AgRP神经元功能造成了显著的影响。 研究者追踪了DIO小鼠体内胰岛素的转运，发现在纤维化PNN这滩浆糊的“保护”下，胰岛素很难进入ARC，神经元中胰岛素诱导的AKT磷酸化现象显著减弱。 当使用软骨素酶ABC（chABC）有目的地注射到脑内、分解ARC PNN，ARC中的胰岛素信号就恢复正常了。 不仅如此，用chABC分解ARC PNN后，DIO小鼠摄食减少、热量消耗和耗氧量增加，小鼠体重显著减轻了。 可见DIO小鼠分解PNN后减重、脂肪组织产热增加 研究者还尝试了体重针对CS-GAG的小分子酶抑制剂fluorosamine，注射到小鼠脑内能够显著减轻ARC神经纤维化，并促进小鼠耗能、抑制食物摄入、减重、控糖。 经鼻腔递送fluorosamine的生物素偶联物，可以在ARC中观察到药物累积，并实现了类似于脑内注射的代谢改善效果。 研究者认为，针对PNN的疗法相较直接靶向神经元应当是更为安全的。 不过与目前其他已知的疾病驱动因素相比，研究者还不能确定PNN纤维化到底影响占比多大，这将在后续的研究中解决。 考虑到没有非侵入性的方法来研究下丘脑，研究者认为现在还很难确认人类中是否也存在着伴随代谢病的PNN纤维化现象。 奇点糕近期推出了《2024ASCO年会深度盘点》课程，为大家系统盘点了2024ASCO年会上实体瘤领域的重磅进展，让您在100分钟内迅速深入把握前沿。长按识别下图中的二维码即可购买，购买后您可以在「奇点网小程序」收听，或下载奇点网「医学奇点」苹果客户端收听。如果遇到任何技术问题大家可以戳我们下图中的客服小伙伴来解决~~ 参考资料： [1]https://www.nature.com/articles/s41586-024-07922-y [2]https://www.nature.com/articles/d41586-024-03025-w 本文作者丨代丝雨