Bimagrumab

Phase 2 EMBRAZE proof-of-concept trial designed to assess apitegromab's ability to safely preserve lean muscle mass in individuals on GLP-1 receptor agonist therapy for obesity New preclinical head-to-head comparison shows that SRK-439 is more potent than an anti-ActRII antibody in maintaining lean mass in diet-induced obesity (DIO) mice; lean mass loss with SRK-439, 1mg/kg dose was equivalent to anti-ActRII antibody, 20mg/kg dose Company hosting Investor Event today in New York City focusing on its selective latent myostatin inhibition programs in Spinal Muscular Atrophy and obesity with presentations from executive leadership and key experts CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Scholar Rock (NASDAQ: SRRK), a late-stage biopharmaceutical company focused on advancing innovative treatments for spinal muscular atrophy (SMA), cardiometabolic disorders, and other serious diseases where protein growth factors play a fundamental role, today announced the initiation of the Phase 2 EMBRAZE proof-of-concept trial, designed to assess the safety and efficacy of apitegromab, a highly selective myostatin inhibitor, to preserve lean muscle mass in individuals living with obesity and on background therapy of a GLP-1 receptor agonist (GLP-1 RA). The results from this trial will inform the development of SRK-439, a novel investigational selective myostatin inhibitor optimized for the treatment of cardiometabolic disorders, including obesity. The Company also announced new preclinical data from a head-to-head comparison of SRK-439 and an anti-activin receptor II (anti-ActRII) antibody, which demonstrate SRK-439’s potential as best in class in preserving lean mass in patients on GLP-1 RAs. This data will be presented by Mo Qatanani, Ph.D., Chief Scientific Officer, at Scholar Rock’s Investor Event, which begins today at 8:30 a.m. ET and is being held in New York City. “We are thrilled to have initiated the EMBRAZE clinical trial ahead of schedule and to share new data from our SRK-439 program, which we believe further support our hypothesis that selective latent myostatin inhibition has advantages over less selective approaches to safely and effectively maintain lean muscle mass,” said Jay Backstrom, M.D., MPH, President and Chief Executive Officer at Scholar Rock. “Selectivity is key in mitigating potential safety concerns for this patient population and we look forward to sharing additional preclinical data at the American Diabetes Association 84th Scientific Sessions in June to support the best-in-class potential of SRK-439.” New SRK-439 Data For the head-to-head preclinical research study, the Company generated and tested an anti-ActRII antibody (a murine equivalent of bimagrumab), along with a murine equivalent of SRK-439 in a weight-stable diet induced obesity (DIO) mouse model. Mice were given either semaglutide (0.04mg/kg, daily) with an IgG control antibody (weekly, 20mg/kg) or semaglutide (0.04mg/kg, daily) in combination with weekly injections of either SRK-439 (0.3-10mg/kg) or of the anti-ActRII antibody (0.3-20mg/kg). Quantitative nuclear magnetic resonance (qNMR) was used to analyze change in lean mass after four weeks of treatment. Lean mass differences were significant in all doses of SRK-439 tested, supporting the hypothesis that SRK-439 could be an important therapy to aid in lean mass preservation and is suitable for subcutaneous dosing in a population of adults with obesity. SRK-439 attenuated the GLP-1 RA-driven lean mass loss in combination with semaglutide at a dose as low as 0.3 mg/kg (8.3% lean mass loss from baseline). Maximal effects observed at all doses over 1 mg/kg (4.2% lean mass loss from baseline at 10mg/kg), as compared to an IgG control + semaglutide (14.1% lean mass loss from baseline). Superiority to anti-ActRII antibody was shown in all equivalent doses tested: 3 mg/kg: -4.7% SRK-439 vs. -12.0% for anti-ActRII 1 mg/kg: -5.0% SRK-439 vs. -12.6% for anti-ActRII 0.3 mg/kg: -8.3% SRK-439 vs. -15.4% for anti-ActRII Equivalent lean mass preservation was seen at the highest dose tested for both drugs; 10 mg/kg SRK-439 (-4.2%) and 20 mg/kg anti-ActRII (-4.3%). “The data from this head-to-head comparison show that selectively inhibiting myostatin alone is sufficient to preserve lean mass on a background of GLP-1 RA, in preclinical models. Combined with the positive data observed at low doses of SRK-439, we believe that our selective myostatin approach is the right potential solution to preserve lean muscle mass while avoiding the potential off-target effects observed in less selective programs for this indication. We view this as strong evidence that SRK-439 could have a more favorable benefit/risk profile,” said Mo Qatanani, Ph.D., Chief Scientific Officer at Scholar Rock. Phase 2 EMBRAZE Trial Design Scholar Rock announced in January that the U.S. Food and Drug Administration cleared the Company’s Investigational New Drug (IND) application for EMBRAZE, a randomized, double-blind, placebo-controlled, Phase 2 proof-of-concept trial evaluating the efficacy, safety and pharmacokinetics of apitegromab in adults with a body mass index (BMI) of >27 (overweight) or a BMI of >30 (obese) and taking a GLP-1 RA (tirzepatide or semaglutide). The target enrollment of EMBRAZE is 100 subjects aged 18-65 who are overweight or obese without diabetes. As part of the study design, the treatment period is 24 weeks, and all subjects will receive a GLP-1 RA. In addition, all subjects will be randomized 1:1 to receive either apitegromab or placebo by intravenous (IV) infusion every four weeks during the 24-week treatment period. The primary endpoint is change from baseline at Week 24 in lean mass assessed by dual-energy X-ray absorptiometry. Secondary endpoints include additional weight loss measures, safety and tolerability, and pharmacokinetic outcomes. Exploratory endpoints at Weeks 24 and 32 include cardiometabolic parameters (e.g. HbA1c), body composition, and physical function. Primary data from EMBRAZE are expected in mid-2025 and will inform Scholar Rock’s development of SRK-439 towards an anticipated IND filing in 2025. The presentation from Scholar Rock’s Investor Day will be available in the Investors and Media section of Scholar Rock’s website. Live webcast of the event may be accessed by visiting the Investors & Media section of the Scholar Rock website at . An archived replay of the webcast will be available on the Company’s website for approximately 90 days following the presentations. About SRK-439 SRK-439 is a novel, preclinical, investigational myostatin inhibitor that has high in vitro affinity for pro- and latent myostatin and maintains myostatin specificity (i.e., no GDF11 or Activin-A binding), and is initially being developed for the treatment of cardiometabolic disorders, including obesity. Based on preclinical data, SRK-439 has the potential to support healthier weight management by preserving lean mass during weight loss. The efficacy and safety of SRK-439 have not been established and SRK-439 has not been approved for any use by the FDA or any other regulatory agency. About Apitegromab Apitegromab is an investigational fully human monoclonal antibody inhibiting myostatin activation by selectively binding the pro- and latent forms of myostatin in the skeletal muscle. It is the first muscle-targeted treatment candidate to demonstrate clinical proof-of-concept in spinal muscular atrophy (SMA). Myostatin, a member of the TGFβ superfamily of growth factors, is expressed primarily by skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species, including humans. Scholar Rock believes that its highly selective targeting of pro- and latent forms of myostatin with apitegromab may lead to a clinically meaningful improvement in motor function in patients with SMA. The U.S. Food and Drug Administration (FDA) has granted Fast Track, Orphan Drug and Rare Pediatric Disease designations, and the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) and Orphan Medicinal Product designations, to apitegromab for the treatment of SMA. The efficacy and safety of apitegromab have not been established and apitegromab has not been approved for any use by the FDA or any other regulatory agency. About Scholar Rock Scholar Rock is a biopharmaceutical company that discovers, develops, and delivers life-changing therapies for people with serious diseases that have high unmet need. As a global leader in the biology of the transforming growth factor beta (TGFβ) superfamily of cell proteins and named for the visual resemblance of a scholar rock to protein structures, the clinical-stage company is focused on advancing innovative treatments where protein growth factors are fundamental. Over the past decade, Scholar Rock has created a pipeline with the potential to advance the standard of care for neuromuscular disease, cardiometabolic disorders, cancer, and other conditions where growth factor-targeted drugs can play a transformational role. Scholar Rock is the only company to show clinical proof-of-concept for a muscle-targeted treatment in spinal muscular atrophy (SMA). This commitment to unlocking fundamentally different therapeutic approaches is powered by broad application of a proprietary platform, which has developed novel monoclonal antibodies to modulate protein growth factors with extraordinary selectivity. By harnessing cutting-edge science in disease spaces that are historically under-addressed through traditional therapies, Scholar Rock works every day to create new possibilities for patients. Learn more about our approach at ScholarRock.com and follow @ScholarRock and on LinkedIn. Availability of Other Information About Scholar Rock Investors and others should note that we communicate with our investors and the public using our company website , including, but not limited to, company disclosures, investor presentations and FAQs, Securities and Exchange Commission filings, press releases, public conference call transcripts and webcast transcripts, as well as on Twitter and LinkedIn. The information that we post on our website or on Twitter or LinkedIn could be deemed to be material information. As a result, we encourage investors, the media and others interested to review the information that we post there on a regular basis. The contents of our website or social media shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended. Scholar Rock® is a registered trademark of Scholar Rock, Inc. Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Scholar Rock’s future expectations, plans and prospects, including without limitation, Scholar Rock’s expectations regarding its growth, strategy, progress and timing of its clinical trials for apitegromab and its preclinical programs, including SRK-439, and indication selection and development timing, including the therapeutic potential, clinical benefits and safety thereof, expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials, the ability of any product candidate to perform in humans in a manner consistent with earlier nonclinical, preclinical or clinical trial data, and the potential of its product candidates and proprietary platform. The use of words such as “may,” “might,” “could,” “will,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “project,” “intend,” “future,” “potential,” or “continue,” and other similar expressions are intended to identify such forward-looking statements. All such forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, without limitation, that preclinical and clinical data, including the results from the Phase 2a clinical trial of apitegromab, or its preclinical data with respect to SRK-439, are not predictive of, may be inconsistent with, or more favorable than, data generated from future or ongoing clinical trials of the same product candidates, including, without limitation, the Phase 3 clinical trial of apitegromab in SMA or the Phase 2a EMBRAZE clinical trial; Scholar Rock’s ability to provide the financial support, resources and expertise necessary to identify and develop product candidates on the expected timeline; the data generated from Scholar Rock’s nonclinical and preclinical studies and clinical trials; information provided or decisions made by regulatory authorities; competition from third parties that are developing products for similar uses; Scholar Rock’s ability to obtain, maintain and protect its intellectual property; Scholar Rock’s dependence on third parties for development and manufacture of product candidates including, without limitation, to supply any clinical trials; and Scholar Rock’s ability to manage expenses and to obtain additional funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives; as well as those risks more fully discussed in the section entitled "Risk Factors" in Scholar Rock’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, as well as discussions of potential risks, uncertainties, and other important factors in Scholar Rock’s subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent Scholar Rock’s views only as of today and should not be relied upon as representing its views as of any subsequent date. All information in this press release is as of the date of the release, and Scholar Rock undertakes no duty to update this information unless required by law. View source version on businesswire.com: Contacts Scholar Rock: Investors Rushmie Nofsinger Scholar Rock rnofsinger@scholarrock.com ir@scholarrock.com 857-259-5573 Media Molly MacLeod Scholar Rock mmacleod@scholarrock.com media@scholarrock.com 802-579-5995 Source: Scholar Rock View this news release online at:

关注并星标CPHI制药在线近日，恒瑞GLP-1产品"出海"的消息刷了屏，恒瑞宣布将其自研GLP-1产品组合的大中华区外全球权益授权给美国Hercules公司。       在这笔大额license-out交易中，Hercules公司支付的首付款加里程金累计可高达60亿美元，其中包括首付款和近期里程金总计1.1亿美元。此外，恒瑞还能获得Hercules公司19.9%的股权。       三款GLP-1产品组合，成色几何？       根据公告，此次恒瑞向Hercules授权了三款产品，分别为口服小分子胰高血糖素样肽-1受体（GLP-1R）激动剂HRS-7535、口服及注射剂型抑胃肽受体（GIPR）/GLP-1R双激动剂HRS9531，以及下一代肠促胰岛素药物HRS-4729。       HRS-7535作为一种GLP-1R激动剂（GLP-1RA），属于肠促胰素类药物，可通过激活GLP-1R刺激胰岛素分泌和抑制胰高血糖素分泌，同时增加肌肉和脂肪组织葡萄糖摄取，抑制肝脏葡萄糖的生成而发挥降糖作用，并可抑制胃排空、抑制食欲，在血糖控制和代谢改善方面具备一定治疗优势。       与注射剂相比，口服制剂具有更好的依从性。然而，GLP-1RA口服剂型的开发并不顺利，在研发进展方面，辉瑞的两款口服小分子GLP-1RA Lotiglipron和Danuglipron分别因肝毒性和耐受性问题已终止后续试验；礼来的Orforglipron研发进展较快，已推进至III期临床。       恒瑞的HRS-7535目前已完成一项Ⅰ期临床试验，数据显示，HRS-7535具有良好的安全性、耐受性及药代动力学特征，支持每日一次的给药方式。而且即使基础体重较低（67.6kg），HRS-7535仍然可以在连续给药四周后观察到明显的体重下降（4.38kg），当前，HRS-7535的减重适应症已进入II期临床研究阶段。       HRS9531作为一种GIPR/GLP-1R双激动剂，可通过同时激动GLP-1和GIP受体，发挥葡萄糖依赖性的促胰岛素分泌、抑制食欲和改善胰岛素敏感性等作用，帮助降低血糖和减轻体重。       在减重适应症的I期临床试验中，结果显示，单剂量爬坡（SAD）部分的受试者体重呈剂量依赖性减轻，第8天时8.1mg组的平均减轻体重为3.8kg（4.9%），而在多剂量爬坡（MAD）部分，4周后0.9-5.4mg组的平均体重减轻4.3-7.7kg（6.7%-9.3%）；第36天5.4mg组减重幅度最大，达到8.0kg（10.0%）。HRS9531目前已进入III期临床。       在GLP-1R/GIPR双重激动剂领域，目前仅有礼来的替尔泊肽（Tirzepatide）获FDA批准上市，在研药物方面，viking公司的VK2735与HRS9531同靶点，在减肥适应症的II期临床研究显示，每周接受VK2735剂量治疗的患者在13周后平均体重显著下降，比基线下降14.7%。未来，HRS9531和VK2735以及Tirzepatide等之间将产生激烈竞争。       以上可以看出，就产品本身，恒瑞授权的三款GLP-1减肥药并不特别，同类产品不少。尽管如此，恒瑞依然获得了一个非常合适的价格，首付款和近期里程金就有1.1亿美元，而且还获得了Hercules公司近20%的股权，可见减重药物仍然是药企的心头好。       公开数据显示，到2030年，全球减重药物市场将会达到1000亿美元左右。因此无论是在国内还是海外，减重赛道均备受青睐。随之而来的，是对于减重效果的"内卷"。目前，已有多个新型减重靶点进入临床试验，下一个"大药"机会可能就藏在这些靶点里。       激活素II型受体 (ActRII)       ActRII是一种在脂肪和肌肉细胞中都表达的激活素受体，ActRII受体传导信号的活化会导致肌肉萎缩和脂肪组织中脂肪的累积，因此靶向该通路有可能在驱动脂肪流失的同时，增加患者身体的肌肉组成，从而帮助肥胖患者在减肥的同时改善身体成分和代谢。       虽然靶向ActRII的研发管线很多，但目前真正进入临床研究的、以肥胖为适应症的ActRII抗体，仅有礼来的Bimagrumab和来凯医药的LAE102。       Bimagrumab是一种单克隆抗体，通过抑制ActRII，阻断激活素和肌肉生长抑制素的信号传导，具有治疗肌肉萎缩和肥胖症的潜力。       在一项名为BELIEVE的IIb期研究中，在带有2型糖尿病的过重或肥胖患者身上，与安慰剂相比，bimagrumab能够造成患者约22%脂肪质量的损失，并增加4.5%的无脂体重。更重要的是，患者在停止治疗12周内并未观察到体重的增加。安全性方面，bimagrumab的副作用主要是肌肉痉挛和腹泻，大多为轻度。       LAE102是由来凯医药自主研发的ActRⅡA单抗。今年4月，LAE102获得FDA批准用于治疗肥胖适应症的新药临床试验。5月9日，LAE102的临床试验申请获得国家药品监督管理局药品审评中心（CDE）用于治疗超重和/或肥胖。       G蛋白偶联受体75（GPR75）       GPR75是G蛋白偶联受体（GPCR）家族中的一员，GPCR是一类广泛存在于细胞表面具有7个疏水性跨膜片段的膜蛋白，也是目前人体中种类和数量最多的受体蛋白家族。多种细胞外配体（如激素、趋化因子、神经递质、自体激素和酶）与GPCR结合时，会导致GPCR发生构象变化，从而进一步与异三聚体G蛋白相互作用而产生许多细胞生理功能。       GPR75作为GPCR家族的新成员，在肥胖、癌症和代谢综合征等许多疾病中发挥重要作用。2021年7月，Regeneron（再生元）在Science期刊上发表研究：通过对来自英国、美国和墨西哥的64.5万人的全外显子测序，分析罕见基因突变与体重指数(BMI)相关性，鉴定出16个非同义基因突变与BMI相关。其中，研究人员发现截短GPR75突变发生率为万分之四。在小鼠体内验证试验表明，敲除GPR75，小鼠体重更轻，血糖更低，胰岛素水平更低。GPR75已成为新兴的肥胖治疗靶点，但目前还没有GPR75靶向药处于临床阶段。再生元正在通过内部和外部组合，开发包括siRNA、小分子和抗体等多种靶向GPR75的疗法。       除此之外，针对肥胖的新型靶点还有NOD样受体热蛋白结构域相关蛋白3（NLRP3），NLRP3是炎性小体受体家族蛋白之一，其能够激发炎性小体的形成，是许多疾病的生物学验证靶点。目前已发现NLRP3炎性小体异常的活化与系统性疾病相关。除肥胖外，还有许多纤维化、皮肤与风湿病以及多种神经障碍疾病有关等。关于肥胖的研究正处于临床前研究阶段。       目前，以司美格鲁肽为首的GLP-1靶点减肥药已席卷全球，但它并非不可超越。一项回顾研究性表明，司美格鲁肽受试者减掉的体重中近40%为肌肉，从而增加患心血管疾病、骨质疏松症的风险，就连替尔泊肽也难以避免这一问题。因此，新的需求应运而生，毫无疑问增肌是减肥市场的下一个赛点。而恒瑞此次赶在减肥药热潮正盛之时对外授权，并获得一个非常合适的价格，可谓明智之举。       参考来源：       1. Petricoul, O., Nazarian, A., Schuehly, U. et al. Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338). Clin Pharmacokinet 62, 141-155 (2023).       2. Chen K, Shen Z, Gu W, et al. Prevalence of obesity and associated complications in China: A cross-sectional, real-world study in 15.8 million adults. Diabetes Obes Metab. 2023;25(11):3390-3399.       3. Echinatin effectively protects against NLRP3 inflammasome- driven diseases by targeting HSP90，2021.       4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. NEJM. June 2022. DOI: 10.1056/NEJMoa2206038.       【智药研习社近期线下课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~