RDX-002(Response Pharmaceuticals)

▎药明康德内容团队编辑本期看点1. 治疗杜氏肌营养不良的候选基因疗法GNT0004在1/2/3期临床试验中展现治疗潜力，治疗后第8周时最高有85%的肌纤维表达微肌营养不良蛋白，治疗后第12周时关键生物标志物肌酸磷酸激酶的水平下降了50%-87%。2. 治疗1型脊髓性肌萎缩症的基因疗法EXG001-307在给药后三个月就使患者的头部控制有所改善，11个月时患者无需外部辅助就能保持坐姿。3. 用于治疗抗精神病药引起的体重增加（AIWG）的候选疗法RDX-002能够使服用抗精神病药的患者的餐后甘油三酯降低约82%，并显著抑制其体重的增加。4. 靶向5种KRAS常见突变的治疗性癌症疫苗HB-700的IND申请获得了FDA的许可。药明康德内容团队整理GNT0004：公布1/2/3期临床试验的初步数据由Genethon与伦敦大学皇家霍洛威学院团队和巴黎肌肉研究所合作开发的候选基因疗法GNT0004的1/2/3期临床试验的初步数据积极。GNT0004是一种基于腺相关病毒8（AAV8）载体的基因疗法，含有一个缩短但功能正常的DMD基因（hMD1），编码杜氏肌营养不良患者缺乏的蛋白质——肌营养不良蛋白。hMD1转基因由Spc5.11启动子驱动，可在骨骼肌和心肌等关键组织中表达。截至目前，已有5名年龄在6至10岁之间的患者接受了GNT0004治疗，其中2名患者接受了第一剂量水平的治疗，3名患者接受了第二剂量水平的治疗。初步的安全性和药效学结果表明，GNT0004与免疫预防治疗相结合具有良好的耐受性，在微肌营养不良蛋白表达和功能改善方面也有疗效。接受第二剂量水平的患者在注射GNT0004后的第8周时，免疫组化检测结果显示，最高有85%的肌纤维表达微肌营养不良蛋白（平均54%；范围15%-85%），并重建了肌营养不良蛋白相关蛋白质复合体。这种表达与每个肌纤维核中的转基因拷贝数量显著相关，最高可达2.4（平均1.2；范围0.4-2.4）。治疗后第12周时，患者肌肉损伤的生物标志物肌酸磷酸激酶的水平下降了50%-87%（平均74%）。此外，队列2中首位患者的一年疗效结果积极，NorthStar门诊评估量表（NSAA）得分明显改善，其他功能评估（10米步行测试和起立能力）也呈现出积极的趋势。EXG001-037：公布1/2期临床试验的初步数据Exegenesis Bio公司公布了其用于治疗1型脊髓性肌萎缩症的重组AAV基因疗法EXG001-307的1/2期临床试验的疗效和安全性数据。EXG001-307具有独特的AAV设计，包括一个新颖的pro-NS启动子，与目前可用的基因疗法相比，可在目标脊髓组织中实现高表达，并减少在肝脏和心脏这类非目标组织中的表达。此次公布的结果显示，EXG001-307低剂量组患者在用药3至6个月后实现了头部控制，在用药11个月后无需外部辅助即可保持坐姿。中剂量组中的首位患者在用药3个月后就能在辅助下保持坐姿。安全性方面，EXG001-307具有高耐受性，无剂量限制性毒性，无>2级试验品相关严重不良事件，无>1级转氨酶或心肌酶升高。RDX-002：公布1b期临床试验数据Response Pharmaceuticals公司公布了其用于治疗抗精神病药引起的体重增加的潜在“first-in-class”候选疗法RDX-002的1b期临床试验的初步结果。RDX-002是一种强效、选择性和肠道特异性的小分子甘油三酯微粒体转移蛋白（MTP）抑制剂，旨在降低餐后体内甘油三酯和胆固醇的含量。RDX-002正在开发中，可作为服用非典型抗精神病药物患者的辅助治疗药物，也可作为临床上体重增加和/或不良代谢变化普遍存在的其他情况下的潜在治疗药物。此次公布的结果显示，在为期两周的开放标签试验中，RDX-002队列中的受试者达到了主要疗效终点，即餐后甘油三酯有所降低。接受奥氮平（一种与AIWG相关的高效抗精神病药物）治疗的受试者在第8天时与第1天相比，餐后甘油三酯的平均AUC增加了54%（p=0.009），并在第15天保持升高。而奥氮平+RDX-002治疗组在第15天时与第8天相比，餐后甘油三酯的平均AUC下降了81.6%（p<0.001）。此外，接受奥氮平单药治疗的受试者在治疗的第一周和第二周体重明显增加，而接受奥氮平+RDX-002治疗的患者在第二周时体重没有明显变化。安全性方面，RDX-002的耐受性良好，不良反应主要限于轻度至中度消化道反应，研究期间没有发生严重不良反应或与治疗相关的停药。HB-700：IND申请获得FDA许可HOOKIPA Pharma公司宣布，其用于治疗KRAS突变癌症的新型治疗性疫苗HB-700的IND申请已获得美国FDA的许可。HB-700旨在通过靶向这些疾病中最常见的五种KRAS突变（G12D、G12V、G12R、G12C和G13D），治疗KRAS突变的肺癌、结直肠癌、胰腺癌和其他癌症。与单一突变抑制剂相比，该候选疫苗有望使更多患者受益。RB-ADSC：1期临床试验完成首例患者输注Regeneration Biomedical公司宣布，其用于治疗轻度至中度阿尔茨海默病患者的自体Wnt激活脂肪来源干细胞（RB-ADSC）的1期临床试验已完成首例患者输注。RB-ADSC是Wnt激活的脂肪源性干细胞，取自患者自身的脂肪组织。采集后，干细胞在体外进行培养和扩增，筛选出Wnt表达的干细胞，然后通过植入位于头皮下，可直接进入大脑的一个侧脑室的Ommaya储存器重新输回患者体内。在两种动物模型中的研究结果表明，注入脑室系统的干细胞会自行分布到大脑实质中。此外，没有观察到炎症、脑脊液循环受阻或其他安全信号。VCN-01：公布1期临床试验数据Theriva Biologics公司公布了其在研溶瘤腺病毒疗法VCN-01在眼内视网膜母细胞瘤患者（9人）中进行两次玻璃体内注射的安全性和耐受性。VCN-01是一种溶瘤腺病毒，旨在选择性地在肿瘤细胞内积极复制，并降解肿瘤基质（一种在癌症治疗中重要的物理和免疫抑制屏障）。此次公布的结果显示，玻璃体内注射VCN-01显示出良好的抗肿瘤活性，似乎不会改变视网膜功能。4名患者的症状有明显改善。截至目前，3名患者避免了眼球摘除术，其中一名患者的眼球在随访4年后仍得以保留。安全性方面，VCN-01玻璃体内给药的耐受性良好，最常报告的治疗相关不良反应为1级或2级。在评估期间，没有出现剂量限制性毒性反应，也没有出现≥3级的眼部或全身毒性反应。注射VCN-01后观察到一定程度的眼部炎症和相关浑浊。通过局部和全身使用抗炎药物，炎症能够得到控制，玻璃体混浊在某些情况下也能够得到改善。ONC-841：IND申请获得FDA许可OncoC4公司宣布，美国FDA已经批准了其用于治疗实体瘤的SIGLEC 10阻断抗体ONC-841的IND申请。SIGLEC 10是一种免疫检查点，可抑制先天性和适应性免疫细胞的激活。ONC-841通过抑制SIGLEC 10，阻止癌细胞的免疫逃逸。支持IND申请的临床前研究表明，ONC-841能改善肿瘤浸润T细胞的功能，增强对癌细胞的吞噬能力。其他体内和异种移植肿瘤模型显示，使用ONC-841治疗后，对癌细胞的免疫排斥反应增强了。ONC-841单药治疗的安全性、药代动力学和临床活性的1期临床试验的初步数据预计将于2025年下半年公布。ALTO-101：公布1期临床试验数据Alto Neuroscience公司公布了其用于治疗精神分裂症相关认知障碍（CIAS）的新型PDE4抑制剂ALTO-101的1期研究的积极结果。ALTO-101采用专有的透皮给药（transdermal formulation）系统，旨在提供稳定的浓度，以提高药物的安全性、耐受性和药代动力学。在1期临床试验中，ALTO-101表现出了脑渗透性、强大的中枢神经系统相关的药效学效应，并且在治疗相关剂量范围内耐受性良好。此次公布的研究结果表明，与口服给药相比，ALTO-101通过透皮给药系统给药时具有良好的耐受性和更好的药代动力学。透皮制剂的药物暴露水平明显高于口服给药的全身暴露水平，并且透皮制剂的血浆浓度在服药后的第2天（24-48小时）内依然保持稳定。此外，透皮制剂大大降低了通常与PDE4抑制剂相关的不良反应。接受口服给药的患者有40%出现了头晕，并有20%的患者出现了恶心，而接受透皮给药的患者只有7.1%出现了头晕，没有患者出现恶心。该公司计划在2024年上半年启动一项概念验证研究，评估ALTO-101在CIAS患者中的疗效，预计在2025年下半年获得初步数据。 ▲ALTO-101口服制剂和透皮制剂的药代动力学曲线（图片来源：参考资料[11]）KNS366：公布1期临床试验数据Kynos Therapeutics公司公布了其用于治疗急性和慢性炎症性疾病的小分子犬尿氨-3-单加氧酶（KMO）抑制剂KNS366的积极1期临床试验数据。KMO是一种在色氨酸代谢的犬尿氨酸途径中起关键作用的酶，能将犬尿氨酸转化为3-HK。通过抑制KMO的活性，KNS366可降低升高的3-HK，从而防止炎症期间出现的过度的组织损伤和免疫系统失调。此次公布的结果显示，所有剂量的KNS366都是安全的，而且该分子显示出极佳的耐受性。药效学指标清楚地表明，KNS366是一种强效的KMO酶抑制剂，代谢产物3-HK的大幅减少证明了它具有很强的抑制作用。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Ocugen Announces Dosing Completion of Subjects with Geographic Atrophy in Cohort 2 of Phase 1/2 ArMaDa Clinical Trial of OCU410—A Modifier Gene Therapy. 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Retrieved April 24, 2024, from extension://emelgiiiemoiljnmikcgbmjkapalgcme/assets/pdf-viewer/web/viewer.html?file=https%3A%2F%2Fpep-therapy.com%2Fwp-content%2Fuploads%2F2024%2F04%2F20240417-PR-First-patients-Phase-Ib-vf.pdf[21] Exegenesis Bio to Present 9-Patient Data from a Phase 1/2 Clinical Trial of EXG001-307, a Novel rAAV Gene Therapy for Spinal Muscular Atrophy (SMA) Type 1: Improved Head Control and Sitting Without External Assistance. Retrieved April 24, 2024, from https://www.businesswire.com/news/home/20240425546173/en/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

The Virginia-based company has revealed promising results from its phase 1b clinical trial assessing RDX-002, a novel small molecule therapy designed to address this pressing medical concern. The trial, conducted over two weeks, has yielded findings that emphasize the potential of RDX-002 in mitigating the adverse metabolic effects associated with antipsychotic medications, the company says. Antipsychotic-induced weight gain is a well-documented phenomenon that poses a significant challenge in the management of mental illnesses such as schizophrenia, depression, and bipolar disorder. These conditions often necessitate the use of antipsychotic medications to alleviate symptoms and improve patients' quality of life. However, a common side effect of many antipsychotics is rapid and clinically meaningful weight gain, which can occur within the first few weeks of treatment and persist over the long term. This weight gain, Response says, not only leads to poor adherence to medication regimens but also contributes to the development of metabolic abnormalities such as hyperlipidemia and hyperglycemia, thereby increasing the risk of cardiovascular disease and diabetes. Dr. Joseph Coyle, emeritus chair of psychiatry and neuroscience at Harvard Medical School, highlighted the significance of addressing AIWG. Rapid weight gain and obesity He said “Antipsychotic medications are essential treatments that help millions of patients live better lives but can be associated with rapid weight gain and obesity. This often leads to poor adherence to treatment and reduced quality of life and contributes to long-term cardiometabolic morbidities including decreased life expectancy.” googletag.cmd.push(function () { googletag.display('text-ad1'); }); In light of these challenges, Response Pharmaceuticals embarked on a clinical trial to evaluate the safety and efficacy of RDX-002, a first-in-class candidate treatment aimed at preventing the rapid weight gain associated with antipsychotic medications. The phase 1b trial enrolled 24 healthy, antipsychotic-naïve volunteers who were initially treated with olanzapine, a widely used antipsychotic known for its propensity to induce weight gain. During the trial, people were randomized to receive either RDX-002 in addition to olanzapine or olanzapine alone for the duration of the second week. The primary endpoint of the trial was to assess the impact of RDX-002 on postprandial triglycerides (ppTGs), a key marker of metabolic health. The results, Response says, were striking, with subjects in the RDX-002 cohort demonstrating a remarkable 82% reduction in postprandial triglycerides compared to those receiving olanzapine alone. Dr. Paul Sweetnam, chief science officer of Response Pharmaceuticals and lead inventor of RDX-002, elaborated on the implications of these findings, he said: “Treatment with the iMTP-inhibitor RDX-002 significantly reduced ppTGs and blunted the weight gain in OLAN-treated subjects indicating a potential role in the treatment and prevention of AIWG.” Reduction in weight gain In addition to the favorable effects on postprandial triglycerides, the company said exploratory analyses revealed a notable reduction in weight gain among patients treated with RDX-002. While patients receiving olanzapine alone experienced a significant increase in body weight during the first and second weeks of treatment, those receiving RDX-002 demonstrated minimal weight change, highlighting the potential of RDX-002 to mitigate the metabolic effects of antipsychotic medications. Response Pharmaceuticals CEO Eric Keller is optimistic about the impact of RDX-002. He said: “This is very promising news for patients who have long fought to manage not only severe mental illness but also the syndrome of AIWG and its associated morbidities.” The positive results from the phase 1b trial have paved the way for further clinical development of RDX-002. Response Pharmaceuticals is now preparing to initiate a phase 2 clinical trial to evaluate the efficacy of RDX-002 in patients with bipolar depression and schizophrenia initiating olanzapine therapy. The trial, the company says, will be a placebo-controlled 12-week study designed to assess changes in weight gain and postprandial triglycerides, to further validate the potential of RDX-002 as a treatment for AIWG. Antipsychotic-induced weight gain remains a significant unmet medical need, affecting millions of individuals worldwide. Response Pharmaceuticals' forward-thinking approach with RDX-002 aims to offer hope for improved outcomes and enhanced quality of life for patients grappling with this challenging side effect of antipsychotic medications. As the company continues to advance its clinical development program, there is optimism that RDX-002 may emerge as a much-needed therapeutic option for individuals at risk of AIWG.