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Pictured: A child covering his ears over a neuron background/Taylor Tieden for BioSpace With the prevalence of autism on the rise in the U.S., the biopharma industry is making a concerted effort to develop new treatments to alleviate the challenges associated with the neurological condition. Diagnoses of autism spectrum disorder (ASD) rose from 1 in 54 in 2016 to 1 in 36 in 2020, according to the Centers for Disease Control and Prevention. However, efforts by the biopharma industry to find treatments have also accelerated; more than 100 drugs are in trial or have completed studies, according to the autism news site Spectrum. But despite this significant push, challenges remain when it comes to developing a successful treatment for ASD. R&D Hurdles Remain One of the biggest hurdles involves measuring the condition precisely. Paul Wang, the director of clinical research associates and a senior clinical research scientist at the Simons Foundation, said that unlike in cancer, where specific metrics such as survival can be measured, or diabetes, where blood sugar can be precisely tracked, measuring improvements in autism is more of an “open question.” “Up to this point, the best things that we have are surveys and questionnaire rating scales, and . . . for kids and for those who have a more severe impairment, they can’t respond to those rating scales themselves,” Wang told BioSpace. “It depends on a parent’s impression or clinicians’ impression, and there’s always going to be a lot of imprecision and noisiness around that.” Additionally, Michael Tranfaglia, medical director and chief scientific officer at the FRAXA Research Foundation—an organization dedicated to finding treatments for Fragile X syndrome, the most common inherited cause of autism—told BioSpace that, despite ongoing research, the specific genetic mutations or factors causing ASD have yet to be determined. The heterogeneity of the condition poses another challenge, Tranfaglia said. Selective serotonin reuptake inhibitors (SSRIs) have been tested for ASD, but the results were “very disappointing” for this reason. “It was really hard to show that [SSRIs] worked in autism because we got a whole mixed bag of results.” He noted that there were subgroups of patients who appeared to have a “dramatically positive response,” while others got worse, and still others had no response at all. Wang agreed that one drug or treatment will not help 100% of individuals with ASD. Because of this, he said there has been a reluctance by most of the larger pharmaceutical companies to go into the ASD treatment space. Autism Candidates in the Clinic One large pharma bucking this trend is Roche. The company is investigating the small molecule alogabat, a highly selective positive allosteric modulator of the GABAA α5 receptor, which is expressed in brain regions that are key to ASD. Roche is investigating the molecule’s efficacy, safety and tolerability in an ongoing Phase II study for patients aged 15–45, a company spokesperson told BioSpace in an email, adding that alogabat has been safe and well tolerated so far. “No approved pharmacological treatment exists for the core social communication and social interaction deficits or restricted and repetitive behaviors of ASD, and this disorder continues to be an area of high-unmet medical need,” the spokesperson said. In Westchester County, New York, Curemark is on a mission to develop new therapies for neurodegenerative and neuro-developmental disorders, including ASD. Founder and CEO Joan Fallon told BioSpace that when autism was first emerging in the 1980s and 1990s, she noticed that affected patients were not eating very much protein. Investigating further, she found that children with ASD could not digest protein due to low enzyme activity. This spurred Fallon to launch Curemark in 2007. The company’s lead asset, an enzyme called CM-AT, aims to enhance protein digestion, restoring the essential amino acids in children to boost neurological performance. In November 2023, Curemark published long-term data from a clinical study of CM-AT in JAMA. Curemark reported that the trial, which investigated the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I), showed a statistically significant difference for individuals taking CM-AT after 12 and 36 weeks. “What we saw in our trials gives me a lot of hope that the children can change, and there can be a sustained change for them over time,” Fallon said. Curemark is in the process of submitting a Biologics License Application for CM-AT and beginning more clinical trials. Also based in New York, Yamo Pharmaceuticals is developing L1-79, a tyrosine hydroxylase inhibitor that aims to improve communication and socialization in individuals with ASD by modulating the catecholaminergic pathways associated with the disorder. Yamo kicked off a Phase II trial in 2022 and is expecting results by early August. CEO Chuck Bramlage told BioSpace that two previous trials have shown “positive results.” Bramlage, the former CEO of Pearl Therapeutics, said he joined Yamo to get back to working in a therapeutic area with a massive unmet need, especially for children. “I feel bad for the parents of children with autism because they’ve been told a lot of things that would work, and nothing has,” he said. Still others are investigating existing medicines as potential treatments for ASD. Tarrytown, New York–based PaxMedica is studying PAX-101 (suramin), a therapy for human African trypanosomiasis, or African sleeping sickness, for autism. An over abundance of purines in cells can offset hemostasis and cause an overproduction of cellular adenosine triphosphate. Suramin targets extra purines with the aim of reducing the symptoms of ASD, PaxMedica CEO Howard Weisman told BioSpace. The company posted results from a 14-week proof-of-concept study of 44 ASD patients who completed the study in the Annals of General Psychiatry last year. Weisman said the results were “encouraging” and noted that PAX-101 was well-tolerated. Preclinical assets for ASD are also showing promise. Calgary-based Marvel Biosciences posted interim results of a study of MB-204, a derivative of an adenosine A2A receptor antagonist used to treat Parkinson’s disease, in early March. The study found that a single oral dose of MB-204 restored social deficits and enhanced certain social interaction behaviors to normal levels in an autism mouse model. Mark Williams, president and chief science officer at Marvel, told BioSpace that based on this result, the company is planning for Phase I study, which it expects to initiate in 2025. “I’m very hopeful that if we’re right, it’s possible that after a short course of therapy, you might see dramatic behavioral changes with people on a drug like [MB]-204,” he said. While these clinical and preclinical data are encouraging, Wang said it will take time to get autism treatments across the line. “The brain is the most complex organ in the body, and we just don’t understand it completely,” Wang said. Despite this, he expressed optimism that progress is being made toward a greater understanding of ASD, and said he is hopeful that “we will eventually get to the point where we have helpful supports.” Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

▲8月03-04日 CMC-China大会 · 限时免费扫码报名中注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。管线消失，但带给我们的启示不会消失。他山之石，可以攻玉。跨国药企在创新方面一直走在前列，其管线项目的布局调整，值得我们密切关注。据不完全统计，上半年辉瑞、BMS、诺华、罗氏、默沙东、GSK、武田、阿斯利康、第一三共等大药企合计砍掉了超50个管线项目，涉及ADC、CGT疗法、新冠药物、小核酸、疫苗和GLP-1等各个方面，或因为技术不成熟，难成药；或由于竞争格局发生变化以及战略失误等原因，我们具体来看看。辉瑞在2023年上半年终止10多个研发项目。今年2月初，辉瑞发布的财报显示，消减了8个研发项目。1.删掉了recicept研发项目，这是一种治疗软骨发育不全的侏儒症的药物，是辉瑞在2019年收购罕见疾病公司Therachon的核心产品。当时，辉瑞公司预付了3.4亿美元。2.削减两个Paxlovid的适应症，这两个适应症在各自的III期试验中都失败了——一个用于标准风险患者，一个用于暴露后预防。3.停止了四种早期候选药物的研发，其中包括一种正在健康志愿者身上测试的治疗自身免疫性疾病的药物。该药被授予孤儿药称号，用于治疗一种称为慢性炎症性脱髓鞘多发性神经病的神经疾病。此外，该公司正在开发一种用于实体瘤的生物制剂，以及用于黑色素瘤和转移性乳腺癌的激酶抑制剂。辉瑞在年初时候表示，将缩小对罕见疾病和癌症的关注，未来计划在血液学和基因编辑等目前的重点领域加大投入。2023年5月初，辉瑞在一季报中更新了其研发管线，其中有6个研发项目已终止，101个项目仍处于临床或注册阶段。图片来源：辉瑞官网辉瑞公司还在1季报中披露了自1月31日以来剔除的6个研发项目，如下图所示：来源：官网BMS在2023年2月发布的财报显示，至少9个管线被砍，包括CTLA-4和TIGIT等靶点。其中在早期研发方面，BMS削减了6项肿瘤资产，包括一项2期抗CTLA-4候选药物BMS986218、一项纤维化候选药物和两项免疫学资产。大多数肿瘤资产为1期实体瘤管线，包括STING激动剂、IL-12 F、SIRPα拮抗剂和anti-CTLA-4药物。此外，BMS也削弱了其血液瘤的前景，终止了处于1期的ROR CAR-T疗法的开发，同时BMS还终止抗TIGIT药物BMS-986207的2期临床试验，该试验是Yervoy和Opdivo三联疗法的一部分，主要是出于安全考虑。罗氏在2023年2月财报显示，12款产品减值超31亿美元。2022年资产减值超31美元，涉及12款主要产品，其中最大的一笔是抗癌药物Gavreto减值7.26亿美元，这是一种口服RET靶向疗法，用于治疗年龄≥12岁的甲状腺癌儿童和成人患者。此外，2022年罗氏在基因疗法方面资产减值金额约7.5亿美元。2023年5月，罗氏终止精神病新药II期临床研究。美国临床试验网显示，罗氏终止了其精神分裂症候选药物ralmitaront的II期（NCT03669640）临床试验，该研究旨在评估ralmitaront相较于安慰剂用于治疗精神分裂症或分裂情感障碍阴性症状患者疗效。试验终止的原因是中期分析表明ralmitaront不太可能在该研究中达到主要终点。2023年6月，据媒体报道，罗氏将终止推进反义寡核苷酸疗法rugonersen治疗天使综合征的临床开发。罗氏表示，该疗法的耐受性良好，这一决定无关安全性问题。停止rugonersen开发的决定并不意味着罗氏放弃天使综合征领域。罗氏补充说，正在进行的alogabat治疗天使综合征的II期研究将不受影响。该小分子是一款GABRA5正向变构调节剂。默沙东停止3个项目。据2月份发布的财报更新显示，默沙东公司放弃了基孔肯雅热(chikungunya)候选疫苗，该疫苗已完成II期研究。默沙东公司于2020年通过收购Themis Bioscience 获得了该疫苗。此外，默沙东还放弃了Lenvima的胶质母细胞瘤适应证，该公司一直在研究Lenvima与Keytruda联合用于LEAP项目的适应证。在一封电子邮件中，默克公司告诉Endpoints News:“作为我们常规管道优先排序的一部分，MSD已经选择停止这两个项目。”在1月25日，MSD宣布，在一项中期分析显示生存率没有改善后，MSD还将停止一项Keytruda晚期前列腺癌研究。GSK在2月份发布的财报显示，删除2个项目。GSK从其管线中删除了一种名为GSK3915393的化合物。该化合物可抑制一种称为转谷氨酰胺酶2或TG2的酶，该公司此前一直在研究其在乳糜泻中的应用。当在媒体电话会议上被问及3915393计划时，首席执行官Emma Walmsley证实没有进一步的计划来测试该药物是否用于乳糜泻。另外，GSK也在放弃一种针对金黄色葡萄球菌的重组蛋白疫苗，该疫苗已进入第二阶段。年初GSK还指出，它“决定停止对细胞和基因疗法的投资，最显著的是，本着在研发方面“极其严格”的精神，断绝了与Lyell、Adaptimmune和Immatics的联盟。武田在2023年5月披露的财报显示，终止6个研发项目。1.TAK-954。武田将放弃II期临床试验失败的术后胃肠功能障碍候选药物TAK-954。这是一款选择性5-HT4受体激动剂，从爱尔兰公司Theravance Biopharma授权引进，由此也结束了两家公司之间的合作。2.TAK-018（sibofimloc）。sibofimloc是一款与法国Enterome Biosciences公司合作开发的FimH 粘附抑制剂，用于克罗恩病（CD）。此款药物终止研发的原因是因为未能招募到足够的患者进行II期试验。3.Ninlaro (ixazomib)。Ninlaro是FDA批准的首个口服蛋白酶体抑制剂，用于治疗复发性或难治性多发性骨髓瘤（R/R MM）。根据研究的最终分析，武田决定停止在美国和欧洲开发新的适应症——治疗首次发作的多发性骨髓瘤，而无需造血干细胞移植。4.LIVTENCITY（马里巴韦）。在与监管当局审查了试验结果后，武田停止了该药物在造血干细胞移植后巨细胞病毒感染的一线治疗适应症的开发。5.Taxilo。该药物在缓激肽介导的血管性水肿研究中未能达到其主要终点。6.Zejura (niraparib)。武田停止Zejura在乳腺癌研究中的患者招募。Zejura是一款PARP抑制剂，目前用于卵巢癌。第一三共终止了2个研发项目。2023年5月份，第一三共发布2022财年（2022年4月1日-2023年3月31日）财报显示，终止了2个研发项目。包括用于杜氏进行性肌营养不良（DMD）的核酸药物DS-5141和用于进行性骨化性纤维发育不良（FOP）的药物DS-6016DS-5141是一款有望治疗DMD的核酸药物，可以跳过45外显子拼接，在信使RNA的处理过程中，在肌细胞中产生不完整但具有功能的肌营养不良蛋白。虽然在临床试验中显示出了一定的有效性，但根据目前的数据判断，想要进一步开发比较困难。DS-6016是一款有望治疗FOP的抗ALK2抗体，由于需要花费时间解决相关抗体非临床试验中发现的潜在安全性风险，因此被判定失去了竞争力，所以终止了开发。阿斯利康砍掉2个GLP-1管线和IL-4Rα拮抗剂开发。2023年6月20日，据外媒fiercebiotech报道，阿斯利康AZD0186（GLP-1R激动剂）没有达到预期目标，未显示出足够的差异性以超过当前的护理标准，故决定终止这项临床研究AZD0186处于1期临床研究阶段，用于治疗2型糖尿病，此项研究主要评估AZD0186 的安全性、耐受性和药代动力学。除了AZD0186，4月12日，阿斯利康宣布放弃一项关于Cotadutide（GLP-1R/GCGR 双重激动剂、日制剂）的 IIb/III 期临床研究，针对伴有肝纤维化但无肝硬化的非酒精性脂肪肝炎（NASH）患者。Cotadutide数据疗效不错，但和已上市的几款药物相比，并不具备竞争优势。阿斯利康表示将重点开发另一款GLP-1R/GCGR激动剂AZD9550（周制剂），目前仍处于临床前开发阶段。6月21日，Pieris Pharmaceuticals宣布收到阿斯利康向其传达的终止elarekibep开发的决定。该决定基于一项为期13周的非临床GLP毒理学研究，与正在进行的临床研究无关，但研究结果不支持elarekibep的长期使用以及临床后期开发。除了跨国大药企砍管线以外，还有不少中小药企也在陆续砍管线，ADC领域也有知名公司砍管线。今年5月份，ADC Therapeutics也砍掉了2道ADC管线，分别是ADCT-212（治疗前列腺癌的临床前抗体药物结合物）和ADCT-701（靶向DLK-1的ADC药物）。ADC Therapeutics执行官补充说，临床前项目的削减将使公司有更多的资金用于上市产品Zynlonta和其后期临床项目。总结此外，据公开报道，强生上半年还搁置了2个“双抗管线”研发；诺华调整Cosentyx、CAR-T疗法、TIGIT 抗体等研发计划；吉利德暂停3个项目，包括IRAK4抑制剂的两个适应症以及一个实体瘤候选物；礼来放弃了一种治疗糖尿病和非酒精性脂肪性肝炎的第一阶段候选药物，赛诺菲也停止了对BTK抑制剂tolebrutinib用于重症肌无力（MG）的III期临床研究等项目，艾伯维也终止开发一款自免ADC药物ABBV-154。管线项目的消失提醒我们，在投入大量资源和精力之前，必须充分评估项目的可行性和潜在风险。这要求药企更加注重风险管理和决策的科学性，以减少研发过程中的失败率。参考资料：各公司官网https://endpts.com/news/https://www.fiercepharma.com/版权声明：本文转自药事纵横，如不希望被转载的媒体或个人可与我们联系，我们将立即删除关于CMC-China 博览会融合产业力量，重构行业未来！本次CMC-China博览会汇聚300+医药及上下游全产业链的企业积极报名参展，数千名专业观众报名参观，展会现场将举办15场专业论坛。充分体现了“医药人办医药展，专业人办专业展”的理念。了解更多：数据看展会丨一文看懂第五届CMC-China制药博览会观众亮点点分享点点赞点在看