RG-7816

5月6日，致力于利用合成致死性开发新型抗癌药物的Eisbach Bio GmbH宣布，美国食品和药品监督管理局 (FDA) 已批准其染色质解旋酶 ALC1 (CHD1L) 的小分子抑制剂 EIS-12656 的研究性新药 (IND)申请。ALC1（也称为 CHD1L）是一种染色质重塑酶，可调节 DNA 损伤和修复。它的表达在以同源重组缺陷（HRD 阳性）为标志的乳腺癌和卵巢癌中增加。它的缺失大大增强了 PARP 抑制剂和各种标准护理化疗的疗效。ALC1 抑制剂有望在 HR 缺陷的肿瘤中诱导合成致死作用，在出现 PARPi 耐药性的患者中增强 PARP 抑制剂的作用，并实现有效的联合治疗。经某数据库检索，时至当日，并未收录ALC1 (CHD1L)靶点，专利检索也只有Eisbach Bio 自家的WO2022117782专利，或许可以说， EIS-12656 是全球首款和唯一一款靶向新型合成致死靶点ALC1 (CHD1L) 的小分子临床抑制剂抑制剂。当然，国内这些年跟踪这类前沿靶点，最后说不定真就自己跑成了First，甚至Only。比如，那个RAD51，幸运之神（“前车之鉴”）啊！推荐阅读：RAD51抑制剂带头大哥折戟，公司解散！RAD51抑制剂单药受挫Pol θ：百济与再明专利的“瑜亮”之战！癌症治疗中合成致死性的一个主要例子涉及 PARP 抑制剂，它会影响我们靶向的相关 DNA 修复途径。虽然这种方法强大且有效，但可能会受到剂量限制性毒性和 PARP 抑制剂耐药性的挑战。新一代PARP1选择性小分子抑制剂被誉为可以具备更优的安全性，但是否对PARP耐药后的肿瘤患者依然有效，恐怕还须时日。EIS-12656 通过变构机制靶向 ALC1，抑制 DNA 损伤引起的与癌症相关的基因组重组。这会导致 ALC1 染色质捕获并杀死癌细胞。EIS-12656 影响 DNA 修复途径缺陷的肿瘤。它在临床前模型中表现出显着的肿瘤生长抑制作用，包括与标准护理疗法相结合。与相关合成致死靶标相比，其变构作用机制应具有选择性，有助于在所有相关临床前模型中观察到的卓越安全性。EIS-12656可不可以me-too?有专利、有蛋白晶体，剩下的看能力财力。▎药端洞察近日，又收集了一些药物结构，包括ORIC-114、azd5055、Alogabat、海思科EGFR降解剂、TYK2抑制剂ESK-001，但在ADC风浪下，是否依旧有人激情澎湃？比如，礼来买了那个组装式NECTIN-4 ADC药物LY4101174 (ETx-22)，在临床研究推进的同时，自己又开发了一款，还有了自己TOP1i毒素LSN3889710。当时写这个文章时（厉害了！这家公司的License in玩出了新境界），提出了这样的假设：近日，Macrogenics公布B7H3 ADC新药Vobramitamab Duocarmazine(MGC018)治疗前列腺癌二期临床TAMARACK的最新数据。详细数据将在ASCO发布，但安全性上，出现5例死亡事件，2.0mg/kg剂量组1例，2.7mg/kg剂量组4例，尽管公司认为与药物无关，Macrogenics股价还是下跌了77%。MGC018和已经消失的HER2 ADC药物SYD985、5T4 ADC药物syd1875一样的毒素设计。这种设计可与纯粹的前药设计不同，SYD985的机制就说明了，这样“九转回肠”呀！LP-184、LP-284就不会出现这样的“意外”吗？所以才有了上述假设，扯远了，文章结束！声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

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.