PTC Therapeutics, Inc.

Taylor Tieden for BioSpace The FDA is set to decide on four promising therapies in the next two weeks, including a CAR T for acute lymphoblastic leukemia. In the coming weeks, the FDA has four big decisions lined up. Among these are verdicts for a gene therapy for a rare disease and another for a lung cancer biologic therapy under Priority Review. Read below for more. Journey’s Rosacea Drug Awaits FDA Verdict By November 4, the FDA will release its decision on Journey Medical Corporation’s DFD-29 (minocycline hydrochloride modified release capsules), which the company is proposing as an oral treatment for inflammatory lesions and erythema in adults with rosacea. Journey is backing its New Drug Application (NDA) with data from two Phase III studies, both of which hit all co-primary and secondary endpoints . Compared with the current standard of care—40-mg Oracea (doxycycline) capsules—DFD-29 showed significant superiority in treatment success, as per the Investigator’s Global Assessment. DFD-29 was likewise better than Oracea at reducing total inflammatory lesion count and erythema in rosacea patients. Both trials also found that DFD-29 significantly outperformed placebo. If approved, DFD-29 would be “the only oral medication to address both inflammatory lesions and erythema” in rosacea “and will be a preferred treatment option by physicians and their patients,” Journey president and CEO Claude Maraoui said in a company statement alongside the FDA’s acceptance of its NDA. Rosacea is an inflammatory dermatologic condition that affects around 16 million people in the U.S. The disease manifests as red, pus-filled bumps on the skin, alongside redness in the face. Merus Seeks Approval for Bispecific Antibody in NSCLC, Pancreatic Cancer Netherlands-based Merus is advancing the investigational bispecific antibody zenocutuzumab for the treatment of non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) patients positive for fusions of the NRG1 gene. The FDA accepted Merus’ Biologics License Application (BLA) on May 6, 2024, and granted it Priority Review, which shortens the usual review period from 10 months to six months. In keeping with this schedule, the regulator is expected to release its decision no later than November 6. The NRG1 gene encodes for the HER3 ligand neuregulin. Though rare, fusion mutations between NRG1 and partner genes result in cancer-causing genomic events that are typically observed in certain malignancies, such as NSCLC and PDAC. Zenocutuzumab utilizes Merus’ proprietary Dock & Block technology to bind to HER2 and disrupt the interaction between the HER3 receptor and neuregulin or NRG1-fusion proteins. Preclinical studies have confirmed that zenocutuzumab effectively blocks the formation of HER2/HER3 heterodimers, in turn preventing cancer cell proliferation and survival. Merus’ data package for zenocutuzumab includes results from the Phase I/II eNRGy study, an October 2023 readout from which demonstrated a 37% objective response rate in NSCLC patients positive for NRG1 fusions. In PDAC patients carrying the same biomarker status, zenocutuzumab elicited a 42% objective response rate. Will FDA Follow Europe in Approving PTC’s Gene Therapy for AADC Deficiency? PTC Therapeutics is seeking U.S. approval for its gene therapy Upstaza (eladocagene exuparvovec) for the treatment of the ultrarare disease aromatic L-amino acid decarboxylase (AADC) deficiency in pediatric patients aged 18 months and up. The FDA’s decision is due on November 13. AADC deficiency is a genetic disorder caused by a mutation in the DDC gene, which leads to insufficient levels of the AADC protein. In turn, AADC deficiency is characterized by compromised production of dopamine, serotonin and other neurotransmitters, resulting in its key symptoms of developmental delays, muscle stiffness, movement problems and lethargy. Most patients with AADC deficiency need lifelong care, and the disease can be fatal. AADC deficiency affects between 1 in 64,000 and 1 in 90,000 births in the U.S. Upstaza targets the underlying cause of AADC deficiency by delivering a functional copy of the DDC gene. The gene therapy is delivered straight into the brain through a minimally invasive procedure and is meant to be a one-time treatment. In July 2022, the European Commission granted the gene therapy is Marketing Authorization, allowing its use in all 27 European Union member states, plus Iceland, Norway and Liechtenstein. The U.K.’s Medicines and Healthcare Products Regulatory Agency followed suit in November 2022. In March 2023, England’s National Institute for Health and Care Excellence recommended the use of Upstaza for the treatment of AADC deficiency, ensuring that the National Health Service will make the gene therapy available for patients who need it. FDA to Decide on Autolus’ CAR T Therapy for Acute Lymphoblastic Leukemia By November 16, the FDA will release its verdict for Autolus Therapeutics’ investigational CAR T therapy obecabtagene autoleucel (obe-cel) for the treatment for adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (ALL). The London-based biotech is backing its BLA, which the FDA accepted in January 2024, with data from the pivotal Phase II FELIX study. An interim readout in December 2022 showed that the next-generation CAR T therapy could induce a 70% overall remission rate, alongside promising expansion and initial persistence at a median follow-up of 6.4 months. Obe-cel was also well-tolerated overall, with 3% of patients developing grade 3 or higher cytokine release syndrome, and 8% experiencing grade 3 or higher immune effector cell-associated neurotoxicity syndrome. If approved, obe-cel will join the limited roster of approved CAR T therapies alongside others such as Bristol Myers Squibb’s Abecma and Breyanzi and Gilead’s Tecartus and Yescarta. Obe-cel previously won the FDA’s Orphan Drug and Regenerative Medicine Advanced Therapy designations.

▎药明康德内容团队编辑 根据PDUFA的预期目标日期，预计11月，美国FDA将对6款创新药物的批准做出监管决定，本文将对这些疗法进行相关介绍。 ▲11月有望在美国获批的新药（药明康德内容团队制图，点击可见大图） 活性成分：Zenocutuzumab 适应症：NRG1阳性非小细胞肺癌（NSCLC）或胰腺癌 公司名称：Merus Zenocutuzumab是一种靶向HER2和HER3的双特异性抗体，通过与HER2独特地结合并有效阻止HER3与NRG1或NRG1融合蛋白的相互作用，显示出对NRG1+癌症的潜在疗效。临床前研究表明，zenocutuzumab能强有力地抑制HER2/HER3异源二聚体的形成，从而抑制致癌信号通路，阻止肿瘤细胞增殖并阻断肿瘤细胞存活。临床研究显示，它在多种NRG1+癌症类型中具有抗肿瘤活性。 根据近期发布的1/2期临床试验的中期数据，zenocutuzumab在治疗晚期NRG1+非小细胞肺癌和胰腺导管腺癌（PDAC）时表现出持久疗效。试验结果显示，在晚期NRG1+非小细胞肺癌患者中，研究者根据RECIST 1.1版评估的总缓解率（ORR）为37.2%（29/78；95% CI，26.5-48.9），中位缓解持续时间（DOR）为14.9个月。在晚期NRG1+胰腺导管腺癌中，研究者根据RECIST 1.1版评估的ORR为42.4%（95% CI，25.5-60.8）；1例（3%）患者达到完全缓解，13例（39%）患者达到部分缓解，82%的患者肿瘤缩小。中位DOR为9.1个月（95% CI，5.5-12.0）。 活性成分：Eladocagene exuparvovec（商品名：Upstaza） 适应症：芳香族L-氨基酸脱羧酶缺乏症（AADCD） 公司名称：PTC Therapeutics Upstaza是一款基于腺相关病毒2（AAV2）载体的基因疗法，携带正常的人类DDC基因。它旨在通过一次性治疗，将功能正常的DDC基因直接递送到大脑的壳核中，提高芳香族L-氨基酸脱羧酶的水平并恢复多巴胺的生产。 Upstaza的疗效和安全性特征在多个临床试验和同情用药项目中得到验证，首例患者在2010年接受治疗。在临床研究中，无法达到预期运动发育里程碑的患者早在接受治疗3个月后就能观察到具有临床意义的运动功能改善，这一转变持续到接受治疗后5年以上。此外，所有接受治疗患者的认知能力得到改善。临床试验的结果已经在Molecular Therapy期刊上发表。2022年，它首次获得欧盟委员会批准上市，成为直接注入大脑的首款获批基因疗法，也是改变AADCD疾病进程的首款获批疗法。 活性成分：Obecabtagene autoleucel（obe-cel） 适应症：B细胞急性淋巴细胞白血病（ALL） 公司名称：Autolus Therapeutics Obe-cel是一款靶向CD19抗原的自体CAR-T细胞疗法。它旨在克服当前CAR-T细胞疗法在临床活性和安全性方面的局限性。它的独特之处在于，设计的嵌合抗原受体在与CD19结合后具有较快的解离速度（fast off-rate），从而能够尽量减少T细胞的过度激活，在降低毒副作用的同时，不易发生T细胞耗竭，提高CAR-T疗法的持久性。 在一项关键性2期临床试验FELIX中，obe-cel展示了对复发/难治性B细胞ALL患者的显著疗效。数据显示，在接受治疗的94位患者中，76%的患者获得完全缓解（CR）或CR伴不完全的血液学恢复（CRi）。在这一患者队列中，112名成年患者入组，其中94名患者接受了治疗。在获得缓解的患者中，97%的患者没有检测到最小残留病（MRD）。此外，在中位随访期为9.5个月时，61%获得缓解的患者在没有接受新抗癌疗法治疗的情况下仍然维持缓解。 此前，obe-cel已被美国FDA和欧洲药品管理局（EMA）授予孤儿药资格，还获得美国FDA授予的再生医学先进疗法（RMAT）认定以及EMA授予治疗成人复发/难治性B细胞急性淋巴细胞性白血病的PRIME认定。 活性成分：Govorestat 适应症：半乳糖血症 公司名称：Applied Therapeutics Govorestat（AT-007）是一种具有中枢神经系统（CNS）渗透性的醛糖还原酶抑制剂，能够阻止葡萄糖转化为山梨醇，目前正被开发用于治疗几种罕见的神经系统疾病，包括半乳糖血症、SORD缺乏症和磷酸甘露糖变位酶2-先天性糖基化障碍（PMM2-CDG）。 临床试验结果表明，接受govorestat治疗患者的日常生活活动、行为症状、认知、精细运动技能和震颤获得改善。Govorestat还显著降低了半乳糖血症成人和儿童的血浆半乳糖醇水平。半乳糖醇是一种毒性代谢物，可导致半乳糖血症患者的组织损伤和长期并发症。 值得一提的是，govorestat用于治疗半乳糖血症已获美国FDA授予孤儿药资格、儿科罕见病资格和快速通道资格。根据新闻稿，如果获得批准，govorestat将成为治疗半乳糖血症的首款药物。 活性成分：Acoramidis 适应症：伴有心肌病的转甲状腺素蛋白介导的淀粉样变性（ATTR-CM） 公司名称：BridgeBio Acoramidis是一款新一代、口服给药的高效转甲状腺素蛋白（TTR）小分子稳定剂。它旨在模拟具有保护作用的TTR T119M突变的功能，维持TTR蛋白的正常四聚体构象，防止具有毒性的淀粉样蛋白的产生。 BridgeBio此前公布的结果显示，acoramidis治疗使血清TTR水平在治疗第28天显著增加且维持稳定，并与ATTR-CM受试者在第30个月时降低的总死亡率（ACM）、心血管死亡率（CVM）和心血管住院率（CVH）风险相关。该疗法被行业媒体Evaluate评估为2024年可能获批上市的关键疗法。BridgeBio公司此前的新闻稿也表示，acoramidis有潜力成为重磅疗法。 活性成分：Zanidatamab 适应症：经治、不可切除、局部晚期或转移性HER2阳性胆道癌（BTC） 公司名称：Jazz Pharmaceuticals、Zymeworks Zanidatamab是一种具有新作用机制的HER2靶向在研双特异性抗体，可靶向HER2蛋白上两个不重复的抗原表位。Zanidatamab与HER2的结合可以阻断其信号传递、促进HER2自细胞表面移除，并已显示在几种表达HER2的癌症中具抗肿瘤活性，无论是作为单药还是与化疗或其他药物联合使用。 临床2b期试验结果显示，在经治HER2阳性胆道癌患者中，独立中央审评（ICR）所评估的zanidatamab治疗组患者的确认客观缓解率（cORR）为41.3%（95% CI：30.4-52.8），而Kaplan-Meier曲线分析显示患者的中位DOR为12.9个月（95% CI：6.0-不可估计）。过往研究显示，BTC患者接受2线标准护理化疗的历史缓解率仅为5-15%。 FDA已授予zanidatamab突破性疗法认定，用以治疗经治HER2基因扩增BTC患者。Zanidatamab亦获FDA授予快速通道资格、孤儿药资格治疗胃食管腺癌，并在中国获得突破性疗法认定。根据新闻稿，如果获得批准，zanidatamab将成为FDA批准用于治疗HER2阳性局部晚期或转移性BTC患者的首个HER2靶向药物。 ▲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： [1] Merus Announces U.S. FDA Acceptance and Priority Review of Biologics License Application for Zeno for the Treatment of NRG1+ NSCLC and PDAC. Retrieved Oct 30, 2024, from https://www.globenewswire.com/news-release/2024/05/06/2876137/37568/en/Merus-Announces-U-S-FDA-Acceptance-and-Priority-Review-of-Biologics-License-Application-for-Zeno-for-the-Treatment-of-NRG1-NSCLC-and-PDAC.html [2] PTC Therapeutics Announces FDA Acceptance and Priority Review of the BLA for Upstaza™. Retrieved Oct 30，2024, from https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-acceptance-and-priority-review [3] Tai et al., (2021). Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Molecular Therapy, DOI:https://doi.org/10.1016/j.ymthe.2021.11.005 [4] Autolus Therapeutics announces acceptance of Biologics License Application for obecabtagene autoleucel (obe-cel) as a potential treatment for relapsed/refractory Adult B-cell Acute Lymphoblastic Leukemia (ALL). Retrieved Oct 30，2024，from https://www.globenewswire.com/news-release/2024/01/22/2812903/0/en/Autolus-Therapeutics-announces-acceptance-of-Biologics-License-Application-for-obecabtagene-autoleucel-obe-cel-as-a-potential-treatment-for-relapsed-refractory-Adult-B-cell-Acute-L.html [5] Applied Therapeutics Announces FDA Acceptance and Priority Review of New Drug Application for Govorestat for the Treatment of Classic Galactosemia. Retrieved Oct 30, 2024 from https://ir.appliedtherapeutics.com/news-releases/news-release-details/applied-therapeutics-announces-fda-acceptance-and-priority [6] BridgeBio Shares Data on Serum TTR Increase When Switching Participants from Placebo and Tafamidis to Acoramidis in ATTRibute-CM and its Open-Label Extension. Retrieved Oct 30, 2024, from https://www.globenewswire.com/news-release/2024/08/30/2938591/0/en/BridgeBio-Shares-Data-on-Serum-TTR-Increase-When-Switching-Participants-from-Placebo-and-Tafamidis-to-Acoramidis-in-ATTRibute-CM-and-its-Open-Label-Extension.html [7] BridgeBio Pharma Announces Submission of New Drug Application (NDA) to U.S. Food and Drug Administration (FDA) for Acoramidis for the Treatment of Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM). Retrieved December 6, 2023, from https://www.globenewswire.com/news-release/2023/12/05/2790824/0/en/BridgeBio-Pharma-Announces-Submission-of-New-Drug-Application-NDA-to-U-S-Food-and-Drug-Administration-FDA-for-Acoramidis-for-the-Treatment-of-Patients-with-Transthyretin-Amyloid-Ca.html [8] Zanidatamab Granted Priority Review for HER2-Positive Metastatic Biliary Tract Cancer. Retrieved May 29, 2024 from https://www.prnewswire.com/news-releases/zanidatamab-granted-priority-review-for-her2-positive-metastatic-biliary-tract-cancer-302157979.html 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

Today, a brief rundown of news from Regeneron Pharmaceuticals and Madrigal Pharmaceuticals, as well as updates from UCB, AbbVie and PTC Therapeutics that you may have missed.Shares of Regeneron Pharmaceuticals fell nearly 10% amid growing uncertainty about the future sales of its flagship Eylea franchise. Regeneron has been looking to a new high-dose version of Eylea to ward off competition from Roches Vabysmo and emerging biosimilar threats. But at $392 million, third-quarter sales missed consensus estimates and fell below the trajectory of Vabysmos matched-quarter revenues, reflecting slower-than-expected adoption, wrote Leerink Partners analyst David Risinger. Still, data readouts expected in the months ahead on drugs for blood clots, lung cancer and obesity could help refocus [the] story, wrote RBC Capital Markets Brian Abrahams in a separate note. Ben FidlerUCB said Thursday there were bright spots in a failed study testing the companys experimental drug for Alzheimers disease. The drug, called bepranemab, binds to a specific region on tau, a protein with well-established ties to Alzhiemers. While the mid-stage trial missed its main goal, UCB said key secondary objectives indicated its drug can slow cognitive decline and the accumulation of tau better than a placebo. After-the-fact analyses also found certain participants who received a high dose of bepranemab experienced 29% slower disease progression. Chief Scientific Officer Alistair Henry said the company is deeply encouraged by the results. Jacob BellSales of Rezdiffra, Madrigal Pharmaceuticals recently approved drug for metabolic dysfunction-associated steatohepatitis, or MASH, widely beat Wall Street expectations during the third quarter. Earnings reported by Madrigal Thursday show Rezdiffra sales totaled $62 million, well above the consensus forecast of around $36 million. Madrigal said that, as of Sept. 30, insurance policies were in place for more than 80% of people covered by private payers in the U.S. Shares in Madrigal, which had already impressed in August with its fast launch, climbed by nearly 40% through Friday morning. Ned PagliaruloAbbvie will work with biotech startup EvolveImmune Therapeutics to develop multispecific antibody drugs for cancer, the companies said Thursday. The deal hands Abbvie an option to license T cell engagers EvolveImmune designs with certain tweaks to boost their potency. AbbVie is paying the startup $65 million in cash and an equity investment to start the deal, and could add another $1.4 billion in future option fees and milestones. Ben FidlerOne other biopharmaceutical company bid to acquire Longboard Pharmaceuticals, but withdrew its offer of $60 per share before Lundbeck secured an acquisition agreement at the same price on Oct. 14. Longboard also contacted three other pharmas, but none expressed interest in discussing a buyout. The background of the $2.6 billion deal, disclosed via a securities filing Wednesday, also shows that Lundbeck upped its offer five times, from an initial proposal of $29 per share. Ned PagliaruloThe Food and Drug Administration will again evaluate whether to approve PTC Therapeutics Translarna for Duchenne muscular dystrophy, the company announced Wednesday. The agency previously rejected PTCs drug, which has long been available in Europe but may soon be withdrawn there due to questions about its effectiveness. The latest U.S. review is the result of PTCs resubmission and, as a result of the company originally filing its application over the FDAs protest, wont be reviewed on typical agency timelines. PTC believes the totality of evidence, including data from a patient registry, proves Translarnas benefits. But, Leerink Partners analyst Joseph Schwartz wrote, we're not getting our hopes up given the FDA's historically overwhelmingly negative view of the drug. Ben Fidler '