Dostarlimab-gxly

Labor Day marks the unofficial end of summer, and children who haven’t already started school will be returning to classrooms soon. Because many children suffer from food allergies, EpiPens have become a staple in schools, standing ready to quickly administer an epinephrine injection to counteract an allergic reaction. This academic year, children will have an alternative. The FDA in August approved the first nasal spray epinephrine, a product from ARS Pharma that will be marketed as neffy. The regulatory decision for the 2 mg spray covers the treatment of type I allergic reactions, which includes reactions caused by food, medications, and insect bites. It may be used by adults as well as children who weigh 30 kilograms (66 pounds) or more. San Diego-based ARS said an application seeking to expand the approval to children weighing less than 30 kg is on track for an FDA submission by the end of this year. Injectable epinephrine for type 1 allergic reactions has been around since 1987. ARS developed neffy as an aqueous formulation of epinephrine and an ingredient that improves its bioavailability — how much of a drug is available to provide its effect when it is administered intranasally. The new approval comes nearly a year after the FDA turned down ARS’s application for neffy. ARS’s submission had relied on human factor studies that tested how people interact with the drug/device. The FDA asked for more clinical data. sponsored content Integrated Enrollment Platforms and Consumer Assistance Centers: The Strongest Advantage for State-Based Exchanges In the ever-evolving landscape of state-based health insurance exchanges, the convergence of technology and customer service is reshaping how these exchanges operate. The increasing advent of automation and artificial intelligence (AI) is rapidly dismantling the traditional business model that relies on the siloing of technology and customer service centers. By Shankar Srinivasan, Co-Founder and General Manager, GetInsured and Jason Sparks, VP, of Project Management and Implementation, GetInsured Neffy’s August approval came nearly two months ahead of the October target date for a regulatory decision, which William Blair analyst Tim Lugo said was expected after the FDA told ARS that it intended to move quickly on the review and the agency was under “significant pressure from patient advocacy groups” after last year’s rejection of the application. “We view the early approval as a positive ahead of the return-to-school season when many patients are expected to renew prescriptions,” Lugo said in a research note sent to investors. Lugo said ARS sees market opportunity in patients who will switch to neffy from a currently available epinephrine product as well as patients who have let their epinephrine prescriptions lapse, including those unwilling to carry or use a needle product. Longer term, the company see opportunity in tapping into an estimated 13.5 million people who have been diagnosed with a condition that could be treated with epinephrine but have not yet received a prescription. In an investor presentation, ARS said it expects to launch neffy later in the current quarter. Last week, the company announced European Commission approval of the nasal spray. ARS said this product, which will be sold in Europe under the brand name EURneffy, will launch by the end of this year. EURneffy will be marketed by another company with an already established commercial footprint in Europe. sponsored content 5 Health Reasons to Ditch Concrete Jungles for Countryside In an increasingly urbanized world, the allure of countryside living is growing stronger, especially when it comes to health and well-being. By Impact Brands With summer wrapping up, here’s a recap of other recent regulatory news: —Emergent BioSolutions smallpox vaccine ACAM2000 expanded its FDA approval to include mpox, which is from the same virus family as smallpox. During the mpox outbreak of 2022, the FDA permitted use of the vaccine under an expanded access investigational new drug application. The additional approval comes amid an ongoing mpox outbreak in Central Africa. —Three updated Covid-19 vaccines now have the FDA’s blessing for use during the upcoming respiratory infection season. The regulator approved and authorized updated Covid-19 vaccines from Moderna and partners BioNTech and Pfizer. The new shots address the KP.2 strain of the omicron variant of SARS-CoV-2. That’s close to the KP.3.1.1 subtype that is currently most prevalent in the U.S., according to the Centers for Disease Control and Prevention. The FDA previously told vaccine makers that shots addressing the KP.2 strain were preferred, if feasible, for the 2024-2025 vaccination season. Late last week, the FDA also authorized an updated version of a protein-based Covid-19 vaccine from Novavax. —Johnson & Johnson cancer drug lazertinib, brand name Lazcluze, is now FDA-approved as a first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). The drug is a once-daily pill designed to target epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, which must be detected by a companion diagnostic. For this indication, the approval specifies Lazcluze must be given in combination with Rybrevant, a J&J drug initially approved in 2021 as a treatment for NSCLC with exon 20 insertion mutations to EGFR. In March, the FDA approved Rybrevant as a first-line treatment for such cancers. —As expected, the FDA turned down Regeneron Pharmaceuticals’ application for linvoseltamab as a treatment for advanced cases of multiple myeloma. Regeneron forecast the rejection earlier this month during its conference call to discuss second quarter 2024 financial results, disclosing that that the FDA flagged unresolved findings with a third-party manufacturer of linvoseltamab, a bispecific antibody that targets the BCMA protein on multiple myeloma cells. Those findings concern another company’s drug candidate and Regeneron believes that matter has been resolved. However, another FDA inspection is required before the agency can approve the drug. —Regeneron did welcome a regulatory approval in Europe that marks the first for its bispecific antibody platform. The European Commission approved odronextamab, brand name Ordspono, as a treatment for follicular lymphoma or diffuse large B-cell lymphoma that has advanced after two or more earlier lines of therapy. The drug is designed to bind to CD20 on cancer cells and CD3 on T cells. Ongoing clinical trials are evaluating this drug as a monotherapy and in combinations as an earlier line of cancer treatment. —Liquidia received tentative FDA approval for Yutrepia as a treatment for pulmonary arterial hypertension (PAH). Yutrupeia is an inhalable powder formulation of treprostinil, a drug that United Therapeutics markets in injectable, oral, and inhaled formulations for the treatment of PAH. According to Liquidia, the FDA said Yutrepia met all benchmarks for quality, safety, and efficacy. However, final approval cannot be granted until the May 23, 2025, when United Therapeutics’ patent for its dry powder formulation of treprostinil expires. Liquidia is challenging the FDA’s decision. —The FDA lifted a partial clinical hold on an antibody drug conjugate (ADC) MediLink Therapeutics is developing in partnership with BioNTech. The partial hold on the drug, BNT326/YL202, was announced in mid-June after MediLink reported treatment-related adverse events. BioNTech said in addition to risk mitigation measures, the study will proceed with doses no higher than 3 mg per kilogram, where the safety profile was manageable and encouraging clinical activity was observed. BioNTech and MediLink began their partnership on the HER-3-targeting ADC last year. —Incyte already has a presence in graft-versus-host disease with Jakafi. FDA approval of axatilimab, brand name Niktimvo, gives the company another GVHD drug with a different approach. While Jakafi is a small molecule JAK inhibitor, Niktimvo is an antibody designed to block a protein called colony stimulating factor-1. FDA approval of the new drug covers the treatment chronic GVHD in adults after at least two prior lines of therapy. Niktimvo was initially developed by Syndax Pharmaceuticals. In 2021, Incyte and Syndax began a partnership on the drug; the two companies will share in commercialization of the therapy in the U.S. while Incyte will commercialize the product in the rests of the world. —The FDA approved Galderma’s nemolizumab, brand name Nemluvio, as a treatment for prurigo nodularis, a rare neuroimmune disease that leads to chronic itch and the formation of nodules on the skin. The antibody drug is designed to inhibit IL-31, a signaling protein associated with multiple inflammatory conditions. The drug is also under FDA review for atopic dermatitis; a regulatory decision is expected later this year. —AstraZeneca cancer drug Imfinzi expanded its approved lung cancer uses to include the treatment of adults with resectable early-stage non-small cell lung cancer (NSCLC). The latest approval covers use of the drug in combination with neoadjuvant chemotherapy before surgery and as an adjuvant monotherapy after surgery. The drug’s first lung cancer approval was in 2018 as a treatment for advanced cases NSCLC. In 2020, the FDA approved the drug for treating extensive-stage small cell lung cancer. —Ascendis Pharma won FDA approval for Yorvipath for hypoparathyroidism, a rare disease in which patients have low levels of parathyroid hormone. Approval of the drug, an engineered version of parathyroid hormone administered as a once-daily injection, comes as Takeda Pharmaceutical plans to discontinue production of Natpara, the only other engineered parathyroid hormone drug currently available. Ascendis plans to launch Yorvipath in the first quarter of next year. —The FDA rejected Lykos Therapeutics’ application seeking approval for midomafetamine (MDMA), a psychedelic drug the company had developed as a treatment for post-traumatic stress disorder (PTSD). According to San Jose-based Lykos, the FDA asked the company to conduct another Phase 3 clinical trial to further study the safety and efficacy of the drug, echoing concerns raised during an June advisory committee meeting. Lykos plans to request an FDA meeting to ask for a reconsideration of the regulatory decision and to discuss a potential resubmission of a new drug application. —Novartis drug iptcaopan, brand name Fabhalta, expanded its label with accelerated FDA approval in the rare kidney disease immunoglobulin A nephropathy. In this indication, the complement inhibitor will compete with Travere Therapeutics’ Filspari and Calliditas Therapeutics’ Tarpeyo. Fabhalta was first approved last December as a treatment for the rare blood disorder paroxysmal nocturnal hemoglobinuria. —The FDA delayed its regulatory decision for Humacyte’s engineered blood vessels. The agency told Humacyte it needs more time to complete its review of ATEV, the company’s bioengineered human tissue intended to serve as an alternative to harvesting a vein from a trauma patient. Durham, North Carolina-based Humacyte said it does not yet have a new target date for a regulatory decision. —Adaptimmune Therapeutics’ Tecelra became the first engineered cell therapy approved by the FDA as a treatment for a solid tumor. The accelerated approval covers the treatment of advanced cases of synovial sarcoma. Tecelra is made by engineering a patient’s T cells with a T cell receptor that recognizes a target on the inside of a cancer cell. —GSK cancer drug Jemperli broadened its label to cover the majority of endometrial cancer cases. The immunotherapy was initially approved in 2021 as a treatment for advanced or recurrent endometrial cancer that carries a particular genetic signature called a mismatch repair deficiency. The latest approval expands use of the drug to patients with mismatch repair proficient/microsatellite stable tumors. Such cases represent between 70% and 75% of endometrial cancer patients. Jemperli’s FDA approval in the expanded indication covers use of the therapy in combination with chemotherapy. Photo from Flickr user US Department of Education

自十多年前靶向CTLA4的伊匹木单抗（Ipilimumab）首次用于转移性黑色素瘤以来，免疫检查点抑制剂（ICIs）的研究和应用可谓如火如荼，如今，至少有8种ICI和35种基于ICI的联合免疫疗法获得FDA批准。对于选择ICI治疗的患者来说，准确的生物标志物既能最大化治疗效果，又能减少不良反应。本篇文章来自 nature reviews cancer，全面总结了用于预测ICI反应或耐药的各类生物标志物（图1），以及当前的挑战和进展。 图1 实体肿瘤免疫检查点抑制剂的预测性生物标志物 01      静态生物标志物 程序性细胞死亡蛋白（PD1）通过与其两个配体——PDL1和PDL2的相互作用负向调节T细胞的免疫活性。PD1和PDL1的单克隆抗体已被FDA批准用于各种癌症类型（图2）。通过对肿瘤组织进行PDL1的免疫组化（IHC），进行TPS评分，即在任何强度下显示部分或完全膜染色的活肿瘤细胞的百分比，最初被FDA批准作为晚期非小细胞肺癌（NSCLC）的伴随诊断测试。 图2 NSCLC的免疫治疗 但是，由于各种原因，PDL1作为预测ICIs反应的生物标志物的广泛应用受到限制。首先，最有可能从治疗中受益的队列临界值因癌症类型而异。其次，评估PDL1表达的细胞群也因癌症类型而异，其中包括肿瘤细胞、免疫细胞或两者组合。再次，许多癌症类型在PDL1表达与免疫治疗应答之间几乎没有相关性。最后，在同一患者中，PDL1在不同肿瘤病变中，甚至在同一肿瘤中表达不一致。 免疫治疗是否有反应主要看T细胞能否识别新抗原。目前，从肿瘤组织和循环肿瘤DNA （ctDNA）中获得样本，进行下一代测序（NGS），可以测量肿瘤突变负荷（TMB）。TMB强弱取决于多种因素，包括：肿瘤呈现的肿瘤新抗原；肿瘤新抗原被免疫系统识别；宿主产生抗原特异性反应的能力等。 基于组织生物标志物具有一下局限性：①分析方法的局限性；②生物标志物的准确性和一致性；③肿瘤的异质性；④患者的异质性。因此，需要寻找新的生物标志物。   02    动态生物标志物 由于生物标志物的表达可能会随着时间的推移和治疗进程而改变，因此，对肿瘤和免疫生物学的静态、单一评估是不够真实的。几项研究表明，当治疗前和治疗后的样本一起纳入时，与ICI治疗相关的反应/无反应变化更易识别,这说明了动态而非静态生物标志物的重要性。 2.1 低侵入性动态生物标志物 动态进行组织取样具有局限性，因此，基于血液的分析被认为是一种更适合纵向评估的模式。其易于获取，并发症风险较低，侵入性小，患者的疼痛更少，可以广泛应用，更具有成本效益。这种方法还具有对个体内所有肿瘤病变进行生物学评估的优势（反映的是平均读数，而不是特定部位的读数），因此可以很好地评估与治疗相关的系统动态变化。 2.2 放射组学作为预测因子 通过使用非侵入性生物标志物（如影像数据），也可以克服基于组织活检的局限性。成像生物标志物的优点是能够可视化任何时间点、任何转移潜在部位的肿瘤，因此它们可以在未来作为非侵入性动态生物标志物发挥作用。 2.3 肠道微生物组生物标志物 大量研究表明，特定的肠道微生物组与各种癌症类型的ICI反应显著相关。四项宏基因组研究的荟萃分析证明某些细菌分类群、代谢组学途径的富集与黑色素瘤患者的ICI反应显著相关（图3）。此外，新的机器学习模型已经能够将特定细菌属与免疫治疗反应联系起来。其他研究甚至揭示了单个细菌类群能正向或负向调节宿主免疫系统，从而在癌细胞免疫逃逸方面发挥作用。 图3 黑色素瘤示意图   03   患者特异性的生物标志物 随着新辅助治疗方法的发展，新的试验如PRADO试验，纳入了患者特异性病理反应数据，来确定下一步的临床干预措施。 离体肿瘤模型也具有预测患者特异性反应的潜力。与用于血液系统恶性肿瘤药物反应分析的体外平台相反，实体肿瘤由于其特定的肿瘤微结构和肿瘤-免疫相互作用，不能通过简单的肿瘤细胞培养轻易复制。而患者来源的肿瘤球体、类器官或芯片上的器官可以克服此难点，因为它们不仅可以通过自体肿瘤细胞，还可以通过结合淋巴细胞和髓细胞免疫群体来以验证ICI反应，具有患者特异性，能够重建更精确的3D环境。   04   当前进展 目前，多机构、多国别合作整合不同时间点的多个来源的数据，通过机器学习构建框架，为识别和验证更精细的生物标志物奠定基础。迄今为止已发表的(表1)和进行中的研究（表2）如下表： 表1 免疫检查点抑制剂反应的预测性生物标志物已发表研究 表2 免疫检查点抑制剂反应的预测性生物标志物的在研试验    结语   目前有各种各样的肿瘤生物标志物正在试验中，随着我们向精准医学时代的过渡，个体患者水平的预测分析终将实现。理想的生物标志物预测模型将通过整合肿瘤、免疫微环境和宿主因素，提供肿瘤反应或进展的动态评估信息。  主要参考文献  [1] Dirk, Schadendorf, Stephen F ,et al.Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma.[J].Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015.DOI:10.1200/JCO.2014.56.2736. [2] Oaknin A , Gilbert L , Tinker A V ,et al.SAFETY AND ANTITUMOR ACTIVITY OF DOSTARLIMAB IN PATIENTS (PTS) WITH ADVANCED OR RECURRENT DNA MISMATCH REPAIR DEFICIENT (DMMR) OR PROFICIENT (MMRP) ENDOMETRIAL CANCER (EC): RESULTS FROM THE GARNET STUDY[J].International journal of gynecological cancer: official journal of the International Gynecological Cancer Society, 2020(suppl.4):30. [3] Kasherman L , Ahrari S , Lheureux S .Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer[J].Future Oncology, 2021, 17(8):877-892.DOI:10.2217/fon-2020-0655. [4] Hendry S , Byrne D J , Wright G M ,et al.Comparison of Four PD-L1 Immunohistochemical Assays in Lung Cancer[J].Journal of Thoracic Oncology, 2017:S155608641733054X.DOI:10.1016/j.jtho.2017.11.112. [5] Deng L , Langley R J , Brown P H ,et al.Structural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor.[J].Nature Immunology, 2007, 8(4):398.DOI:10.1038/ni1447. [6] Ss F , Sade-Feldman M , Kim J ,et al.Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma[J].Cell reports. Medicine, 2022, 3(2):100500.DOI:10.1101/2021.07.03.450733. 共建Biomedical创新生态圈！ 如何加入BiG会员？