SERM program(QuatRx)

SAN DIEGO and GAINESVILLE, Ga., May 23, 2023 (GLOBE NEWSWIRE) -- Societal CDMO, Inc. (“Societal CDMO”; Nasdaq: SCTL), a contract development and manufacturing organization (CDMO) dedicated to solving complex formulation and manufacturing challenges primarily in small molecule therapeutic development, today announced that it has been selected by Atossa Therapeutics, Inc. (Nasdaq: ATOS) to provide a range of its Clinical Trial Services (CTS) offerings focused on Atossa’s proprietary Selective Estrogen Receptor Modulator (SERM), (Z)-endoxifen. The agreement spans a range of activities including analytical method transfer/development and validation, cleaning verification method validation, manufacturing of multiple R&D engineering batches, and stability testing of the R&D engineering batches. “Societal’s demonstrated expertise in the technology transfer of established drug products, along with our long track record of successfully formulating and manufacturing innovative small molecules, positions us well to align with Atossa and support the ongoing clinical development of the company’s proprietary oral formulation of (Z)-endoxifen. We are eager to initiate this important work and deliver exceptional results for Atossa,” said David Enloe, chief executive officer of Societal CDMO. “It is important to highlight that we are continuing to see growing demand for the CTS portion of our business, which is helping to both grow our overall revenue and diversify our expanding customer base.” About (Z)-Endoxifen (Z)-endoxifen is the most active metabolite of the FDA approved Selective Estrogen Receptor Modulator (SERM), tamoxifen. Studies by others have demonstrated that the anti-estrogenic effects of tamoxifen are driven in a concentration-dependent manner by (Z)-endoxifen. In addition to its potent anti-estrogen effects, (Z)-endoxifen at higher concentrations has been shown to target PKCβ1, a known oncogenic protein. Atossa has developed a proprietary oral formulation of (Z)-endoxifen that does not require liver metabolism to achieve therapeutic concentrations and is encapsulated to bypass the stomach as acidic conditions converts a greater proportion of (Z)-endoxifen to the inactive (E)-endoxifen. Atossa’s (Z)-endoxifen has been shown to be well tolerated in Phase 1 studies and in a small Phase 2 study of women with breast cancer. The company is currently studying (Z)-endoxifen in healthy women with measurable breast density and premenopausal women with ER+/HER2- breast cancer. Atossa’s (Z)-endoxifen is protected by two issued U.S. patents and numerous pending patent applications. About Atossa Therapeutics Atossa Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing innovative medicines in areas of significant unmet medical need in oncology with a current focus on breast cancer. For more information, please visit About Societal CDMO Societal CDMO (NASDAQ: SCTL) is a bi-coastal contract development and manufacturing organization (CDMO) with capabilities spanning pre-Investigational New Drug (IND) development to commercial manufacturing and packaging for a wide range of therapeutic dosage forms with a primary focus in the area of small molecules. With an expertise in solving complex manufacturing problems, Societal CDMO is a leading CDMO providing therapeutic development, end-to-end regulatory support, clinical and commercial manufacturing, aseptic fill/finish, lyophilization, packaging and logistics services to the global pharmaceutical market. In addition to our experience in handling DEA controlled substances and developing and manufacturing modified-release dosage forms, Societal CDMO has the expertise to deliver on our clients’ pharmaceutical development and manufacturing projects, regardless of complexity level. We do all of this in our best-in-class facilities, which total 145,000 square feet, in Gainesville, Georgia and San Diego, California. Societal CDMO: Bringing Science to Society. For more information about Societal CDMO’s customer solutions, visit societalcdmo.com. Forward-Looking Statements This press release includes forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. These statements, among other things, the Company’s expectations regarding the completion of the proposed public offering, the Company’s use of proceeds from the proposed offering, and other statements. The words “anticipate”, “believe”, “could”, “estimate”, “upcoming”, “expect”, “intend”, “may”, “plan”, “predict”, “project”, “will” and similar terms and phrases may be used to identify forward-looking statements in this press release. Our operations involve risks and uncertainties, many of which are outside our control, and any one of which, or a combination of which, could materially affect our results of operations and whether the forward-looking statements ultimately prove to be correct. Factors that could cause the company’s actual outcomes to differ materially from those expressed in or underlying these forward-looking statements include risks and uncertainties associated with demand for the company’s services, which depends in part on customers’ research and development and the clinical plans and market success of their products; customers’ changing inventory requirements and manufacturing plans; customers and prospective customers decisions to move forward with the company’s manufacturing services; the average profitability, or mix, of the products the company manufactures; the company’s ability to enhance existing or introduce new services in a timely manner; fluctuations in the costs, availability, and suitability of the components of the products the company manufactures, including active pharmaceutical ingredients, excipients, purchased components and raw materials, or the company’s customers facing increasing or new competition. These forward-looking statements should be considered together with the risks and uncertainties that may affect our business and future results presented herein along with those risks and uncertainties discussed in our filings with the Securities and Exchange Commission at These forward-looking statements are based on information currently available to us, and we assume no obligation to update any forward-looking statements except as required by applicable law. Contacts: Stephanie Diaz (Investors) Vida Strategic Partners 415-675-7401 sdiaz@vidasp.com Tim Brons (Media) Vida Strategic Partners 415-675-7402 tbrons@vidasp.com Ryan D. Lake (CFO) Societal CDMO 770-531-8365 ryan.lake@societalcdmo.com

在过去的二十年里，新型抗肿瘤药物的扩散彻底改变了癌症的治疗方法，并提高了许多以前难以治愈的恶性肿瘤的存活率。然而，许多药物都与特有的眼科不良反应有关，随之而来的是一系列不同程度的眼睛毒性（表1）。因此，肿瘤医生和眼科工作者需要熟悉新型抗肿瘤药物以及这些药物可能造成的眼部后遗症。本文就几类新型抗肿瘤药物的眼部不良反应以及处理方法做一个简要介绍。表1. 治疗药物对眼部不良反应的级别划分ADC目前ADC药物成为了一类重要的癌症靶向治疗药物，已在多类型肿瘤类型中显示优异的疗效。但眼毒性已成为一些ADC药物常见的副作用。毒性在临床试验中，有眼毒性的ADC药物角膜毒性的发生率从11%到37%不等。例如，在临床试验中，3.2%患者中在服用Tivdak (tisotumab vedotin-tftv)后会出现严重的溃疡性角膜炎，40%的患者出现结膜不良反应，包括结膜炎、结膜擦伤和结膜充血。Elahere (mirvetuximab soravtansine-gynx) 可在1%的患者中引起葡萄膜炎。在一些ADC药物治疗中会出现微囊样上皮变(MECs)。MECs发生在角膜上皮层，但目前导致角膜MECs的机制仍不完全清楚。目前最新的文献表明，ADC进入角膜上皮细胞，细胞发生凋亡(观察到MECs)，这些细胞最终脱落并被新的上皮细胞取代。治疗和管理MECs目前还没有治疗方法，如果患者视力没有变化，通常会被观察到。如果停止治疗，MECs将在几周到几个月内消失。干眼的治疗包括每天至少三次不含防腐剂的人工泪液和环孢素眼液或乳剂，或着lifitegast眼液。治疗伴随的眼缘炎被推荐用眼睑卫生处理或热敷。葡萄膜炎或结膜炎的治疗包括皮质类固醇滴注。隐形眼镜在这些患者中应限制使用，因为药物可能会滞留在泪膜中，从而吸收到隐形眼镜中，从而加剧角膜病变。基线眼科检查是确保角膜健康和记录任何其他眼部病理的关键。在开始治疗之前，应该对患者进行彻底的眼部副作用指导，包括视力模糊和干眼，以便他们能够预料到可能会发生的变化。Tivdak和Elahere都有FDA的黑匣子警告。Tivdak在每次给药之前，根据临床指示，需要将患者转诊至眼科护理提供者进行眼科检查，包括基线检查时的视力和裂隙灯检查。坚持术前用药和所需的眼部护理，以降低眼部不良反应的风险。如有任何新的或恶化的眼部体征和症状，应立即将患者转诊至眼科护理机构。根据不良反应的严重程度，停止、减少剂量或永久停止Tivdak。服用Elahere的患者必须在每个治疗周期的第一天之前至第八天期间使用皮质类固醇滴眼液。每次就诊时，必须向肿瘤科医生报告眼睛检查结果，包括眼睛毒性分级，以确定患者是否应该继续治疗，并可能影响剂量。对于严重的角膜病变或角膜溃疡，可能需要眼科医生的治疗。免疫检查点抑制剂(ICI)免疫检查点抑制剂(ICI)现在已被FDA批准用于治疗各种类型的癌症，如黑色素瘤、非小细胞肺癌、肾细胞癌、尿路上皮癌和霍奇金淋巴瘤。ICI主要通过激活免疫系统攻击癌细胞，但其也可能在健康细胞中引起炎症反应，从而导致与免疫有关的眼部不良事件。毒性约1%的患者会发生与眼免疫相关的不良事件。ICI治疗可引起眼部任何部位的炎症。潜在的不良事件包括眼睑炎症、结膜炎、角膜炎、葡萄膜炎(前部或后部)、玻璃体炎、视网膜炎、眼眶肌炎、颅神经炎和视神经炎。治疗和管理眼前段炎症的治疗包括局部皮质类固醇滴眼液，例如，双眼每天四次使用醋酸泼尼松龙眼用混悬剂。后段炎症(包括视神经炎)的治疗包括全身性激素治疗。如果眼部状况没有改善，就应该停止使用这种药物。在将眼部疾病归因于药物毒性之前，应通过血检排除其他炎症的感染原因。如ESR、CRP、HSV1/2滴度、RF、QuantiFERON-TB、RPR、ANCA和Lyme。任何眼眶或视神经病变的患者还应进行大脑/眼眶的MRI成像。出现视力模糊、疼痛或发红的患者应及时检查，包括眼底检查。特别注意前房和玻璃体将有助于发现细微的炎症。酪氨酸激酶抑制剂(TKIs)酪氨酸激酶使底物酶上的氨基酸磷酸化，进而改变信号转导途径。在许多人类癌症中发现了这些通路的失调，TKI通过阻断这些信号发挥作用。虽然目前市场上有许多TKI，但最有可能导致眼部毒性的是格列卫(imatinib)。该药已被用于治疗白血病、骨髓增生异常疾病、高嗜酸性粒细胞综合征、隆起皮肤纤维肉瘤和胃肠道间质瘤。毒性服用格列卫的患者中有47%出现轻度至中度眼眶周围水肿，此外还有结膜松弛，这会导致眼睑贴合不良，导致溢泪。这些患者还可能经历自发性结膜下出血，在极少数情况下，还会出现视网膜出血、黄斑囊样水肿和视神经水肿。治疗和管理眼眶周围水肿的治疗包括局部皮质类固醇滴注，在某些情况下，口服利尿剂。停止治疗后，溢泪将会改善。目前还没有已知的治疗这些患者视神经炎的方法。患者应定期监测，并在出现视觉症状时进行监测。BRAF抑制剂BRAF抑制剂药物被批准用于治疗BRAF V600E突变的黑色素瘤。丝裂原活化蛋白激酶(MAPK)信号通路调节黑色素瘤细胞的增殖，而这些BRAF抑制剂可以干扰了这一MAPK通路。BRAF抑制剂现经常与MEK抑制剂联合使用，并增加眼睛毒性的可能性。FDA批准的BRAF抑制剂的例子包括Zelboraf(vemurafenib)、Tafinlar and Rafinlar(dradfenib)和Braftovi(encorafenib)。毒性BRAF抑制剂药物治疗最常见的眼部毒性是干眼/结膜炎，这在大约2%的患者中发生，以及葡萄膜炎(从前部到后部)，在服用Zelboraf的患者中出现的比例为4%到9%。这种药物还可能导致皮肤鳞状细胞癌、寻常疣皮损和角化棘皮瘤，这些都可以在眼皮上发现。治疗和管理BRAF抑制剂引起的干眼症状一般较轻，通常不需要干预或可以通过人工泪液滴眼液来控制。根据葡萄膜炎的位置，除了停止、暂停或更低剂量药物治疗外，还可以使用局部、眼周或眼内皮质类固醇进行治疗。Braftovi的说明书规定，对于眼科治疗无效的1级或2级葡萄膜炎，或任何3级葡萄膜炎，都停止使用该药物。鳞状增生性病变(特别是鳞状细胞癌)应该进行手术切除，患者通常能够继续药物治疗。Braftovi的说明书规定，患者应定期进行眼科评估，并对任何新的或恶化的干扰进行评估。临床上或视觉上有重要意义的发现，必须报告给肿瘤医生，因为它们可能影响剂量和治疗，可能需要与眼科医生一起处理。丝裂原活化蛋白激酶(MEK)抑制剂MEK抑制剂通过阻断MAPK途径发挥作用，而MAPK途径在人类癌症中通常是不受调控的。这些药物已被用于治疗BRAF V600E突变黑色素瘤、组织细胞肿瘤和I型神经纤维瘤病。许多MEK抑制剂现在与BRAF抑制剂联合用于治疗某些癌症，增加了眼睛毒性的可能性。FDA批准的MEK抑制剂的例子包括Mekinist(trametinib)、Cotelic(cobimetinib)、Koselugo(selumetinib)和Mektovi(binimetinib)。毒性MEK抑制剂相关视网膜病变可能发生在第一剂MEK抑制剂治疗的第一周内。特点是双侧视网膜呈黄灰色隆起，呈圆形，无下轨。OCT显示交错区和视网膜色素上皮之间的液体以不同的形态出现。48%的患者会出现视力模糊或视力变形。另一个潜在的眼部并发症是视网膜静脉阻塞，发生率为0.2%，易患危险因素包括青光眼、高血压和糖尿病。治疗和管理在患有MEK抑制剂相关视网膜病变（MEKAR）的患者中，液体往往会自行溶解，不需要干预。然而，对于眼睛毒性，应该遵循药物说明说明：在患有MEKAR的患者中停用Mekinist和Cotelic，但如果液体在三到四周内溶解，患者可以恢复药物治疗。服用Mektovi的患者只有在出现MEKAR并出现视觉症状时才需要暂停药物。对于那些发生视网膜静脉阻塞的患者，治疗可能需要玻璃体内注射anti-VEGF。患者应定期接受监测，如果视力发生变化，应立即进行检查。EGFR抑制剂表皮生长因子受体(EGFR)是一种糖蛋白，在多种癌症中被异常激活，导致细胞增殖、分化和存活。EGFR抑制剂已被用于靶向EGFR，治疗转移性结直肠癌、头颈癌、非小细胞肺癌、胰腺癌和一些类型的乳腺癌。目前FDA批准的大分子EGFR抑制剂包括Erbitux(cetuximab)、Vectibix(panitumab)和Rybrevant(amivantamab)。小分子EGFR抑制剂的例子有Tarceva(erlotinib)、Iressa(gefitinib)和Exkivity(mobocertinib)。毒性干眼症是EGFR抑制剂药物常见的副作用，由于角膜上皮愈合不良，可能导致永久性的上皮缺陷。眼前段的其他发现包括结膜炎、眼睑炎，极少数情况下，角膜变薄。所有药物都被报道与多毛症和毛发增大有关，在某些情况下，由于睫毛错误地指向角膜而导致角膜溃疡。治疗和管理干眼症可以用润滑剂滴眼液和环孢素眼液或乳剂或脂糖眼液来治疗。眼睑炎症可以通过眼睑卫生、热敷和类固醇/抗生素软膏来控制。应定期监测这些患者，特别是在出现症状时。这些药物的眼毒性监测没有固定的间隔。临床或视觉上有意义的发现，必须报告给肿瘤医生，因为它们可能影响剂量和治疗。FGFR抑制剂抑制成纤维细胞生长因子受体(FGFR)会干扰MAPK信号通路，而视网膜表达这一通路的靶点，从而导致视网膜毒性。FGFR抑制剂药物已被治疗FGFR突变的尿路上皮癌和胆管癌等癌症。FDA批准的药物包括Balversa(erdafitinib)、Pemazyre(pemigatinib)和Truseltiq(infigratinib)。毒性FGFR抑制剂药物治疗的患者可能发展为浆液性视网膜病变，并具有与MEK抑制剂相关的视网膜病变相似的特征。OCT(光学相干断层成像)显示交叉区和视网膜色素上皮之间有不同形态的液体。这些药物的副作用还包括干眼症和脱发。治疗和管理如果发生浆液性视网膜病变，服用Balversa的患者应停止治疗。如果液体在四周内溶解，可能会重新使用，否则应该停止药物治疗。在出现4级眼毒性的情况下，也应停止使用。如果服用Pemazyre的患者没有症状，并且视网膜病变稳定，可以对其进行药物监测。如果他们有症状或他们的视网膜病变恶化，应该暂停药物并重新检查。只有在症状和视网膜病变改善的情况下，患者才可能恢复药物治疗。如果发生视网膜病变，患者可以继续服用相同剂量的Truseltiq；但是，如果在两周内没有缓解，则暂停该药物使用，直到液体消失。然后可以以相同或更低的剂量重新给药。Balversa治疗的患者应该在治疗的前四个月每月检查一次，然后每三个月检查一次。服用Pemazyre的患者应该在基线上进行检查，在治疗的前六个月每两个月检查一次，然后每三个月检查一次。服用Truseltiq的患者应在基线时进行监测，然后在治疗期间一个月、三个月和此后每三个月进行一次。所有患者应紧急就诊以发现任何视觉症状，检查应包括视力测试、裂隙灯评估和OCT成像。临床上或视觉上有重要意义的发现必须报告给肿瘤学家，因为它们可能影响剂量和治疗，可能需要与眼科治疗一起处理。选择性雌激素受体调节剂(SERM)这类药物通过与雌激素受体(ER)结合来阻断雌激素的作用，从而治疗ER+乳腺癌或转移性乳腺癌等癌症。目前FDA批准SERM药物有Nolvadex 或Soltamox (tamoxifen)和 Fareston (toremifene)。毒性SERM药物治疗的患者可能会出现无症状的角膜沉积，但发生率低于0.7%。这类药物还可能导致不可逆的屈光性视网膜沉积，进而导致黄斑水肿并影响视力。治疗和管理如果发现角膜沉积，继续用药可能是安全的选择。目前，除了停用tamoxifen外，还没有治疗与tamoxifen相关的黄斑水肿的方法。如果患者出现视力变化，应立即定期监测。小结新型的抗肿瘤药物已使癌症治疗发生了革命性变化。但眼部毒性已成为一些新型抗肿瘤药物常见和不可忽视的毒副作用。肿瘤医生对这些药物带来的眼部副作用保持高度关注是至关重要的。大多数副作用只需要针对副作用的特定眼科治疗。然而，对于更严重、危及生命或可能致盲的不良反应，患者的肿瘤医生应与眼科医生合作来找到最佳的治疗手段。参考文献1.Ocular Side Effects of New Cancer Agents.2.Ocular Toxicity of Targeted Anticancer Agents.3.Ocular side effects of biological agents in oncology: what should the clinician be aware of?