tgDCC-E1A gene therapy(AmpliPhi Biosciences Corp.)

阻塞性睡眠呼吸暂停概述阻塞性睡眠呼吸暂停（Obstructive sleep apnea，OSA）是最常见的睡眠相关呼吸障碍，其特征是睡眠期间反复发生部分或完全上气道梗阻，导致间歇性低氧血症、大声打鼾、睡眠中断和白天嗜睡或疲劳。OSA与代谢和心血管等并发症有关，并可能增加死亡率，并可能损害工作效率、降低生活质量。图1. OSA的发生状态OSA在全球30至49岁的女性和男性中的发病率分别为3%和10%，在50至70岁的女性和男性中分别为9%和17%。在我国，OSA的总患病率为3%-4%，65岁以上人群的患病率近40%。根据目前的诊断标准，全球估计有4.25亿中年人患有中度至重度OSA。2015年美国诊断和治疗阻塞性睡眠呼吸暂停的费用约为120亿美元。阻塞性睡眠呼吸暂停的治疗研究发现未经治疗的重度0SA患者病死率比普通人群高3.8倍。现有数据表明，即使在发达国家，大多数阻塞性睡眠呼吸暂停病例仍未得到诊断和治疗。发展中国家的人们对阻塞性睡眠呼吸暂停的认识普遍很少，而且往往没有诊断和治疗方案。阻塞性睡眠呼吸暂停的治疗目标为解除睡眠呼吸暂停，纠正睡眠期低氧，改善睡眠结构，提高睡眠质量和生命质量，降低OSA的相关合并症发生率和病死率。目前的治疗方案有以下几种：危险因素控制应控制体重，包括饮食控制、加强锻炼。戒酒、戒烟、慎用镇静催眠药物及其他可引起或加重OSA的药物。病因治疗纠正引起OSA或使之加重的基础疾病，如应用甲状腺素治疗甲状腺功能减低等。体位治疗侧卧位睡眠，应对患者进行体位睡眠教育和培训。无创气道正压通气治疗成人OSA患者的首选和初始治疗手段。口腔矫治器适用于单纯鼾症及轻中度的OSA患者，特别是有下颌后缩者。对于不能耐受CPAP、不能手术或手术效果不佳者可以试用，也可作为CPAP治疗的补充或替代治疗措施。外科治疗仅适合于手术确实可解除上气道阻塞的患者，需严格掌握手术适应证。通常手术不宜作为本病的初始治疗手段。药物治疗目前尚无疗效确切的药物可以使用。图2. CPAP治疗示意图持续气道正压(CPAP)是针对阻塞性睡眠呼吸暂停的一线治疗方法，在吸气和呼气期间提供恒定水平的正压。但CPAP装置的依从性很低，且相关治疗费用高昂，预估全球每年使用CPAP设备检测和治疗OSA的市场超过100亿美元。其他疗法，如上气道手术、口内装置、体位训练器和植入式神经/肌肉刺激系统的疗效不太可预测。对OSA有效药物治疗的医疗需求尚未得到满足。阻塞性睡眠呼吸暂停的上市药物目前没有针对OSA的上市药物，以下药物已获FDA/EMA的批准用于OSA的辅助治疗，分别是：Sunosi（solriamfetol）NUVIGIL（armodafinil）PROVIGIL （modafinil）Ozawade（pitolisant）上述4款药物的活性成分是选择性多巴胺和去甲肾上腺素再摄取抑制剂（DNRI），被FDA批准用于治疗成人患者与发作性睡病或OSA相关的白天过度嗜睡（EDS）。这些药物均不适用于OSA潜在气道阻塞的治疗。在OSA患者中，需要确保在开始使用这类DNRI治疗之前的至少一个月对潜在气道阻塞进行了治疗（例如，持续气道正压通气[CPAP]）。在使用DNRI治疗期间，应继续采用治疗潜在气道阻塞的方法。Ozawade（pitolisant）活性成分是一种选择性组胺3（H3）受体拮抗剂/反向激动剂，通过增强组胺能神经元活性增加大脑中促进觉醒的神经递质组胺的合成和释放，提高患者的清醒度和警觉性。2021年10月，该药在欧洲被批准用于成人患者治疗与OSA相关的白天过度嗜睡。当其他治疗（例如持续气道正压通气（CPAP，使用呼吸机保持气道畅通））不能令人满意地改善白天过度嗜睡或患者无法耐受时，使用Ozawade。国内唯一获批用于辅助治疗OSA的药物PROVIGIL（modafinil），属于我国精神药品品种目录中的第一类精神药物，具有成瘾性大、耐受性强的特点，可能会对患者的神经系统造成不可逆伤害。药企主导开发的阻塞性睡眠呼吸暂停的临床阶段药物根据药渡数据，查询近五年开启的治疗阻塞性睡眠呼吸暂停相关临床试验，排除学校、医院及科研机构开展的研究，筛选到目前仍处于活跃状态的、治疗阻塞性睡眠呼吸暂停相关疾病的16个临床阶段药物。Tirzepatide是礼来开发的一款新型GLP-1R/GIPR双重激动剂，今年5月被FDA批准用于治疗2型糖尿病。该药物治疗阻塞性睡眠呼吸暂停的临床试验处于临床III期，研究（NCT05412004）的目的是评估Tirzepatide对阻塞性睡眠呼吸暂停和肥胖参与者的影响和安全性，将参与者分为不愿意或无法使用气道正压通气（PAP）治疗的和正在并计划继续接受 PAP 治疗的两部分。Pitolisant是Bioprojet公司开发的选择性组胺3（H3）受体拮抗剂/反向激动剂，琅铧医药2020年底与Bioprojet正式签署合同，获得中国市场的商业化权益。此前，pitolisant已获批用于治疗伴或不伴猝倒的发作性睡病，2022年2月开启用于治疗阻塞性睡眠呼吸暂停相关EDS的III期临床试验。该研究（NCT05223166）的目的是在12周的双盲试验期间，验证pitolisant与安慰剂的疗效和安全性，以治疗不耐受或拒绝鼻持续气道正压(nCPAP)治疗或接受nCPAP治疗但仍有EDS症状的阻塞性睡眠呼吸暂停(OSA)患者的日间过度嗜睡(EDS)。三贝苎鼾胶囊是宝仁堂药业开发用于治疗阻塞性睡眠呼吸暂停的中药，目前正在国内完成临床III期研究（CTR20221425）。该III期研究于2022年开启，目的是评价治疗阻塞性睡眠呼吸暂停低通气综合征（痰瘀互结证）有效性和安全性。AD109是Apnimed所开发的具选择性的去甲肾上腺素再摄取抑制剂（norepinephrine reuptake inhibitor）托莫西汀（atomoxetine）与抗毒蕈碱aroxybutynin的组合配方，可能是潜在“first-in-class”的OSA疗法。AD109在今年6月时此药物获得美国FDA授予快速通道资格。近日，AD109治疗OSA的2b临床试验MARIPOSA（NCT05071612）达到主要终点：与安慰剂组相比，两种剂量组患者在AHI上均达成具统计意义的下降（p<0.001）。明年上半年，AD109将启动III期临床。AD504是Apnimed的第二个核心项目，是去甲肾上腺素再摄取抑制剂托莫西汀和5-羟色胺再摄取拮抗剂曲唑酮的组合，Apnimed正在开发AD504组合的专有配方。AD504治疗阻塞性睡眠呼吸暂停的II期MARIPOSA研究（NCT05071612）正在进行中。AD182、AD113、AD098、AD313、AD639、AD036是Apnimed开发的系列治疗阻塞性睡眠呼吸暂停的药物，目前均处于临床II期。目前这些药物的靶点和作用机制尚未公布。Sulthiame是一种碳酸酐酶抑制剂可减轻通气不稳定，可能用于治疗阻塞性睡眠呼吸暂停，此前Sulthiame主要用于癫痫的治疗。Desitin Arzneimittel于2022年开启一项Sulthiame在阻塞性睡眠呼吸暂停（OSA）患者中的有效性、安全性和耐受性的研究（NCT05236842），目前该研究在招募患者状态。TAK-925是武田制药开发的选择性食欲肽2型受体(OX2R)激动剂，以治疗尽管使用 CPAP 但仍因OSA而患有白天过度嗜睡的患者，目前处于I期研究阶段。该研究（NCT05180890、NCT04091425）将评估OSA参与者单次静脉注射剂量TAK-925的药代动力学（PK）、药效学（PD）、安全性和耐受性。Daridorexant是Idorsia Pharmaceuticals开发的双促食欲素受体拮抗剂，主要适应症为失眠（已上市），治疗阻塞性睡眠呼吸暂停的临床试验处于临床I期，该I期临床研究（NCT05458193）是关于Daridorexant对严重阻塞性睡眠呼吸暂停患者夜间呼吸功能影响的研究。TS-142是大正制药开发的双促食欲素受体拮抗剂，主要适应症为失眠（临床III期），治疗轻度阻塞性睡眠呼吸暂停的临床试验处于临床I期，该I期研究（NCT04746105）主要评估TS-142在轻度阻塞性睡眠呼吸暂停低通气患者中的吸安全性。BAY2925976是Bayer开发的ADRA2C拮抗剂，通过α2c肾上腺素能受体拮抗作用增加的舌下神经的运动神经元的活动度，可以稳定上气道并保护其免于缩陷和阻塞。此外，还可以通过稳定上气道来抑制打鼾。BAY2925976目前处于临床I期阶段，NCT号暂未公布。小结-阻塞性睡眠呼吸暂停是最常见的睡眠相关呼吸障碍，对应超百亿美元的市场。-目前阻塞性睡眠呼吸暂停的治疗手段有限，对有效药物治疗的医疗需求尚未得到满足。-临床阶段药物开发方面，Bayer、Eli Lilly、Takeda等跨国药企有布局治疗阻塞性睡眠呼吸暂停管线。国内方面，琅铧医药引进了Pitolisant，宝仁堂药业开发了三贝苎鼾胶囊，两者均处于临床III期阶段。参考来源Veasey SC et al. N Engl J Med. 2019 Apr 11;380(15):1442-1449.Benjafield AV et al. Lancet Respir Med. 2019 Aug;7(8):687-698.成人阻塞性睡眠呼吸暂停基层诊疗指南(2018年)Hedner J, Stemlof K, Zou D, et al. Am J Respir Crit Care Med 2022: Epub 2022 Feb 24.

Feb. 12, 2021 11:45 UTC European Commission Approves Seagen’s TUKYSA® (tucatinib) for the Treatment of Patients with Locally Advanced or Metastatic HER2-Positive Breast Cancer - Approved for Adult Patients with HER2-Positive Metastatic Breast Cancer Who Have Received at Least Two Prior Anti-HER2 Treatment Regimens - - First HER-2 Tyrosine Kinase Inhibitor Combination Regimen to Improve Overall and Progression-Free Survival in Previously Treated Patients with Metastatic HER2-Positive Breast Cancer With or Without Brain Metastases - BOTHELL, Wash.--(BUSINESS WIRE)-- Seagen, Inc. (Nasdaq:SGEN) today announced that the European Commission (EC) has granted marketing authorization for TUKYSA® (tucatinib) in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least two prior anti-HER2 treatment regimens. TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.1,2 “This approval is a significant advancement for patients in Europe, who will for the first time have an approved medicine demonstrating a survival benefit for HER2-positive metastatic breast cancer after disease progression following two standard anti-HER2 treatment regimens,” said Prof. Dr. Med Volkmar Mueller, Deputy Director at the University Medical Center Hamburg-Eppendorf, Hamburg, Germany and investigator for the pivotal trial. “In the HER2CLIMB pivotal trial, the tucatinib combination regimen improved overall and progression-free survival compared to trastuzumab and capecitabine alone, including in patients with active, untreated or progressing brain metastases, a population with significant unmet need.” “The TUKYSA combination is a landmark therapy for patients with HER2-positive metastatic breast cancer with or without brain metastases, extending overall survival in these patients after two prior anti-HER2 treatment regimens,” said Clay Siegall, Ph.D., Chief Executive Officer at Seagen. “We are pleased TUKYSA is now approved in Europe, and we look forward to further collaborating with individual countries to ensure it is available to patients.” The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion for TUKYSA in December 2020. The approval of TUKYSA is valid in all countries of the European Union, as well as Norway, Liechtenstein, Iceland and Northern Ireland. HER2CLIMB Efficacy and Safety Patients who received TUKYSA in combination with trastuzumab and capecitabine in the pivotal trial had a 46 percent reduction in the risk of cancer progression or death (PFS), the primary endpoint, compared to patients who received trastuzumab and capecitabine alone (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001) and improved overall survival with a reduction in the risk of death by 34 percent (HR=0.66 [95% CI: 0.50, 0.87]; p=0.0048). The most common adverse reactions occurring in 20 percent or more of patients who received TUKYSA were diarrhea, nausea, vomiting, stomatitis, AST increase, ALT increase, and rash.1 The pivotal trial, HER2CLIMB, is a randomized (2:1), double-blind, placebo-controlled, active comparator, global trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received, either separately or in combination, trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1 SmPC). About HER2-Positive Breast Cancer Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. In 2020, more than two million new cases of breast cancer were diagnosed worldwide, including 531,086 in Europe.3 Between 15 and 20 percent of breast cancer cases are HER2-positive.4 HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.4,5,6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.7,8,9 About TUKYSA (tucatinib) TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone. U.S. Important Safety Information Warnings and Precautions Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA. Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients. Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA. Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose. Adverse Reactions Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock. Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%). The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Lab Abnormalities In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed. Drug Interactions Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA. Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors. CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage. P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity. Use in Specific Populations Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose. Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment. Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment. For more information, please see the full Prescribing Information for TUKYSA here. About Seagen Seagen is a global biotechnology company that discovers, develops, and commercializes transformative cancer medicines to make a meaningful difference in people’s lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland, and the European Union. For more information on the company’s marketed products and robust pipeline, visit and follow @SeagenGlobal on Twitter. Forward-Looking Statements Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of TUKYSA including its efficacy, safety and therapeutic uses, and the potential to make TUKYSA available to patients in Europe. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibilities that we may experience delays or setbacks in seeking pricing and reimbursement approvals or otherwise in commercializing TUKYSA in Europe; that adverse events or safety signals may occur; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seagen is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2020 and the company’s Current Report on Form 8-K dated December 30, 2020 filed with the U.S. Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. ________________ 1 TUKYSA [package insert]. Bothell, WA: Seagen Inc. 2 Anita Kulukian, Patrice Lee, Janelle Taylor, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor ModelsMol Cancer Ther2020;19:976-987. 3 Breast. Globocan 2020. World Health Organization. 2020. 4 Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087): 2415-29. 5 Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu onco­gene. Science. 1987; 235(4785): 177-82. 6 Breast Cancer HER2 Status. American Cancer Society website. . Accessed March 9, 2020. 7 Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37:1081-1089. 8 Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22:525-531. 9 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-2977.