The purpose of this is study is to evaluate the long-term safety of DCCR (diazoxide choline) extended-release tablets) in patients with Prader-Willi syndrome.

开始日期2023-01-31

申办/合作机构

Soleno Therapeutics, Inc.

NCT05532020 / Not yet recruiting临床2期

An Open-Label Study to Assess the Preliminary Efficacy and Safety of DCCR (Diazoxide Choline) Extended-Release Tablets in Patients With Genetic Obesities

This is a phase 2 open-label, one-arm, clinical study to evaluate the efficacy and safety of DCCR (diazoxide choline) extended-release tablets over 1 year of treatment, in patients with genetic obesities.

开始日期2023-01-01

申办/合作机构

Soleno Therapeutics, Inc.

NCT04086810 / Withdrawn临床3期

An Open-Label Study of Diazoxide Choline Controlled-Release Tablet in Patients With Prader-Willi Syndrome

The primary objective of this study is to monitor the long-term safety of DCCR in PWS patients.

开始日期2019-10-01

申办/合作机构

Soleno Therapeutics, Inc.

100 项与二氮嗪胆碱相关的临床结果

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100 项与二氮嗪胆碱相关的转化医学

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100 项与二氮嗪胆碱相关的专利（医药）

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项与二氮嗪胆碱相关的文献（医药）

2024-02-01·Obesity

Diazoxide choline extended‐release tablet in people with Prader‐Willi syndrome: results from long‐term open‐label study

Article

作者: Goldstone, Anthony P ; Gevers, Evelien ; Bridges, Nicola ; Salehi, Parisa ; Felner, Eric I ; Lah, Melissa ; Yen, Kristen ; Stevenson, David ; Butler, Merlin G ; Obrynba, Kathryn S ; Yanovski, Jack A ; Fleischman, Amy ; Wilding, John ; Cowen, Neil M ; Shoemaker, Ashley H ; Littlejohn, Elizabeth ; Hirano, Patricia ; Bird, Lynne M ; Miller, Jennifer L ; Angulo, Moris ; Bhatnagar, Anish ; Abuzzahab, M Jennifer ; Shaikh, M Guftar

AbstractObjectiveThis study assessed the effect of 1‐year administration of diazoxide choline extended‐release tablet (DCCR) on hyperphagia and other complications of Prader‐Willi syndrome (PWS).MethodsThe authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open‐label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ‐CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety.ResultsDCCR administration resulted in significant improvements in HQ‐CT (mean [SE] −9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ‐CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment‐emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%).ConclusionsDCCR administration to people with PWS was well tolerated and associated with broad‐ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

2023-06-16·The Journal of Clinical Endocrinology & Metabolism

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial

Article

作者: Holland, Prof Anthony ; Bridges, Nicola ; Fleischman, Amy ; Stevenson, David ; Obrynba, Kathryn S ; Mathew, Verghese ; Shaikh, Mohammed ; Littlejohn, Elizabeth ; Miller, Jennifer L ; McCandless, Shawn ; Abuzzahab, Jennifer ; Goldstone, Anthony ; Gevers, Evelien ; Salehi, Parisa ; Felner, Eric I ; Lah, Melissa ; Das, Urmi ; Butler, Merlin G ; Yanovski, Jack A ; Shea, Heidi ; Kimonis, Virginia ; Harwood, Katerina ; Shoemaker, Ashley H ; Bhatnagar, Anish ; Cowen, Neil M ; Schillaci, Lori Anne ; Bird, Lynne M ; Wilding, Prof John ; Angulo, Moris ; Barrett, Timothy ; Viskochil, David

AbstractContextPrader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.ObjectiveThe primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones.MethodsIn DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo.ResultsDCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] −5.94 [0.879] vs −4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] −9.67 [1.429] vs −4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).ConclusionDCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

PLOS ONE3区 · 综合性期刊

A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome

3区 · 综合性期刊

ArticleOA

作者: Wencel, Marie ; Surampalli, Abhilasha ; Gold, June-Anne ; Cowen, Neil M ; Kimonis, Virginia

INTRODUCTIONPrader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS.METHODThis was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period.RESULTSFive female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide.CONCLUSIONDCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.

项与二氮嗪胆碱相关的新闻（医药）

2024-08-28

·Pharmaceutical Technology

Soleno wins FDA priority review for Prader-Willi therapy

The news also resulted in a modest increase in Soleno’s stock price; it was up by 6.3% when markets closed on 27 August. Credit: eamesBot / Shutterstock. The US Food and Drug Administration (FDA) is set to decide on whether to approve Soleno Therapeutics ’ lead therapy, diazoxide choline (DCCR), for treating hyperphagia associated with Prader-Willi syndrome, a rare genetic disorder. The regulatory agency has accepted the new drug application (NDA) for DCCR and has granted it priority review status . The priority status allows for various privileges including a faster approval process of six months, compared to the usual ten months. The FDA has also set a Prescription Drug User Fee Act (PDUFA) target action date of 27 December 2024. The agency has also announced its intention to hold an advisory committee (AdComm) meeting to “discuss the application for DCCR”. An AdComm is convened upon request of the FDA to review and evaluate the safety and efficacy data of a therapy. While the AdComm recommendations can affect a therapy’s FDA approval, its recommendations are non-binding, and the final decision is made by the FDA. The news also resulted in a modest increase in Soleno’s stock price; it was up by 6.3% when markets closed on 27 August after the news was released compared to the previous day. The company’s market cap currently stands at $1.9bn. See Also: Catalent gets grant for activated formylglycine-generating enzymes for protein production Novo Nordisk’s Wegovy sales weaken as Eli Lilly’s Zepbound exerts pressure DCCR is an extended-release tablet containing a crystalline salt formulation of diazoxide, an activator of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel. These channels are present in a variety of cells including pancreatic β cells, and adipocytes. The regulation of these cells can help manage hyperphagia, an excessive desire to eat, which is a hallmark of Prader-Willi syndrome. Soleno’s NDA is supported by data from five studies; a Phase I trial in healthy volunteers, three Phase II trials, and a Phase III trial. The placebo-controlled open-label Phase III DESTINY PWS study (NCT03440814) enrolled 125 participants with Prader-Willi syndrome aged four years or younger. After a year of follow-up, the trial met its primary endpoint by demonstrating significant improvements in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Greater improvements in HQ-CT scores were seen in patients with more severe baseline hyperphagia, with an HQ-CT score of over 22. Patients on DCCR also observed reductions in leptin, insulin, and insulin resistance, along with an increase in adiponectin. Soleno is also evaluating DCCR as a treatment for paediatric patients with genetic obesities, including SH2B1 deficiency obesity, obesity associated with PCSK1 mutation (rs6232 variant), and SIM1 deficiency obesity. The open-label Phase II trial (NCT05532020) is expected to enrol approximately 30 patients aged five years or younger suffering from either of the three genetic obesity disorders.

临床2期临床结果临床3期优先审批申请上市

2024-08-27

·药明康德

突破性小分子疗法获FDA优先审评资格；别构AKT抑制剂获得临床概念验证……

▎药明康德内容团队编辑小分子疗法获FDA优先审评资格 Soleno Therapeutics今天宣布，美国FDA已接受为其在研疗法DCCR缓释片递交的新药申请（NDA），用于治疗4岁及以上经基因检测确认的Prader-Willi综合征（PWS）患者的暴食症。FDA同时授予这一申请优先审评资格，预计在今年年底之前完成审评。DCCR是一款二氮嗪胆碱（diazoxide choline）缓释片剂，已经获得美国FDA授予的突破性疗法认定和快速通道资格，并在美国和欧盟获得孤儿药资格。 DCCR是一种含有二氮嗪胆碱的创新专有缓释剂型，每日口服一次。DCCR开发项目的数据支持来自五项在健康志愿者中完成的1期临床研究和3项完成的2期临床研究，其中一项是在PWS患者中进行的。在PWS的3期临床开发项目中，DCCR在解决PWS的标志性症状暴食症以及其他几种症状（如攻击性/破坏性行为、脂肪质量和其他代谢参数）方面显示出可喜的效果。别构AKT抑制剂概念验证临床试验获积极结果 Vaderis Therapeutics公司今日宣布，在研别构AKT抑制剂VAD044在治疗遗传性出血性毛细血管扩张症（Hereditary Haemorrhagic Telangiectasia，HHT）患者的随机双盲、安慰剂对照概念验证（POC）临床试验中取得了积极结果。 HHT是世界上第二常见的遗传性出血性疾病，常常导致严重的疾病负担、降低预期寿命和生活质量。尽管如此，目前全球范围内尚无获批的HHT治疗方法。Vaderis正在开发VAD044，这是一种口服、每日一次的别构AKT抑制剂。在这项双盲对照试验中，75名来自美国和欧洲的患者被随机分配接受安慰剂、30 mg或40 mg的VAD044治疗，为期12周。安全性是主要终点，VAD044在脱靶不良事件（AEs）的发生频率和严重程度上与安慰剂相似。与AKT通路抑制相关的不良事件大多为轻度、短暂并可在研究期间解决。几乎所有HHT患者都遭受不可预测、频繁且使人衰弱的鼻出血，这被认为是衡量整体HHT疾病活动和疾病负担的关键指标。在本研究中，VAD044在HHT的次要和探索性疗效终点上表现出剂量依赖性应答，包括关键的鼻出血终点。在12周治疗期结束时，接受40 mg剂量的患者在鼻出血频率、持续时间和无鼻出血天数方面均有临床意义的改善。为癌症患者发现靶向治疗选择，FDA批准Illumina癌症生物标志物检测 Illumina公司今天宣布，其体外诊断（IVD）产品TruSight Oncology（TSO）Comprehensive检测获得美国FDA的批准，并获得了首批两项伴随诊断（CDx）适应症的批准。该检测可分析超过500个基因，以对患者的实体瘤进行全面分析，从而提高识别免疫肿瘤学生物标志物或临床可操作性生物标志物的可能性，这些标志物可以用于指导靶向治疗的选择或帮助临床试验患者入组。 TSO Comprehensive已获FDA批准作为伴随诊断工具，识别携带神经营养性酪氨酸受体激酶（NTRK）基因融合的成人和儿童实体瘤患者，这些患者可能从拜耳公司的Vitrakvi（larotrectinib）治疗中受益。该检测还获批用于识别RET融合阳性的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者，这些患者可能从礼来公司的Retevmo（selpercatinib）治疗中受益。新闻稿指出，大多数CDx测试通常仅针对一种类型的癌症，而TSO Comprehensive获得批准用于NTRK伴随诊断的所有实体瘤适应症，这有助于最大化每位患者活检中找到可针对信息的可能性。 ▲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] Soleno Therapeutics Announces U.S. FDA Acceptance for Filing and Priority Review of NDA for DCCR (Diazoxide Choline) Extended-Release Tablets in Prader-Willi Syndrome. Retrieved August 27, 2024, from https://www.globenewswire.com/news-release/2024/08/27/2936152/0/en/Soleno-Therapeutics-Announces-U-S-FDA-Acceptance-for-Filing-and-Priority-Review-of-NDA-for-DCCR-Diazoxide-Choline-Extended-Release-Tablets-in-Prader-Willi-Syndrome.html [2] Vaderis Announces Positive Clinical Proof-of-Concept Trial in HHT. Retrieved August 27, 2024, from https://www.prnewswire.com/news-releases/vaderis-announces-positive-clinical-proof-of-concept-trial-in-hht-302230320.html [3] FDA approves Illumina cancer biomarker test with two companion diagnostics to rapidly match patients to targeted therapies. Retrieved August 27, 2024, fromhttps://www.prnewswire.com/news-releases/fda-approves-illumina-cancer-biomarker-test-with-two-companion-diagnostics-to-rapidly-match-patients-to-targeted-therapies-302230979.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

优先审批临床2期孤儿药突破性疗法快速通道

2024-08-27

·GlobeNewswire-Health Care

Soleno Therapeutics Announces U.S. FDA Acceptance for Filing and Priority Review of NDA for DCCR (Diazoxide Choline) Extended-Release Tablets in Prader-Willi Syndrome

PDUFA target action date set for December 27, 2024 FDA currently plans to hold an Advisory Committee meeting REDWOOD CITY, Calif., Aug. 27, 2024 (GLOBE NEWSWIRE) -- Soleno Therapeutics, Inc. (“Soleno”) (NASDAQ: SLNO), a clinical-stage biopharmaceutical company developing novel therapeutics for the treatment of rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing its New Drug Application (NDA) for DCCR for the treatment of Prader-Willi syndrome (PWS) in individuals four years and older who have hyperphagia. The FDA granted Priority Review for the NDA and assigned a Prescription Drug User Fee Act (PDUFA) target action date of December 27, 2024. Priority review is designated to applications for drugs that, if approved, would provide a significant improvement in safety or effectiveness of the treatment, prevention or diagnosis of a serious condition. In its Priority Review Designation letter, the FDA also stated that it is currently planning to hold an advisory committee meeting to discuss the application for DCCR. “PWS is a devastating, rare condition that significantly impacts the lives of patients and their families,” said Anish Bhatnagar, M.D., Chief Executive Officer of Soleno. “The FDA’s acceptance of our NDA is a significant milestone, and designating our application for priority review reaffirms that the FDA views PWS as a serious condition. We are immensely grateful to the entire PWS community, including patients, caregivers and advocacy groups, for their ongoing support. We remain committed to continuing to work closely with the FDA through the NDA review process.” Diazoxide choline has Breakthrough and Fast Track Designations in the U.S., as well as Orphan Drug Designation for PWS in the U.S. and E.U. About PWSThe Prader-Willi Syndrome Association USA estimates that PWS occurs in one in every 15,000 live births. The hallmark symptom of this disorder is hyperphagia, a chronic and life-threatening condition characterized by feelings of intense, persistent hunger, food pre-occupation, and an extreme drive to seek and consume food, which can severely diminish the quality of life for individuals with PWS and their families. Additional characteristics of PWS include behavioral problems, cognitive disabilities, low muscle tone, short stature (when not treated with growth hormone), the accumulation of excess body fat, developmental delays, and incomplete sexual development. Hyperphagia can lead to significant mortality (e.g., stomach rupture, choking, accidental death due to food seeking behavior) and longer term, co-morbidities such as diabetes, obesity, and cardiovascular disease. In a global survey conducted by the Foundation for Prader-Willi Research, 96.5% of respondents (parents and caregivers) rated hyperphagia and 92.9% rated body composition as either the most important or a very important symptom to be relieved by a new medicine. There are currently no approved therapies to treat the hyperphagia/appetite, metabolic, cognitive function, or behavioral aspects of the disorder. About DCCR (Diazoxide Choline) Extended-Release TabletsDCCR is a novel, proprietary extended-release dosage form containing diazoxide choline, the crystalline salt of diazoxide and is administered once-daily. The parent molecule, diazoxide, has been used for decades in thousands of individuals in a few rare diseases in neonates, infants, children and adults, but is not approved for use in PWS. Soleno conceived of and established extensive patent protection for the therapeutic use of diazoxide, diazoxide choline and DCCR in individuals with PWS. The DCCR development program is supported by data from five completed Phase 1 clinical studies in healthy volunteers and three completed Phase 2 clinical studies, one of which was in individuals with PWS. In the PWS Phase 3 clinical development program, DCCR showed promise in addressing hyperphagia, the hallmark symptom of PWS, as well as several other symptoms such as aggressive/destructive behaviors, fat mass and other metabolic parameters. About Soleno Therapeutics, Inc.Soleno is focused on the development and commercialization of novel therapeutics for the treatment of rare diseases. An NDA for its lead candidate, DCCR (diazoxide choline) extended-release tablets, a once-daily oral tablet for the treatment of Prader-Willi syndrome (PWS) is currently under review by the FDA and was granted Priority Review. For more information, please visit www.soleno.life. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward-looking statements, including statements regarding the timing of any regulatory process or ultimate approvals and determining a path forward for DCCR for the treatment of PWS. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including the risks and uncertainties associated with the FDA’s review of our NDA, market conditions, as well as risks and uncertainties inherent in Soleno’s business, including those described in the company's prior press releases and in the periodic reports it files with the SEC. The events and circumstances reflected in the company's forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, the company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Corporate Contact:Brian RitchieLifeSci Advisors, LLC212-915-2578

临床2期申请上市优先审批临床3期快速通道

100 项与二氮嗪胆碱相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
普拉德-威利综合症	申请上市	美国	Soleno Therapeutics, Inc.	2024-06-29
高甘油三酯血症	申请上市	-	Essentialis, Inc.初创企业	2011-03-01
肥胖	临床2期	-	Soleno Therapeutics, Inc.	2023-01-01
糖尿病	临床1期	-	Essentialis, Inc.初创企业	2010-10-01
高甘油三酯血症	临床前	-	Essentialis, Inc.初创企业	2011-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03714373 (C602, GlobeNewswire) 人工标引	临床3期	普拉德-威利综合症	77	DCCR	築膚築願繭構鹹糧網構(鹹醖觸獵蓋遞壓遞觸製): P-Value = 0.0022 更多	积极	2023-09-26
				Placebo
NCT03440814 (CTgov)	临床3期	普拉德-威利综合症	127	DCCR	鏇糧夢鹽壓觸淵憲願淵(築襯簾淵醖網選遞夢遞) = 遞積遞夢壓構膚觸獵衊糧簾憲簾餘鏇糧蓋醖衊 (願構鹽醖窪鹹築顧壓顧, 夢膚鏇鏇餘餘餘齋廠餘 ~ 鏇製壓鏇觸簾鹹夢餘構) 更多	-	2023-09-21
NCT03714373 (C602 \| DESTINY PWS extension study, GlobeNewswire) 人工标引	临床3期	普拉德-威利综合症	115	Diazoxide Choline	(壓製淵艱繭齋糧觸廠蓋) = 膚憲齋選衊齋窪窪齋鬱築鏇膚顧鹽選選廠壓鏇 (顧憲衊餘憲鏇糧壓艱積 )	积极	2021-09-08
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C601 (NAASO2020)	临床3期	普拉德-威利综合症	127	DCCR	願遞範範窪簾鹹鑰憲憲(鏇遞鹹範鏇範願衊膚壓) = 鏇齋築襯構鑰鹹構鬱築構積獵醖襯鏇獵網襯觸 (廠艱顧鹹鏇衊簾願獵鏇 ) 更多	-	2020-11-04
				Placebo	願遞範範窪簾鹹鑰憲憲(鏇遞鹹範鏇範願衊膚壓) = 願齋鬱選鏇艱蓋鑰製簾構積獵醖襯鏇獵網襯觸 (廠艱顧鹹鏇衊簾願獵鏇 ) 更多