LUVENIQ™

LUVENIQ (LX211) is the oral form of a next-generation calcineurin inhibitor, voclosporin. Like other molecules of this class, the compound reversibly inhibits immunocompetent lymphocytes, particularly T-lymphocytes, and it also inhibits lymphokine production and release.

LUVENIQ (oral voclosporin) was discovered by the team of scientists currently at Isotechnika Pharma, Inc. in Edmonton, Alberta, Canada based on unique insights into the in vivo metabolism of calcineurin inhibitors. LUVENIQ is highly potent in various animal models of autoimmune diseases, including experimental uveitis. LUVENIQ is differentiated from the first-generation calcineurin inhibitors by its molecular structure and binding to its biologic target calcineurin phosphatase, and by its metabolic pathway and the associated pharmacokinetic and pharmacodynamic features, which may be linked to advantages in safety.

Lux Biosciences recently announced the results of its Phase 2/3 clinical development program of LUVENIQ in non-infectious uveitis. LUVENIQ at the 0.4 mg/kg BID dose was superior to placebo in reducing active posterior segment inflammation in the LX211-01 study at both Week 16 (p<0.01) and Week 24 (p<0.05), the co-primary efficacy endpoints of the study. In the LX211-02 study, LUVENIQ at the 0.4 mg/kg BID dose demonstrated a 50% greater reduction than placebo (p<0.05) in the primary endpoint of the study, inflammatory exacerbation rate at 6 months in subjects with medically controlled posterior segment disease. Increased blood pressure, decreased renal function and hirsutism were the drug related adverse events observed at a rate of approximately 5% increment over placebo, overall giving rise to a safety profile that appears conducive for chronic use. A New Drug Application (NDA) and a Marketing Authorization Application (MAA) are currently being prepared for submission to the US Food and Drug Administration (FDA) and to the European Medicines Agency (EMEA), respectively.  Lux Biosciences has exclusive worldwide rights to voclosporin for ophthalmic use and is cooperating with the team at Isotechnika Pharma who develop it in other indications. If regulatory approval is granted, LUVENIQ would be the first immunomodulatory therapy for the treatment of uveitis available in the United States.
 葡萄膜炎概述
葡萄膜炎指的是虹膜、睫状体、脉络膜的炎症；虹膜和睫状体的血液供给同为虹膜大环，故二者经常同时发炎，而总称为虹膜睫状体炎。如果脉络膜也同时发炎，则称为葡萄膜炎。葡萄膜炎是一种多发于青壮年的眼病，种类繁多，病因相当复杂，治疗不当可导致失明，在致盲眼病中占有重要地位，已引起世界范围内的重视。由于其发病及复发机制尚不完全清楚，故其预防无从着手，治疗效果也很不理想。因此，寻求合理而有效的治疗药物，已成为眼科领域里一个亟待解决的问题。
目录[隐藏]

临床诊断前葡萄膜炎
后葡萄膜炎（脉络膜炎）
全葡萄膜炎
病症分类病因分类
临床病理分类
解剖部位分类
病理
治疗方法西医治疗
中医治疗
治疗原则
注意事项
食疗方法 临床诊断 前葡萄膜炎
后葡萄膜炎（脉络膜炎）
全葡萄膜炎
病症分类 病因分类
临床病理分类
解剖部位分类
病理
治疗方法 西医治疗
中医治疗
治疗原则
注意事项
食疗方法 

临床诊断
　　
前葡萄膜炎

　　1、眼痛、畏光、流泪、视力下降
　　2、睫状充血或混合充血
　　3、房水混浊、角膜后有沉着物，甚则前房纤维渗出或前房积脓
　　4、虹膜肿胀，纹理不清，瞳孔后粘连
　　5、伴见全身病变表现
　　
后葡萄膜炎（脉络膜炎）

　　1、视力严重下降，视力减退程度取决于病变部位和玻璃体混浊的程度。如发生在黄斑部，严重影响视力。
　　2、闪光感，为炎症引起的视网膜刺激症状。
　　3、视力变形，为水肿或渗出导致视网膜、视细胞排列紊乱所致。
　　4、眼底检查：可见多处渗出灶，网膜水肿及眼底出血；晚期病人可见眼底色素沉着，晚霞状眼底，瘢痕，增殖性改变，以及网膜下新生血管。
　　
全葡萄膜炎

　　当虹膜、睫状体及脉络膜同时或先后发生炎症时，称为全葡萄膜炎。[4]
病症分类
　　
病因分类

　　按病因可将其分为感染性和非感染性两大类，前者包括细菌、真菌、螺旋体、病毒、寄生虫等所引起起感染；后者包括特发性、自身免疫类、风湿性疾病、创伤性、伪装综合征等。
　　
临床病理分类

　　可分为肉芽肿性和非肉芽肿性葡萄膜炎。以往认为肉芽肿性葡萄膜炎主要与病原体感染有关，而非肉芽肿性与过敏有关。实际上，感染和非感染因素均可引起两种类型的炎症，并且一些类型的葡萄膜炎，有时可表现为肉芽肿性，有时又可表现为非肉芽肿性炎症。
　　
解剖部位分类

　　是国际葡萄膜炎研究组（1979）制定的分类，并得到国际眼科学会的认可，是目前最常用的分类法。此法将葡萄膜炎分为前葡萄膜炎、中间葡萄膜、后葡萄膜炎和全葡萄膜炎；同时，还对病程进行了规定，小于3个月为急性，大于3个月为慢性。[2]
　　1、前部葡萄膜炎(anterior uveitis)包括虹膜炎、前部睫状体炎，虹膜睫状体炎三种。
　　2、中间葡萄膜炎(intermediate uveitis)炎症累及睫状体平坦部、周边部视网膜、玻璃体基部。
　　3、后部葡萄膜炎(posterior uveitis)炎症累及玻璃体膜以后的脉络膜、视网膜组织。
　　4、全葡萄膜炎(panuveitis)指前部、中间、后部葡萄膜炎的混合型。[3]
病理
　　葡萄膜炎的病因病机，主要是由于外邪侵袭，或有内热；多与肝、肾、脾三脏功能失调有关。肝为多气多血之脏，肝主疏泄，肝开窍于目，肝经风热或肝郁化火，热邪上扰，灼伤眼仁，或嗜好肥甘厚味，酿成脾胃湿热，热邪上蒸于目，熏灼瞳仁，或素体阴虚，病久伤阴，肝肾阴亏，虚火上炎，目睛受损，或由眼部邻近组织病变波及眼内脉络致使气血瘀积。血循环障碍而致病。
　　葡萄膜炎的发病原因和机制相当复杂，涉及有外伤感染，自身免疫等多种因素。主要分为感染性和非感染性两大类。
　　1、感染性：由细菌、病毒、真菌、立克次体、寄生虫等病源体感染所致。
　　2、非感染性：又分为外源性和内源性
　　（1）外因性原因：是由外界致病因素所致。①感染性：如细菌、真菌等经外伤或手术创口直接进入眼内，易引起化脓性炎症。②非感染性：如机械性、化学性和热烧伤等均可引起葡萄膜炎，往往伴有眼部其他改变。
　　（2）继发性原因：是其他疾病继发引起的眼部葡萄膜炎症。①邻近眼组织炎症的蔓延，如严重的角膜炎或巩膜炎可引起虹膜睫状体炎。②眼内毒素或刺激物的反应，如失明萎缩变性的眼球、长期视网膜脱离、眼内反复陈旧性出血以及恶性肿瘤坏死都可引起葡萄膜炎。
　　（3）内因性原因：①感染性：病原体或其产物通过血行播散，从身体其他部位进入眼内，例如有明显感染灶的转移或发生于感染源已清楚的疾病过程中。如结核、梅毒、钩端螺旋体病等细菌感染或单纯疱疹、带状疱疹等病毒感染或弓形体病等原虫感染，以及蛔虫、囊虫等寄生虫感染等都可能引起葡萄膜炎。②非感染性：很多内因性葡萄膜炎检查不出病原体，往往有免疫异常表现。如晶体源性葡萄膜炎、交感性眼炎、Fuchs虹膜异色性虹膜睫状体炎、中间葡萄膜炎等，或伴有全身病如风湿病性关节炎的前葡萄膜炎、Vogt-小柳-原田氏病、Behcet病、系统性红斑性狼疮、结节病等。[5]
治疗方法
　　
西医治疗

　　葡萄膜炎的治疗，西医主要用激素，但无法根治，易于反复。根据不同的临床表现，需要采取不同的治疗措施。急性期，以热邪为主，予以清热解毒，活血化瘀。慢性期多见阴虚，肝肾不足，重在滋养肝肾，养阴清热，活血化瘀，以防复发。病情十分严重者，中西医结合治疗，全身使用皮质激素，及时有效的控制炎症。再用中药进行调整，巩固疗效，直至彻底治愈。
　　
中医治疗

　　葡萄膜炎，如发生在前中部即虹膜睫状体炎，类似中医“瞳神紧小”，在后部葡萄膜（即脉络膜炎），则归属“云雾移晴”、“视瞻昏渺”等范畴。中医药治疗该病，贵在辨证论治。
　　
治疗原则

　　立即扩瞳以防止虹膜后粘连，迅速抗炎以防止眼组织破坏和并发症的发生。由于前葡萄膜炎绝大多数为非感染因素所致，因此一般不需用行生素治疗，对高度怀疑或确诊的并原体感染所致者，则应给予相应抗感染治疗。对非感染因素所致的葡萄膜炎，由于局部用药在眼前段能够达到有效浓度，所以一般不需要全身用药治疗。
　　1、睫状肌麻痹剂
　　是治疗急性前葡萄膜炎的必需药物，一旦发病应立即给药，其目的在于：
　　①预防和拉开虹膜后粘连，避免并发症；
　　②解除睫状肌、瞳孔括约肌的痉挛，以减轻充血、水肿及疼痛，促进炎症恢复和减轻患者痛苦。最常用的睫状肌麻痹剂为后马托品眼膏（1％、2％、4％）而不是阿托品，这是因为后者的睫状肌麻痹作用和红瞳孔扩大作用持续时间长（10－14d），使瞳孔处于固定的开大状态，易发生瞳孔开大状况下的虹膜后粘连，给患者带来更为严重的后果。后马托品的作用时间约18－36h，可使瞳孔处于不断运动状态，因此可有效预防虹膜后粘连的发生。但后马托品的扩瞳及睫状肌麻痹作用不及阿托品，因此，对急性严重的前葡萄膜炎，可给予1％－2％阿托品眼膏一日1－2次，治疗1－3d后，改用2％后马托品眼膏点眼，一日1－2次；新鲜的虹膜后粘连不易拉开时，可结膜下注射散瞳合剂（1％阿托品、1％可卡因、0.1％肾上腺素等量混合）0.1－0.2ml，对炎症恢复期可给予0.5％－1％的托品酰胺滴眼液点眼，一日一次。
　　2、糖皮质激素滴眼液
　　常用的制剂有醋酸氢化可的松（0.2％、0.25％）、醋酸氟美松龙（0.1％）、醋酸泼尼松龙（0.12％、0.125％、0.5％、1％）和地塞米松磷酸盐（0.1％）悬液或溶液。对严重的急性前葡萄膜炎，可给予0.1％地塞米松磷酸盐溶液每15min点眼一次，连续4次后改为每小时一次，连续应用数天后，根据炎症消退情况逐渐减少点眼次数。一般不宜或不宜反复给予糖皮质激素结膜下注射，因为滴眼液点眼可在房水中达到足球的浓度，达到与结膜注射相同的效果，并能避免结膜下注射给患者带来痛苦和并发症。
　　3、非甾体消炎药
　　非甾体消炎药主要通过阻断前列腺素、白三烯等花生四烯酸代谢产物而发挥其抗炎作用。已经证明，急性前葡萄膜炎，特别是手术后或外伤后所致者有花生四烯酸代谢产物的参与，因此可给予吲哆美辛、双氯芬酸钠等滴眼液点眼治疗，每日3－8次。一般不需用口服治疗。
　　4、糖皮质激素眼周和全身治疗
　　对于出现反应性视乳头水肿或黄斑囊样税种的患者，可给予地塞米松2.5mg后Tenon囊下注射。方法是，选用25号针头，从颞上或颞下方穹隆部结膜和球结膜移行处进针，在进针过程中要注意左右摆动，以避免针头误刺入眼球内。对于不宜后Tenon囊下注射、或双侧急性前葡萄膜炎出现反应性黄斑水肿、视乳头水肿，可给予泼尼松口服，开始剂量为30－40mg，早晨顿服，使用一周后减量，一般治疗时间为2－4周。[6]
注意事项
　　如果患了葡萄膜炎，一定要在早期进行及时彻底的治疗，要按疗程坚持用中药，争取一次性彻底治愈。急性炎症治疗及时得当，炎症得到控制，可较快恢复视力；若治疗不当，反复发作，缠绵不愈，导致严重视力损害，甚至失明，丧失劳动力，影响生活质量。
　　因为葡萄膜炎失治或误治，可引起许多并发症，后果非常严重。如带状角膜变性、白内障、黄斑部及视盘水肿，黄斑表面褶纹样改变，角膜水肿、青光眼、视网膜脱离等。所以及时有效的治疗，可以阻止这些并发症的发生。
　　葡萄膜炎防治4点注意
　　1、如发现眼红、痛、畏光、流泪、视力下降或无红、痛，但眼前有黑影漂浮，视物模糊或视物变形，闪光感、视力下降者有可能患葡萄膜炎，应到有关专科作详细检查，以明确诊断。
　　2、一旦诊断为葡萄膜炎，应积极进行治疗，散瞳是治疗前葡萄膜炎的必要措施，可防止瞳孔粘连，避免继发性青光眼和并发性白内障的产生;激素是治疗葡萄膜炎的常用药物，但有副作用，不论全身或局部用药，一定要在医生指导下使用，不宜滥用。
　　3、葡萄膜炎患者，应定期复查，预防复发，如自觉有复发症状，应及早诊治。
　　4、积极锻炼身体，增强体质，预防感冒，少吃刺激性食物，注意劳逸结合，保持身心健康，对预防葡萄膜炎也有重要意义。[7]
食疗方法
　　葡萄膜炎的病因复杂，除了诊断病因及对症治疗外，辨证配制一些食疗套餐，有利于疾病的康复。下面介绍一些常用配餐。
　　1、银花菊花茶：银花50克，菊花50克，绿茶20克。上药混合共为粗末，用纱布分装成袋，每袋15克。每次1包，代茶饮用。可清凉解热、疏风明目。用于头眼胀痛、目睛红赤者。
　　2、蔓荆子粥：蔓荆子15克，粳米50克。将蔓荆子捣碎，加水500毫升，浸泡后煎取汁，入粳米煮粥，空腹食用。每日1剂。可辛凉解散，用于目赤头痛者。
　　3、青葙子茶：青葙子15克，绿茶5克。将青葙子和绿茶置于纱布袋中，沸水泡10分钟饮用。每日1剂。可祛风热、清肝火、适用于目赤肿痛者。
　　4、石膏粥：生石膏50克，粳米100克。先将石膏水煎半小时，去渣后放入粳米熬粥。每日1剂。可辛凉清热、除烦止渴，适用于眼红痛、口干重的患者。
　　5、绿豆藕羹：藕1节，绿豆30克。将藕洗净切成小块，与绿豆同煮至熟烂后食用。每日1剂。可清热凉血、去赤止痛，适用于眼热赤痛者。
　　6、二仁粥：生薏仁30克，杏仁6克(捣碎)，粳米100克。三物共用水煮，至米开粥稠即可食用。每日1剂。可清热利湿，宣畅气机，适用于葡萄膜炎反复发作者。
　　7、香菇烧冬瓜：冬瓜300克，香菇20克，调料适量。冬瓜去皮瓤、洗净、切片。香菇浸泡透，洗净。二味用油炒后，烧熟。每日1剂。可清湿热、益胃气，适用于脾胃湿热重的葡萄膜炎患者。[1]

First oral uveitis drug reduces both inflammation and recurrence in potentially blinding eye disease
If approved, LX211 would address an important unmet medical need for patients with uveitis
Fort Lauderdale, FL (May 4, 2009): Uveitis, or inflammation within the eye, is a group of diseases responsible for years of visual loss roughly comparable to that caused by diabetes. Now, results from a pioneering international Phase 3 program in uveitis, the LUMINATE trials sponsored by Lux Biosciences, demonstrate the ability of LX211 (LUVENIQ™, voclosporin oral capsule) to significantly improve this chronic eye inflammation. Additionally, in patients who are discontinuing potentially toxic medications for uveitis, such as the corticosteroid prednisone, LX211 actively reduces the rate of inflammatory exacerbations by 50% at six months, compared to placebo. The study results also show a safety profile for LX211 at the 0.4 mg/kg bid dose that suggests the experimental drug would be suitable for chronic use as the first oral treatment for this sight-threatening inflammatory eye disease, while also providing a means to greatly reduce the serious health risks associated with long-term corticosteroid use. LX211 is a novel and proprietary next-generation calcineurin inhibitor that Lux Biosciences is developing for ophthalmic uses.

Dr. James T. Rosenbaum, M.D., Professor of Ophthalmology, Medicine and Cell Biology and Vice-Chair of the Department of Ophthalmology of the Casey Eye Institute – Oregon Health Sciences University (OHSU), represented the LUMINATE Investigator Network in presenting the Phase 3 LUMINATE program results for the first time at the 2009 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). The LUMINATE program, consisting of three randomized, double-masked, dose-ranging and placebo-controlled trials that enrolled a total of 558 patients at 56 sites in 7 countries (United States, Canada, United Kingdom, France, Germany, Austria and India), is the largest clinical program ever conducted in uveitis.

"Uveitis, a term used to classify a group of autoimmune diseases characterized by chronic inflammation of the eye, is the 4th leading cause of blindness and often affects patients under the age of 40, but the disease remains frequently mistreated," commented Dr. Rosenbaum. "Uveitis has many causes and experts often disagree about what constitutes successful treatment. Accordingly, no pharmaceutical company previously has attempted to demonstrate that an oral medication can successfully treat uveitis, and there are currently no FDA-approved oral medications for this condition. Treating physicians often prescribe corticosteroids, which are burdened with a variety of serious systemic side effects when given orally. Even if applied as drops to the eye, corticosteroids can cause cataract formation and glaucoma. Based on the results of the LUMINATE trial program, LX211 appears to offer a therapeutic and safety profile that would meet the critical need for an oral medication for uveitis. LX211 is not a corticosteroid, but allows the reduced use of corticosteroids like prednisone, which in turn reduces the serious side-effects associated with those drugs."

Dr. Rosenbaum noted that a poster presentation at ARVO from a survey of U.S. ophthalmologists and rheumatologists from 27 states, presented by researchers from the Wilmer Eye Institute of Johns Hopkins University, Baltimore, found that the dose of oral corticosteroids used commonly to keep chronic inflammation within the eye under control is in the range of 25 mg/day. This compares to a recommended chronic dose by the uveitis community of 10 mg/day or less. Of additional note, patients enrolled in the LX211-02 protocol, which evaluated the use of LX-211 in subjects with treated but quiescent disease, received doses of corticosteroids that were more than 50% higher than this recommendation. It is well documented that systemic steroids at doses above 10 mg/day cause a myriad of adverse effects, such as osteoporosis, resulting in increased risk for hip or spinal fractures, and metabolic disturbances including obesity, heart disease, and diabetes. Mood disturbances are also associated with chronic corticosteroid use.

"The tapering of systemic corticosteroids to 5 mg or less per day, as implemented successfully in the LUMINATE studies, provides for additional safety from steroid morbidities," Dr. Rosenbaum commented.

"We are pleased with the demonstrated clinical effect of LX211 (Luveniq™) in uveitis, coupled with what appears to be an acceptable side effect profile while reducing the need for systemic corticosteroid to half of the current guideline recommendation," commented Ulrich Grau, Ph.D., Lux Biosciences' President and Chief Executive Officer. "We're now pursuing regulatory filings, and if approved for commercialization by the appropriate regulatory agencies, LX211 would become the first agent in this class available in the United States and most other markets for the treatment of uveitis."

Overview of LUMINATE Trial Results

The LUMINATE program consists of three protocols that included 218 patients with active non-infectious uveitis with posterior (behind the lens of the eye) manifestation of the disease (LX211-01); 232 patients with clinically quiescent disease (LX211-02); and 108 patients with active uveitis with anterior (front of the eye) manifestation of the disease (LX211-03). Data from these trials showed:

•Of the three doses studied, the 0.4 mg/kg BID dose had the most acceptable safety profile relative to effect on the disease. The adverse effects on the kidney (8.2% of subjects with decrease from baseline by ≥30% in glomerular filtration rate vs. 4.1 % in placebo) and blood pressure (mean increase in systolic BP by 6 mm Hg) will require monitoring, but were overall moderate and manageable. Triglycerides and cholesterol were not elevated and had no negative impact on the cardiovascular safety profile. Hair growth (hirsutism) was observed in 5% of patients. Otherwise the safety profile was similar to placebo.


•In study LX211-01 the 0.4 mg/kg BID dose fully met the primary endpoint of superiority to placebo at both weeks 16 (p=0.008) and week 24 (p=0.027) for mean change from baseline in vitreous haze, a validated measure of inflammation of the posterior segment of the eye. The magnitude of the effect was >1 step change from baseline, demonstrating a clinically relevant benefit.

•In study LX211-02 the 0.4 mg/kg BID dose showed a reduction by 50% vs. placebo in rate of recurrence of inflammation at 6 months using a pre-specified analysis that accounted for data censoring due to non-efficacy-related discontinuations. This reduction was statistically significant (p=0.045), thus confirming the positive results from LX211-01.

•In study LX211-03, treated patients reduced the cellular response in the front of the eye from an average of more than 25 white blood cells per high power microscopic field to an average of 6 to 10 cells per high power field. However, placebo-treated patients also improved in this study and it was therefore not possible to show that LX211 was effective for this rare subset of uveitis patients, those with refractory disease in the anterior portion of the eye.

The LUMINATE program was conducted under the sponsorship of Lux Biosciences.

About Lux Biosciences

Lux Biosciences, Inc. is a privately held biotechnology company focused on ophthalmic diseases. The company has a staged product portfolio of potentially first-in-class therapies distinguished by their short-term path to commercialization and potential to generate high revenue growth. The portfolio includes:

•Two Phase 3 clinical-stage projects including: i) LUVENIQ™, the oral formulation of a next-generation calcineurin inhibitor (voclosporin) developed as steroid-sparing therapy for the treatment of sight-threatening non-infectious uveitis, and ii) LUMITECT™, a silicone matrix ocular (episcleral) implant that steadily releases therapeutic doses of cyclosporine A locally to the eye for the prevention of rejection in corneal transplant recipients. Both the LUMINATE pivotal clinical program for LUVENIQ for the treatment of uveitis, as well as the LUCIDA pivotal clinical program with LUMITECT™, for the prevention of corneal transplant rejection were initiated in early 2007 and include sites in North America, Europe and India. Enrollment in the LUMINATE program was completed in June 2008. Enrollment in the LUCIDA program was completed in March 2009. Lux Biosciences has licensed voclosporin from Isotechnika, Inc. for development in ophthalmic indications.

•LX214 is a novel topical eye drop formulation that entered human clinical testing for dry eye syndrome in February 2009. Based on Lux's proprietary next-generation calcineurin inhibitor, LX214 is targeted towards other chronic inflammatory diseases of the eye, most notably dry eye syndrome, blepharitis and atopic keratoconjunctivitis.

•Several earlier stage projects based on proprietary product-enabling bio-erodible polymer technologies that facilitate targeted and sustained delivery of molecules to the eye.