ZimuraTM Anti-C5 Clinical Development Ophthotech has completed a multicenter, ascending-dose, parallel-group, open-label Phase 2a clinical trial evaluating the safety and tolerability of ZimuraTM administered in combination with an anti-VEGF drug for the treatment of wet AMD. ZimuraTM was generally well tolerated in this trial when tested in combination with anti-VEGF treatment. In a subgroup of 43 patients who had not previously been treated with anti-VEGF therapy and who received six injections of ZimuraTM in combination with anti-VEGF treatment, there was a mean increase in visual acuity from baseline at all timepoints. At a follow-up visit at week 24 of the trial, there was an improvement in mean visual acuity from baseline of 13.6 letters for patients receiving 0.3 mg, 11.7 letters for those treated with 1.0 mg, and 15.3 letters for patients receiving 2.0 mg of ZimuraTM. Based on results of our Phase 2a trial, data from a third-party clinical trial and multiple published studies suggesting that the complement pathway plays a significant role in dry AMD, we plan to initiate a Phase 2/3 clinical trial investigating ZimuraTM for treatment of geographic atrophy, a severe form of dry AMD affecting approximately 8 million patients worldwide. In addition, a Phase 2 clinical trial is planned for Zimura™ and Fovista® in combination with anti-VEGF therapy for the treatment of anti-VEGF resistant wet AMD patients believed to have complement-mediated inflammation.
How ZimuraTM Works Based on preclinical and pharmacogenetic studies, there is evidence that development of AMD involves a complement-mediated inflammatory component. ZimuraTM is a chemically synthesized aptamer that inhibits complement factor C5, a central component of the complement cascade believed to be involved in the development of AMD. The complement pathway is part of the innate immune system and is a complex system of proteins that interact in a cascade. Independent studies have implicated local inflammation and activation of the complement cascade in drusen formation, a hallmark of dry AMD that can be a precursor to the development of wet AMD.
What Treatments Are Available for Dry Macular Degeneration? By Lylas G. Mogk, M.D. The dry (atrophic) type of AMD affects approximately 80-90% of individuals with AMD. Its cause is unknown, it tends to progress more slowly than the wet type, and there is not - as of yet - an approved treatment or cure; however, there are a number of clinical trials underway. In dry age-related macular degeneration, small white or yellowish deposits, called drusen, form on the retina, beneath the macula, causing it to deteriorate or degenerate over time. Drusen are the hallmark of dry AMD. These small yellow deposits beneath the retina are a buildup of waste materials. They are made up of cholesterol, protein and fats. Typically, when drusen first form, they don't cause any vision loss. However, they are a risk factor for progressing to vision loss. When a person has more advanced dry macular degeneration, there are many more of these small yellowish deposits and they are larger. The Macular Degeneration Partnership and Macular Degeneration Support provide the following recommendations for slowing down, or preventing the progression of, both dry and wet AMD:
Nutrition and Weight Control Studies suggest that eating antioxidant-rich foods, such as fresh fruits and dark green leafy vegetables (kale, collard greens, and spinach, for example), may delay the onset or reduce the severity of dry AMD. These types of vegetables contain lutein, which may protect the macula from sun damage, just as it protects the leaves of these vegetables from sun damage. Eating at least one serving of fatty fish per week may also delay the onset or reduce the severity of dry AMD. These types of fish are high in omega-3 fatty acids, which help decrease inflammation and promote eye health. Avoid packaged foods as much as possible. It's important to keep a balance between omega-6 fatty acids and omega-3 fatty acids in our diets. Virtually every food in a package contains omega-6 fatty acids in the form of vegetable oil. We need to increase our intake of omega-3s and decrease our intake of omega-6s. Avoid artificial fats. Low-fat foods are good options if they've achieved their low-fat status through a process that physically removes the fat. Skim milk and low fat cottage cheese are examples of these types of good low-fat foods. A low-fat cookie or a no-fat cake, however, is a nutritional contradiction. Usually a low-fat or no-fat label on baked goods doesn't mean less fat was used in the production of the food, but that an artificial fat was used, usually partially hydrogenated vegetable oil. These types of fats are artificial ingredients made in a laboratory and our bodies can't metabolize them. So it's best to eat real cookies - just don't eat the whole dozen! Incorporate exercise into your everyday life. Obesity may increase the risk for progression to advanced AMD.
一、疾病治療現況 黃斑部位於視網膜中心，因此當黃斑部發生病變時，病人的中心視力會受到影 響，變得模糊不清，造成閱讀與近距離工作（例如開車）有困難。黃斑部退化病 變與年齡有高度相關(age-related macular degeneration, AMD)，多發生於 55 歲以 上的老人，並且為 65 歲以上老人失去視力的常見原因，但老化並非為 AMD 的 唯一原因，真正原因至今仍不明。有一些研究顯示，除老化外，維生素 A、E 不 足、紫外線曝曬、眼部感染、炎症等都可能為導致黃斑部病變的原因。另有未經 確切證明的研究顯示，若家庭中有成員發生黃斑部病變，或二眼中已有一隻眼發生黃斑部病變，則發生黃斑部病變的風險會明顯較高[1,2]。在美國，50 歲以上老人的 AMD 發生率(incidence)約為 1/100。65 歲至 75 歲間 之盛行率(prevalence)約為 100/1,000，75 歲以上之盛行率視地區不同，約為 300 ~800/1,000[1]。UK 每年新發生的 wet AMD 約有 26,000 人[8]。曾等人於 2004 年 發表，AMD 在台灣 50 歲以上老人之發生率為千分之 1~2，估計約有五千五百人 罹患此眼疾[3]。而陳等人發表於 2008 年，在台灣石牌地區進行研究，65 歲以上 老人早期和晚期的黃斑部退化之盛行率，分別為 9.2%和 1.9%[15]。 AMD 的診斷常使用 Amsler grid 或 Fluorescein angiography 等方式。Amsler grid 的做法為將卡片放置距離眼前三十公分處，請病人一次檢查一個眼睛，用單眼注視此 grid 的中心點，正常人可清楚看見 grid 的四個角，並且所有垂直線與水平 線應為直線，如果有任何區域模糊或不完整，或是直線變成扭曲或斷裂，則顯示黃斑部可能有病變。Fluorescein angiography 則可分辨視網膜是否存在不正常血管[1]。AMD 的病理機轉為視網膜上的細胞因退化而逐漸產生 drusen 沉積物，當 drusen 持續堆積，會造成視網膜色素上皮細胞(retinal pigment epithelium, RPE)退化。因此依病程進展又可分為二型：atrophic form macular degeneration (又稱為乾型 dry type)與 exudative form (又稱為溼型 wet type)。乾型(非血管新生型)約佔全部 AMD 病例的 90%，對視力的影響是漸進的，病程發展僅造成輕度至中度的視力喪失；少數黃斑部退化患者的病情會持續進展成濕型 AMD，發生比例約佔全部 AMD 病例的 10%，但因脈絡膜血管增生(choroidal neovascularization, CNV)至視網膜深層，這些血管也會造成血液的滲漏甚至出血，因而導致視力快速且嚴重的惡化。目前乾型 AMD 尚無有效治療，因此 AMD 的治療以溼性黃斑部病變為主[1]。抗血管新生藥物(anti-angiogenic agents) 是老人濕性黃斑部退化病變目前藥物治療的主要研究方向，其他治療方法還包括手術及雷射等。手術包括網膜下新生血管膜及疤痕組織移除術、黃斑部轉位術及色素上皮細胞移植手術等，但適用範圍 及 對 視 力 恢 復 的 幫 助 有 限 。 雷射治療方面有雷射光凝固法 (argon photocoagulation)、光動力學治療法（photodynamic therapy, PDT）、經瞳孔透熱療 法（transpupillary thermotherapy, TTT）及利用血管攝影術(Phi-motion indocyaninegreen angiography)，找出新生血管，然後以 pulse-diode laser 封閉這些血管等。其他的研究方向還包括放射線治療(radiation therapy)、黃斑部退化的基因研究、營養學研究，低視力輔助療法等[3]。
Immunology of age-related macular degeneration
Compound | Target | Structure | Indications | Trial status | Trial number |
| POT-4 (Alcon) | C3 | Cyclic peptide inhibitor | Neovascular AMD | Phase I has been completed | NCT00473928 |
| 93% of patients had no improvement in visual acuity (S. Bakri, personal communication) |
| Eculizumab (Alexion) | C5 | Monoclonal antibody | Dry AMD (presence of drusen) and geographic atrophy | Phase II is ongoing | NCT00935883 |
| There was no improvement in mean visual acuity or area of geographic atrophy in the first 6 months of the trial (P. Rosenfeld, personal communication) |
| LFG316(Novartis) | C5 | Monoclonal antibody | Geographic atrophy
Advanced neovascular AMD | Phase II is ongoing (Phase I data are unpublished) | NCT01527500
NCT01535950 |
| ARC1905 (Ophthotech) | C5 | Aptamer | Neovascular AMD
Geographic atrophy | Phase I has been completed (Phase I data are unpublished)
Phase I is ongoing | NCT00709527
NCT00950638 |
| FCFD4514S (Genentech) | Factor D | Monoclonal antibody (Fab fragment) | Geographic atrophy | Phase II is ongoing (Phase I data are unpublished) | NCT01602120 |
| Sonepcizumab (Lpath) | Sphingosine-1-phosphate | Monoclonal antibody | Neovascular AMD, 'subresponders' to VEGFA-targeted therapy | Phase II is ongoing (Phase I data are unpublished) | NCT01414153 |
| Glatiramer acetate (Teva) | Unknown anti-inflammatory target | Small peptide | Early and intermediate dry AMD | Phase II and Phase III are inactive | NCT00466076 |
| A small cohort (N = 8) showed reduction in drusen size156 |
| RN6G (Pfizer) | Amyloid-β | Monoclonal antibody | Geographic atrophy | Phase II is ongoing (Phase I data are unpublished) | NCT01577381 |
| Daclizumab (Hoffman-La Roche) | IL-2 receptor subunit-α | Monoclonal antibody | Neovascular AMD, co-administered with VEGFA-targeted therapy | Phase II has been completed | NCT00304954 |
| It reduced the frequency of VEGFA-specific injections in four patients157 |
| Bromfenac (ISTA) | Cyclooxygenase | NSAID | Neovascular AMD, co-administered with VEGFA-targeted therapy | Phase II has been completed | NCT00805233 |
| It reduced the number of VEGFA-specific injections in 16 patients but had no benefit for visual acuity158 |
| Infliximab (Janssen) | TNF | Monoclonal antibody | Neovascular AMD, co-administered with VEGFA-targeted therapy | Phase II has been completed | NCT00304954 |
| It reduced the number of VEGFA-specific injections in three patients157 |
| Adalimumab (Abbott) | TNF | Monoclonal antibody | Neovascular AMD, co-administered with VEGFA-targeted therapy | Phase II has been completed (data are unpublished) | NCT01136252 |
| Triamcinolone acetonide (Bristol-Myers Squibb) | Broad anti-inflammatory target | Corticosteroid | Neovascular AMD, co-administered with VEGFA-targeted therapy | Phase III has been completed | NCT00370370 |
| It reduced the number of VEGFA-specific injections but had no benefit for visual acuity159 |
| Fluocinolone acetonide (Alimera Sciences) | Broad anti-inflammatory target | Corticosteroid | Geographic atrophy | Phase II (Phase I data are unpublished) | NCT00695318 |
Nature Reviews Immunology 13, 438–451 (2013)
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