High-Yield Biosynthesis Process and Characterization of Brolucizumab

Macular degeneration, patients' groups, and pharma

Here we discuss antibody, cell and gene-based therapies that are currently available and under investigation for both wet and dry age-related macular degeneration (AMD). We initially discuss ocular anatomy, AMD modelling as well as the underlying pathophysiology of AMD. The antibody-based trials which have revolutionised the management of wet AMD are reviewed. The latest concepts in antibody therapy for wet AMD such as the port delivery systems, bispecific antibodies, designed ankyrin repeat protein (DARPINs) and brolucizumab are explored. Furthermore, the antibody-based trials targeting the complement pathway to reduce progression of geographic atrophy (GA) in dry AMD are discussed. Stem cell therapy and gene therapy are novel treatment modalities with no established clinical use in wet or dry AMD. Here, we discuss their efficacy so far in clinical trials. Their benefits and risk in the treatment of both wet and dry AMD are evaluated.

At present, the standard treatment of neovascular age-related macular degeneration (AMD) is the repeated administration of antivascular endothelial growth factor (VEGF) agents. However, we often encounter patients who develop tachyphylaxis for anti-VEGF agents. In this study, we investigated the characteristics of patients who developed tachyphylaxis on repeated intravitreal aflibercept (IVA) injections for neovascular AMD and the frequency of tachyphylaxis. Three hundred thirteen eyes (313 patients) with treatment-naïve AMD who achieved resolution soon after starting IVA and were followed up for ≥ 12months were enrolled in this retrospective, interventional, consecutive case series. The eyes were investigated for tachyphylaxis to aflibercept. Tachyphylaxis was defined as absence of any improvement (more than 100μm) in or worsening of CRT within 1month after more than two repeated monthly IVA injections when the exudative change remained. Twenty-eight (8.9%) of the 313 eyes developed tachyphylaxis (occult with no classic, n = 14; polypoidal choroidal vasculopathy, n = 14) at an annual rate of about 3%. The mean number of IVA injections was 10.5 ± 7.8, and the mean interval until tachyphylaxis was 20.9 ± 14.0months. There was a significant difference in the AMD subtypes between the group with tachyphylaxis and the group without it (p = 0.0029). Occult with no classic type and polypoidal choroidal vasculopathy were the only AMD subtypes in the eyes with tachyphylaxis. In the analysis of the eyes that had occult with no classic or polypoidal choroidal vasculopathy, only intraretinal edema was significantly less common (p = 0.042). A combination of photodynamic therapy and aflibercept was effective in 13 (87%) of 15 eyes with tachyphylaxis, and switching to intravitreal ranibizumab was effective in 5 (56%) of 9 eyes. Tachyphylaxis occurs after repeated IVA injections in a minority of patients with AMD for a long term and is more likely to occur in eyes with lesions beneath the retinal pigment epithelium and no intraretinal edema. Treatment of AMD should be performed keeping this fact in mind, while considering the consecutive treatment.

Aging is the major cause of age-related macular degeneration, but its mechanism of action is still unclear. Research has indicated that aging, macrophages and age-related macular degeneration are closely correlated. Owing to the heterogeneity of ocular macrophages and their diverse/plastic phenotypes, recognition of the role of macrophages in age-related macular degeneration is relatively rare, which hinders the development of precision treatments for age-related macular degeneration. In this narrative review, we discuss the classification of retinal macrophages and their diverse polarization states in age-related macular degeneration. To better understand the causal relationship between senescent macrophages and age-related macular degeneration, a novel model for manipulating the macrophage senile state in age-related macular degeneration was proposed. By transplanting senescent macrophages into an age-related macular degeneration model, we can test the ability of senescent macrophages to increase the age-related macular degeneration phenotype; moreover, by replacing senescent macrophages in an age-related macular degeneration model with young macrophages, we can test the necessity of senescent macrophages to cause an age-related macular degeneration phenotype and validate the effectiveness of transplantation of therapeutic macrophages as a treatment for advanced age-related macular degeneration based on the modulation of the inflammatory environment. This proposal is expected to solve the controversy regarding the role of macrophages in age-related macular degeneration and inspire future research on macrophage therapy for senescent diseases.

Economic evaluation of photodynamic therapy with verteporfin

Economic evaluation of photodynamic therapy with verteporfin

Cloning, expression, purification, and characterization of a novel single-chain variable fragment antibody against the 2-nitrobenzaldehyde derivative of a furaltadone metabolite in Escherichia coli

Objectives:To analyze the current preferences of ophthalmologists for the treatment of macular edema and age-related macular degeneration (AMD) and to evaluate off-label use of bevacizumab in Turkey.Materials and Methods:All members of the Turkish Ophthalmological Association were contacted by e-mail to complete an anonymous, 47-question internet-based survey. The second part of the survey (questions 36-47) was evaluated.Results:When current legal regulations were considered, ophthalmologists used bevacizumab as the first-line agent in patients with diabetic macular edema (DME), AMD, and retinal vein occlusion (RVO) (58.25%, 55.89%, and 52.29%, respectively). When economic and legal constraints were disregarded, the participants’ preference for bevacizumab in the treatment of DME, AMD, and RVO decreased (11.64%, 10.58%, and 10.93%, respectively). Approximately three-quarters (75.75%) of ophthalmologists stated that dispensing multiple syringes from a single bevacizumab bottle could increase the risk of endophthalmitis. Most participants (93.68%) did not feel legally safe from harm caused by off-label bevacizumab use. However, 66.43% of ophthalmologists stated that bevacizumab is as effective as other anti-vascular endothelial growth factor (anti-VEGF) drugs.Conclusion:Bevacizumab is widely used as a first-line treatment for all indications of anti-VEGF use in the current reimbursement conditions, which preclude the right of ophthalmologists to treat according to their own preferences.

A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin-retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the Abca4-/- mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. Abca4-/- mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD.

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Age-related macular degeneration is one of the most common irreversible causes of visual loss. It has been well established from both animal and human studies that vascular endothelial growth factor plays an important role in the pathogenesis of this process. Ranibizumab is a monoclonal antibody fragment directed towards human vascular endothelial growth factor that was developed to halt the progression of wet age-related macular degeneration. The antibody fragment has a molecular weight of 48 kDa and is produced by an Escherichia coli expression system. Ranibizumab received approval in the USA in July 2006 and the European Union in January 2007. It is introduced into the eye by injection into the vitreous cavity. Conjunctival hemorrhage, vitreous floaters, intraocular inflammation, increased intraocular pressure and eye pain were the most common ocular complaints of patients receiving ranibizumab injections over sham treatments. The rates of retinal detachment, cataract and endophthalmitis do not exceed that of other intravitreal injections and patients should be treated under strict aseptic conditions to reduce this risk. No unanticipated systemic adverse events were found during any phase of the studies of ranibizumab thus far and the risk of thromboembolic events was less than 4% and not different to sham. Combined data from the Minimally classic/occult trial of the Anti-vascular endothelial growth factor antibody Ranibizumab In the treatment of Neovascular Age-related macular degeneration (MARINA), ANti-vascular endothelial growth factor antibody for the treatment of predominantly classic CHORoidal neovascularization in age-related macular degeneration (ANCHOR), and Phase IIIb, multicenter, randomized, double-masked, sham Injection-controlled study of the Efficacy and safety of Ranibizumab in subjects with subfoveal choroidal neovasularization with or without classic choroidal neovascularization secondary to age-related macular degeneration (PIER) studies have validated the safety and efficacy of ranibizumab amongst a large population compared with sham and standard treatment (photodynamic therapy). Intravitreal administration is recommended monthly for patients. However, an alternative dosing of every 3 months is better than no treatment but probably less effective than sham treatment.

Photodynamic therapy (PDT) with verteporfin has been used less comprehensively in the treatment of exudative age-related macular degeneration (AMD), and specifically of choroidal neovascularization (CNV), since the advent of antiangiogenic therapies. Recently, there has been a renewed interest in PDT as an adjunct to these and other agents in the treatment of neovascular AMD. In light of this new development and the European Medicines Evaluation Agency's (EMEA) recent labelling decision to rescind approval for the use of PDT in occult CNV lesions, the present systematic review was undertaken to revisit the evidence supporting its clinical application. Photodynamic therapy provided the first pharmacological treatment for patients suffering from subfoveal CNV, the major cause of severe vision loss in AMD. Key clinical trials evaluating efficacy and safety have examined patients with all lesion subtypes, with the primary labelled indication (i.e. lesions containing a classic component of > or = 50% ) deriving from the results of the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study. The subsequent TAP Study Group post hoc categorization of lesions as predominantly classic is open to question, however, as it appears that the overall efficacy in this group only may have reflected the especially strong response in 100% classic lesions. Based on a subgroup analysis of the Verteporfin in Photodynamic Therapy Study, the indication for PDT subsequently was expanded in some jurisdictions, including that of the EMEA, to include occult lesions with no classic component. However, the subsequent Visudyne in Occult Study found no benefit in 100% occult lesions, resulting in the EMEA rescinding its approval for this indication.

Given the relatively high prevalence of age-related macular degeneration (AMD) and the increased incidence of AMD as populations age, the results of trials of novel treatments are awaited with much anticipation. The complement cascade describes a series of proteolytic reactions occurring throughout the body that generate proteins with a variety of roles including the initiation and promotion of immune reactions against foreign materials or micro-organisms. The complement cascade is normally tightly regulated, but much evidence implicates complement overactivity in AMD and so it is a logical therapeutic target in the treatment of AMD. To assess the effects and safety of complement inhibitors in the prevention or treatment of advanced AMD. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2013), EMBASE (January 1980 to November 2013), Allied and Complementary Medicine Database (AMED) (January 1985 to November 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1990 to November 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 November 2013. We also performed handsearching of proceedings, from 2012 onwards, of meetings and conferences of specific professional organisations. We planned to include randomised controlled trials (RCTs) with parallel treatment groups which investigated either the prevention or treatment of advanced AMD by inhibition of the complement cascade. Two authors (MW and GMcK) independently evaluated all the titles and abstracts resulting from the searches. We contacted companies running clinical trials which had not yet reported results to request information. Since no trials met our inclusion criteria, we undertook no assessment of quality or meta-analysis. We identified and screened 317 references but there were no published RCTs that met the inclusion criteria. We identified two ongoing studies: one phase I study and one phase II study. There is insufficient information at present to generate evidence-based recommendations on the potential safety and efficacy of complement inhibitors for prevention or treatment of AMD. However we anticipate the results of ongoing trials.

Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. There are two types of AMD: dry and wet. The exact cause of the disease is unknown, but is thought to result from interplay of genetic and environmental factors. Smoking, hypertension and low intake and/or low levels of serum antioxidants are known risk factors for both forms. As yet there are no treatments available for the dry form of AMD. Smoking cessation and healthy lifestyles are important in the prevention of progression of AMD. Progression of early stages of AMD to advanced forms is slowed by regular intake of ocular nutritional supplements as found in the Age-Related Eye Disease Study (AREDS) Study. Recently, there have been significant breakthroughs in the treatment of wet or neovascular AMD, including photodynamic therapy (PDT), intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs, including pegaptanib, ranibizumab and bevacizumab. Newer agents including aflibercept and anti-platelet-derived growth factor (anti-PDGF) compounds are under investigation. The current gold standard for treatment of wet AMD is intravitreal injections of ranibizumab. Combination therapy with PDT and anti-VEGF agents is useful especially in idiopathic polypoidal choroidopathy (IPCV) or when anti-VEGF monotherapy has failed. Rapid referral of patients with neovascular AMD is important as the visual outcome is dependent on the visual acuity at treatment. Diagnostic confirmation with retinal imaging, particularly fundus fluorescein angiography and optical coherent tomography, are required before treatment commencement. The new treatments for wet AMD are repetitive, and have significant service implications. These implications occur irrespective of which anti- VEGF agent is adopted. Visual rehabilitation is still important in the management of AMD.

Objective To observe the clinical efficacy of ranibizumab intravitreal injections for the treatment of exudative age-related macular degeneration (AMD). Methods Seventy-one eyes of 60 patients with active exudative AMD in the First Affiliated Hospital of Zhengzhou University from June 2013 to June 2014 were collected. The treatment was performed according to the following schedule: intravitreal injection of 0.5 mg ranibizumab once a month for 3 months. Central macula thickness (CFT) was measured by optical coherence tomography (OCT) after the third injection and further injections were based on the measuring process. The best corrected visual acuity (BCVA), and the fundus situation at the third month and the sixth month after this treatment were analysed. Results The effective rate of this treatment was 91.55%. The differences in BCVA and the CFT between pre-treatment and the third month or the sixth month after this treatment were both statistically significant (P=0.002, P=0.001). Conclusion Ranibizumab intravitreal injections for exudative AMD is an effective and safe method. Key words: Age-related macular degeneration, exudative; Ranibizumab; Intavitreal injection; Efficacy