Managed care opportunities and approaches to supporting appropriate selection of treatment for sight preservation.

When evaluating the impact of vision-destroying diseases, pharmacologic therapies represent a significant cost to patients, insurance providers, and society. Currently, up to 11 million people in the United States have some form of age-related macular degeneration (AMD), which is one of the leading causes of vision loss in older Americans. Ophthalmologists have administered more than 6 million intravitreal injections of aflibercept, bevacizumab, pegaptanib, and ranibizumab last year. Comprehensive assessment requires managed care administrators and clinicians to understand the direct and indirect costs of vision loss as well as the comparative safety and efficacy profiles for each agent. In AMD, it is critical to understand the established and emerging treatment patterns.

Molecular Selection, Modification and Development of Therapeutic Oligonucleotide Aptamers.

Monoclonal antibodies are the dominant agents used in inhibition of biological target molecules for disease therapeutics, but there are concerns of immunogenicity, production, cost and stability. Oligonucleotide aptamers have comparable affinity and specificity to targets with monoclonal antibodies whilst they have minimal immunogenicity, high production, low cost and high stability, thus are promising inhibitors to rival antibodies for disease therapy. In this review, we will compare the detailed advantages and disadvantages of antibodies and aptamers in therapeutic applications and summarize recent progress in aptamer selection and modification approaches. We will present therapeutic oligonucleotide aptamers in preclinical studies for skeletal diseases and further discuss oligonucleotide aptamers in different stages of clinical evaluation for various disease therapies including macular degeneration, cancer, inflammation and coagulation to highlight the bright commercial future and potential challenges of therapeutic oligonucleotide aptamers.

Cost and effectiveness of therapy for wet age-related macular degeneration in routine clinical practice.

PURPOSE: Evaluation of the cost and effectiveness of therapy for patients with the wet form of age-related macular degeneration (AMD) in routine clinical practice. METHODS: A retrospective multicentre evaluation of changes in the best-corrected visual acuity in applied kinds of therapy and a comparison with the cost of individual therapeutic procedures. RESULTS: An overall total of 788 eyes of 763 patients with an average age of 73.2 ± 8.6 years was evaluated for a 1-year minimum period. In the ranibizumab and pegaptanib therapy groups, a reduction of 1.3 letters (p = 0.303) and 1.4 letters (p = 0.197) was found, respectively. In the group of photodynamic therapy (PDT) with verteporfin, a reduction of 5.2 letters was achieved (p < 0.001). Under the conditions of routine practice in the Czech Republic, the annual cost is highest (EUR 5,467.63/patient) in patients with pegaptanib therapy. The annual cost in patients with ranibizumab therapy is lower by EUR 1,220.16. The cost is nearly half (EUR 2,783.65) in the group treated with PDT with verteporfin. CONCLUSION: An initiation of AMD therapy by ranibizumab is cost-effective as compared to pegaptanib. Both ranibizumab and pegaptanib are significantly more efficient as compared to PDT with verteporfin. Therapy with ranibizumab and pegaptanib, as compared to PDT with verteporfin, prevents the loss of 1 line of vision on the ETDRS chart for EUR 1,225.98 and 2,286.18, respectively.

Highly parallel single-molecule amplification approach based on agarose droplet polymerase chain reaction for efficient and cost-effective aptamer selection.

We have developed a novel method for efficiently screening affinity ligands (aptamers) from a complex single-stranded DNA (ssDNA) library by employing single-molecule emulsion polymerase chain reaction (PCR) based on the agarose droplet microfluidic technology. In a typical systematic evolution of ligands by exponential enrichment (SELEX) process, the enriched library is sequenced first, and tens to hundreds of aptamer candidates are analyzed via a bioinformatic approach. Possible candidates are then chemically synthesized, and their binding affinities are measured individually. Such a process is time-consuming, labor-intensive, inefficient, and expensive. To address these problems, we have developed a highly efficient single-molecule approach for aptamer screening using our agarose droplet microfluidic technology. Statistically diluted ssDNA of the pre-enriched library evolved through conventional SELEX against cancer biomarker Shp2 protein was encapsulated into individual uniform agarose droplets for droplet PCR to generate clonal agarose beads. The binding capacity of amplified ssDNA from each clonal bead was then screened via high-throughput fluorescence cytometry. DNA clones with high binding capacity and low K(d) were chosen as the aptamer and can be directly used for downstream biomedical applications. We have identified an ssDNA aptamer that selectively recognizes Shp2 with a K(d) of 24.9 nM. Compared to a conventional sequencing-chemical synthesis-screening work flow, our approach avoids large-scale DNA sequencing and expensive, time-consuming DNA synthesis of large populations of DNA candidates. The agarose droplet microfluidic approach is thus highly efficient and cost-effective for molecular evolution approaches and will find wide application in molecular evolution technologies, including mRNA display, phage display, and so on.

[Cost-effectiveness of ranibizumab, photodynamic therapy and pegaptanib sodium in the treatment of neovascular age-related macular degeneration in Japanese].

PURPOSE: To perform cost-utility analysis of ranibizumab, photodynamic therapy (PDT) and pegaptanib sodium treatment of neovascular age-related macular degeneration (AMD) with subfoveal choroidal neovascularization. MATERIALS AND METHODS: The analyses were performed on a 75-year old man with the starting visual acuity of letter score of 50 on an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart, with the affected eye having better sight than the contralateral eye, for the time horizons of 1 and 11 year (s). Visual acuity data from the large controlled studies for ranibizumab, photodynamic therapy and pegaptanib sodium, were applied. The results were compared with best supportive care (BSC) data. Cost indications included direct medical costs and costs related with social blindness. Utility values were estimated from the time trade off method. This analysis was performed from a societal perspective. RESULTS: In the 1-year model, cost of treatment was dominant in the treatment groups, whereas the cost of blindness was dominant in the BSC. In the 11-year model, influence of cost of blindness resulted in the increasing costs for BSC. Of note, ranibizumab and PDT were less costly and showed an increase in utility compared to the BSC. Pegaptanib sodium was found to be costly. Sensitivity analysis found that the results were robust to changes in various model parameters. CONCLUSION: In the current model, ranibizumab and PDT confer quality-adjusted life years (QALY) gains and are less costly compared to BSC in the lifetime treatment. In contrast, pegaptanib sodium treatment could be considered to be of minimal cost-effectiveness. Ranibizumab and PDT confer excellent value in the models of the lifetime treatment.

[Differences in the treatment of exudative age-related macular degeneration in Germany and Great Britain]. / Unterschiede in der Therapie der exsudativen altersabhängigen Makuladegeneration in Deutschland und Großbritannien.

The treatment of age-related macular degeneration with anti-VEGF medications has resulted not only in significant improvements in eye treatment but also in rising costs of ophthalmological therapy. This new treatment has been rapidly introduced into daily practice in Germany with its social security healthcare system and also in Great Britain with its National Health Service. In both countries the most prevalent treatment scheme currently includes three baseline injections of ranibizumab followed by additional injections depending on persisting disease activity.

A cost-effectiveness analysis of three treatments for age-related macular degeneration.

PURPOSE: The purpose of this study was to evaluate the cost effectiveness of pegaptanib sodium and ranibizumab injections compared with photodynamic therapy (PDT) with verteporfin for the treatment of choroidal neovascularization secondary to age-related macular degeneration. METHODS: The analyses were performed using outcomes data from the pivotal trials for each treatment and the medicare reimbursable costs for each treatment and associated medical procedures. A multistate transition model with 3-month cycles was created to compare incremental medical costs associated with pegaptanib or ranibizumab versus PDT for patients with starting vision of 20/40, 20/80, and 20/200 Snellen equivalent. RESULTS: Two-year medical treatment costs ranged from $3,100 to $54,100 depending on treatment and lesion type. Photodynamic therapy was less costly and more effective than pegaptanib for predominantly classic and minimally classic lesions. Ranibizumab was not only more effective but also more costly than PDT for all lesion types. CONCLUSION: Compared with PDT, pegaptanib is inferior in both cost and effectiveness, whereas ranibizumab has a greater effectiveness. Because ranibizumab does not meet 1 of the common thresholds for being considered cost effective (<$50,000 per quality-adjusted life year), there is rationale to seek other therapies that are more cost effective.

Cost-effectiveness of ranibizumab compared with pegaptanib in neovascular age-related macular degeneration.

OBJECTIVE: To assess the cost-effectiveness of ranibizumab compared with pegaptanib in the treatment of patients with minimally classic/occult neovascular age-related macular degeneration (AMD), from a societal perspective in Spain. METHODS: We constructed a Markov model with five states defined by visual acuity (VA) in the better-seeing eye (Snellen scale): VA >20/40, < or =20/40 to >20/80, < or =20/80 to >20/200, < or =20/200 to >20/400, < or =20/400, and an additional death state. Two cohorts of patients were distributed along the VA states, and treated with either ranibizumab or pegaptanib. Transition probabilities assigned for movement between these states with both drugs were obtained from published randomized clinical trials. Medical costs related to AMD treatment and follow-up, medical costs related to AMD comorbidities, and non-medical-related costs were taken into account. Costs (2008 Euro), health outcomes (Quality-adjusted life years--QALYs), both discounted at a 3.5% annual rate, and incremental cost-effectiveness ratios (ICER: euro/QALY), were determined for a lifetime horizon in the base case analysis. Sensitivity analyses were conducted to explore different scenarios and assumptions in the model. RESULTS: Treating patients with varying degrees of visual impairment with monthly ranibizumab instead of pegaptanib was 71,206 euro more costly and provided 2.437 additional QALYs (29,224 euro/QALY). When administered on an as-needed basis, as in the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (PrONTO) trial, the cost per QALY gained with ranibizumab was reduced to 4,623 euro. CONCLUSIONS: The cost per QALY gained with monthly ranibizumab compared with pegaptanib in the minimally classic/occult neovascular AMD population is just below the 30,000 euro threshold below which new drugs are sometimes regarded as cost-effective strategies in Spain. In this model, the key variables with greater impact on the cost-effectiveness results were the selected time horizon and the chosen extrapolation method, the source for data on pegaptanib efficacy and the number of ranibizumab injections. When administered on an as-needed basis, ranibizumab was a cost-effective strategy compared to pegaptanib in this population.

Cost-effectiveness of ranibizumab compared with photodynamic treatment of neovascular age-related macular degeneration.

OBJECTIVE: This study compared the cost-effectiveness of ranibizumab with that of photodynamic therapy (PDT) in the treatment of predominantly classic choroidal neovascularization secondary to age-related macular degeneration (AMD) from the perspective of a third-party payer in a Spanish setting. METHODS: We constructed a Markov model with 5 states defined by visual acuity (VA) in the better-seeing eye (Snellen scale), as follows: VA >20/40, 20/80, 20/200, 20/400, and

Cost-effectiveness of pegaptanib compared to photodynamic therapy with verteporfin and to standard care in the treatment of subfoveal wet age-related macular degeneration in Canada.

BACKGROUND: Age-related macular degeneration (AMD) is characterized by loss of central vision and is the leading cause of blindness among persons over the age of 50 years in Canada. The wet form of AMD has 3 subtypes-occult, minimally classic, and predominantly classic. Photodynamic therapy (PDT) with verteporfin is indicated only for the category of predominantly classic wet AMD. Currently, there are no treatments available for the other AMD subtypes. Pegaptanib sodium was the first pharmacologic therapy approved in Canada for the treatment of subfoveal wet AMD regardless of subtype. OBJECTIVE: The aim of this study was to examine the cost-effectiveness of pegaptanib versus PDT with verteporfin and versus standard care for the treatment of subfoveal wet AMD in patients aged 65 years in Canada. METHODS: A Markov model based on visual acuity in the better-seeing eye was developed. Clinical efficacy was taken from the clinical trials. Costs of treatment, comorbidities (eg, depression, fractures, need for assisted living), vision rehabilitation, visual aids, and adverse events were considered. Costs, utilities, and mortality were estimated from data from the available published literature. Costs were reported in 2004 Canadian dollars, and costs and outcomes were discounted at 3% per annum. Lifetime costs, quality-adjusted life-years (QALYs), and vision years gained (VYGs) were estimated. Sensitivity analyses were performed to determine model robustness. RESULTS: Patients who received pegaptanib experienced more QALYs gained (4.17) and VYGs (3.83) compared with patients who received PDT (3.87 and 3.01, respectively) or standard care (3.96 and 3.26). Mean total costs per patient were greater in patients who received pegaptanib compared to those who received PDT or standard care ($20,016 vs $15,345 or $7669, respectively). The incremental cost per QALY in patients receiving pegaptanib compared to those receiving PDT was $49,052 and $59,039 for patients receiving pegaptanib versus standard care. The incremental cost per VYG was $20,401 and $21,559 with pegaptanib versus PDT and standard care, respectively. Sensitivity analyses found that the model was relatively robust to changes in various model parameters. CONCLUSION: The results of this analysis suggest that in Canada, pegaptanib is a cost-effective treatment for subfoveal wet AMD in elderly patients, regardless of lesion subtype, compared to PDT with verteporfin and to standard care.

Cost effectiveness of pegaptanib for the treatment of age-related macular degeneration in the UK.

BACKGROUND: Age-related macular degeneration (AMD) is the primary cause of vision loss in the elderly and results in significant economic and humanistic burden. The selective vascular endothelial growth factor inhibitor, pegaptanib (Macugen) is indicated for patients with neovascular AMD. Guidance is needed regarding the cost effectiveness of treatment, any variation between sub-populations of differing clinical characteristics and the optimum duration of treatment. OBJECTIVE: To estimate the cost effectiveness of pegaptanib versus best supportive care (BSC) for AMD from the perspective of the UK government, and to evaluate the impact of patient characteristics and differing treatment discontinuation scenarios. METHODS: A cohort of 1000 patients aged >45 years with a best-corrected visual acuity (VA) in their better-seeing eye of < or =6/12 was modelled. Patients were either treated with pegaptanib (0.3mg every 6 weeks for a maximum of 2 years in their better-seeing eye only) or received BSC (no active treatment). Supportive services were provided for patients with a VA < or =6/60. A 10-year Markov model composed of 12 VA states (defined by individual Snellen lines) and a dead state was constructed. The model reported herein was used to support submissions to the National Institute for Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium (SMC). NICE guidance is expected to be available in October 2007 and the SMC advice was issued on 7 July 2006. SMC accepted pegaptanib for use in patients with visual acuity between 6/12 and 6/60 (inclusive) and should be stopped if visual acuity falls below 6/60 during treatment or where severe visual loss is experienced. Time-dependent transition probabilities for the loss and gain of Snellen lines were derived from parametric survival curves fitted to patient-level data from the VISION trials. Survival curves were fitted with treatment and baseline Snellen scores as covariates; additional curves were fitted with the addition of age, gender, lesion type or lesion size as covariates. Mortality rates were adjusted for the age, gender and VA of the population. Cost effectiveness was expressed as the incremental cost (IC) per vision-year saved and IC/QALY. Uncertainty was explored by probabilistic and univariate sensitivity analysis. Costs (year 2005 values) and outcomes were discounted at 3.5% per anum. RESULTS: In the base-case analysis, treatment was targeted to patients with a VA of 6/12 to 6/95 and discontinued after 2 years, or earlier if VA fell below 6/95 or by > or =6 lines. The IC/QALY was estimated as 8023 pounds(upper 95% CI 20,641 pounds). Cost effectiveness varied by age (age <75 years = 2033 pounds/QALY; age > or =75 years = 11,657 pounds/QALY) and by pre-treatment VA (6/12-6/95 = 8023 pounds/QALY; 6/12-6/60 = 6664 pounds/QALY; 6/12-6/24 = 1920 pounds/QALY). Gender and lesion type or size had little effect. Cost effectiveness was not sensitive to precise rules for treatment discontinuation, but was maximised if treatment was discontinued in patients no longer likely to benefit. CONCLUSIONS: The results suggest that pegaptanib treatment is likely to be cost effective across all groups studied, and marginally more cost effective in younger patients and those with better pre-treatment VA. Cost effectiveness appears to be optimised if treatment is discontinued after 1 year if individual patients' VA has dropped by > or =6 lines from pre-treatment levels, or at any time if it drops below 6/95. However, strict application of discontinuation rules does not appear to be necessary for pegaptanib to be cost effective. Clinical judgement and patient preference should be an important determinant in decisions about stopping treatment.

Pegaptanib for the treatment of age-related macular degeneration.

Although neovascular (wet) age-related macular degeneration (AMD) only accounts for 10-20% of all AMD, the majority (about 90%) of severe vision loss associated with AMD is due to this form. Results from recent studies have implied that vascular endothelial growth factor (VEGF), particularly VEGF(165), plays a predominant role in the development of ocular neovascularization and vascular leakage secondary to AMD. Thus VEGF is an important therapeutic target in neovascular AMD. Pegaptanib, an anti-VEGF aptamer, can selectively bind with VEGF(165) and inhibit both the growth of blood vessels and vascular leakage, and was approved by the Food and Drug Administration in the United States as the therapy for the treatment of all subtypes of neovascular AMD in December 2004. This review summaries the mechanism, preclinical and clinical studies, and adverse events of pegaptanib treatment.