Anti-VEGF Pharmaceutical Prior Authorization in Retina Practices.

Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration. Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices. Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US. Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures. Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes. Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.

Real-world treatment patterns and economic burden of post-cataract macular edema.

BACKGROUND: Post-cataract macular edema (PCME) is a condition that can occur in patients following cataract surgery without risk factors and complications. Although 80% of patients experience spontaneous resolution after 3 to 12 months, in persistent cases, it can lead to permanent vision loss if left untreated. There are currently no standardized treatment guidelines for PCME, and there have been limited studies showing the impact of PCME on annual Medicare spending and ophthalmology-related outpatient visits per case compared to those without the complication. This study aims to evaluate real-world treatment patterns and the economic burden of patients with PCME. METHODS: This retrospective claims analysis identified patients from the IBM® MarketScan® Commercial and Medicare Supplemental databases. Patients with (n = 2430) and without (n = 7290) PCME 1 year post cataract surgery were propensity score matched 1:3 based on age, geographic region, diabetes presence, cataract surgery type, and Charlson Comorbidity Index. Treatment pattern analysis for each PCME patient summarized the distribution of medications across lines of therapy. Economic burden analysis compared the mean number and costs of eye-related outpatient visits, optical coherence tomography imaging scans, and ophthalmic medications between the 2 groups using linear regression models. RESULTS: Treatment pattern analysis found 27 different treatment combinations across 6 treatment lines. The most common first-line treatments were topical steroid drops (372 [30%]), topical nonsteroidal anti-inflammatory drug drops (321 [27%]), and intraocular or periocular injectable steroids (189 [15%]). Compared to match controls, PCME patients averaged 6 additional eye-related outpatient office visits (95% CI: 5.7-6.2) resulting in an additional $3,897 (95% CI: $3,475 - $4,319) in total costs. Patients filled 3 more ophthalmology-related outpatient prescription medications (95% CI: 2.8-3.2), adding $371 in total cost (95% CI: $332 - $410). CONCLUSIONS: PCME treatment patterns showed wide clinical variability in treatments and time, specifically regarding injectable treatments and combination therapy. Additionally, significantly higher healthcare resource use and economic burden were found for both patients and payers when comparing PCME patients to non-PMCE controls. These results highlight the need for treatment standardization and demonstrate that interventions targeted at preventing PCME may be valuable.

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.

BACKGROUND: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate. METHODS: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 µg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing. FINDINGS: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group. INTERPRETATION: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. FUNDING: German Federal Ministry of Education and Research and CureVac.

INTRAVITREAL DEXAMETHASONE IMPLANT IN RETINITIS PIGMENTOSA-RELATED CYSTOID MACULAR EDEMA.

PURPOSE: To report the clinical outcome after intravitreal dexamethasone implant in patients with retinitis pigmentosa and cystoid macular edema. METHODS: Multicenter retrospective case series of eyes with retinitis pigmentosa and cystoid macular edema that underwent intravitreal dexamethasone implant. Primary outcome measures were best-corrected visual acuity in LogMAR and central macular thickness. Statistical analyses used two-tailed comparison with Wilcoxon signed-rank test. RESULTS: There were a total of 45 eyes from 34 patients with a mean age of 32.7 years (range 16-57) and mean follow-up of 15.5 ± 13.0 months. At Month 3 after the first injection, mean initial best-corrected visual acuity improved from 0.61 ± 0.38 (20/81) to 0.37 ± 0.16 (20/47) (P = 0.012), whereas mean central macular thickness (µm) decreased from 506 ± 288 µm to 311.7 ± 71.6 µm (P < 0.001) and mean intraocular pressure increased from 15.7 ± 2.3 mmHg to 19.8 ± 11.0 mmHg (P = 0.01). Fourteen eyes had multiple injections (1-7 reinjections) at a mean interval of 6 months. Treatment effect was durable with multiple injections, but with seven eyes developing visually significant cataracts. CONCLUSION: Best-corrected visual acuity improved up to 4 months in around half of the eyes. Eyes that benefited the most were pseudophakic, steroid nonresponsive, with large initial central macular thickness, and profuse fluorescein dye leakage.

Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare, multisystemic, progressive lysosomal storage disease caused by deficient activity of the iduronate-2-sulfatase (I2S) enzyme. Accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate results in a broad range of disease manifestations that are highly variable in presentation and severity; notably, approximately two-thirds of individuals are affected by progressive central nervous system involvement. Historically, management of this disease was palliative; however, during the 1990s, I2S was purified to homogeneity for the first time, leading to cloning of the corresponding gene and offering a means of addressing the underlying cause of MPS II using enzyme replacement therapy (ERT). Recombinant I2S (idursulfase) was produced for ERT using a human cell line and was shown to be indistinguishable from endogenous I2S. Preclinical studies utilizing the intravenous route of administration provided valuable insights that informed the design of the subsequent clinical studies. The pivotal Phase II/III clinical trial of intravenous idursulfase (Elaprase®; Shire, Lexington, MA, USA) demonstrated improvements in a range of clinical parameters; based on these findings, intravenous idursulfase was approved for use in patients with MPS II in the USA in 2006 and in Europe and Japan in 2007. Evidence gained from post-approval programs has helped to improve our knowledge and understanding of management of patients with the disease; as a result, idursulfase is now available to young pediatric patients, and in some countries patients have the option to receive their infusions at home. Although ERT with idursulfase has been shown to improve somatic signs and symptoms of MPS II, the drug does not cross the blood-brain barrier and so treatment of neurological aspects of the disease remains challenging. A number of novel approaches are being investigated, and these may help to improve the care of patients with MPS II in the future.

Development and validation of the angiotensin-converting enzyme inhibitor (ACEI) induced angioedema investigator rating scale and proposed discharge criteria.

BACKGROUND: The use of angiotensin-converting enzyme inhibitors (ACEI) has been associated with the development of bradykinin-mediated angioedema. With ever-widening indications for ACEI in diseases including hypertension, congestive heart failure and diabetic nephropathy, a concomitant increase in ACEI-Angioedema (ACEI-A) has been reported. At present there is no validated severity scoring or discharge criteria for ACEI-A. We sought to develop and validate an investigator rating scale with corresponding discharge criteria using clinicians experienced in treating ACEI-A. METHODS: In-depth, 60-min qualitative telephone interviews were conducted with 12 US-based emergency physicians. Beforehand, clinicians were sent four case studies describing patients experiencing different severities of angioedema attacks. Clinicians were initially asked open-ended questions about their experience of patients' symptoms, treatment and discharge decisions. Clinicians then rated each patient case study and discussed patient diagnoses, ratings of symptom severity and discharge evaluation. The ratings were used to assess inter-rater reliability of the scale using the intra-class correlation coefficient (ICC) using IBM SPSS analysis Version 19 software. RESULTS: The findings provide support focusing on four key symptoms of airway compromise scored on a 0-4 scale: 1) Difficulty Breathing, 2) Difficulty Swallowing, 3) Voice Changes and 4) Tongue Swelling and the corresponding discharge criteria of a score of 0 or 'No symptoms' for Difficulty Breathing and Difficulty Swallowing and a score of 0 or 1 indicating mild or absence of symptoms for Voice Change and Tongue Swelling. Eleven clinicians agreed the absence of standardized discharge criteria supported the use of this scale. All physicians concurred with the recommended discharge criteria. The clinician ratings provided evidence of strong inter-rater reliability for the rating scale (ICC > 0.80). CONCLUSION: The investigator rating scale and discharge criteria are clinically valid, relevant and reliable. Moreover, both address the current unmet need for standardized ED discharge criteria.

Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema.

BACKGROUND: Upper airway angioedema is a rare, unpredictable, and at times life-threatening adverse effect of angiotensin-converting enzyme inhibitors (ACE-Is) with no existing effective pharmacologic treatment. Icatibant is a bradykinin B2 receptor antagonist that may be beneficial in patients with ACE-I-induced angioedema. OBJECTIVE: We aimed to evaluate the efficacy of icatibant in subjects with ACE-I-induced angioedema. METHODS: At 31 centers in 4 countries, adults on ACE-Is who presented within 12 hours of the onset of at least moderately severe angioedema were randomized 1:1 to icatibant 30 mg or placebo administered subcutaneously. The primary efficacy end point was time to meeting discharge criteria after study drug administration, based on the severity of airway symptoms assessed hourly by a blinded physician using clinical ratings across 4 domains. RESULTS: A total of 121 subjects were randomized (icatibant, n = 61; placebo, n = 60); 118 received treatment a median of 7.8 hours from symptom onset. We observed no difference in time to meeting discharge criteria between groups (median, 4.0 hours in each group; P = .63). There also was no difference in time to onset of symptom relief (median, icatibant, 2.0 hours; placebo, 1.6 hours; P = .57) or any other secondary end point. Similar findings were noted in prespecified and post hoc subgroup analyses stratified by symptom severity, time interval to treatment, age, and other clinical covariates. No new safety signals were detected. CONCLUSIONS: Icatibant was no more efficacious than placebo in at least moderately severe ACE-I-induced angioedema of the upper airway.

Diabetic retinopathy screening and the use of telemedicine.

PURPOSE OF REVIEW: Evidence-based practice guidelines and treatments are highly effective in reducing vision loss from diabetic retinopathy. However, less than half of the total number of patients with diabetes mellitus receive recommended annual retinal evaluations, and vision loss due to diabetic retinopathy remains the leading cause of blindness in adults. Poor adherence to screening recommendations stems from a number of challenges which telemedicine technology may address to increase the evaluation rates and ultimately reduce vision loss. The aim of this review was to provide an update on the recent advances in tele-ophthalmology and how it may expand our current concept of eye care delivery for diabetic eye disease. RECENT FINDINGS: The benefits of telemedicine diabetic retinopathy are proven for large population-based systems. Outcomes information from community-based programs is now also beginning to emerge. Improved screening rates and less vision loss from diabetic retinopathy are being reported after implementation of telemedicine programs. New imaging platforms for telemedicine programs may enhance the ability to detect and grade diabetic retinopathy. However, financial factors remain a barrier to widespread implementation. SUMMARY: Telemedicine diabetic retinopathy screening programs may have a significant impact on reducing the vision complications and healthcare burden from the growing diabetes epidemic.

Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.

BACKGROUND: Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population. METHODS: We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145. FINDINGS: We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181­1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99­100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82­86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75­91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95­100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB. INTERPRETATION: 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers. FUNDING: Novartis Vaccines and Diagnostics.

Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial.

CONTEXT: In the absence of an effective vaccine, serogroup B Neisseria meningitidis (MenB) remains a major cause of invasive disease in early childhood in developed countries. OBJECTIVE: To determine the immunogenicity and reactogenicity of a multicomponent MenB vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately. DESIGN, SETTING, AND PARTICIPANTS: Phase 2b, multicenter, open-label, parallel-group, randomized controlled study of 1885 infants enrolled at age 2 months from August 2008 to July 2010 in Europe. INTERVENTION: Participants were randomized 2:2:1:1 to receive (1) 4CMenB at 2, 4, and 6 months with routine vaccines (7-valent pneumococcal and combined diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae type b vaccines); (2) 4CMenB at 2, 4, and 6 months and routine vaccines at 3, 5, and 7 months; (3) 4CMenB with routine vaccines at 2, 3, and 4 months; or (4) routine vaccines alone at 2, 3, and 4 months. MAIN OUTCOME MEASURES: Percentage of participants with human complement serum bactericidal activity (hSBA) titer of 1:5 or greater against 3 MenB strains specific for vaccine antigens (NZ98/254, 44/76-SL, and 5/99). RESULTS: After three 4CMenB vaccinations, 99% or more of infants developed hSBA titers of 1:5 or greater against strains 44/76-SL and 5/99. For NZ98/254, this proportion was 79% (95% CI, 75.2%-82.4%) for vaccination at 2, 4, and 6 months with routine vaccines, 86.1% (95% CI, 82.9%-89.0%) for vaccination at 2, 4, and 6 months without routine vaccines, and 81.7% (95% CI, 76.6%-86.2%) for vaccination at 2, 3, and 4 months with routine vaccines. Responses to routine vaccines given with 4CMenB were noninferior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. Fever was seen following 26% (158/602) to 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% (380/624) after 4CMenB and routine vaccines administered together. CONCLUSION: A 4CMenB vaccine is immunogenic against reference strains when administered with routine vaccines at 2, 4, and 6 or at 2, 3, and 4 months of age, producing minimal interference with the response to routine infant vaccinations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00721396.

Early clinical experience with a candidate meningococcal B recombinant vaccine (rMenB) in healthy adults.

BACKGROUND: The development of a broadly protective vaccine against meningococcal serogroup B is a well-recognized public health need. Whole-genome sequencing was used to identify meningococcal surface proteins that are conserved across strains. These proteins were incorporated into two investigational vaccines. METHODS: Three randomized studies were performed to evaluate a three-component recombinant meningococcal serogroup B vaccine (rMenB) and rMenB plus outer membrane vesicles from the Norwegian outbreak strain 44/76 (rMenB+OMVNW). Participants were randomized to receive 3 or 4 doses of rMenB or rMenB+OMVNW or control vaccines and provided sera for exploratory immunogenicity testing against a panel of meningococcal serogroup B strains. A booster dose was administered 12 months after the initial primary series in one of the studies. The control cohort received a licensed quadrivalent meningococcal polysaccharide vaccine against serogroups A, C, W-135 and Y as well as hepatitis B vaccine as safety comparators. Solicited reactions within 7 days of any vaccination and adverse events throughout the studies were recorded. RESULTS: One hundred four participants enrolled into the clinical trials. Both rMenB and rMenB+OMVNW induced immune responses to multiple serogroup B strains in the majority of participants. Compared with rMenB, rMenB+OMVNW appeared somewhat more immunogenic and reactogenic; the study was not adequately powered for statistical assessment of these small differences. Both investigational vaccines were more reactogenic than the licensed vaccines. Few vaccinees discontinued any study due to reactogenicity to any study vaccine administered. CONCLUSION: Based on the immunogenicity and reactogenicity results in these participants, both rMenB and rMenB+OMVNW were promising candidates for further investigation.

Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents.

AIMS: To report the rate of intraocular pressure (IOP) elevation associated with repeated intravitreal injections of antivascular endothelial growth factor (VEGF) agents and to determine if a pre-existing diagnosis of glaucoma is a risk factor for this phenomenon. METHODS: The charts of 215 eyes undergoing intravitreal injection with anti-VEGF agents for wet age-related macular degeneration (AMD) were retrospectively examined with respect to frequency of injections, number of injections and changes in IOP. Data were analysed independently for two groups (1) pre-existing glaucoma and (2) no history of glaucoma. RESULTS: Of the 215 eyes receiving injections with bevacizumab and/or ranibizumab, 6% (n=13) had sustained IOP elevation requiring medical or laser interventions. Of the eyes receiving only bevacizumab, 9.9% (10/101) had sustained elevated IOP, while 3.1% (3/96) of eyes receiving only ranibizumab experienced increases (p=0.049). Patients with pre-existing glaucoma experienced higher rates of elevated IOP when compared with patients without pre-existing glaucoma (33% vs 3.1% respectively; p<0.001). The glaucoma subgroup had a lower median number of injections (6; interquartile range 5-10) compared with the non-glaucoma group (9.5; interquartile range 6-13.7; p=0.031). CONCLUSIONS: The incidence of sustained elevated IOP in patients receiving intravitreal anti-VEGF injections is significant. Additionally, these data suggest the possibility of a heightened risk for further elevation of IOP in patients with pre-existing glaucoma who receive either bevacizumab or ranibizumab. Prospective studies are needed to verify these results and better understand the implications of these findings.

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome.

PURPOSE: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. METHODS: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. RESULTS: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. CONCLUSIONS: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.

Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates.

Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.

Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections.

This retrospective case series reports sustained elevation of intraocular pressure (IOP) after single or repeated intravitreal injections of bevacizumab (Avastin; Genentech, San Francisco, CA) for wet age-related macular degeneration (AMD). All six cases experienced significant and sustained elevation in IOP after single or repeated intravitreal injections of bevacizumab. Initiation or advancement of IOP-lowering therapy was required in all cases. The results support the need for further studies investigating the incidence of this potential side effect and the need for close long-term surveillance of IOP after injection of bevacizumab, particularly in patients with glaucoma or suspected glaucoma. Future in vitro and in vivo studies are needed to better understand the reasons for this observed phenomenon.

Phase 1 first-in-human studies of the reactogenicity and immunogenicity of a recombinant meningococcal NspA vaccine in healthy adults.

BACKGROUND: Neisserial surface protein A (NspA) is a highly conserved, surface-exposed outer membrane protein of Neisseria meningitidis that has been shown to induce a bactericidal immune response in animals against all pathogenic Neisserial serogroups. METHODS: Healthy 18-50-year-old adults were assigned to receive, in a dose escalating manner, 3 doses of 1 of 5 formulations of an experimental, unfolded, recombinant NspA (rNspA) vaccine or placebo, or 1 dose of commercially available quadravalent (A, C, Y, W-135) meningococcal polysaccharide vaccine (Menomune((R))). Adverse events were collected during the first week post-immunization, prior to the next dose and 1 month after the last dose. Serum for measurement of hematological and biochemical parameters and antibodies by enzyme immunoassay and bactericidal assay were measured before the first dose, prior to the second dose and 1 month after the last dose of vaccine. RESULTS: The rNspA vaccine was well tolerated by recipients. Injection-site pain was reported more frequently by recipients of the three highest doses of rNspA compared to placebo but at similar rates to the licensed meningococcal polysaccharide vaccine. Adverse events were reported less frequently after subsequent doses in the three-dose series. An antibody rise measured by enzyme immunoassay was elicited with a dose-related increase that reached a maximum with the 125mug dose. Prolongation of the dosing interval between the second and third dose appeared to be associated with increased antibody levels. No bactericidal antibodies were detected after any of the rNspA formulations. CONCLUSIONS: The unfolded rNspA meningococcal vaccine was well tolerated and immunogenic in healthy adult volunteers but did not elicit bactericidal antibodies.

A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome).

OBJECTIVE: To evaluate the safety and explore the efficacy of idursulfase (recombinant human iduronate-2-sulfatase) treatment for mucopolysaccharidosis II (MPS II). STUDY DESIGN: Twelve patients were enrolled into a randomized, double-blind, placebo-controlled trial for 24 weeks followed by an open-label extension study. Three groups of 4 patients were enrolled sequentially, with 3 patients in each group receiving idursulfase and 1 patient receiving placebo. The first group received idursulfase at 0.15 mg/kg infused every other week with the 2nd and 3rd groups receiving 0.5 and 1.5 mg/kg, respectively. After 24 weeks the placebo-treated patients were changed to idursulfase at the dose of their group. The primary endpoint was a change from baseline in urinary excretion of glycosaminoglycans. Results were pooled for analysis by ANOVA and compared to baseline. RESULTS: Urinary glycosaminoglycans were reduced within 2 weeks of initiating idursulfase and were decreased 49% after 48 weeks of treatment (P<0.0001). Both liver and spleen volume were decreased at 24 weeks (P<0.01) and 48 weeks (P<0.001). The 6-minute walk test distance increased an average of 48 meters after 48 weeks (P=0.013). Six patients in the higher dose groups developed IgG antibodies that did not influence the clinical effects of idursulfase. CONCLUSIONS: This study describes the first experience with enzyme replacement therapy for the treatment of patients with MPS II. Idursulfase was generally well tolerated and was associated with reductions in urine glycosaminoglycans levels and organ size, as well as an increased 6-minute walk test distance.

A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome).

PURPOSE: To evaluate the safety and efficacy of recombinant human iduronate-2-sulfatase (idursulfase) in the treatment of mucopolysaccharidosis II. METHODS: Ninety-six mucopolysaccharidosis II patients between 5 and 31 years of age were enrolled in a double-blind, placebo-controlled trial. Patients were randomized to placebo infusions, weekly idursulfase (0.5 mg/kg) infusions or every-other-week infusions of idursulfase (0.5 mg/kg). Efficacy was evaluated using a composite endpoint consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity based on the sum of the ranks of change from baseline. RESULTS: Patients in the weekly and every-other-week idursulfase groups exhibited significant improvement in the composite endpoint compared to placebo (P = 0.0049 for weekly and P = 0.0416 for every-other-week) after one year. The weekly dosing group experienced a 37-m increase in the 6-minute-walk distance (P = 0.013), a 2.7% increase in percentage of predicted forced vital capacity (P = 0.065), and a 160 mL increase in absolute forced vital capacity (P = 0.001) compared to placebo group at 53 weeks. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 46.9% of patients during the study. CONCLUSION: This study supports the use of weekly infusions of idursulfase in the treatment of mucopolysaccharidosis II.