Utility of real-world evidence in biosimilar development.

Biosimilar development refers to the process of creating a biologic drug that is similar to an existing approved biologic drug, also known as a reference drug. Due to the complex nature of biologics drugs and the inherent variability in their manufacturing process biosimilars are not identical but highly similar to the reference drug in terms of quality, safety, and efficacy. Efficacy and safety trials for biosimilars involve large numbers of patients to confirm comparable clinical performance of the biosimilar and the reference product in appropriately sensitive clinical indications and for appropriate sensitive endpoints. The objective of a biosimilar clinical data is to address slight differences observed at previous steps and to confirm comparable clinical performance of the biosimilar and the reference product. In recent years with advances in big data computing, there has been increasing interest to incorporate the totality of information from different data sources (e.g. Real World data and published literature) in design and conduct of clinical trial to support regulatory objectives. The biosimilar development is an ideal framework for utilization of Real-World Evidence in design of trials as potentially large amount of data are available for the reference dug. Hence there may be an opportunity to use RWD in establishing, improving or validating equivalence margins (EQM) for biosimilar designs, specifically in the case there is no historical published data in the intended sensitive population. In this article, we propose a variation of matching method that seems promising to identify the matched set from a real-world data for which the effect size of targeted endpoint would be comparable to historical data. We believe this is a reasonable approach because in design stage, we can view covariates and secondary endpoints as data feature that can be used in a matching method. This approach was illustrated through a case study which indicated the estimate of the primary endpoint is within 1% of published results and thus RWD may be used to justify or estimate the equivalence margin. To ensure consistent results we recommend using this approach in different indications and endpoint scenarios. Thus utilization of RWD/RWE can provide an important opportunity to increase access to biologic therapies, reducing cost by repurposing existing data.

Bleb revision with Tenon's transposition flap: Case report.

INTRODUCTION: To describe the use and technique of a Tenon's transposition flap without overlying conjunctiva to cover bare sclera following bleb excision and tube shunt implantation. PRESENTATION OF CASE: A 76-year-old man with severe stage primary open-angle glaucoma in both eyes presented with a nonfunctioning trabeculectomy with a thin-walled, cystic bleb overhanging the cornea. A Baerveldt-350 Glaucoma Implant in the ciliary sulcus was recommended for further lowering of intraocular pressure, along with concurrent excision of the bleb due to patient dissatisfaction with the cosmesis of the bleb and to prevent future bleb-associated complications. Conjunctiva could be closed without tension over the new tube entry site; however, a defect remained at the prior trabeculectomy site. A Tenon's transposition flap without overlying conjunctiva was created to cover this site. By postoperative week 6, new conjunctiva had grown over the Tenon's transposition graft, appearing as if there had never been a bleb. DISCUSSION: This case illustrates the use of a Tenon's transposition flap to cover bare sclera following bleb excision. This technique proves valuable when conjunctiva is limited, offering an alternative when adjacent conjunctiva cannot be mobilized. CONCLUSION: In cases requiring non-water-tight coverage of bare sclera with limited available conjunctiva, a Tenon's transposition flap can be used, permitting new conjunctiva to safely grow over bare Tenon's. This technique is useful during a variety of scenarios, including tube shunt and trabeculectomy revisions, where conjunctival closure may be difficult.

Case study and pilot results: Stepwise approach to teach a resident tube shunt surgery.

Purpose: To illustrate the utility of a previously published stepwise rubric for evaluating a resident's progress learning aqueous tube shunt surgery. Method: Using a stepwise rubric, a single PGY3 ophthalmology resident and attending glaucoma surgeon evaluated the resident's performance after each aqueous tube shunt surgery. The rubric subdivides the surgery into 12 consecutive steps and scores the resident's proficiency in each step with either a 0 (observation), 2 (novice), 3 (beginner), 4 (advanced beginner), or 5 (competent). Results: The resident's cumulative score increased significantly throughout the 17 surgeries performed, with the resident's self-evaluated score and attending's score increasing from 12 to 27 and 14 to 27 from the first to last surgery, respectively. Scores were consistent between the resident and attending; for any given surgery, the resident's own score never deviated from the attending's score by more than 1 point. The resident completed at least 50% of the steps in 11 of the 17 cases. While some surgical steps were mastered earlier on ("tube tying" and "suture implantation"), other steps were more challenging to master ("tunnel in sclera and enter the AC" and "close conjunctiva", as demonstrated by fewer overall attempts or never attaining a score of '5' despite multiple attempts. Conclusions and Importance: This study demonstrates the utility of the stepwise rubric in tracking resident surgical scores chronologically via self and attending assessment. The ability to compare their own scores to that of an attending allows the resident to learn how to effectively evaluate their own performance. Most importantly, statistics obtained for each step provides the resident with personalized and real-time feedback for learning specific surgical steps. In conclusion, the stepwise rubric is a useful add-on to a resident's aqueous tube shunt surgery education.

FULL-THICKNESS MACULAR HOLE CLOSURE WITH TOPICAL MEDICAL THERAPY.

PURPOSE: To examine the efficacy and clinical characteristics of successful full-thickness macular hole closure with topical therapy. METHODS: Retrospective case series of full-thickness macular holes managed by a single retinal physician (DS) diagnosed and treated from 2017 to 22. RESULTS: Of 168 patients with full-thickness macular holes, 71 patients were started on steroid, carbonic anhydrase inhibitor, and nonsteroidal antiinflammatory (NSAID) drops. 49 patients (mean 67 years, 59% women) were included in the analysis, and 22 patients were excluded for poor follow-up. In total, 7/49 were secondary post-PPV holes and 42/49 were idiopathic. In addition, 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10 µm decrease in size and odds of closure increased by 1.2× ( P = 0.001, CI 1.1-1.4). Average time to closure was 107.2 days (range 20-512 days) and was not correlated with hole size ( P = 0.217, CI -0.478 to +1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, P = 0.029, CI 1.2-31.3). There was no significant difference in final best-corrected visual acuity for eyes undergoing primary pars plana vitrectomy versus those trialing drops before undergoing pars plana vitrectomy ( P = 0.318, CI -0.094 to +0.112). CONCLUSION: In the first study to date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in central foveal thickness acted as predictors of effectiveness of drop therapy.

Baerveldt-350 with 3-0 Prolene Ripcord to Minimize Hypotony-Associated Complications after Spontaneous Ligature Dissolution.

PURPOSE: To describe the technique and demonstrate the utility and outcomes of using a thick 3-0 Prolene ripcord in the lumen of a Baerveldt-350 aqueous shunt until after the ligature suture dissolves. DESIGN: Single-center, noncontrolled, retrospective case series. PARTICIPANTS: A total of 50 eyes from 50 patients with glaucoma undergoing placement of Baerveldt-350 aqueous shunts with 3-0 Prolene ripcords. METHODS: A retrospective chart review was performed for all eyes of adult patients that had undergone a Baerveldt-350 aqueous shunt placement by a single surgeon at a single academic center between October 1, 2019 and June 30, 2022. MAIN OUTCOME MEASURES: Data collected included demographic and clinical characteristics of the patients, preoperative and postoperative clinical data including intraocular pressure (IOP) and glaucoma medications, postoperative timepoints of ligature suture dissolution, and timepoints of 3-0 Prolene ripcord removal or whether they were permanently left in place. RESULTS: In total, 50 eyes from 50 patients were included; mean age was 69.5 years, 54.0% of patients were female, 92% of patients were Black, and 66% of eyes had primary open-angle glaucoma. Twenty-six of 50 (52%) eyes had ripcord removal at the soonest postoperative visit after spontaneous ligature dissolution, 19/50 (38%) eyes had delayed ripcord removal, and 5/50 (10%) eyes had no ripcord removal. There were no cases of hypotony-associated complications (shallow anterior chamber, hypotony maculopathy, choroidal effusion, suprachoroidal hemorrhage) in this subgroup of eyes that underwent no ripcord removal. CONCLUSIONS: Our results demonstrate that routine use of a 3-0 Prolene ripcord to partially occlude the lumen of a Baerveldt-350 is a useful strategy to minimize sudden hypotony-associated complications when the ligature suture dissolves. This strategy allows for a more controlled postoperative course and a safe 2-step decrease in IOP (1: when the ligature dissolves, and 2: when the ripcord is removed). FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Signal-to-noise ratio to assess magnitude, kinetics and impact on pharmacokinetics of the immune response to an adalimumab biosimilar.

Background: The antidrug antibody (ADA) signal-to-noise (S/N) ratio was explored as a novel immunogenicity measure to evaluate the immune response of healthy subjects to a single dose of GP2017, an adalimumab biosimilar. Methodology/results: Bioanalytical methods used for the analysis of ADA S/N ratios and ADA titers were validated for sensitivity, precision and drug interference. ADA S/N ratios strongly correlated with ADA titers. Correlations between ADA area under the curve and ADAmax and pharmacokinetics (PK) were stronger for ADA S/N ratio than for ADA titers. Conclusion: ADA S/N ratio allowed for a more sensitive evaluation of the magnitude and kinetics of the immune response, was better correlated with adalimumab PK and was superior to ADA titers in assessing the impact of the immune response on PK.

Same-quadrant Baerveldt Glaucoma Implant-250 to Baerveldt Glaucoma Implant-350 exchange.

Purpose: In eyes with a prior failed aqueous shunt (or "tube") requiring additional intraocular pressure (IOP) control, options include angle surgery, cyclodestruction, second tube, tube revision, or tube exchange. We present a case of a same-quadrant tube exchange of a Baerveldt-250 (BGI-250) to BGI-350. Observations: The patient is a 71-year-old African American female with severe-stage primary open angle glaucoma of both eyes, and this case focuses on the right eye. This eye had prior cataract surgery with iStent, prior BGI-250 in the anterior chamber (AC), and prior iStent removal with gonioscopy assisted transluminal trabeculotomy (GATT). The visual acuity (VA) was 20/150, and the IOP was 26 mmHg on 3 IOP-lowering medications. The prior superotemporal BGI-250 had its "wings" on top of the superior and lateral rectus muscles and its tube tip in the AC. The implant was removed in its entirety including the superficial and deep layers of its capsule. The new BGI-350 was stented with a 3-0 polypropylene ripcord, ligated with a 7-0 polyglactin suture, and implanted with its wings under the rectus muscles and the tube tip in the sulcus. For early IOP-lowering prior to ligature dissolution, 2 needle stab fenestrations and an additional 7-0 polyglactin wick was used. The capsule from the prior BGI-250 was used as a patch graft for the new BGI-350. The ligature dissolved at postoperative week (POW) 6. By POW8, the IOP was 18 mmHg on 3 IOP-lowering medications and frequent topical steroid, the AC was quiet, and the ripcord was removed. A slow steroid taper finished at postoperative month (POM) 6. By POM 12, the VA was still at baseline 20/150, and the IOP was 14 mmHg on 3 IOP-lowering medications. Conclusions & importance: Patients with a prior failed tube requiring additional IOP-lowering can undergo a same-quadrant tube exchange. BGI-350s may offer more IOP-lowering than BGI-250s, but the IOP-lowering achieved in this patient's case could be attributable to differences in postoperative management in addition to endplate size; longer follow-up is needed. A tube exchange offers the opportunity to reposition the tube tip from the AC to the sulcus and to use the prior tube's capsule as a patch graft for the new tube.

Associations Between Autoimmune Disease and the Development of Age-Related Macular Degeneration.

Purpose: The pathogenesis of age-related macular degeneration (AMD) likely implicates the dysregulation of immune response pathways. Several studies demonstrate that the pathogenic elements of AMD resemble those of autoimmune diseases, yet the association between AMD development and most autoimmune diseases remain unexplored. Methods: We conducted a case-control analysis of patients ages 55 and older with new-onset International Classification of Diseases (ICD) coding of dry, wet, or unspecified AMD between 2005 and 2019 in the Merative MarketScan Commercial and Medicare Databases. The diagnosis of an autoimmune disease was defined by an outpatient or inpatient claim with a relevant ICD code in the 12 months before the index visit. Conditional multivariable logistic regression, adjusted for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals. Results: We identified 415,027 cases with new-onset ICD coding for AMD matched with propensity scores to 414,853 controls. In total, 16.1% of cases and 15.9% of controls were diagnosed with any autoimmune disease. The diagnosis of any autoimmune disease did not affect the odds of new-onset ICD coding for AMD in multivariable regression (OR = 1.01; 95% CI, 0.999-1.02). Discoid lupus erythematosus (OR = 1.29; 95% CI, 1.12-1.48), systemic lupus erythematosus (SLE) (OR = 1.21; 95% CI, 1.15-1.27), giant cell arteritis (OR = 1.19; 95% CI, 1.09-1.30), Sjogren's syndrome (OR = 1.17; 95% CI, 1.09-1.26), and Crohn's disease (OR = 1.13; 95% CI, 1.06-1.22) increased the odds of a new-onset ICD coding for AMD. Conclusions: Most autoimmune diseases do not affect the odds of developing AMD but several common autoimmune disorders such as SLE and Crohn's disease were associated with modestly increased odds of AMD. Further studies are needed to validate and investigate the underlying mechanisms of these associations.

Cyclophotocoagulation in Neovascular Glaucoma with Near-Total Synechial Angle Closure.

Objective: To describe a single surgeon's experience utilizing prompt primary slow-burn transscleral cyclophotocoagulation (CPC) with prior or concurrent anti-VEGF and subsequent aqueous shunt as needed in NVG eyes with near-total synechial angle closure at presentation. Methods: Retrospective chart review of all NVG patients with uncontrolled IOP, active anterior segment NV, near-total synechial angle closure, and no contraindications to prompt anti-VEGF who received CPC within 3 days of presentation with at least 6 months of follow-up. Results: Eight patients with mean age 60.6 years were included. Underlying etiologies were CRVO (N = 3), PDR (N = 2), CRAO (N = 1), BRVO (N = 1), and chronic RD (N = 1). All eyes underwent CPC with intravitreal anti-VEGF within 3 days of presentation. Five patients did not require subsequent aqueous shunts through a mean follow-up of 15 months; most recent visual acuities ranged from 20/40 to LP, and IOPs ranged from 5 to 11 mmHg on 0 to 3 IOP-lowering medications. Three patients who required subsequent tubes had complete regression of active anterior segment NV at the time of surgery. Most recent visual acuities ranged from 20/100 to 20/125, and IOPs ranged from 8 to 14 mmHg on 0 meds at a mean follow-up of 10 months. No eyes developed uncontrolled inflammation, sympathetic ophthalmia, or phthisis. Conclusion: Prompt primary slow-burn CPC with prior or concurrent anti-VEGF may be an effective strategy to immediately lower IOP in acute NVG eyes with active anterior segment NV and near-total synechial angle closure. If IOP becomes uncontrolled later, an aqueous shunt can be implanted in a controlled setting after active anterior segment NV has regressed.

The Association of Antibiotic Use and the Odds of a New-Onset ICD Code Diagnosis of Age-Related Macular Degeneration: A Large National Case-Control Study.

Purpose: The widespread use of antibiotics has many well-documented impacts on the human microbiome, which may be associated with the development of various inflammatory diseases. Despite age-related macular degeneration (AMD) featuring an inflammatory pathogenesis, the relationship between antibiotics and AMD has remained unexplored. We conducted the first study to determine the association between antibiotic exposure and a new-onset International Classification of Diseases (ICD) diagnosis of AMD. Methods: We performed a case-control analysis of patients aged 55 and older with new-onset AMD between 2008 and 2017 from a nationwide commercial health insurance claims database. Exposure to antibiotics in the two years before the index date was determined for cases and controls matched one-to-one by age, year, region, anemia, hypertension, and a comorbidity index. Conditional multivariable logistic regression, adjusted for AMD risk factors, was performed to calculate odd ratios (OR) and 95% confidence intervals (CI). Results: Among the antibiotic classes, exposure to aminoglycosides (OR = 1.24; 95% CI, 1.22-1.26) and fluoroquinolones (OR = 1.13; 95% CI, 1.12-1.14) was associated with the greatest odds of a new-onset ICD code diagnosis of AMD. Broad-spectrum antibiotics were associated with nearly three times greater odds of a new-onset ICD code diagnosis of AMD (OR = 1.15; 95% CI, 1.13-1.16) compared to narrow-spectrum antibiotics (OR = 1.05; 95% CI, 1.03-1.07). We also identified a frequency- and duration-dependent association, with a greater cumulative number of antibiotic prescriptions or day supply of antibiotics conferring increased odds of a new-onset ICD code diagnosis of AMD. Conclusions: Greater cumulative exposure to antibiotics, particularly fluoroquinolones, aminoglycosides, and those with broader-spectrum coverage, may be associated with the development of AMD, a finding that requires further investigation using prospective studies.

Long-Term Effectiveness of Dupilumab in Patients with Atopic Dermatitis: Results up to 3 Years from the RELIEVE-AD Study.

INTRODUCTION: Atopic dermatitis (AD) can require long-term therapy. Few real-world studies have evaluated long-term effectiveness from the patients' perspective. The aim of this study was to evaluate patient-reported outcomes (PROs) during long-term dupilumab treatment. METHODS: Adults with moderate-to-severe AD who initiated dupilumab through the US manufacturer patient support program and participated in RELIEVE-AD (a prospective patient survey study with a 12-month follow-up) were recontacted 30-36 months post-initiation regardless of current dupilumab use. The online questionnaire consisted of PROs, including the Atopic Dermatitis Control Tool (ADCT), use of concomitant AD therapies, satisfaction with current therapy, global change in itch relative to before dupilumab initiation, non-itch skin symptoms (skin pain/soreness, hot/burning feeling, and sensitivity to touch), flares, Dermatology Life Quality Index, sleep problems, and the AD-specific Work Productivity and Activity Impairment Questionnaire. RESULTS: Of 698 patients who initiated dupilumab (baseline) and were recontacted, 425 completed the 30-36-month survey. Significant reductions from baseline were reported in concomitant AD therapy use (P < 0.05); 54.4% reported not using other AD medications vs. 12.8% at baseline. At 30-36 months, all results (non-itch skin symptoms, flares, sleep problems, health-related quality of life work/activity impairment, disease control, and treatment satisfaction) were similar to or incrementally better than the 12-month timepoint, with significant improvements vs. baseline (P < 0.001). Global change in itch was reported as "very much better" by 75.3% of respondents. Adequate disease control (score < 7 on ADCT) was reported by 80.7% of respondents, and 86.8% were satisfied with the treatment. CONCLUSIONS: In clinical practice settings, patient-reported benefits of dupilumab were maintained in survey respondents during long-term treatment up to 36 months while the use of concomitant AD therapies reduced.

Atopic dermatitis (also known as eczema) is a chronic skin disease that can have a profoundly negative effect on patients' quality of life. To control disease symptoms, patients often need long-term treatment. Dupilumab is a treatment that has shown benefits in adults with moderate-to-severe atopic dermatitis (AD) when used in long-term (under 4 years) clinical trials; however, few studies have evaluated patients' experiences of long-term dupilumab treatment outside of a clinical trial setting. This study was conducted to do so: 425 adults with moderate-to-severe AD who received dupilumab through a US manufacturer patient support program filled in an online questionnaire 30­36 months after starting treatment. The questionnaire included items on use of additional AD therapies, AD symptoms, quality of life, disease control, and satisfaction with treatment. Patients' responses showed that, at 30­36 months after starting dupilumab treatment, 54% of patients reported not using any other medications for AD vs. 13% of patients when starting dupilumab treatment. In addition, since starting dupilumab, 75% of patients reported one of the most burdensome AD symptoms, itch, as being "very much better" vs. before starting treatment; 81% reported control of AD symptoms; 85% reported a meaningful improvement in quality of life; and 76% were "extremely" or "very" satisfied with the treatment. In summary, this study showed that long-term dupilumab treatment provides continued improvement in symptoms, treatment satisfaction, disease control, and quality of life in adults with moderate-to-severe AD while reducing the need for other AD treatments. Video abstract: How do patients with atopic dermatitis perceive long-term dupilumab treatment in the real world? (MP4 31888 kb).

Accelerated high-throughput imaging and phenotyping system for small organisms.

Studying the complex web of interactions in biological communities requires large multifactorial experiments with sufficient statistical power. Automation tools reduce the time and labor associated with setup, data collection, and analysis in experiments that untangle these webs. We developed tools for high-throughput experimentation (HTE) in duckweeds, small aquatic plants that are amenable to autonomous experimental preparation and image-based phenotyping. We showcase the abilities of our HTE system in a study with 6,000 experimental units grown across 2,000 treatments. These automated tools facilitated the collection and analysis of time-resolved growth data, which revealed finer dynamics of plant-microbe interactions across environmental gradients. Altogether, our HTE system can run experiments with up to 11,520 experimental units and can be adapted for other small organisms.

Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy.

BACKGROUND: Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. RESEARCH DESIGN AND METHODS: Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). RESULTS: Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: -5.3 [95% confidence interval (CI): -9.4, -1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: -18.3 [95% CI: -28.6, -8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). CONCLUSIONS: This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis is a rare genetic disease that runs in families, affecting about 50,000 people worldwide. This condition results in abnormal protein deposits building up, causing damage to multiple nerves (polyneuropathy) and other organs, which can shorten lifespan and have other harmful effects. Polyneuropathy symptoms include weakness, numbness, pain, dizziness, and diarrhea. Over time, everyday activities become more difficult as patients become increasingly disabled and dependent on others. Several treatments have been approved for the polyneuropathy of ATTRv amyloidosis. Many of these work in different ways to impact the disease process. An indirect treatment comparison is a well-established statistical method used by healthcare decision-makers to compare treatments when head-to-head trials are unavailable. Indirect treatment comparisons using a common approach, the Bucher method, yield similar conclusions to head-to-head studies over 90% of the time. This method was used to compare clinical trial data for tafamidis and vutrisiran, two approved treatments for ATTRv amyloidosis with polyneuropathy. The findings show that vutrisiran is more effective than tafamidis at addressing the polyneuropathy of ATTRv amyloidosis as measured by changes to sensory or motor nervous system functioning and nutritional status. Also, vutrisiran showed greater maintenance of health-related quality of life compared to tafamidis. The expected benefits of vutrisiran over tafamidis are large enough to be noticeable and clinically meaningful to a patient or clinician. This highlights the potential advantages of vutrisiran compared to tafamidis with regard to preservation of physical function and quality of life when treating ATTRv amyloidosis with polyneuropathy.

Prevalence of potential drug-drug interactions with ritonavir-containing COVID-19 therapy.

BACKGROUND: Patients with COVID-19 receiving ritonavir-containing therapies are at risk of potential drug-drug interactions (pDDIs) because of ritonavir's effects on cytochrome P450 3A4. OBJECTIVE: To assess the prevalence of pDDIs with ritonavir-containing COVID-19 therapy in adults with COVID-19 using the Optum Clinformatics Data Mart database. METHODS: In this retrospective, observational cohort study, patients with COVID-19 aged 18 years or older prescribed cytochrome P450 3A4-mediated medications with supply days overlapping the date of COVID-19 diagnosis between January 1, 2020, and June 30, 2021, were classified as having pDDIs. pDDI was classified as contraindicated, major, moderate, or mild using established drug interaction resources. Prevalence of pDDIs with ritonavir-containing COVID-19 therapy was estimated for the entire cohort and in patient groups with high risk of severe COVID-19 progression or pDDIs. Actual COVID-19 treatments received by the patients, if any, were not considered. Outcomes were presented descriptively without adjusted comparisons. RESULTS: A total of 718,387 patients with COVID-19 were identified. The age-sex standardized national prevalence of pDDIs of any severity was estimated at 52.2%. Approximately 34.5% were at risk of contraindicated or major pDDIs. Compared with patients without pDDI, patients exposed to pDDIs were older and more likely to be female, reside in long-term care facilities, and have risk factors for progression to severe COVID-19. Higher prevalence of major/contraindicated pDDIs was observed in older patients (76.1%), female patients (65.0%), and patients with multiple morbidities (84.6%). CONCLUSIONS: Study findings demonstrate that more than one-third of patients with COVID-19 were at risk of significant pDDIs if treated with ritonavir-containing COVID-19 therapy and highlight the need to assess all patients with COVID-19 for pDDIs. Ritonavir-based therapies may not be appropriate for certain patient groups, and alternative therapies should be considered. DISCLOSURES: Drs Igho-Osagie, Puenpatom, and Grifasi Williams are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Dr Song and Ms He are employees of Analysis Group, Inc., and served as paid consultants for Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Drs Yi and Wang, and Mr Berman, and Ms Gu were employees of Analysis Group, Inc., at the time of study conduct. Financial support for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. The study sponsor was involved in the design and conduct of the study; collection, management, analysis, interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Tracking energy scale variations from scan to scan in nuclear resonant vibrational spectroscopy: In situ correction using zero-energy position drifts ΔEi rather than making in situ calibration measurements.

Nuclear resonant vibrational spectroscopy (NRVS) is an excellent modern vibrational spectroscopy, in particular, for revealing site-specific information inside complicated molecules, such as enzymes. There are two different concepts about the energy calibration for a beamline or a monochromator (including a high resolution monochromator): the absolute energy calibration and the practical energy calibration. While the former pursues an as-fine-as-possible and as-repeatable-as-possible result, the latter includes the environment influenced variation from scan to scan, which often needs an in situ calibration measurement to track. However, an in situ measurement often shares a weak beam intensity and therefore has a noisy NRVS spectrum at the calibration sample location, not leading to a better energy calibration/correction in most cases. NRVS users for a long time have noticed that there are energy drifts in the vibrational spectra's zero-energy positions from scan to scan (ΔEi), but their trend has not been explored and utilized in the past. In this publication, after providing a brief introduction to the critical issue(s) in practical NRVS energy calibrations, we have evaluated the trend and the mechanism for these zero-energy drifts (ΔEi) and explored their link to the energy scales (αi) from scan to scan. Via detailed analyses, we have established a new stepwise procedure for carrying out practical energy calibrations, which includes the correction for the scan-dependent energy variations using ΔEi values rather than running additional in situ calibration measurements. We also proved that one additional instrument-fixed scaling constant (α0) exists to convert such "calibrated" energy axis (E') to the real energy axis (Ereal). The "calibrated" real energy axis (Ereal) has a preliminary error bar of ±0.1% (the 2σE divided by the vibrational energy position), which is 4-8 times better than that from the current practical energy calibration procedure.

Changes in Rat Scleral Collagen Structure Induced by UVA-Riboflavin Crosslinking at Various Tissue Depths in Whole Globe Versus Scleral Patch.

Purpose: To investigate structural changes in scleral collagen fibers at various tissue depths before and after photosensitized crosslinking (CXL) both isolated scleral patch versus whole globe using second-harmonic generation (SHG) imaging. Methods: Scleral tissues were harvested from Sprague-Dawley rats and separated into three groups: untreated sclera (control), full-thickness scleral patch for CXL (Free Scleral CXL group), and sclera in intact globe for CXL (Globe CXL group). The CXL groups were soaked in 0.1% riboflavin and irradiated with 365 nm ultraviolet-A light (power, 0.45 mW/cm2) for 30 minutes. SHG images were acquired every 5 µm between 10 and 60 µm from the outer scleral surface. Collagen fiber waviness was calculated as the ratio of the total length of a traced fiber and the length of a straight path between the fiber ends. Results: In the Free Scleral CXL group, collagen waviness was significantly increased compared to the control group at 35 to 50 µm (P < 0.05). In the Globe CXL group, collagen waviness was decreased compared to control at all depths with statistical significance (P < 0.05) achieved from 10 to 45 µm. Conclusions: Depending upon its initial state (i.e., free scleral patch versus mechanically loaded intact globe under pressure), collagen may experience different structural changes after CXL. In addition, the extent of the CXL effects may vary at different depths away from the surface. Translational Relevance: Understanding the CXL effects on collagen structure may be important in optimizing the scleral crosslinking protocol for future clinical applications such as preventing myopic progression.

Cost-effectiveness analysis of semaglutide 2.4 mg for the treatment of adult patients with overweight and obesity in the United States.

BACKGROUND: The rising prevalence and associated public health burden of obesity has led to advancements in pharmaceuticals for weight management. Semaglutide 2.4 mg, an anti-obesity medication (AOM) recently approved by the US Food and Drug Administration, has demonstrated clinically relevant weight loss in its phase 3 clinical trials. Economic evaluation comparing semaglutide 2.4 mg with other available weight management therapies is essential to inform payers for decision-making. OBJECTIVES: To assess the cost-effectiveness of semaglutide 2.4 mg in the treatment of adult patients with obesity (ie, body mass index [BMI] ≥ 30) and adult patients who are overweight (ie, BMI 27-29.9) with 1 or more weight-related comorbidities from a US third-party payer perspective. METHODS: A cohort Markov model was constructed to compare semaglutide 2.4 mg with the following comparators: no treatment, diet and exercise (D&E), and 3 branded AOMs (liraglutide 3 mg, phentermine-topiramate, and naltrexone-bupropion). All AOMs, including semaglutide 2.4 mg, were assumed to be taken in conjunction with D&E. Changes in BMI, blood pressure, cholesterol level, experience of acute and chronic obesity-related complications, costs, and quality-adjusted life years (QALYs) were simulated over 30 years based on pivotal trials of the AOMs and other relevant literature. Drug and health care prices reflect 2021 standardized values. Cost-effectiveness was examined with a willingness-to-pay (WTP) threshold of $150,000 per QALY gained. Sensitivity analyses were conducted to test the robustness of the cost-effectiveness results to plausible variation in model inputs. RESULTS: In the base-case analysis, treatment with semaglutide 2.4 mg was estimated to improve QALYs by 0.138 to 0.925 and incur higher costs by $3,254 to $25,086 over the 30-year time horizon vs comparators. Semaglutide 2.4 mg is cost-effective against all comparators at the prespecified WTP threshold, with the incremental cost per QALY gained ranging from $23,556 to $144,296 per QALY gained. In the sensitivity analysis, extended maximum treatment duration, types of subsequent treatment following therapy discontinuation, and weight-rebound rates were identified as key drivers for model results. The estimated probability of semaglutide 2.4 mg being cost-effective compared with comparators ranged from 67% to 100% when varying model parameters and assumptions. CONCLUSIONS: As a long-term weight management therapy, semaglutide 2.4 mg was estimated to be cost-effective compared with no treatment, D&E alone, and all other branded AOM comparators under a WTP threshold of $150,000 per QALY gained over a 30-year time horizon. DISCLOSURES: Financial support for this research was provided by Novo Nordisk Inc. The study sponsor was involved in several aspects of the research, including the study design, the interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication. Dr Kim and Ms Ramasamy are employees of Novo Nordisk Inc. Ms Kumar and Dr Burudpakdee were employees of Novo Nordisk Inc at the time this study was conducted. Dr Sullivan received research support from Novo Nordisk Inc for this study. Drs Wang, Song, Wu, Ms Xie, and Ms Sun are employees of Analysis Group, Inc, who received consultancy fees from Novo Nordisk Inc in connection with this study.

Treatment Outcomes Associated With Dupilumab Use in Patients With Atopic Dermatitis: 1-Year Results From the RELIEVE-AD Study.

IMPORTANCE: Clinical trial populations may not reflect clinical practice: knowledge generated in other settings can inform clinical decision-making. OBJECTIVE: To evaluate self-reported disease control and quality of life after initiating dupilumab treatment in patients with atopic dermatitis (AD) in the the clinical setting. DESIGN, SETTING, AND PARTICIPANTS: This cohort study using an online survey administered prior to (baseline) and at 1, 2, 3, 6, 9, and 12 months after dupilumab initiation included adults with moderate-to-severe AD who initiated treatment with dupilumab through the US patient support program and agreed to participate in the study. Data were collected between January 2018 and January 2020 and the analysis was completed in May 2020. INTERVENTIONS: Clinically driven treatment with dupilumab. MAIN OUTCOMES AND MEASURES: Disease control measured by the Atopic Dermatitis Control Tool (ADCT); concomitant AD therapies; satisfaction with therapy; skin symptoms (skin pain/soreness, hot/burning feeling, sensitivity to touch) assessed using numerical rating scales; flares; health-related quality of life assessed using the Dermatology Life Quality Index; sleep problems assessed using the ADCT item and a stand-alone question; and the AD-specific Work Productivity and Activity Impairment Questionnaire. RESULTS: Of 699 patients who initiated dupilumab (431 [61.7%] female, 515 [73.7%] White), 632 and 483 completed the survey at months 1 and 12, respectively. As-observed results showed that most patients achieved adequate disease control (ADCT total score) at month 1 with further improvement at month 12 (385 of 632 patients [60.9%] and 374 of 483 [77.4%] for the 2 time points, respectively, vs 41 of 699 [5.3%] at baseline; both P < .001). Use of other AD therapies was reduced at each follow-up vs baseline, including topical and systemic corticosteroids, which were reduced at month 12 to 40.4% (195 of 483 patients) and 6.2% (30 of 483 patients), respectively, from 68.1% (476 of 699) and 34.9% (244 of 699), respectively, at baseline (both P < .001 vs baseline). Patient satisfaction with AD treatment was higher than baseline (120 of 699 [17.7%]) at each follow-up to 85.1% (411 of 483) at month 12 (P < .001). At each follow-up, patients reported reductions in flares, itch, skin symptoms, and improved sleep, health-related quality of life, and daily activities vs baseline. Results were consistent based on observed data and imputed data using pattern mixture models for missing data. CONCLUSIONS AND RELEVANCE: Consistent with patient-reported outcomes in clinical trials, this cohort study found that dupilumab treatment was associated with rapid and sustained disease control for up to 12 months as demonstrated by statistically significant improvements relative to baseline on all patient-reported outcomes including treatment satisfaction.

Impact of Risankizumab on PASI90 and DLQI0/1 Duration in Moderate-to-Severe Psoriasis: A Post Hoc Analysis of Four Phase 3 Clinical Trials.

INTRODUCTION: Novel therapies have allowed psoriasis patients to achieve high levels of skin clearance and meaningful improvements in health-related quality of life measures; however, duration of these outcomes has not been evaluated. This study aimed to estimate the duration of Psoriasis Area and Severity Index (PASI) 90 and Dermatology Life Quality Index (DLQI) 0/1 among patients with moderate-to-severe psoriasis receiving risankizumab and other treatments. METHODS: Pooled data from four phase 3 randomized clinical trials of risankizumab were used to estimate the number and proportion of days with PASI90 and DLQI0/1 during the 1-year post-baseline period with an area-under-the-curve approach. Patients were classified into five cohorts on the basis of their treatment experience during the follow-up period: risankizumab (RISA) only, RISA followed by re-randomization to RISA or placebo (RISA and RISA/PBO), adalimumab (ADA) followed by re-randomization to ADA or RISA (ADA and ADA/RISA), ustekinumab (UST) only, and placebo followed by risankizumab (PBO/RISA). RESULTS: A total of 2101 patients were included in this analysis. Mean age was 47.5 years, 70% were males, and mean duration since psoriasis diagnosis was 18.6 years. Patients treated with RISA only throughout the study period experienced the longest PASI90 [245.7 days (67% over 1 year)] and DLQI0/1 [213.7 (59%)] duration. Patients treated with PBO/RISA [156.8 (43%)] and UST only [154.2 (42%)] experienced the shortest PASI90 duration. Similarly, patients treated with PBO/RISA experienced the shortest DLQI0/1 duration during the 52-week study period [90.5 (25%)]. CONCLUSION: Patients with moderate-to-severe psoriasis treated with risankizumab exhibited longer durations of PASI90 and DLQI0/1 than patients treated with other therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: UltIMMa-1 (NCT02684370), NCT02684357 (UltIMMa-2), IMMvent (NCT02694523), IMMhance (NCT02672852).

Impact of PASI response on work productivity and the effect of risankizumab on indirect costs using machine learning in patients with moderate-to-severe psoriasis.

OBJECTIVES: To compare the impact of Psoriasis Area and Severity Index (PASI) response on total work productivity impairment (TWPI) in patients with moderate-to-severe psoriasis; to compare TWPI and associated indirect costs among patients treated with risankizumab, adalimumab, ustekinumab, and placebo. METHODS: Data from REVEAL (adalimumab phase III trial) were used to assess differences in trial-observed TWPI across PASI response cohorts. A machine learning model used REVEAL data to predict TWPI for patients in the risankizumab trials. These values were used to estimate work loss hours and work impairment-related indirect costs for each treatment cohort. RESULTS: Among REVEAL patients (N = 741), TWPI in the PASI 100, 90-99, 75-89 cohorts was lower than the PASI <75 cohort (p < .05); mean TWPI was lowest with PASI 100 (1.7%) vs. 90-99 (2.5%) vs. 75-89 (4.8%) vs. <75 (14.3%). There was a significant (p < .0001) monotonic relationship between higher PASI response and lower TWPI. In the risankizumab trials (N = 2046), incremental TWPI relative to risankizumab was 3.4%/week for ustekinumab/adalimumab, and 17.1%/week for placebo; incremental indirect cost savings for risankizumab were $2179/year vs. adalimumab, $2321/year vs. ustekinumab, and $11,284/year vs. placebo. CONCLUSIONS: Higher PASI responses were associated with reduced TWPI. Risankizumab was associated with less work impairment/indirect costs vs. ustekinumab/adalimumab/placebo.