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What Is Known and Objective: Aflibercept, a recombinant protein designed to suppress the vascular endothelial growth factor (VEGF) signalling pathway, has been used in patients with metastatic colorectal cancer (mCRC). We conducted the first meta-analysis to systematically review the efficacy and safety of aflibercept in mCRC., Methods: PubMed Central/Medline, Embase and cochrane library were systematically searched for randomized controlled trials and single-arm clinical trials on aflibercept plus chemotherapy for the treatment of mCRC through 9 September 2021., Results: Ten studies comprising 2049 patients met the inclusion criteria. The pooled estimate rates were 16.0% for 12mPFS, 64.4% for 12mOS, 32.5% for ORR, 83.5% for DCR, while the rates of III/IV AEs rate were 80.2% respectively. The pooled estimate rates were 16.8% for III/IV diarrhoea, 22.3% for III/IV hypertension, 29.5% for III/IV neutropenia, 7.3% for III/IV proteinuria and 8.6% for III/IV oral mucositis., Conclusions: Analysis of data from randomized controlled trials(RCT) and single-arm clinical trials confirmed the good efficacy of aflibercept plus chemotherapy in mCRC, while the safety of the treatment is concerning., (© 2022 John Wiley & Sons Ltd.)

Introduction: The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label., Methods: Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52., Results: Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min-max) of 10.0 (2-14; T&E), 11.5 (1-25; PRN), and 12.3 (3-13; fixed) injections over 100 weeks, with 13.3 (4-23), 25.0 (3-29), and 16.1 (5-25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [- 1.46, 1.47] and PRN 0.95 (- 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies., Conclusion: The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan., Trial Registration: ClinicalTrials.gov identifier: NCT02818998., (© 2022. The Author(s).)

Introduction: Anti-angiogenic drugs are an efficacious class of therapy in the treatment of patients with metastatic colorectal cancer (mCRC). Aflibercept, a vascular endothelial growth factor (VEGF) trap which binds the angiogenic factors VEGF-A, VEGF-B, and placental growth factor (PIGF) is approved in combination with FOLFIRI chemotherapy following progression after an oxaliplatin-containing regimen., Areas Covered: This report provides a review of the practice-changing clinical studies which have established the use of anti-angiogenic therapy as second-line therapy in mCRC including aflibercept with FOLFIRI (5FU, leucovorin, irinotecan). This review also evaluates aflibercept with other chemotherapy regimens as well as efficacy and safety data from real-world studies., Expert Opinion: Aflibercept in combination with FOLFIRI chemotherapy is an established safe and efficacious regimen for the treatment of mCRC as second-line chemotherapy. Although several toxicities have been described, the majority are either low grade or manageable by drug cessation and supportive therapies. For optimal outcomes, patient selection and close observation of toxicities is essential.

Objective: To review the pharmacology, efficacy, and safety of rilonacept for the prevention and treatment of recurrent pericarditis (RP)., Data Sources: A MEDLINE search was conducted between January 2006 and April 2021 using the following terms: rilonacept, pharmacology, pericarditis, recurrent pericarditis, interleukin (IL) antagonist, and pharmacology; prescribing information was also used., Study Selection and Data Extraction: English-language studies assessing pharmacology, efficacy, and safety of IL antagonists were reviewed., Data Synthesis: Rilonacept traps IL-1α and IL-1β. In the Phase III trial, rilonacept was associated with a lower risk of recurrence, more persistent clinical response, and higher amount of days with no or minimal pericarditis symptoms, compared with placebo. The median time to pain response was 5 days, and median time to normalization of C-reactive protein was 7 days with rilonacept. All patients receiving rilonacept during the run-in period were able to be weaned off of standard background therapy, leading to transition to rilonacept monotherapy. The most common adverse effects were upper respiratory tract infections and injection site reactions., Relevance to Patient Care and Clinical Practice: Rilonacept may be used for the prevention and treatment of multiple recurrences in patients receiving background therapy for RP, and reduction in risk of recurrence in adults and adolescents ≥12 years with elevated C-reactive protein. Rilonacept may be considered to wean patients from standard background therapy., Conclusion: Rilonacept is a safe, once weekly, subcutaneously administered IL-1 "trap," indicated for the treatment of RP, and reduction in risk of recurrent pericarditis in adults and children ≥12 years of age.

Aims: Currently, no head-to-head data are available comparing semaglutide 2.0 mg with dulaglutide 3.0 mg or 4.5 mg. We conducted an indirect treatment comparison (ITC) of their effects on glycated hemoglobin (HbA1c) and body weight in patients with type 2 diabetes., Materials and Methods: Multilevel network meta-regression was conducted, based on a connected evidence network of published results from the A Study of the Efficacy and Safety of Dulaglutide (LY2189265) in Participants With Type 2 Diabetes 11 trial and individual patient data from the A Research Study to Compare Two Doses of Semaglutide Taken Once Weekly in People With Type 2 Diabetes (SUSTAIN) and SUSTAIN 7 trials., Results: Semaglutide 2.0 mg significantly reduced HbA1c vs dulaglutide 3.0 mg and 4.5 mg, with estimated treatment differences (ETDs) of -0.44% points (95% credible interval [CrI], -0.68 to -0.19) and -0.28% points (95% CrI, -0.52 to -0.03), respectively. Semaglutide 2.0 mg also significantly reduced body weight vs dulaglutide 3.0 mg and 4.5 mg with ETDs of -3.29 kg (95% CrI, -4.62 to -1.96) and -2.57 kg (95% CrI, -3.90 to -1.24), respectively. Odds of achieving HbA1c < 7.0% were significantly greater for semaglutide 2.0 vs dulaglutide 3.0 mg (odds ratio [OR]: 2.23 [95% CrI, 1.15-3.90]), whereas this did not reach significance for semaglutide 2.0 mg vs dulaglutide 4.5 mg (OR: 1.58 [95% CrI, 0.82-2.78]). Sensitivity analyses supported the main analysis findings., Conclusions: This ITC demonstrated significantly greater reductions from baseline in HbA1c and body weight with semaglutide 2.0 mg vs dulaglutide 3.0 mg and 4.5 mg. The findings of this study provide important comparative effectiveness information until randomized head-to-head studies become available., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: To compare intravitreal aflibercept injection with intravitreal ranibizumab injection for the risk of major arterial thromboembolic events (ATEs) and glaucoma., Methods: This retrospective, nationwide cohort study investigated 15 611 and 3867 patients aged >50 years with at least one pharmacy claim for intravitreal ranibizumab injection and aflibercept injection between 2011 and 2016, respectively. The inverse probability of treatment weighting method was performed to adjust the baseline difference between the two groups and the hazard risk of adverse events was estimated using the Cox proportional regression model., Results: No significant difference was noted between intravitreal ranibizumab and aflibercept injection for arterial thromboembolic risk, including ischemic stroke and acute myocardial infarction, during a 2-year follow-up (adjusted hazard ratio (HR): 0.87, 95% confidence interval (CI): 0.53-1.42; P = .583). Subgroup analyses revealed that patients age >65 years (adjusted HR: 0.64, 95% CI: 0.45-0.92) and those without coronary artery disease (adjusted HR: 0.59, 95% CI: 0.37-0.95) had significantly lower arterial thromboembolic risk in the aflibercept group than in the ranibizumab group. Additionally, the risk of glaucoma development after intravitreal injection did not significantly differ between the two groups (adjusted HR: 0.63, 95% CI: 0.37-1.06; P = .084)., Conclusions: No significant differences in the risk of major ATEs and glaucoma were found between ranibizumab and aflibercept, and aflibercept might be safe for use in elderly patients., Competing Interests: The authors have declared that no competing interests exist.

Aim: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo., Materials and Methods: Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure., Results: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure., Conclusion: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes., (© 2022 John Wiley & Sons Ltd.)

Introduction: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA., Methods: In this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7-24 months of age when administered). They were all previously treated with nusinersen, 4-5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration., Results: Liver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment., Conclusion: Our experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment., (Copyright © 2022. Published by Elsevier B.V.)

One possible side effect of thrombopoietin receptor agonists in immune thrombocytopenia is thrombosis. Our aim is to systematically review whether patients with ITP that were treated with a TPO-RA have an increased risk for thrombosis as compared to ITP patients without TPO-RA. Patients in the intervention group were required to receive TPO-RA therapy. The primary outcome was the incidence of thromboembolic events. Eleven studies were included in the pooled analysis. More thromboembolic events were noted in the TPO-RA group than in the control group: 25 compared to 4. Ten out of 11 studies showed a relative risk greater than 1. However, none of these individual risk ratios was statistically significant. The meta-analysis showed a RR of 1.82 [95 % CI 0.78-4.24]. Our findings indicate there is a non-significant higher chance of thrombosis in ITP patients with TPO-RA treatments versus ITP patients without TPO-RA treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The association between intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment and the risk of major thromboembolic adverse events (TAEs) remains under debate. This study aimed to examine associated risks of TAEs in patients receiving intravitreal anti-VEGF treatment, and effect modification by different indications., Methods: This retrospective cohort study analyzed Taiwan's National Health Insurance Database during 2011-2017 to identify neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) patients newly receiving intravitreal aflibercept or ranibizumab. We followed up patients for 2 years, or until the occurrence of TAEs, including ischemic heart disease, ischemic stroke, transient ischemic attack, deep vein thrombosis, and pulmonary embolism, death, or the end of the study period (i.e., 31 December 2018). We compared the risk of TAEs between patients with aflibercept and ranibizumab using Cox-proportional hazard models. We examined statistical interactions between the anti-VEGF treatment (i.e., ranibizumab and aflibercept) and indications (i.e., nAMD and DME) with regard to the outcome of TAEs., Results: We included 12,215 nAMD and 7532 DME patients. Among nAMD patients, those receiving aflibercept had lower risk of TAEs (adjusted hazard ratio [HR] 0.85; 95% CI 0.77-0.94) compared with those receiving ranibizumab. However, among DME patients, those receiving aflibercept had no differences in the risk of TAEs (1.14; 0.97-1.35) compared with those receiving ranibizumab. Among patients treated with ranibizumab, the DME group had a higher risk of TAEs than the nAMD group (HR 1.15; 95% CI 1.03-1.28); similar results were observed in patients treated with aflibercept (HR 1.53; 95% CI 1.27-1.85). When DME patients were treated with aflibercept, the risk of TAEs was 31% higher than when nAMD patients were treated with ranibizumab (HR 1.31; 95% CI 1.09-1.56; p < 0.05). The p-value for statistical interaction between the anti-VEGF treatment and indications was 0.0033., Conclusions: Patients treated with aflibercept or ranibizumab for different indications may be associated with varying risk of TAEs. The findings provide evidence to support treatment selection, taking indications and TAE risk into consideration., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody., Methods: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593)., Findings: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%])., Interpretation: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests CCW reports research support from Adverum, Aerie, Aldeyra, Alimera, Allergan, Amgen, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Gemini, Genentech, Graybug Vision, Gyroscope, Ionis, iRenix Medical, Iveric Bio, Kodiak, Lowy Medical Research Institute, Neurotech, NGM Bio, Novartis, Oxurion, RecensMedical, Regeneron, Regenxbio, Roche, SamChunDang Pharm, Samsung Bioepis, Taiwan Liposome Company, and Xbrane BioPharma, outside the submitted work. CCW reports consulting fees from Adverum, Aerie, Aerpio, Allergan, Allgenesis, Apellis, Arrowhead, Bausch and Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong, Clearside, EyePoint, Genentech, Gyroscope, Iveric Bio, Janssen, Kato, Kodiak, Long Bridge Medical, NGM Bio, Novartis, OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea, Oxurion, Palatin, PolyPhotonix, RecensMedical, Regeneron, Regenxbio, Roche, Santen, Surrozen, Takeda, Verana Health, and Vitranu, outside the submitted work. CCW reports other personal fees from Regeneron, stock or stock options from ONL Therapeutics, PolyPhotonix, RecensMedical, and Visgenx, and has served on advisory boards for Kato, outside the submitted work. CCW has served as a board member of the American Society of Retina Specialists and the Vit-Buckle Society, outside the submitted work. FA is an employee of Genentech. APA was an employee of Genentech during the course of this study and reports stock or stock options from Roche. KB was an employee of Genentech during the course of this study and is a current employee of Roche Products (Ireland). DAE reports research support from Alkahest, AsclepiX, Bayer, Chengdu Kanghong, EyePoint, Gemini, Genentech, Gyroscope, Ionis, Iveric Bio, Kodiak, Mylan, NGM Bio, Novartis, Ocular Therapeutix, Opthea, RecensMedical, Regeneron, and Regenxbio, outside the submitted work. DAE reports consulting fees from Alimera, Allergan, Apellis, Bausch and Lomb, Dutch Ophthalmic, EyePoint, Genentech, Gyroscope, Iveric Bio, KKR, Kodiak, Notal Vision, Novartis, RecensMedical, Regeneron, and Regenxbio, outside the submitted work. DAE reports other personal fees from Allergan, Apellis, Bayer, Dutch Ophthalmic, EyePoint, Genentech, and Novartis; stock or stock options from Boston Image Reading Center, Clearside, Hemera, and Network Eye; and has served on advisory boards for Genentech, Iveric Bio, and RecensMedical, outside the submitted work. DAE has served as a board member of the Florida Society of Ophthalmology, outside the submitted work. ZH is an employee of Genentech, and reports stock or stock options from Genentech. HL is an employee of Genentech, reports personal fees and stock or stock options from Roche/Genentech, and is a coauthor on patent application WO202123804 involving the PTI algorithm. AL reports research support from Notal Vision and Novartis, and consulting fees from Allergan, Bayer, Beyeonics Surgical, and Syneos Health, outside the submitted work. SM is an employee of Genentech, and reports stock or stock options from Genentech. IAP reports consulting and other personal fees from Allergan, Bayer, Novartis, and Roche, and has served on advisory boards for Bayer, Novartis, and Roche, outside the submitted work. TS reports research support from Bayer, Chugai, Novartis, Santen, and Senju; consulting and other personal fees from Bayer, Novartis, and Senju; and has served on advisory boards for Bayer, Novartis, and Roche, outside the submitted work. PGS reports personal fees and has served on advisory boards for Roche, outside the submitted work. DS is an employee of Roche Products, reports personal fees and stock or stock options from Roche, and is a coauthor on patent application WO202123804 involving the PTI algorithm. JKS reports research support from Boehringer Ingelheim, Jaeb Center for Health Research, Juvenile Diabetes Research Foundation, KalVista, Novartis, Optovue, and Physical Sciences; personal fees from Merck, Novartis, and Novo Nordisk; and equipment loans from Adaptive Sensory Technology, Boston Micromachines, and Optovue, outside the submitted work. JAW reports research support from Adverum, Alimera, Bayer, Clover Therapeutics, Genentech, Iveric Bio, Kodiak, Lowy Medical Research Institute, NIH National Eye Institute, Neurotech, Opthea, and Regeneron, and consulting fees from Genentech, outside the submitted work. JRW is an employee of Genentech, reports stock or stock options from Genentech, and is a coauthor on patent application WO202123804 involving the PTI algorithm. RT reports consulting and personal fees and has served on advisory boards for AbbVie, Alcon, Allergan, Apellis, Bayer, Chengdu Kanghong, Genentech, Iveric Bio, Novartis, Oculis, Roche, and Thea, and reports equipment from Zeiss, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD)., Methods: TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300)., Findings: Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%])., Interpretation: Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests JSH reports support from Genentech/Roche for the present manuscript; grants from Apellis, AsclepiX, Bayer, Gyroscope, Hemera, Iveric Bio, Kanghong, Kodiak, NGM, Notal Vision, Novartis, Regeneron, Regenxbio, and Stealth, outside the submitted work; and consulting fees from Apellis, AsclepiX, Bayer, Gyroscope, Hemera, Iveric Bio, Kanghong, Kodiak, NGM, Notal Vision, Novartis, Regeneron, Regenxbio, and Stealth. AMK reports grants or contracts to institution from Adverum, Allergan, Chengdu Kanghong, Genentech, Graybug, Novartis, Ophthea, Regenxbio, and Roche, outside the submitted work; consulting fees from Adverum, Allergan, Chengdu Kanghong, Genentech, Graybug, Novartis, Ophthea, Regenxbio, and Roche, outside the submitted work; payment or honoraria for lectures, presentations, or speaker bureaus from Allergan, Genentech, and Novartis, outside the submitted work; and has served on advisory boards for Adverum, Allergan, Chengdu Kanghong, Genentech, Novartis, Ophthea, Regenxbio, and Roche. CQR is an employee of Genentech and reports owning stocks in Roche. KB is an employee of Roche Products (Ireland). PJF reports patient care grants to institution (Vitreoretinal Consultants of New York) for various national clinical trials from Alkeus, Apellis, Chengdu Kanghong, Genentech, Gyroscope, Iveric Bio, Kodiak, NGM, and Regeneron; has served on advisory boards for Allergan and Genentech; and is the president of the American Association of Retinal Specialists (unpaid). CB is an employee of Genentech, and reports owning stocks in Roche. MSF reports consulting fees from Alcon, Bayer, Novartis, Roche, and Zeiss. HL is an employee of Genentech, and has received stock from Genentech/Roche as an employee; has received support from Genentech/Roche to attend meetings as an employee; and is a coauthor on patent application WO202123804 involving the PTI algorithm. FGH reports research grants or contracts to institution from Bayer, Bioeq/Formycon, Kanghong, Novartis, and Roche/Genentech; consulting fees from Bayer, Kanghong, Novartis, and Roche/Genentech; and payment or honoraria for lectures, presentations, or speaker bureaus from Bayer and Novartis. VP is an employee of F Hoffmann-La Roche (UK). TYYL reports grants or contracts to institution from Bayer, Chengdu Kanghong, and Novartis, outside the submitted work; consulting fees from Bayer, Boehringer Ingelheim, Novartis, Oculis, and Roche, outside the submitted work; and payment or honoraria for lectures, presentations, or speaker bureaus from Bayer, Chengdu Kanghong, Novartis, and Roche, outside the submitted work. DS is an employee of F Hoffmann-La Roche (UK); owns stock and stock options in Roche; and is a coauthor on patent application WO202123804 involving the PTI algorithm. CR reports research support from Allergan, Kodiak, Novartis, and Regeneron, outside the submitted work; and consulting fees from Allergan, Genentech, Kodiak, and Novartis, outside the submitted work. BS is an employee of F Hoffmann-La Roche. FV reports consulting fees from Bayer and Roche; payments for expert testimony from Bayer and Roche; and payments for participation on advisory boards for Bayer and Roche. CMGC reports grants or contracts from Bayer, Boehringer Ingelheim, Novartis, and Topcon, outside the submitted work; consulting fees from Novartis and Roche, outside the submitted work; speaker fees from Allergan, Bayer, Novartis, Roche, Topcon, and Zeiss, outside the submitted work; and support for travel to meetings from Bayer and Topcon. TYW reports clinical trial grants from Aldropika, Allergan, Bayer, Boehringer Ingelheim, Eden Ophthalmic, Genentech, Iveric Bio, Merck, Novartis, Oxurion (ThromboGenics), Roche, Samsung, Shanghai Henlius, and Zhaoke, outside the submitted work; consulting fees from Aldropika, Allergan, Bayer, Boehringer Ingelheim, Eden Ophthalmic, Genentech, Iveric Bio, Merck, Novartis, Oxurion (ThromboGenics), Roche, Samsung, Shanghai Henlius, and Zhaoke, outside the submitted work; payment or honoraria from Allergan, Bayer, Boehringer Ingelheim, Eden Ophthalmic, Genentech, Iveric Bio, Merck, Novartis, Oxurion (ThromboGenics), Roche, Samsung, Shanghai Henlius, and Zhaoke, outside the submitted work; support for travel from Aldropika, Allergan, Bayer, Boehringer Ingelheim, Eden Ophthalmic, Genentech, Iveric Bio, Merck, Novartis, Oxurion (ThromboGenics), Roche, Samsung, Shanghai Henlius, and Zhaoke; and has served on advisory boards of Aldropika, Allergan, Bayer, Boehringer Ingelheim, Eden Ophthalmic, Genentech, Iveric Bio, Merck, Novartis, Oxurion (ThromboGenics), Roche, Samsung, Shanghai Henlius, and Zhaoke., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the mean change in visual acuity at 52 weeks in patients with idiopathic choroidal neovascularization treated with aflibercept., Methods: We conducted a prospective noncomparative open-label Phase-II trial. The dosage regimen evaluated in this study was structured into two periods: (1) from inclusion to 20 weeks: a treat-and-extend period composed of three mandatory intravitreal injections, and complementary intravitreal injections performed if needed; (2) from 21 weeks to 52 weeks: a pro re nata period composed of intravitreal injections performed only if needed., Results: A total of 19 patients were included, and 16 completed the 52-week study. At baseline, the mean best corrected visual acuity was 66.56 (±20.72) letters (≈20/50 Snellen equivalent), and the mean central retinal thickness was 376.74 µm (±93.77). At 52 weeks, the mean change in the best-corrected visual acuity was +19.50 (±19.36) letters [95% confidence interval = +9.18 to +29.82]. None of the patients included lost ≥15 letters at 24 weeks or 52 weeks. The mean change in central retinal thickness was -96.78 µm (±104.29) at 24 weeks and -86.22 µm (±112.27) at 52 weeks. The mean number of intravitreal injections was 5.4 (±3.0) at 52-weeks. No ocular serious adverse events related to the treatment were reported., Conclusion: The present analysis shows clinically significant functional and anatomical treatment effect of aflibercept in case of idiopathic choroidal neovascularization. The treat-and-extend regimen proposed after the first injection seems adequate to treat most neovessels.

Aim: To evaluate HbA1c and body weight changes when semaglutide 0.5- or 1.0-mg once-weekly (QW) is switched to dulaglutide 3.0- or 4.5-mg QW via exposure-response modelling., Methods: HbA1c and body weight time-course models were developed and validated with data from the SUSTAIN 1 to 10 trials for semaglutide and the AWARD-11 trial for dulaglutide. Simulations were conducted for HbA1c and body weight over 52 weeks. In the initial 26 weeks, semaglutide was initiated at 0.25-mg and titrated to 0.5- or 1.0-mg QW via 4-weekly stepwise titration, followed by 26 weeks of dulaglutide initiated at 0.75- or 1.5-mg QW and escalated to 3.0- or 4.5-mg QW via 4-weekly stepwise titration., Results: At 26 weeks, model-predicted mean changes from baseline in HbA1c and weight for semaglutide 0.5 mg were up to -1.55% and -3.44 kg, respectively. After switching to dulaglutide 3.0 mg, further reductions were 0.19% and 1.40 kg, respectively, at 52 weeks. Predicted mean HbA1c and weight changes for semaglutide 1.0 mg at 26 weeks were -1.84% and -4.96 kg, respectively; after switching to dulaglutide 4.5 mg, HbA1c was maintained with additional weight reduction of up to 0.57 kg at 52 weeks. Glycaemic control was preserved when switching from semaglutide 1.0 mg to dulaglutide 3.0 mg., Conclusion: Switching from semaglutide 0.5 mg to dulaglutide 3.0 or 4.5 mg with dose escalation potentially yields additional HbA1c and weight reductions; switching from semaglutide 1.0 mg to dulaglutide 4.5 mg may enhance weight loss., (© 2021 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: To evaluate and compare the efficacy and safety of bevacizumab and aflibercept in second-line treatment in metastatic colorectal cancer (mCRC) in real-life clinical practice., Methods: Retrospective observational study of patients treated with second-line bevacizumab (BFIR) and aflibercept (AFIR) in mCRC, associated with a FOLFIRI scheme, in the last 12 years (January 2009-January 2021) in a tertiary hospital. Patients with prior oxaliplatin-based treatment were included., Variables Measured: previous chemotherapy, treatment time (TT), progression-free survival (PFS), overall survival (OS). To assess toxicity, adverse effects that caused delay in cycle administration were recorded. The lost cycles/month of treatment (CP/MT) were also calculated., Results: Eighty-four patients [40 (47.6%) AFIR and 44 (52.4%) BFIR]. Average age: 60.2 ± 10.7 years. In 79.8% the previous scheme was FOLFOX type. Efficacy of AFIR vs BFIR: median HR of TT (95% CI) = 0.816 (0.527-1.266); p = 0.365, PFS HR (95% CI) = 0.674 (0.389-1.117); p = 0.159, OS HR (95% CI) = 0.566 (0.342-0.936); p = 0.026. The main reason for the delay in administration was neutropenia (28.7% AFIR vs 24.7% BFIR), and the greatest difference found was thrombopenia (13.9% AFIR vs 2.5% BFIR), without observing large differences between the rest of adverse reactions. Mean CP/MT: 0.49 ± 0.46 cycles with AFIR and 0.33 ± 0.27 with BFIR; p = 0.046., Conclusion: Although no statistically significant differences have been found in TT or PFS, it would be more advisable to use BFIR scheme due to its better results in OS and toxicity profile., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Atagündüz, Keser and Soy.)

Context: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss., Objective: Assess plasma metabolome changes mediated by tirzepatide., Design: Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed., Setting: Post hoc analysis., Participants: 259 subjects with T2D., Intervention(s): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo., Main Outcome Measure(s): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction., Results: At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species., Conclusions: Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Real-world data comparing the effectiveness of various glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM) are limited. We investigated the clinical effectiveness of liraglutide and dulaglutide in Japanese T2DM in a real-world setting. This retrospective study included 179 patients with T2DM who were treated with GLP-1 RA for at least 12 months (liraglutide, n = 97; dulaglutide, n = 82). We used stabilized propensity score-based inverse probability of treatment weighting (IPTW) to reduce selection bias and confounding by observed covariates. Changes in glycated hemoglobin (HbA1c) at the end of the 12-month treatment were evaluated. After adjustment by stabilized propensity score-based IPTW, no significant differences were observed in patient characteristics between the liraglutide and dulaglutide groups. HbA1c was significantly lower at 12 months in both groups (liraglutide, 8.9 to 7.4%; dulaglutide, 8.7 to 7.5%). Multivariate linear regression analysis showed no differences in the extent of changes in HbA1c at 12 months between the two agents. High baseline HbA1c, the addition of GLP-1 RA treatment modality, and in-hospital initiation of GLP-1 RA treatment were identified as significant contributing factors to HbA1c reduction. The effects of liraglutide and dulaglutide on lowering HbA1c levels at 12 months were comparable in a real-world setting., (© 2022. The Author(s).)

Introduction: This study evaluated the pharmacokinetics, pharmacodynamics, and safety of a single dulaglutide dose in Chinese healthy subjects and of multiple dulaglutide doses in Chinese patients with type 2 diabetes mellitus (T2DM)., Methods: This two-part, double-blind, placebo-controlled study included 16 healthy subjects randomized to receive a single dose of placebo and two of three dulaglutide doses (0.5 mg, 0.75 mg, or 1.5 mg) in three treatment periods, and 42 patients with T2DM randomized to receive placebo or one of the three dulaglutide doses once weekly for 4 weeks. Pharmacokinetics and safety parameters were assessed in all participants, and pharmacodynamics effects were investigated in patients with T2DM., Results: Following a single-dose administration of 0.5 mg, 0.75 mg, or 1.5 mg dulaglutide in healthy subjects, geometric mean maximum concentrations (C max ) were 29.4, 44.2, and 81.5 ng/mL, respectively. Following weekly administration in patients with T2DM for 4 weeks, C max were 26.3, 41.4, and 70.2 ng/mL, respectively, with accumulation ratios of 1.33-1.39. Geometric mean for half-life of 4-5 days and median time to C max (t max ) of approximately 48 h were observed in both study populations. Dose-proportional increases in drug exposure were observed after both single and multiple dosing. Significant reductions in baseline-corrected fasting glucose and hemoglobin A1c (HbA1c) were observed in patients with T2DM who received dulaglutide 0.75 mg and 1.5 mg. Dulaglutide was well tolerated, with the majority of adverse events being gastrointestinal disorders of mild severity., Conclusions: Pharmacokinetics, pharmacodynamics, and safety profiles of dulaglutide demonstrated in the present study support a once-weekly dosing regimen in Chinese patients with T2DM., Trial Registration: NCT01667900 (ClinicalTrials.gov)., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Introduction: Neovascular age-related macular degeneration (nAMD) is characterized by exudation of fluid from abnormally growing blood vessels in the macula. Anti-vascular endothelial growth factor (VEGF) therapy is standard treatment for nAMD. Fluid resolution is used both as an indicator of disease control and to guide the frequency of treatment because of anti-VEGF therapy effectiveness in reducing neovascularization-related exudation. Herein reports a post hoc assessment of the HAWK and HARRIER trials comparing the efficacy and safety of brolucizumab with aflibercept in patients with nAMD., Materials and Methods: HAWK randomized 1,078 patients with untreated, active choroidal neovascularization due to AMD in the study eye to receive brolucizumab 3, 6 mg or aflibercept 2 mg. In HARRIER, 739 patients received brolucizumab 6 mg or aflibercept 2 mg. Brolucizumab was injected at weeks 0, 4, and 8, and thereafter q12w unless disease activity was identified (injection interval: q8w). Aflibercept was injected q8w after the loading phase, aligned with approved dosing at study initiation. The objective of this analysis was to assess effects of brolucizumab versus aflibercept on retinal fluid resolution during two phase 3 trials (HAWK and HARRIER) in patients with nAMD. Anatomical assessments for intraretinal fluid (IRF) and subretinal fluid (SRF) were performed every 4 weeks by spectral domain optical coherence tomography. Sustained dryness was defined as a patient being fluid-free (SRF and IRF) on ≥3 consecutive visits. Time to sustained dryness was determined by Kaplan-Meier estimates., Results: At week 96, fluid resolution (absence of IRF and SRF) was achieved by more brolucizumab- (6 mg; 76.1%) versus aflibercept-treated patients (63.1%; p = 0.0002, HAWK); 75.4% versus 61.8% (p < 0.0001, HARRIER). More patients achieved sustained dryness with brolucizumab versus aflibercept: at 96 weeks, 87.9% (brolucizumab 3 mg) and 86.1% (brolucizumab 6 mg) versus 82.0% (aflibercept) in HAWK, and 91.2% (brolucizumab) versus 78.0% (aflibercept) in HARRIER. Sustained dryness was achieved faster and hence with fewer brolucizumab injections., Discussion/conclusion: Brolucizumab dried the macula in patients with nAMD faster and to a greater degree than aflibercept. Achieving sustained dryness faster, and therefore with fewer injections, provides an opportunity for earlier decisions relating to treatment interval extension potentially reducing treatment burden., (© 2022 S. Karger AG, Basel.)

Importance: Limited data exist on the real-world safety outcomes of patients with neovascular age-related macular degeneration treated with brolucizumab (Beovu)., Objective: To determine the real-world incidence of intraocular inflammation (IOI), including retinal vasculitis (RV) and/or retinal vascular occlusion (RO), for patients with neovascular age-related macular degeneration who underwent brolucizumab treatment. Additionally, potential risk factors associated with these adverse events were evaluated., Design, Setting, and Participants: This cohort study included patients with neovascular age-related macular degeneration in the Intelligent Research in Sight (IRIS) Registry and Komodo Healthcare Map. Patients initiating and receiving 1 or more brolucizumab injections from October 8, 2019, to June 5, 2020, with up to 6 months of follow-up were included., Intervention: Brolucizumab injections., Main Outcome and Measures: Incidence of IOI (including RV) and/or RO and RV and/or RO and risk stratification for the identified risk factors., Results: Of 10 654 and 11 161 included eyes (from the IRIS Registry and Komodo Health database, respectively), the median follow-up times were 97 and 95 days. Most eyes switched from another anti-vascular endothelial growth factor agent (9686 of 10 654 [90.9%] and 10 487 of 11 161 [94.0%], respectively), most commonly aflibercept (7160 of 9686 [73.9%] and 7156 of 10 487 [68.2%]), and most were from women (6105 of 10 654 [57.3%] and 6452 of 11 161 [57.8%]). The overall incidence of IOI and/or RO was 2.4% (255 of 10 654 eyes) and 2.4% (268 of 11 161 eyes) for the IRIS and Komodo groups, respectively, and RV and/or RO, 0.6% (59 of 10 654 eyes and 63 of 11 161 eyes), respectively. Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7% [95% CI, 6.0%-11.4%] and 10.6% [95% CI, 7.5%-13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets). There was an increased estimated incidence rate in women (2.9% [95% CI, 2.5%-3.3%] and 3.0% [95% CI, 2.6%-3.4%]) compared with men (1.3% [95% CI, 1.0%-1.7%] and 1.4% [95% CI, 1.0%-1.7%]), but this risk was not as large as that of a prior IOI and/or RO. Similar findings were observed for patients with RV and/or RO events., Conclusions and Relevance: The incidence rate of IOI and/or RO was approximately 2.4%. Patient eyes with IOI and/or RO in the 12 months prior to first brolucizumab injection had the highest observed risk rate for IOI and/or RO in the early months after the first brolucizumab treatment. However, given study limitations, the identified risk factors cannot be used as predictors of IOI and/or RO events, and causality with brolucizumab cannot be assessed.

Introduction: Recurrent pericarditis (RP) is a debilitating disease that has an underlying autoinflammatory pathophysiology mediated by cytokine interleukin (IL)-1. Rilonacept, a recombinant dimeric fusion protein that blocks IL-1α and IL-1β signaling has emerged as a valuable therapeutic option of RP. Rilonacept has been evaluated in Phase 2 and 3 clinical trials and was recently approved for RP treatment., Areas Covered: This article reviews available clinical trials assessing the efficacy and safety of rilonacept for the treatment of RP., Expert Opinion: Findings from the Rhapsody study) trial suggest that rilonacept represents a promising new therapy for those patients with colchicine resistant or glucocorticoid-dependent disease. Treatment leads to rapid clinical response, with a median resolution of symptoms in 5 days, normalization of C-reactive protein (CRP) in a median of 7 days, and successful weaning from glucocorticoids. This novel therapy also reduces recurrence rates compared with placebo. Rilonacept has also demonstrated a good safety profile, with the most common adverse events including injection-site reactions and upper respiratory tract infections. This anti-IL 1 agent has emerged as an efficacious treatment for RP, with potential use for glucocorticoid-free regimens and as monotherapy. Future trials are needed to explore these treatment options and to clarify the appropriate therapy duration.

Intravitreal anti-VEGF (anti-vascular endothelial growth factor) biologics have revolutionized the pharmacological management of chorioretinal diseases. However, the systemic adverse events such as stroke or bleeding are the concerns for many patients and physicians. The mechanism to develop these side effects are poorly understood. Consecutive 95 patients with retinal diseases were studied for their blood activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR), and concentration of fibrinogen before and after intravitreal conbercept. Additionally, plasma nitric oxide (NO) and endothelin-1 (ET-1) were investigated on 38 of the 95 patients. Compared with the pre-injection, 4-week post-injection values of APTT and PT were increased by 0.582 s (p = 0.038, paired t test) and by 0.086 s (p = 0.080, paired t test; p = 0.0475, Sign test), respectively. At the same time, fibrinogen decreased by 0.048 g/L. Plasma levels of NO or ET-1 or VEGF did not significantly change from pre-injection levels. Our findings advanced the understanding of mechanism for systemic side effects associated with intravitreal anti-VEGF and emphasized paying more attention to higher risk of possible bleedings for patients following intravitreal conbercept., (© 2021. The Author(s).)

Objectives: The objective of this analysis was to assess the effectiveness and safety of romiplostim in the real-world by duration of primary immune thrombocytopenia (ITP): <3 ('newly diagnosed'), 3-12 ('persistent'), and >12 ('chronic') months., Methods: This was a post-hoc analysis of the PLATON single-arm, observational cohort study of adults from five Central and Eastern European countries receiving ≥1 romiplostim dose as second-line therapy, or where surgery was contraindicated. Durable (≥75% of measurements with ≥50 × 10 9 platelets/L during weeks 14-24) and overall platelet response (≥30 or ≥50 × 10 9 platelets/L at least once), rescue therapy, bleeding, discontinuation of other ITP medications, and adverse drug reactions (ADRs) were assessed., Results: Of 100 participants, 22.0% had newly diagnosed, 17.0% had persistent, and 61.0% had chronic ITP. Prior splenectomy was most frequently reported in chronic ITP (32.8%), prior bleeding was predominant in newly diagnosed patients (68.2%). Durable platelet response was achieved in 50.0% (95% confidence interval [CI]: 28.2-71.8%) of newly diagnosed, 35.3% (95% CI: 14.2-61.7%) of persistent, and 31.1% (95% CI: 19.9-44.3%) of chronic ITP patients. Overall platelet response was achieved in >80% across all strata. Safety was comparable across groups, with a low incidence of thrombotic ADRs and no bone marrow ADRs., Discussion: In this real-world study, platelet response to romiplostim was consistent across all strata of ITP duration. ADRs were infrequent and similar across ITP settings., Conclusion: These findings support the utilization of romiplostim in patients with newly diagnosed and persistent ITP in accordance with recent guidelines and the recent romiplostim label extension.

Purpose: To report a case of infectious necrotizing scleritis secondary to Aspergillus terreus after intravitreal injection therapy., Methods: This is a case report with literature review., Results: A 98-year-old woman receiving intravitreal aflibercept injections for neovascular age-related macular degeneration in the left eye presented with severe pain, redness, and purulent discharge at the injection site. She was initially treated with topical fortified antibiotics, and clinical improvement was achieved, although microbial cultures showed negative results. Two months later, she presented with severe ocular pain and was diagnosed with anterior necrotizing scleritis. Scleral scrapings were collected for cultures, and intensive topical antibiotic therapy was reintroduced. Evaluation for autoimmune etiology and microbiological testing showed negative results. Because of the progression of the scleral necrotic area, empirical therapy with topical voriconazole was initiated, and surgical debridement was performed. Finally, the culture was positive for A. terreus. The modified therapy consisted of topical voriconazole and oral voriconazole for 3 months with an excellent clinical outcome., Conclusions: To our knowledge, this is the first case of fungal necrotizing scleritis secondary to intravitreal injection. Diagnosis was delayed due to its chronic clinical course and the slow fungal growth in culture media, but the combined medical and surgical approach resulted in a satisfactory outcome., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: GAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase 1b study (NCT03639246) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D)., Methods: Eligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival., Results: No dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach., Conclusion: AVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial., Competing Interests: Declaration of competing interest Dr. Fuh reports grants from Merck, funding to her institution from Aravive in support of conduct of the study; personal fees from Aravive, Myriad, and Tesaro outside the submitted work. In addition, Dr. Fuh has a patent PCT/US2011/022125 with royalties paid. Dr. Bookman reports personal fees from Aravive, during the conduct of the study; personal fees from AstraZeneca, Merck Sharp & Dohme, Genentech Roche, Seattle Genetics, and Immunogen, outside the submitted work. Dr. Liu reports funding to her institution from Aravive in support of conduct of the study; advisory board participation for AstraZeneca, Clovis, Genentech, Merck, Regeneron, and Tesaro/GSK, outside the submitted work; consulting for Genentech, outside the submitted work; and funding to her institution for study conduct as PI on trials from 2× Oncology, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics, outside the submitted work. Dr. Coleman reports grants from Merck; grants and personal fees from AstraZeneca, Clovis, Genmab, Roche/Genentech, and Janssen; personal fees from GSK, Agenus, Regeneron, and OncoQuest, outside the submitted work. Dr. Herzog reports personal fees from J & J, Clovis, AstraZeneca, GSK, Roche Genentech, Caris, Abbvie, Aravive, Merck, and Eisai, outside the submitted work. Dr. Thaker reports personal fees from Aravive, during the conduct of the study; grants and personal fees from Merck and Glaxo Smith Kline/Tesaro; personal fees from Astra Zeneca, Novocure, Iovance, Celsion, and Stryker, outside the submitted work. Dr. Monk reports personal fees from Aravive, during the conduct of the study; personal fees from AstraZeneca, Easai, Elevar, Genmab/Seattle Genetics, GOG Foundation, Merck, McKesson, TESARO/GSK, Gradalis, ImmunoGen, Mersana, Novocure, Myriad, Pfizer, Roche/Genentech, and VBL, outside the submitted work. Dr. Anderson reports other from Aravive, outside the submitted work. Dr. McIntyre reports other from Aravive, outside the submitted work. Dr. Rangwala reports other from Aravive, outside the submitted work. Dr. Moore reports personal fees from Aravive, during the conduct of the study; personal fees and other from Astra Zeneca and Onco Med; grants, personal fees and other from Genentech/Roche, Immunogen, and GSK/Tesaro; other from Pfizer; grants and other from Lilly; personal fees from Aravive, Eisai, Vavotar, Abbvie, Tarveda, Myriad, Rubius, Elevar, Merck, Mersana, Sorrento, OncXerna, Alkemeres, Mereo, and VBL Therapeutics, outside the submitted work. In addition, service as the Associate Director for GOG Partners and the NRG ovarian cancer committee chair., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Thrombocytopenia is a tough complication after hematopoietic stem cell transplantation (HSCT) with elusive pathogenesis and lack of well-established therapies. Thrombopoietin receptor agonists (TPO-RAs) have been used for thrombocytopenia post HSCT in recent years, but the outcomes remain debatable. We conducted this meta-analysis and systematic-review to evaluate the efficacy and safety of TPO-RAs for platelet recovery after HSCT. We searched PubMed, EMBASE, and Cochrane databases for studies on the application of TPO-RAs (eltrombopag and romiplostim) in the settings of primary or secondary thrombocytopenia after HSCT by 17 March 2021. Efficacy outcomes included response rate and survival rate, and adverse events were also evaluated. A total of 19 studies involving 378 patients were included. The pooled response rate was 73% (95%CI: 68-78%), which was significantly higher than recombinant human thrombopoietin (rhTPO) (27.8%). The pooled survival rate was 66% (95%CI: 54-77%), and infection was found to be the main cause of death. In addition, the pooled rate of adverse events was 3% (95%CI: 1-7%), with no severe adverse events reported. TPO-RAs could effectively and safely promote the recovery of platelets in patients after HSCT.

Aim: Patients with type 2 diabetes (T2DM) who require injectable therapy have been conventionally treated with insulin. A glucagon-like peptide 1 receptor agonist was recently recommended as first-line injectable treatment, but few studies have investigated the effects of switching from insulin to dulaglutide. This study investigated the clinical efficacy and parameters affecting responses to dulaglutide as an alternative to insulin in patients with T2DM in a real-world clinical setting., Methods: Ninety-eight patients with T2DM who were switched from insulin to dulaglutide therapy were retrospectively evaluated. Changes in HbA1c concentrations were assessed after 6 months of consistent treatment with dulaglutide. Multiple linear regression analysis was performed to evaluate parameters affecting the response to dulaglutide treatment., Results: After treatment with dulaglutide for 6 months, patients experienced changes in HbA1c of -0.95% (95% confidence interval [CI]: -1.30% to -0.59%, P < 0.001) and in body weight of -1.75 kg (95% CI: -2.42 to -1.08 kg, P < 0.001). Multiple linear regression analysis showed that higher baseline HbA1c was significantly associated with a greater reduction in HbA1c. The most frequent adverse events were gastrointestinal symptoms., Conclusion: Switching from insulin to dulaglutide can lead to significant improvement in HbA1c levels and body weight ​reduction in T2DM patients over 6 months. Higher baseline HbA1c is associated with a better clinical response to dulaglutide., (© 2021 John Wiley & Sons Ltd.)

Efmoroctocog alfa (Elocta ® , Eloctate ® , Eloctate™), an extended half-life (EHL) recombinant factor VIII (rFVIII)-Fc fusion protein, is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A. The efficacy of efmoroctocog alfa in the prevention and treatment of bleeding in previously treated patients (PTPs) and previously untreated patients (PUPs) with severe haemophilia A has been demonstrated in phase III studies; this includes its use in the perioperative setting (in PTPs). Furthermore, the effectiveness of efmoroctocog alfa in clinical practice has been confirmed in numerous real-world studies; compared with conventional, standard half-life (SHL) FVIII products, prophylaxis with this EHL FVIII product achieved similar or reduced bleeding rates with fewer injections. Efmoroctocog alfa was generally well tolerated; inhibitors occurred in approximately one-third of PUPs in a phase III study. Efmoroctocog alfa is an established and effective EHL FVIII replacement therapy for the management of haemophilia A. Compared with SHL FVIII products, EHL FVIII products such as efmoroctocog alfa have the potential to optimise prophylactic outcomes by decreasing the burden of treatment or increasing the level of bleed protection., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aims: To evaluate the change in circulating serum irisin and interleukin-6 (IL-6), in patients with type 2 diabetes mellitus (T2DM) after 6 and 12 months of GLP-1 treatment., Methods and Results: Eighty-five patients with T2DM inadequately controlled with insulin or other hypoglycaemic drugs were added to dulaglutide (N° = 44) and liraglutide (N° = 41) treatment. After 6 months of GLP-1 analogues a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (p < 0.001), HbA1c (p < 0.001), total cholesterol (p < 0.001), LDL-cholesterol (p = 0.003), triglycerides (p = 0.017), IL-6 (p = 0.045) and a significant increase in serum irisin (p < 0.001) were observed compared to baseline. After 12 months of treatment no significant differences were found compared to the levels at 6 months. The change in irisin from baseline (Δ&#95;irisin) was significantly related to the changes in total-cholesterol (Δ&#95;total-cholesterol) (r = -0.293; p = 0.020), while the change in IL-6 (Δ&#95;IL-6) was significantly related to the changes in WC (Δ&#95;WC) (r = 0.347; p = 0.006)., Conclusions: Additive treatment with GLP1-analogues results in an increase in serum circulating irisin levels and a decrease in IL-6. The post-treatment change in irisin was correlated with a decrease in total cholesterol, while the change in IL-6 was correlated with a decrease in WC., Competing Interests: Declaration of competing interest Authors have nothing to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B&#95;162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment., Methods: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured., Results: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group., Conclusion: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sato, Enoki, Karasawa, Someya, Taguchi, Harimoto, Takayama, Kanda, Ito and Takeuchi.)

What Is Known and Objective: One of the effective and consistent ways to achieve glycaemic control for patients with type 2 diabetes mellitus (T2DM) is once-daily basal insulin. But it is also associated with adverse outcomes such as hypoglycaemia. Dulaglutide, a novel long-acting GLP-1 receptor agonist, may be a more suitable therapy. The present meta-analysis aims to assess the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide compared with insulin glargine for the treatment of T2DM., Methods: We searched PubMed, Embase and Cochrane Library from inception to December 2020. Randomized clinical trials comparing dulaglutide with insulin glargine in adults with T2DM were included. Revman5.2 software was used for meta-analysis., Results and Discussion: We included 5 studies with 3383 randomized participants. Compared with insulin glargine, dulaglutide 1.5 mg led to greater mean HbA1c reduction (MD = -0.33%, 95% CI = -0.52, -0.15) whereas dulaglutide 0.75 mg did not (MD = -0.21%, 95% CI = -0.43, 0.01). Body weight loss was seen with dulaglutide whereas weight gain was seen with insulin glargine. The risk of hypoglycaemia was lower in dulaglutide 0.75 mg and 1.5 mg groups than in insulin glargine group,whereas dulaglutide had a statistically higher gastrointestinal adverse events incidence than insulin glargine., What Is New and Conclusions: Compared with insulin glargine, dulaglutide may serve as an effective alternative to provide improvement in glycaemic control with weight loss and less hypoglycaemia in patients with T2DM. It may be a more suitable therapy instead of basal insulin., (© 2021 John Wiley & Sons Ltd.)

Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial., Methods: Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model., Results: Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively)., Conclusions: Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952., (© 2021. The Author(s).)

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells., Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival., Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported., Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)., (Copyright © 2021 Massachusetts Medical Society.)

The fundamental treatment goal for patients with immune thrombocytopenia (ITP) is reduced or ameliorated bleeding. Although various treatment options exist for the management of ITP, recent advances have led to the approval of three thrombopoietin receptor agonists (TPO-RAs; romiplostim, eltrombopag, and avatrombopag) in the United States and European Union. Current treatment guidelines for ITP indicate that medical therapy is preferred over surgical therapy and support the use of TPO-RAs as early as 3 months after disease onset. More recent data are available on the use of romiplostim in patients who have had ITP for <1 year, and romiplostim is now indicated for the treatment of adults who have not responded adequately to initial treatment, as well as children aged ≥1 year who have had ITP for ≥6 months. Here we review the role of romiplostim in the management of ITP, with a focus on efficacy and safety data, emerging data on early use (beginning within 3 months of disease onset) and treatment-free remission, and practical considerations for optimal management of ITP., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Phagocytic resistance plays a key role in tumor-mediated immune escape, so phagocytosis immune checkpoints are a potential target for cancer immunotherapy. CD47 is one of the important phagocytosis immune checkpoints; thus, blocking the interaction between CD47 and signal regulatory protein α (SIRP α ) may provide new options for cancer treatment. Using computer-aided targeted epitope mammalian cell-displayed antibody library, we screened and obtained an engineered SIRP α variant fragment crystallizable fusion protein, FD164, with higher CD47-binding activity than wild-type SIRP α Compared with wild-type SIRP α , FD164 has approximately 3-fold higher affinity for binding to CD47, which further enhanced its phagocytic effect in vitro and tumor suppressor activity in vivo. FD164 maintains the similar antitumor activity of the clinical research drug Hu5F9 in the mouse xenograft model. Furthermore, FD164 combined with rituximab can significantly improve the effect of single-agent therapy. On the other hand, compared with Hu5F9, FD164 does not cause hemagglutination, and its ability to bind to red blood cells or white blood cells is weaker at the same concentration. Finally, it was confirmed by computer structure prediction and alanine scanning experiments that the N 45 , E 47 , 52 TEVYVK 58 , K 60 , 115 EVTELTRE 122 , and E 124 residues of CD47 are important for SIRP α or FD164 recognition. Briefly, we obtained a high-affinity SIRP α variant FD164 with balanced safety and effectiveness. SIGNIFICANCE STATEMENT: Up to now, few clinically marketed drugs targeting CD47 have been determined to be effective and safe. FD164, a potential signal regulatory protein α variant fragment crystallizable protein with balanced safety and effectiveness, could provide a reference for the development of antitumor drugs., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Aflibercept, as a soluble decoy vascular endothelial growth factor receptor, Which has been used as a first-line monotherapy for cancers. Aflibercept often causes cardiovascular toxicities including hypertension, but the mechanisms underlying aflibercept-induced hypertension remain unknown. In this study we investigated the effect of short-term and long-term administration of aflibercept on blood pressure (BP), vascular function, NO bioavailability, oxidative stress and endothelin 1 (ET-1) in mice and cultured endothelial cells. We showed that injection of a single-dose of aflibercept (18.2, 36.4 mg/kg, iv) rapidly and dose-dependently elevated BP in mice. Aflibercept treatment markedly impaired endothelial-dependent relaxation (EDR) and resulted in NADPH oxidases 1 (NOX1)- and NADPH oxidases 4 (NOX4)-mediated generation of ROS, decreased the activation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) concurrently with a reduction in nitric oxide (NO) production and elevation of ET-1 levels in mouse aortas; these effects were greatly attenuated by supplementation of L-arginine (L-arg, 0.5 or 1.0 g/kg, bid, ig) before aflibercept injection. Similar results were observed in L-arg-pretreated cultured endothelial cells, showing markedly decreased ROS accumulation and AKT/eNOS/NO signaling impairment induced by aflibercept. In order to assess the effects of long-term aflibercept on hypertension and to evaluate the beneficial effects of L-arg supplementation, we administered these two drugs to WT mice for up to 14 days (at an interval of two days). Long-term administration of aflibercept resulted in a sustained increase in BP and a severely impaired EDR, which are associated with NOX1/NOX4-mediated production of ROS, increase in ET-1, inhibition of AKT/eNOS/NO signaling and a decreased expression of cationic amino acid transporter (CAT-1). The effects caused by long-term administration were greatly attenuated by L-arg supplementation in a dose-dependent manner. We conclude that aflibercept leads to vascular dysfunction and hypertension by inhibiting CAT-1/AKT/eNOS/NO signaling, increasing ET-1, and activating NOX1/NOX4-mediated oxidative stress, which can be suppressed by supplementation of L-arg. Therefore, L-arg could be a potential therapeutic agent for aflibercept-induced hypertension., (© 2020. CPS and SIMM.)

The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered., (© 2021 by The American Society of Hematology.)

In patients with severe haemophilia receiving clotting factor concentrates, the risk of immunisation against their usual treatment is still patent and feared. New haemophilia drug treatments with an extended half-life have become available over the past few years. The risk of inhibitor development to these new treatments is unclear. We report the case of a 51-year-old man with severe haemophilia A, who was previously treated with no history of inhibitor development. Soon after a switch in his treatment to efmoroctocog alfa he developed an inhibitor against this recombinant Fc fusion extended half-life FVIII (rFc-FVIII) product. The patient was on an on-demand treatment regimen and was treated for mucosal bleeding. The inhibitor was characterised as type I, with classical epitope mapping. The spontaneous evolution of this inhibitor was favourable, but an anamnestic response led to a switch in his treatment to emicizumab., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Beta-thalassemia is an autosomal recessive hereditary anemia characterized by reduced or absent β-globin chain synthesis, affecting about 60,000 people peryear. Management for β-thalassemia major includes regular blood transfusions followed by iron chelating therapy and drug targeting ineffective erythropoiesis. Areas covered: The safety of licensed drugs for the management of β-thalassemia is reviewed, using evidence from clinical trials and observational research. Such drugs include the iron chelators and the erythrocyte maturation agent luspatercept. The safety of emerging treatment, such as hydroxyurea and thalidomide is also reviewed. Expert opinion : Beta-thalassemia is arare disease, and is not surprising that there are limited studies investigating the safety of drugs used in this disease. Indeed, although observational studies are the main source of drug safety information in areal-world setting, only eleven studies were identified for iron-chelators and none of these estimated the risk of agiven safety outcome. Future work should aim to better leverage existing sources of real-world datato investigate drug safety in thalassemia.

Background: Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes., Methods: The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952., Findings: Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006)., Interpretation: Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests HSB has received speaking honoraria from Eli Lilly and Novo Nordisk, and research funding paid to LMC Healthcare from Amgen, AstraZeneca, Boehringer Ingelheim, Ceapro, Eli Lilly, Gilead, Janssen, Kowa Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sanofi, and Tricida. HCG holds the McMaster–Sanofi Population Health Institute Chair in Diabetes Research and Care and reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi, honoraria for speaking from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, DKSH, and Zuellig, and consulting fees from Abbott, Covance, Eli Lilly, Novo Nordisk, Sanofi, Pfizer and Kowa. JB reports consulting fees from Medtronic and Eli Lilly, and grant support from Eli Lilly, ReCor, and Ablative Solutions. HC reports grants from the University of Edinburgh, AstraZeneca, Novo Nordisk, Bayer, Roche, and Eli Lilly. IC reports personal fees from Medtronic, Eli Lilly, Novo Nordisk, Sanofi Aventis, Astra Zeneca, Boehringer Ingelheim, and Merck Sharp and Dohme. WCC reports a research grant to his institution (University of Tennessee, TN, USA) for the REWIND trial. GRD has received honoraria for lectures from Bayer and Eli Lilly. EF reports personal fees from AstraZeneca, Bioton, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Polfa–Tarchomin, Sanofi, and Servier. FL reports honoraria from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Sanofi, Merck Sharp and Dohme, and research grants from the Population Health Research Institute. LAL reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier, GlaxoSmithKline, and Lexicon. PL-J reports speaking honorarium from Menarini and Abbott. JP reports payment through the University of Washington (WA, USA) for the REWIND trial. JES reports grants from Eli Lilly and Astra Zeneca, and personal fees from Astra Zeneca, Eli Lilly, Novo Nordisk, Sanofi, Mylan Pharmaceuticals, Boehringer Ingelheim, Merck Sharp and Dohme, Abbott, and Pfizer. DX reports grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Coco Cola India, the Indian Council of Medical Research, Pfizer, the UK Medical Research Council, and Wellcome Trust, and speaker fees from Eli Lilly and Sanofi. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Proteinuria associated with podocyte effacement is a hallmark of focal segmental glomerulosclerosis (FSGS). Preclinical studies implicated ROBO2/SLIT2 signaling in the regulation of podocyte adhesion, and inhibition of this pathway is a novel target to slow FSGS disease progression. This first-in-human dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of PF-06730512, an Fc fusion protein that targets the ROBO2/SLIT2 pathway, in healthy adults. In this Phase 1, double-blind, sponsor-open study, single ascending dose (SAD) cohorts were randomized to receive up to 1000 mg or placebo intravenously (IV); multiple ascending dose (MAD) cohorts were randomized to receive up to 400 mg subcutaneous (SC) doses, 1000 mg IV dose, or matching placebo. Safety evaluations were performed up to 71 (SAD) and 113 (MAD) days after dosing; blood samples were collected to measure serum PF-06730512 concentrations and antidrug antibodies (ADA) to PF-06730512. Seventy-nine participants (SAD, 47; MAD, 32) were enrolled. There were 108 mild (SAD, 46; MAD, 62) and 21 moderate (SAD, 13; MAD, 8) treatment-emergent adverse events (TEAEs); no deaths, treatment-related serious AEs, severe TEAEs, or infusion reactions were reported. PF-06730512 exposure generally increased in an approximately dose-proportional manner; mean t 1/2 ranged from 12-15 days across 50-1000 mg doses. Immunogenicity incidence was low (SAD, 0 ADA+; MAD, 2 ADA+). In conclusion, single IV doses of PF-06730512 up to 1000 mg and multiple IV and SC dosing up to 1000 and 400 mg, respectively, were safe and well tolerated in healthy participants. Further trials in patients with FSGS are warranted. Clinical trial registration: Clinicaltrials.gov: NCT03146065., (© 2021 Pfizer Inc. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Purpose: To evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) treat-and-extend dosing in patients with macular edema secondary to central retinal vein occlusion (CRVO)., Design: CENTERA (Evaluation of a Treat and Extend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) was an open-label, Phase 4 clinical study., Methods: Patients received 2 mg of IVT-AFL at baseline and every 4 weeks thereafter, until disease stability criteria were met (or until week 20), at which point treatment intervals were adjusted in 2-week increments based on functional and anatomic outcomes., Results: From baseline to week 76, 105 patients (65.6%) (P <.0001 [test against threshold of 40%]) gained ≥15 letters; and, during the treat-and-extend phase, 72 patients (45.0%) (P = 0.8822 [test against threshold of 50%]) achieved a mean treatment interval of ≥8 weeks. A last and next planned treatment interval of ≥8 weeks was achieved by 101 patients (63.1%) and by 108 patients (67.5%), respectively. Mean ± SD best-corrected visual acuity increased from 51.9 ± 16.8 letters at baseline to 72.3 ± 18.5 letters at week 76 (mean change: +20.3 ± 19.5 letters), and central retinal thickness decreased from 759.9 ± 246.0 µm at baseline to 265.4 ± 57.9 µm at week 76 (mean change: -496.1 ± 252.4 µm). The safety profile of IVT-AFL was consistent with that of previous studies., Conclusions: Clinically meaningful improvements in functional and anatomic outcomes were achieved with IVT-AFL treat-and-extend dosing. Most patients achieved a last actual and last intended treatment interval of ≥8 weeks; therefore, treatment intervals may have been extended even further with a longer study duration., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)