Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).

Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

INTRODUCTION: Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. AIM: To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. METHODS: A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. RESULTS: Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n = 9, 50.0%) versus 38.9% (n = 7) of patients treated with octocog alfa. Patients' good quality of life was maintained. CONCLUSION: This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

Recombinant factor IX Fc for the treatment of hemophilia B.

Current hemophilia B treatment guidelines recommend routine prophylaxis with factor IX (FIX) replacement products, tailored to maintain plasma activity at levels that will prevent bleeds. However, plasma FIX activity may not be the primary determinant or best indicator of hemostatic efficacy due to its extravascular distribution. FIX replacement therapy has evolved to include extended half-life (EHL) products that provide effective bleed protection when administered at intervals of 7 days or longer. rFIXFc is a recombinant fusion protein with an extended circulation time. rFIXFc has a biodistribution profile consistent with distribution into extravascular space, where it may support hemostasis at sites of vessel injury independent of circulating plasma activity levels. The safety and efficacy of rFIXFc prophylaxis is well established in adults, adolescents and children including previously untreated patients with hemophilia B, with substantial evidence from clinical trials and real-world clinical practice. This review describes the pharmacokinetic characteristics of rFIXFc, summarizes available safety and efficacy data, and evaluates the use of rFIXFc in special populations. Current hemophilia B treatment challenges, including target FIX plasma levels, perioperative use, and management of patients with comorbidities, are discussed together with the potential role of EHL products in the future treatment landscape of hemophilia B.

Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B.

BACKGROUND: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed. OBJECTIVES: To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health-related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE. MAIN RESULTS: Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion. Prophylaxis versus on-demand therapy in people with inhibitors Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on-demand therapy in people with inhibitors. Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD -22.80, 95% CI -37.39 to -8.21), treated bleeds (MD -20.40, 95% CI -35.19 to -5.61), and annualized spontaneous bleeds (MD -15.50, 95% CI -24.06 to -6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate-certainty evidence). Fitusiran also likely reduced ABR for all bleeds (MD -28.80, 95% CI -40.07 to -17.53), treated bleeds (MD -16.80, 95% CI -25.80 to -7.80), joint bleeds (MD -12.50, 95% CI -19.91 to -5.09), and spontaneous bleeds (MD -14.80, 95% CI -24.90 to -4.71; 1 trial; 57 participants; moderate-certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on-demand therapy on AtjBR. Concizumab may reduce ABR for all bleeds (MD -12.31, 95% CI -19.17 to -5.45), treated bleeds (MD -10.10, 95% CI -17.74 to -2.46), joint bleeds (MD -9.55, 95% CI -13.55 to -5.55), and spontaneous bleeds (MD -11.96, 95% CI -19.89 to -4.03; 2 trials; 78 participants; very low-certainty evidence), but not target joint bleeds (MD -1.00, 95% CI -3.26 to 1.26). Emicizumab prophylaxis resulted in an 11.31-fold increase, fitusiran in a 12.5-fold increase, and concizumab in a 1.59-fold increase in the proportion of participants with no bleeds. HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low-certainty evidence). Non-serious adverse events were higher with non-clotting factor therapies versus on-demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab. Prophylaxis versus on-demand therapy in people without inhibitors Two trials (208 participants) compared emicizumab and fitusiran with on-demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi-weekly). Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi-weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD -20.21, 95% CI -32.12 to -8.30) and emicizumab 3.0 mg/kg bi-weekly (MD -15.30, 95% CI -30.46 to -0.14), but not with emicizumab 1.5 mg/kg/week (MD -14.60, 95% CI -29.78 to 0.58). The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi-weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on-demand therapy. Emicizumab 1.5 mg/kg/week did not improve Haem-A-QoL physical and total health scores, EQ-5D-5L VAS, or utility index scores (low-certainty evidence) when compared with on-demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi-weekly may improve HRQoL measured by the Haem-A-QoL physical health score (MD -15.97, 95% CI -29.14 to -2.80) and EQ-5D-5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low-certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem-A-QoL total score (MD -7.06, 95% CI -11.50 to -2.62) and physical health score (MD -19.75, 95% CI -25.76 to -11.94; 1 trial; 103 participants; low-certainty evidence). The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on-demand therapy (moderate-certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering. A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient-reported outcomes. No case of treatment-related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes. None of the included studies evaluated marstacimab. AUTHORS' CONCLUSIONS: Evidence from RCTs shows that prophylaxis using non-clotting factor therapies compared with on-demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non-serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long-term joint outcomes, and assessment of economic outcomes will improve evidence-based decision-making for the use of these therapies in bleed prevention.

Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review.

INTRODUCTION: The standard of care in severe haemophilia A is prophylaxis, which has historically aimed for a factor VIII (FVIII) trough level of ≥1%. However, despite prophylactic treatment, people with haemophilia remain at risk of bleeds that have physical and quality of life implications, and that impact everyday life. AIM: The aim of this review was to evaluate evidence supporting the relationship between targeting higher FVIII activity levels with prophylaxis and improved outcomes in people with haemophilia A. METHODS: We conducted a narrative review that defined the unmet needs and treatment goals in people with haemophilia A, evaluated evidence to support targeting higher FVIII activity levels, and highlighted therapies that may support higher and sustained FVIII activity levels and improved outcomes for people with haemophilia A. RESULTS: Despite recent advances in treatment, unmet needs remain, and people with haemophilia continue to experience joint and functional impairment, acute and chronic pain, and poor mental health. All these negatively impact their health-related quality of life. Evidence suggests that FVIII activity levels of up to 50% may be needed to achieve a near-zero joint bleed rate. However, achieving high FVIII activity levels with current standard and extended half-life (EHL) FVIII replacement therapies is associated with a high treatment burden. Innovative treatment options may provide high sustained FVIII activity levels and improved patient outcomes. CONCLUSION: Evidence suggests that FVIII activity levels in people with haemophilia A should be sustained at higher levels to improve joint and patient outcomes and enable progression towards health equity.

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation.

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.

The Function of extravascular coagulation factor IX in haemostasis.

INTRODUCTION: The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis. AIM: We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX® and the extended half-life FIX, Alprolix® , to extravascular type IV collagen (Col4). METHODS: Three mouse models of haemophilia were used: the FIX knockout as the CRM- model and two knock-in mice, representing a CRM+ model of a commonly occurring patient mutation (FIXR333Q ) or a mutation that binds poorly to Col4 (FIXK5A ). The murine saphenous vein bleeding model was used to assess haemostatic competency. Clinical publications were reviewed for relevance to extravascular FIX. RESULTS: CRM status affects recovery and prophylactic efficacy. Prophylactic protection decreases ~5X faster in CRM+ animals. Extravascular haemostasis can explain unexpected breakthrough bleeding in patients treated with some EHL-FIX therapeutics. In mice, both Alprolix® and BeneFIX® bind Col4 with similar affinities (Kd~20-40 nM) and show dose-dependent recoveries. As expected, the concentration of binding sites in the mouse calculated for Alprolix® (574 nM) was greater than for BeneFIX® (405 nM), due to Alprolix® binding to both Col4 and the endothelial cell neonatal Fc receptor. CONCLUSION: Preclinical and clinical results support the interpretation that FIX plays a role in haemostasis from its extravascular location. We believe that knowing the CRM status of haemophilia B patients is important for optimizing prophylactic dosing with less trial and error, thereby decreasing clinical morbidity.

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B.

BACKGROUND: The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. OBJECTIVES: To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect.   AUTHORS' CONCLUSIONS: There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI.  When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons.  Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.

Inferior vena cava syndrome in neonates: An evidence-based systematic review of the literature.

Neonatal inferior vena cava syndrome (IVCS), though uncommon, is associated with significant morbidity and mortality. Information on risk factors, diagnosis, treatment, and outcomes is limited. This review comprised 61 neonates across 33 reports. Thrombosis occurred in 98% and 42% involved a central venous catheter. Diagnosis was mainly established by ultrasound in 82%. Therapeutically, heparin was employed in 36% and thrombolysis in 18% of the cases. The overall mortality was 23%. An algorithm of clinical signs, investigation, and management is presented. Well-designed prospective studies are needed to establish a concrete investigational approach to neonatal IVCS and institute safe, evidence-based treatment.

Aryl hydrocarbon receptor control of a disease tolerance defence pathway.

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.

Consensus statements on vaccination in patients with haemophilia-Results from the Italian haemophilia and vaccinations (HEVA) project.

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.

CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS), and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immunity is clearly pivotal in the pathogenesis of EAE, with an essential role of CD4+ T cells, little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs), typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs). In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type A ODN (CpG-A), known to induce high amounts of IFN-α in pDCs, significantly reduced disease severity in EAE, relative to controls (12.63 ± 1.86 versus 23.49 ± 1.46, resp.; p = 0.001). Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+ CD4+) T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γ in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A-treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.

Stem cells from human amniotic fluid exert immunoregulatory function via secreted indoleamine 2,3-dioxygenase1.

Although human amniotic fluid does contain different populations of foetal-derived stem cells, scanty information is available on the stemness and the potential immunomodulatory activity of in vitro expanded, amniotic fluid stem cells. By means of a methodology unrequiring immune selection, we isolated and characterized different stem cell types from second-trimester human amniotic fluid samples (human amniotic fluid stem cells, HASCs). Of those populations, one was characterized by a fast doubling time, and cells were thus designated as fHASCs. Cells maintained their original phenotype under prolonged in vitro passaging, and they were able to originate embryoid bodies. Moreover, fHASCs exhibited regulatory properties when treated with interferon (IFN)-γ, including induction of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). On coculture with human peripheral blood mononuclear cells, IFN-γ-treated fHASCs caused significantly decreased T-cell proliferation and increased frequency in CD4(+)  CD25(+)  FOXP3(+) regulatory T cells. Both effects required an intact IDO1 function and were cell contact-independent. An unprecedented finding in our study was that purified vesicles from IFN-γ-treated fHASCs abundantly expressed the functional IDO1 protein, and those vesicles were endowed with an fHASC-like regulatory function. In vivo, fHASCs were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. This was concurrent with the expansion of CD4(+)  CD25(+)  Foxp3(+) T cells in graft-draining lymph nodes from recipient mice. Thus fHASCs, or vesicles thereof, may represent a novel opportunity for immunoregulatory maneuvers both in vitro and in vivo.

Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors.

BACKGROUND: In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors. OBJECTIVES: To determine the clinical effectiveness of recombinant factor VIIa concentrate compared to plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Coagulopathies Trials Register: 23 September 2015. SELECTION CRITERIA: Randomised and quasi-randomised controlled clinical trials comparing recombinant factor VIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant factor VIII or factor IX concentrate; non-activated prothrombin complex concentrates; activated prothrombin complex concentrates) in people with haemophilia. Comparisons with animal-derived products were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials (eligibility and risk of bias) and extracted data. No combined meta-analyses were performed due to the unavailability of outcomes and comparisons common to the included trials. MAIN RESULTS: A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. AUTHORS' CONCLUSIONS: Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.

Ligand binding and functional selectivity of L-tryptophan metabolites at the mouse aryl hydrocarbon receptor (mAhR).

The aryl hydrocarbon receptor (AhR) is a nuclear receptor regulating a wide range of biological and toxicological effects. Metabolites of L-tryptophan are able to bind and activate AhR, providing a link between tryptophan catabolism and a novel mechanism of protective tolerance, referred to as "disease tolerance". The notion that pharmacologic modulation of genes associated with endotoxin tolerance would be beneficial in clinical settings dominated by acute hyperinflammatory responses to infection thrusts AhR into the limelight as an interesting druggable target. Combining homology modeling, docking studies, and molecular dynamic simulations with mutagenesis experiments and gene profiling, in this work we report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and two different L-tryptophan metabolites, namely L-Kynurenine and FICZ (6-formylindolo[3,2-b]carbazole), are able to bind to mAhR, exploiting different key interactions with distinct set of fingerprint residues. As a result, they stabilize different conformations of mAhR that, in turn, selectively regulate downstream signaling and transcription of specific target genes. Collectively, these results open new avenues for the design and development of selective AhR modulators that, by targeting specific receptor conformations associated with specific AhR functions, may offer novel therapeutic opportunities in infectious diseases and other morbidity that may be associated with the receptor.

Noninterventional study assessing joint health in persons with hemophilia A after switching to turoctocog alfa pegol: design of pathfinderReal.

Background: Joint damage affects the quality of life of persons with hemophilia A. The long-term safety and efficacy of turoctocog alfa pegol (N8-GP) prophylaxis in persons with hemophilia A has been investigated in pivotal phase 3 trials in children, adolescents, and adults (pathfinder program). However, there is a lack of data on joint health in adult persons with hemophilia A treated with N8-GP. Objectives: To describe the design of the ongoing pathfinderReal study investigating the joint health status in adult persons with hemophilia A after switching to N8-GP. Methods: pathfinderReal is a multicountry, noninterventional, single-arm study (NCT05621746) of joint health in adult (≥18 years) male persons with hemophilia A who have switched to N8-GP. Patients enrolled in other interventional studies and those who have previously terminated N8-GP treatment will be excluded. Approximately 124 adults with hemophilia A will be enrolled and followed up for a maximum of 24 months. Data from routine clinical assessments of patients' joint health will be collected. The primary endpoint is change in Hemophilia Joint Health Score (defined as a change in total score of ≤2) from initiation of N8-GP treatment until the end of the study. Secondary endpoints include number of bleeding episodes, number and resolution of target joints, patient-reported outcomes of problem joint score, pain score, and change in physical function levels. An exploratory endpoint is included to measure the number of patients achieving improved Hemophilia Joint Health Score from the initiation of N8-GP until the end of the study. Conclusion: The pathfinderReal study will provide insights regarding the impact of N8-GP on joint health in persons with hemophilia A in a real-world setting.

Use of nonacog beta pegol during surgery in persons with hemophilia B: a case series.

Background: Hemophilia B is a coagulation disorder that puts patients at an increased risk of bleeding. Factor (F) IX replacement therapy is traditionally used in such cases to maintain hemostasis. Nonacog beta pegol (N9-GP; Refixia) is a glycoPEGylated, extended half-life, recombinant FIX product that has demonstrated safety and efficacy when used to manage persons with hemophilia B. Key clinical question: Given the limited real-world evidence, we aimed to explore the role of N9-GP in maintaining hemostasis in persons with hemophilia B undergoing surgery. Clinical approach: In this case series, we report real-world clinical experience with N9-GP to maintain hemostasis in persons with hemophilia B undergoing major and minor surgeries. Conclusion: The majority of cases presented in this case series had an excellent or very good hemostatic response, with no reported surgical complications related to the use of N9-GP.

Treatment switch to nonacog beta pegol factor IX in hemophilia B: A Canadian cost-consequence analysis based on real-world factor IX consumption and clinical outcomes.

Background: The Canadian Bleeding Disorders Registry (CBDR) is a source of real-world data for Canadian patients with hemophilia B. Nonacog beta pegol (N9-GP), an extended half-life (EHL) recombinant factor IX (FIX) concentrate, was awarded a Canadian Blood Services contract in 2018 and subsequently made available across Canada (except Québec) to adult patients. For most patients already on another EHL FIX treatment, a switch to N9-GP occurred. Objectives: This study estimates the impact on treatment costs of a switch from a prior FIX to N9-GP based on annualized bleed rates and FIX consumption volumes before and after N9-GP switch from the CBDR. Methods: Real-world data from the CBDR for total FIX consumption and annualized bleed rates were used to inform a deterministic 1-year cost-consequence model. The model considered that the EHL to N9-GP switches were from eftrenonacog alfa and the standard half-life switches were from nonacog alfa. Because FIX prices are confidential in Canada, the model assumed cost parity for annual prophylaxis with each FIX based on the product monograph recommended dosing regimen to calculate an estimated price per international unit for each product. Results: The switch to N9-GP resulted in improvements in real-world annualized bleed rates and therefore reductions in annual breakthrough bleed treatment costs. Switching to N9-GP also resulted in reduced real-world annual FIX consumption for prophylaxis. Overall, annual treatment costs were 9.4% and 10.5% lower after the switch to N9-GP from nonacog alfa and eftrenonacog alfa, respectively. Conclusion: N9-GP improves clinical outcomes and may be cost-saving vs nonacog alfa and eftrenonacog alfa.

Inhibitors in hemophilia: association with surgery plans and outcomes in a retrospective cohort study.

Background: The development of antibodies (inhibitors) to clotting factors compromises the management of hemophilia A and B, resulting in resistance to clotting factor replacement and, in many cases, the need for bypassing agents to achieve hemostasis. Objectives: To evaluate the association between the presence of inhibitors and achievement of perioperative hemostasis, development of complications, and presurgical plan deviations. Methods: We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center surgical database (1998-2019). Associations between perioperative outcomes and inhibitor status were assessed while controlling for patient and procedural characteristics. Results: A total of 1492 surgeries were performed in 539 persons with hemophilia, with 72 procedures performed in 20 patients with inhibitors (15 with hemophilia A; 5 with hemophilia B). High-responding inhibitors (>5 BU/mL) were present in 27 procedures, low-responding inhibitors (≤5 BU/mL) were present in in 13 procedures, and 32 procedures were performed in patients with historically persistent inhibitors. Adjusting for age, diagnosis, surgery setting, hemostatic agent, data collection period, and surgery type (major/minor), inhibitors were associated with a higher risk of inadequate perioperative hemostasis (33.4% vs 8.6%; adjusted relative risk [adjRR], 3.78; 95% CI, 1.89-7.56; P < .001). Reported complications include hemorrhage, fever, pain, thrombosis, and infections. Complications were not statistically different based on inhibitor status (31.7% vs 14.6%; adjRR, 1.25; 95% CI, 0.63-2.49; P = .526). Presurgical plan deviations (eg, hemostatic medication dose adjustments, procedure rescheduling, and changes in the length of postoperative hospitalization) occurred more frequently in surgeries involving inhibitors (70.8 vs 39.5%; adjRR, 1.47; 95% CI, 1.12-1.93; P = .005). Conclusion: Inhibitors are associated with higher risks of adverse perioperative outcomes. Strategies to address inhibitor development should be prioritized to avoid undesirable perioperative outcomes.