BACKGROUND:Hereditary angioedema is a bradykinin-mediated disorder characterised by recurrent painful swelling attacks. Treatment relies on medications to prevent attacks and on-demand therapies for attack manifestations. Parenteral administration associated with most available on-demand therapies often leads to treatment being delayed or forgone. Deucrictibant is an orally bioavailable bradykinin B2 receptor antagonist under development for prophylaxis and on-demand treatment of hereditary angioedema attacks. We aimed to investigate the efficacy and safety of deucrictibant for the on-demand treatment of hereditary angioedema attacks. METHODS:RAPIDe-1 was a double-blind, randomised, placebo-controlled, crossover, dose-ranging, phase 2 trial that recruited adults aged 18-75 years with hereditary angioedema type 1 or 2 from 38 sites (eg, university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Participants were required to have experienced two or more attacks within the past 2 months or three or more attacks within the past 4 months before screening. An interactive response technology system randomly assigned eligible patients (1:1:1) to receive a blinded dose of oral deucrictibant (immediate-release capsule) 10 mg, 20 mg, or 30 mg during an attack-free period to assess pharmacokinetics and safety in the part 1 of the study; and, subsequently, to receive a crossover treatment sequence of two administrations of the same deucrictibant dose (10 mg, 20 mg, or 30 mg) and one of placebo to treat three investigator-confirmed angioedema attacks in the part 2. Randomisation was stratified by whether the participant was willing to participate in full pharmacokinetic sampling. Participants, investigators, site personnel, and the sponsor were masked to treatment assignment and capsules of deucrictibant and placebo were identical. For each attack, patients self-administered the oral study drug within 3 h after at least one symptom (skin pain, skin swelling, or abdominal pain) reached a visual analog scale (VAS) individual score of 30 or more out of 100 and within 6 h from symptom onset. The primary endpoint was change in the patient-reported composite VAS-3 score measuring severity of attack manifestations from before treatment to 4 h post-treatment and assessed in the modified intention-to-treat and per-protocol populations. Safety was assessed in all patients who received any dose of study drug. RAPIDe-1 is registered with ClinicalTrials.gov (NCT04618211) and is completed. FINDINGS:Between Feb 3, 2021, and June 23, 2022, 89 patients were screened, of whom 74 were randomly assigned between Feb 23, 2021, and July 26, 2022. For the primary analysis set, the median follow-up was 130·0 (IQR 92·5 to 212·5) days for the deucrictibant 10 mg group, 166·5 (80·0 to 275·0) days for the deucrictibant 20 mg group, and 172·0 (65·0 to 242·0) days for the deucrictibant 30 mg group. The primary efficacy analysis included 147 attacks in 62 patients, of whom 42 (68%) were female and 60 (97%) were White. Least squares mean differences of change in VAS-3 score between deucrictibant and placebo was -16·75 (95% CI -21·52 to -11·97) for 10 mg, -15·02 (-20·22 to -9·81; p<0·0001) for 20 mg, and -16·28 (-21·27 to -11·29; p<0·0001) for 30 mg. In part 1, all treatment-emergent adverse events were grades 1-2, with the most common in two or more patients being headache (two [8%] of 25) and nasopharyngitis (two [8%] of 25) in the deucrictibant 30 mg group. In part 2, no single treatment-emergent adverse event was reported by two or more patients in any treatment group. Most adverse events were considered unrelated to the study drug and there were no grade 3 or worse adverse events. INTERPRETATION:Deucrictibant significantly reduced the severity of hereditary angioedema attacks compared with placebo; these results support continued investigation of antagonism of the bradykinin B2 receptor with an orally available agent as a potentially effective approach, with a safety profile similar to placebo, for on-demand treatment. FUNDING:Pharvaris.

BackgroundHereditary angioedema (HAE) is a genetic disorder characterized by episodic subcutaneous and submucosal swelling. Patient-reported outcome measures (PROMs) are recommended for routine clinical assessment by international guidelines and are used as secondary outcome measures in pivotal clinical trials for novel investigational drugs. The Angioedema Control Test (AECT) and Hereditary Angioedema Activity Score (HAE-AS) are validated tools designed to aid in HAE patient assessment, but the extent to which they measure different disease outcomes is unclear. The aim of this study was to examine how these measures correlate and inform clinical practice.MethodsWe conducted a retrospective study of patients with HAE types 1 and 2 at the Edmonton Angioedema Center of Reference and Excellence. AECT and HAE-AS scores were obtained from patient-completed questionnaires during routine visits. Multiple linear regression was used to examine the association between HAE-AS and AECT scores with age, sex, and long-term prophylaxis (LTP) status as predictors. Receiver operating characteristic (ROC) analysis was used to determine the optimal HAE-AS score cutoff that predicts poor disease control as determined by the AECT.ResultsThere were 25 participants included with a mean age of 39.4 years (SD = 13.7), 72% of whom were female. Most had HAE Type 1 (76%) and 52% were receiving LTP. SC C1-inhibitor therapy was the most common LTP (36%). Most had well managed disease with a median AECT score of 11.88 (range: 5-16) and HAE-AS of 5.84 (range: 0-13). A statistically significant but weak negative correlation was found between AECT and HAE-AS (β=−0.67, p=0.002). ROC analysis showed that an HAE-AS score >5 had a sensitivity of 100% and specificity of 61% for poor disease control.ConclusionsThe AECT and HAE-AS instruments are weakly correlated, indicating that they provide related but distinct information to the practicing clinician. Using both AECT and HAE-AS in clinical practice can thus provide a more comprehensive patient evaluation.

Inborn errors of immunity (IEIs) comprise a heterogeneous group of rare disorders, characterized by a wide spectrum of immunological alterations that influence the presentation and age at onset of disease. Approximately 30,000 Canadians suffer from primary immunodeficiency. Canada is home to several specific populations with a higher incidence of unique IEIs. Canada lacks a comprehensive database detailing the epidemiology, clinical and immunological phenotypes, and genotypes of patients with IEIs. We developed the novel and innovative Canadian Inborn Errors of Immunity National Registry (CIEINR), a machine-readable, high-quality dataset that promotes research through standardized data exchange and supports patient advocacy. CIEINR was established by a national steering committee of 13 clinician scientists from 9 Canadian provinces, through monthly virtual meetings. Following a literature review of existing international IEI registries, the peer-reviewed study protocol, consent forms, and governance documents were developed. ImmUnity Canada, the national patient organization, was consulted to review the protocol. Ontology-based data collection forms were developed in collaboration with bioinformatics scientists to capture input data in a structured fashion. Regulatory documents and standardized data collection forms were harmonized with United States Immunodeficiency Network and European Society for Immunodeficiencies to support data sharing, methodological consistency, and interoperability. A continuous quality improvement framework aligns with the Canadian Drug Agency’s Best Practices and Standards to Enhance the Quality of Rare Disease Registries in Canada. The CIEINR has been established and includes 25 centers across Canada. Electronic clinical research forms in the Research Electronic Data Capture (REDCap) platform were successfully piloted including the embedded analytic tools such as RareLink and Phenopackets on patients’ data with variable forms of IEIs. By collecting high-quality, precise, ontology-based patient data, the CIEINR will improve understanding of the Canadian IEI landscape, identify challenges and opportunities for patients and their healthcare providers, and support research and advocacy.

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell–mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH.

Primary and secondary antibody deficiencies (PAD and SAD) are amongst the most prevalent immunodeficiency syndromes, often necessitating long-term immune globulin replacement therapy (IRT). Both intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) have demonstrated efficacy in antibody deficiency. Comparative analyses of these two routes of administration are limited to nurse-administered IVIG and home therapy with self-administered SCIG. A third programmatic approach, SCIG administered by nurses in hospital-based outpatient infusion clinics, combines certain advantages of IVIG and home SCIG such as the provision of nursing support and the reduced risk of systemic reactions associated with the subcutaneous route. This cross-sectional study aimed to compare the viability and resource utilization of nurse-administered SCIG with IVIG in patients with antibody deficiency. We hypothesized that nurse-administered SCIG would require a similar amount of infusion clinic time per month as IVIG, despite more frequent dosing, due to shorter individual appointments, while maintaining high patient satisfaction. Information on infusion duration, time in the infusion chair, direct nursing time, and treatment satisfaction using the Life Quality Index was collected. Time measures for each patient were expressed as minutes/4 weeks to account for the more frequent dosing of nurse-administered SCIG compared to IVIG. We determined that the total time, infusion time, and nursing time needed to provide nurse-administered SCIG was comparable to IVIG. The more frequent dosing of SCIG was offset by the shorter times required per infusion. Patients reported favorable treatment satisfaction with both nurse-administered SCIG and IVIG. We conclude that nurse-administered SCIG may be a useful treatment modality for well-selected individuals.

BackgroundHereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022.MethodsWe conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy.ResultsFrom June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3.ConclusionBerotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.

Background Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long -term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. Methods This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double -blind, placebo-controlled) and a treatment period 2 (TP2: >= 44-week open -label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open -label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long -term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. Findings Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open -label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 390 years (IQR 270-530), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 879 weeks (IQR 500-1066) in the garadacimab 200 mg group and 441 weeks (241-561) in the garadacimab 600 mg group. Median monthly attack rates were 00 (IQR 00-01) in the garadacimab 200 mg group and 0 center dot 1 (00-04) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run -in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. Interpretation Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long -term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema.

Source Citation Alexander M, Harris S, Underhill C, et al. Risk-directed ambulatory thromboprophylaxis in lung and gastrointestinal cancers: the TARGET-TP randomized clinical trial. JAMA Oncol. 2023;9:1536-1545. 37733336 Clinical Impact Ratings GIM/FP/GP: Hematology:

Introduction: Short-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15-20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear. Methods: A multicenter, observational study of 215 vaccine-na & iuml;ve patients with clinically recovered COVID-19, studied at 3-6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized. Discussion: Long-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease.

There is a need to investigate novel strategies in order to create an effective, broadly protective vaccine for current and future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. The currently available vaccines demonstrate compromised efficacy against emerging SARS-CoV-2 variants of concern (VOCs), short-lived immunity, and susceptibility to immune imprinting due to frequent boosting practices. In this study, we examined the specificity of cross-reactive IgG antibody responses in mRNA-vaccinated, AstraZeneca-vaccinated, and unvaccinated donors to identify potentially conserved, cross-reactive epitopes to target in order to create a broadly protective SARS-CoV-2 vaccine. Our study provides evidence for cross-reactive IgG antibodies specific to eight different spike (S) variants. Furthermore, the specificities of these cross-variant IgG antibody titers were associated to some extent with spike S1- and S2-subunit-derived epitopes P1 and P2, respectively. In addition, nucleocapsid (N)- and membrane (M)-specific IgG antibody titers correlated with N- and M-derived epitopes conserved across beta-CoVs, P3–7. This study reveals conserved epitopes of viral antigens, targeted by natural and/or vaccine-induced human immunity, for future designs of next-generation COVID-19 vaccines.

Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare inborn error of immunity that presents with episodic swelling. Management is multifaceted and includes on-demand treatment of swelling episodes, short-term prophylaxis to prevent swelling episodes from procedures, and long-term prophylaxis (LTP) to prevent angioedema on an ongoing basis. All approved on-demand therapies are parenteral, necessitating patient training for home administration, particularly intravenous C1 inhibitor. These complexities can result in care gaps for rural HAE patients. We conducted a cross-sectional study at our Angioedema Center of Reference and Excellence to assess the care provided to urban and rural patients. The proportion of patients receiving LTP, proportion of patients diagnosed as children, and disease control measured using the Angioedema Control Test (AECT) were collected. Logistic and Poisson regression models adjusted for age and sex were used to compare the two groups. The proportion using LTP was similar at 62% and 61% in urban and rural patients, respectively (odds ratio [OR] 1.01 (CI 95% 0.34-2.99)). Among urban patients, 52% were diagnosed as children compared to 60% among rural residents (1.43 (0.37-5.56)). The mean (IQR) AECT score was 14.0 (8.5-15.5) in urban patients and 13.0 (10.0-14.0) in rural patients (Poisson β -0.001 (-0.23-0.23). These data indicate that rural patients received similar high-quality care. We attribute these findings to the centralized care model employed in which HAE patients in the region are seen at a single comprehensive care clinic.

Background X-linked agammaglobulinemia (XLA) is the most common form of agammaglobulinemia and is caused by mutations in Btk, which encodes Bruton tyrosine kinase (BTK).Case Description We describe a 36-year-old male who presented as an infant with hypogammaglobulinemia and sinopulmonary infections and was initially diagnosed with common variable immunodeficiency. Genetic testing showed he was hemizygous for Btk c.240G > A. This synonymous variant affecting the last nucleotide of exon 3 leads to aberrant splicing of most but not all mRNA transcripts.Conclusion We demonstrated reduced BTK protein expression confirming the pathogenicity of the variant and related our findings to genotype-phenotype relationship studies ina XLA caused by synonymous mutations.

We report an approximately 80% reduction in angioedema attacks with lanadelumab, a mAb targeting plasma kallikrein, in a case of hereditary angioedema with normal C1 inhibitor levels. This finding supports a central pathophysiologic role for kallikrein in hereditary angioedema with normal C1 levels and supports the need for prospective studies of lanadelumab use with this condition.

The efficacy and safety of garadacimab, a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII for the prevention of hereditary angioedema (HAE) attacks, were evaluated in a randomized, placebo-controlled, 6-month, Phase 3 trial (NCT04656418). Patients aged ≥12 years with type I/II HAE were randomized (3:2) to receive monthly subcutaneous (SC) garadacimab 200 mg or placebo after an initial SC loading dose of garadacimab 400 mg or volume-matched placebo. Efficacy, safety, and quality-of-life (QOL) measures were assessed. Once-monthly SC garadacimab significantly reduced the attack rate (AR) compared with placebo (p<0.001), resulting in an AR reduction of 86.5% (95% CI: 57.8–95.7). Adjusted for baseline AR, garadacimab-treated patients (n=39) experienced mean monthly ARs of 0.22 vs 2.07 for placebo-administered patients (n=24), resulting in an AR reduction vs placebo of 89.2% (95% CI: 75.6–95.2). Twenty-four (61.5%) garadacimab-treated patients were attack-free during the 6-month study, and 74.4% achieved ≥90% attack reduction vs the run-in period. The time to first attack was ≥72 days for 75% of garadacimab-treated patients vs 5 days for placebo-administered patients. Forty (62.5%) patients experienced ≥1 treatment-emergent adverse event (TEAE), totaling 129 events, including one severe, serious non-related TEAE (overnight hospital observation for laryngeal attack). The most common TEAEs were 5 mild injection-site reactions from 4 (6%) patients. No adverse events led to discontinuation. Angioedema-QOL total mean score improved by 23.7 points following first garadacimab administration. Once-monthly SC garadacimab was well tolerated throughout the treatment period and significantly reduced the AR vs placebo in patients with HAE.