-
The Journal of Allergy and Clinical... Mar 2024Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older.
OBJECTIVE
This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat.
METHODS
APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL).
RESULTS
Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n = 70), the mean (standard error) change in attack rate from baseline was -2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain.
CONCLUSION
Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.
Topics: Humans; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Double-Blind Method; Pyrazoles; Quality of Life; Treatment Outcome
PubMed: 38122865
DOI: 10.1016/j.jaip.2023.12.019 -
Journal of Clinical Medicine Nov 2023: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in , resulting in C1-inhibitor (C1-INH)...
: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in , resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The gene was sequenced. In two severely affected sisters, we identified a homozygous missense variant in (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. These studies of the variant's effects on the structure-function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease.
PubMed: 38068351
DOI: 10.3390/jcm12237299 -
Iranian Journal of Kidney Diseases Nov 2023This study utilized serum proteomics with tandem mass tags (TMT) to investigate potential biomarkers associated with femoral central venous catheter (CVC) thrombosis in...
INTRODUCTION
This study utilized serum proteomics with tandem mass tags (TMT) to investigate potential biomarkers associated with femoral central venous catheter (CVC) thrombosis in endstage kidney disease (ESKD) patients. TMT proteomics analysis on serum samples was conducted to identify proteins with distinct expression levels that may be linked to thrombosis. The findings have important implications for enhancing anticoagulant procedures, catheter closure techniques, and determining optimal intervention timing for post-catheterization dialysis.
METHODS
Thirty ESKD patients with CVC receiving hemodialysis between May 2021 and October 2022 at the First Affiliated Hospital of Chengdu Medical College were included in the study, and grouped according to vascular color Doppler ultrasound results, including 23 patients in the thrombo-positive group and 7 patients in the thrombo-negative group. Selection criteria were: 1) Patients with ESKD candidate for hemodialysis initiation; 2) no dialysis access has been placed previously, and CVC needs to be inserted as a temporary access; 3) patients volunteered to participate in this clinical study. Clinical data, blood tests, coagulation function, and biochemical parameters were collected and analyzed on the 14th day after catheterization. Color ultrasonography was conducted on the same day to categorize patients into two groups: those with thrombus-positive results and those with thrombus-negative results.
RESULTS
TMT proteomics analysis identified twenty-eight differently expressed proteins, including 16 upregulated and 12 downregulated proteins. Enrichment analysis demonstrated nine proteins that were significantly enriched in four pathways within the thrombus-positive group after CVC insertion. Enzyme-linked immunosorbent assay (ELISA) test confirmed the TMT proteomics findings, specifically highlighting significant differences in human plasma kallikrein B1 (KLKB1) and angiopoietin-like protein 3 (ANGPTL3) levels on the 14th day after CVC insertion. Additionally, KLKB1, fibrinogen (FIB), D-dimer, and fibrinogen degradation products (FDP) levels were significantly elevated, while ANGPTL3 levels were decreased on the 14th day after CVC insertion in the thrombus-positive ESKD patient group.
CONCLUSION
Monitoring coagulation status post-CVC catheterization and evaluating potential biomarkers like KLKB1 and ANGPTL3 can contribute to the development of personalized treatment plans, improving the quality of hemodialysis and the overall quality of life for ESKD patients. DOI: 10.52547/ijkd.7671.
Topics: Humans; Catheterization, Central Venous; Proteomics; Quality of Life; Thrombosis; Kidney Failure, Chronic; Renal Dialysis; Biomarkers; Fibrinogen; Angiopoietin-Like Protein 3
PubMed: 38043111
DOI: No ID Found -
Clinical Immunology Communications Dec 2022From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to... (Review)
Review
From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to SARS-CoV-2 is imperative since variants such as Omicron negatively impact adaptive antibody neutralization. Severe COVID-19 is, in part, associated with aberrant activation of complement and Factor XII (FXIIa), initiator of contact system activation. Paradoxically, a protein that inhibits the three known pathways of complement activation and FXIIa, C1 esterase inhibitor (C1-INH), is increased in COVID-19 patient plasma and is associated with disease severity. Here we review the role of C1-INH in the regulation of innate and adaptive immune responses. Additionally, we contextualize regulation of C1-INH and SERPING1, the gene encoding C1-INH, by other pathogens and SARS viruses and propose that viral proteins bind to C1-INH to inhibit its function in severe COVID-19. Finally, we review the current clinical trials and published results of exogenous C1-INH treatment in COVID-19 patients.
PubMed: 38013973
DOI: 10.1016/j.clicom.2022.05.001 -
Allergy Mar 2024Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381).
METHODS
In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments.
RESULTS
Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen.
CONCLUSION
The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.
Topics: Humans; Angioedemas, Hereditary; Prekallikrein; Quality of Life; Treatment Outcome; Complement C1 Inhibitor Protein; Oligonucleotides
PubMed: 38009241
DOI: 10.1111/all.15948 -
Annals of Allergy, Asthma & Immunology... Apr 2024Berotralstat, a first-line, once-daily, oral plasma kallikrein inhibitor for long-term prophylaxis of hereditary angioedema (HAE), is an effective and well-tolerated...
BACKGROUND
Berotralstat, a first-line, once-daily, oral plasma kallikrein inhibitor for long-term prophylaxis of hereditary angioedema (HAE), is an effective and well-tolerated treatment option.
OBJECTIVE
To summarize the safety, effectiveness, and impact on treatment satisfaction in patients who switched from injectable long-term prophylactics to oral berotralstat monotherapy (150 mg daily) at US sites in the international open-label APeX-S study.
METHODS
APeX-S was an open-label, Phase II study of berotralstat conducted in 22 countries. Here, we focus on APeX-S patients enrolled at US sites who switched from injectable long-term prophylactics to berotralstat 150 mg once-daily monotherapy.
RESULTS
A total of 34 patients discontinued lanadelumab (n = 21), subcutaneous C1 esterase inhibitor (n = 11), or intravenous C1 esterase inhibitor (n = 2) and switched to berotralstat 150 mg monotherapy. Vomiting, diarrhea, and upper respiratory tract infection were the most common adverse events (each 11.8%). Mean monthly attack rates were consistently low after the switch to berotralstat. The mean (SEM) monthly attack rate was 0.29 (0.11) at Month 1, 0.48 (0.15) at Month 6, and 0.58 (0.23) at Month 12. The median attack rate was 0 attack/mo throughout 12 months of treatment. Improvements were observed in the Treatment Satisfaction Questionnaire for Medication from baseline to Month 12 after the switch to berotralstat monotherapy, with the greatest improvements in convenience.
CONCLUSION
The transition from injectable prophylactic medication to berotralstat was generally well tolerated. Patients switching to berotralstat monotherapy maintained good control of their HAE symptoms and reported improved treatment satisfaction.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03472040.
Topics: Humans; Administration, Intravenous; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Pyrazoles; Treatment Outcome
PubMed: 38006972
DOI: 10.1016/j.anai.2023.11.016 -
Blood Feb 2024Hereditary angioedema (HAE) is associated with episodic kinin-induced swelling of the skin and mucosal membranes. Most patients with HAE have low plasma C1-inhibitor...
Hereditary angioedema (HAE) is associated with episodic kinin-induced swelling of the skin and mucosal membranes. Most patients with HAE have low plasma C1-inhibitor activity, leading to increased generation of the protease plasma kallikrein (PKa) and excessive release of the nanopeptide bradykinin from high-molecular-weight kininogen (HK). However, disease-causing mutations in at least 10% of patients with HAE appear to involve genes for proteins other than C1-inhibitor. A point mutation in the Kng1 gene encoding HK and low-molecular weight kininogen (LK) was identified recently in a family with HAE. The mutation changes a methionine (Met379) to lysine (Lys379) in both proteins. Met379 is adjacent to the Lys380-Arg381 cleavage site at the N-terminus of the bradykinin peptide. Recombinant wild-type (Met379) and variant (Lys379) versions of HK and LK were expressed in HEK293 cells. PKa-catalyzed kinin release from HK and LK was not affected by the Lys379 substitutions. However, kinin release from HK-Lys379 and LK-Lys379 catalyzed by the fibrinolytic protease plasmin was substantially greater than from wild-type HK-Met379 and LK-Met379. Increased kinin release was evident when fibrinolysis was induced in plasma containing HK-Lys379 or LK-Lys379 compared with plasma containing wild-type HK or LK. Mass spectrometry revealed that the kinin released from wild-type and variant kininogens by PKa is bradykinin. Plasmin also released bradykinin from wild-type kininogens but cleaved HK-Lys379 and LK-Lys379 after Lys379 rather than Lys380, releasing the decapeptide Lys-bradykinin (kallidin). The Met379Lys substitutions make HK and LK better plasmin substrates, reinforcing the relationship between fibrinolysis and kinin generation.
Topics: Humans; Bradykinin; Lysine; Angioedemas, Hereditary; Fibrinolysin; Methionine; HEK293 Cells; Kininogens; Kallikreins; Racemethionine
PubMed: 37992228
DOI: 10.1182/blood.2023022254 -
ACS Medicinal Chemistry Letters Nov 2023Provided herein are novel plasma kallikrein inhibitors, pharmaceutical compositions, use of such compounds in treating hereditary angioedema, diabetic macular edema, and...
Provided herein are novel plasma kallikrein inhibitors, pharmaceutical compositions, use of such compounds in treating hereditary angioedema, diabetic macular edema, and diabetic retinopathy, and processes for preparing such compounds.
PubMed: 37974944
DOI: 10.1021/acsmedchemlett.3c00441 -
Biochemical and Biophysical Research... Dec 2023The incidence and mortality rates of colorectal cancer (CRC) have significantly increased in recent years. It has been shown that early diagnosis of CRC improves the...
The incidence and mortality rates of colorectal cancer (CRC) have significantly increased in recent years. It has been shown that early diagnosis of CRC improves the five-year survival of patients compared to late diagnosis, as patients with stage I disease have a five-year survival rate as high as 90 %. Through bioinformatics analysis, we identified Kallikrein 10 (KLK10), a member of the Kallikrein family, as a reliable predictor of CRC progression, particularly in patients with early-stage CRC. Furthermore, single-cell analysis revealed that KLK10 was highly expressed in tumor and partial immune cells. Analysis of the biological functions of KLK10 using the Kyoto encyclopedia of genes and genomes and gene ontology indicated that KLK10 plays a role in the proliferation and differentiation of cancer cells, along with the maintenance of tumor function and immune regulation, explicitly by T cells and macrophages. EdU cell proliferation staining, plate clone formation assay, and cell scratch assay demonstrated that KLK10 inhibition by siRNA affected the proliferation and migration of CRC cells. Cell cycle detection by flow cytometry demonstrated that KLK10 inhibition led to cell cycle arrest in the G1 phase. In addition, the proportion of M1 and M2 macrophages in 45 tumor specimens was analyzed by immunohistochemistry, the proportion of CD4 T cells and CD8 T cells in plasma was identified by flow cytometry, and their correlation with KLK10 was analyzed. The effects of KLK10 on T cells and macrophages were verified in independent cell experiments. The results revealed that KLK10 also activates CD4 T cells, mediating M2-type macrophage polarization.
Topics: Humans; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Kallikreins
PubMed: 37972446
DOI: 10.1016/j.bbrc.2023.149217 -
Frontiers in Immunology 2023Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation.
METHODS
We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively.
RESULTS
The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms ( = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms ( = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug.
CONCLUSION
The study results do not support the use of ConA to prevent COVID-19 progression.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov, identifier NCT04414631.
Topics: Adult; Humans; COVID-19; SARS-CoV-2; Endothelial Cells; Inflammation; Thrombosis
PubMed: 37965347
DOI: 10.3389/fimmu.2023.1255292