Kalbitor (ecallantide) / Takeda - LARVOL DELTA

Systematic Literature Review of Recombinant C1 Esterase Inhibitor (rhC1-INH) and Other Products for the On-Demand Treatment of Hereditary Angioedema Attacks (ISPOR 2025) - "Eligible publications included phases 2, 3, and 4 randomized controlled trials (RCTs) and open-label extension (OLE) studies assessing HAE attacks in patients aged ≥12 years with the following interventions: Ruconest® (conestat alfa), Firazyr® (icatibant), Kalbitor® (ecallantide), sebetralstat (KVD900), and Berinert (C1 esterase inhibitor, human). The study populations and end point definitions used in clinical trials assessing acute HAE treatments have changed over time. Key study differences included route of administration, trial setting, time of treatment, attack severity at enrollment, attack location, redosing and rescue therapy criteria, patient-reported outcome assessments, and outcome definitions. Further investigation is warranted to evaluate these differences and determine whether they affected study outcomes."

Review • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema

Indirect treatment comparison of oral sebetralstat and intravenous recombinant human C1 esterase inhibitor for on-demand treatment of hereditary angioedema attacks. (PubMed, Allergy Asthma Clin Immunol) - P2/3, P3 | "This ITC found no significant differences in time to beginning of symptom relief and overall treatment-related treatment-emergent adverse events between sebetralstat and rhC1INH."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • STAT3

Targeting the Contact-Kinin System: A Cyclopeptide with Anti-Thromboinflammatory Properties Against Stroke. (PubMed, Eur J Pharmacol) - "The peptide also exerted comparable anti-ischemic stroke effects to those of ecallantide (DX-88), a kallikrein inhibitor approved for the treatment of hereditary angioedema, in a mouse model of transient middle cerebral artery occlusion. Thus, this short peptide CycloSD6, which dual targets FXII and PKa, harbors anti-thromboinflammation and anti-stroke properties with low bleeding risk. And these findings suggest that cycloSD6 may serve as a potential therapeutic candidate or template for the development of agents targeting ischemic stroke."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Hereditary Angioedema • Infectious Disease • Inflammation • Influenza • Ischemic stroke • Respiratory Diseases • Thrombosis • IGH

A Case of Status Epilepticus in a Patient Experiencing an Acute Attack of Hereditary Angioedema. (PubMed, Clin Pract Cases Emerg Med) - "We present a case of status epilepticus in a patient with HAE-nl-C1-INH. The focus of emergent medical management of status epilepticus includes airway protection, respiratory support, and administration of abortive and prophylactic antiepileptic drugs. The emergency medicine physician should also consider and treat possible underlying etiologies. The treatment of an acute attack of HAE should focus on replacing C1-INH and preventing the formation and limiting the action of bradykinin."

Journal • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Dermatology • Epilepsy • Genetic Disorders • Hereditary Angioedema • Immunology • Pruritus • Urticaria

Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines. (PubMed, J Allergy Clin Immunol) - "Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors. (PubMed, PLoS Comput Biol) - "The present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies."

Journal • Preclinical • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • Hypertension • Inflammation

Perioperative Hereditary Angioedema Exacerbation Necessitating Diverse Management (ASA 2024) - "She was immediately given famotidine, diphenhydramine, and ecallantide which resolved her symptoms. Despite optimization, the stress of surgery and general anesthesia can be potential triggers of hereditary angioedema requiring aggressive medical management with different classes of medications."

Anesthesia • Cardiovascular • Complement-mediated Rare Disorders • Dysphonia • Gastrointestinal Disorder • Hereditary Angioedema

ACE – inhibitors induced angioedema (EUSEM 2024) - "A suspected angioedema after a pill of Ramipril...In the ICU angioedema specific treatment consisted of : hydrocortisone infusion, 1g of TXA i/v and 2 units of FFP...While some of the drugs as C1 inhibitor concentrate, ecallantide and icatibant are definitely unavailable in all the ED's. TXA and FFP might be helpful and should be easily reachable for many. TXA of 1 g is sufficient for most presenting with ACE – inhibitors induced angioedema and 2 units of FFP is the recommended dose for the adults.Having all this knowledge, facing a patient with a condition of ACE – inhibitors induced angioedema will not look that scary anymore."

Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Extension of the circulatory half-life of recombinant ecallantide via albumin fusion without loss of anti-kallikrein activity. (PubMed, J Biotechnol) - "HSA fusion decreases rEcall clearance in vivo, but LRP1-mediated clearance remains more important than FcRn-mediated recycling for rEcall fusion proteins. The properties of H6-rEcall-HSA warrant investigation in a murine model of HAE."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Dyslipidemia • Hereditary Angioedema • LRP1

Enhanced Long-Term Efficacy of an AAV8-DX88-HSA Vector for Treating Hereditary Angioedema (ASGCT 2024) - "In vitro and in vivo data demonstrated that AAV8-DX88-HSA robustly inhibited pKal activity. A single injection of the vector stably expressed DX88-HSA for at least 24 weeks in mice. These results support further development of expressing DX88 fusion protein mediated by AAV as a potential approach to treat HAE."

Clinical • Cardiovascular • Complement-mediated Rare Disorders • Gene Therapies • Hereditary Angioedema

Design, expression and biological evaluation of DX-88mut as a novel selective factor XIa inhibitor for antithrombosis. (PubMed, Bioorg Chem) - "Here, we designed the FXIa inhibitory peptide DX-88mut by replacing Loop1 (DGPCRAAHPR) and Loop2 (IYGGC) in DX-88, which is a clinical drug targeting PKa for the treatment of hereditary angioedema, using Loop1 (TGPCRAMISR) and Loop2 (FYGGC) in the FXIa inhibitory peptide PN2KPI, respectively...Additionally, DX-88mut did not show a significant bleeding risk at a dose of 5 µmol/kg. Taken together, these results show that DX-88mut is a potential candidate for the development of a novel antithrombotic agent."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Hereditary Angioedema • Myocardial Infarction • Thrombosis • Venous Thromboembolism

Reasons Not To Treat HAE Attacks And Satisfaction For On-Demand Treatment (ACAAI 2023) - "76% of patients treated their most recent attack with icatibant (59.1%), pdC1-INH (26.9%), rhC1-INH (10.8%), or ecallantide (1.1%). Conclusion Physicians reported some patients reserve ODT for more severe attacks, despite the US HAEA Medical Advisory Board and WAO/EAACI recommendation that all attacks are considered for on-demand treatment. Physicians reported some dissatisfaction with the route of ODT administration and the ease of portability associated to it."

Pain

Pseudo-Allergies in the Emergency Department: A Common Misdiagnosis of Hypersensitivity Type 1 Allergic Reaction. (PubMed, Cureus) - "Histamine-mediated reactions, such as SFP, histamine-mediated angioedema, and mast cell degranulation induced by NSAIDs, and opioids can be treated with antihistamines, epinephrine, and corticosteroids. Bradykinin-induced angioedema, including hereditary angioedema and acquired angioedema, can be treated with fresh frozen plasma. Hereditary angioedema can be treated with many FDA-approved targeted medications, such as plasma-derived C1-INH, plasma kallikrein inhibitor (Ecallantide), and selective bradykinin-2 receptor antagonist (Icatibant). However, these targeted agents are not well-studied enough to be used for acquired angioedema. It is crucial for emergency medicine physicians to be familiar with and predict these reactions to prevent misdiagnosis, be prepared to treat these life-threatening conditions appropriately without delay and eliminate patients' exposure to any unnecessary investigations or treatments."

Journal • Review • Addiction (Opioid and Alcohol) • Allergy • Cardiovascular • Celiac Disease • Complement-mediated Rare Disorders • Eosinophilic Esophagitis • Gastrointestinal Disorder • Hereditary Angioedema • Immunology

"Management is awesome 1: icarubant 2: ecallantide @Sthanu5 @AaronGoodman33" (@kumar_inguva34)

Specificity of contact pathway inhibitors with regard to other coagulation and fibrinolysis proteases. (ISTH 2023) - "CTI was very specific for factor XIIa with little inhibition of other factors (Figure). SBTI, ecallantide, and avoralstat were, as expected, very potent inhibitors of kallikrein. Avoralstat, at concentrations well above therapeutic levels, had weak inhibitory effect on many other coagulation enzymes."

Cardiovascular • Hematological Disorders • Thrombosis

Extending the Circulatory Half-life of an Engineered Kallikrein-Specific Inhibitor (ISTH 2023) - "Several drugs are licensed for HAE treatment and/or prophylaxis, including C1INH concentrates and recombinant Ecallantide (rEcall)... Fusion to HSA increased Ki values by 31% (Ki 2.9 ± 0.4 nM for H6-rEcall-HSA vs. 2.2 ± 0.1 nM for H6-rEcall, p = 0.008). 2h post-injection, 26 ± 2 % of H6-rEcall-HSA remained in circulation vs."

Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Study to Assess the Tolerability and Safety of Ecallantide in Children and Adolescents With Hereditary Angioedema (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: NYU Langone Health | N=10 ➔ 0 | Unknown status ➔ Withdrawn

Enrollment change • Trial withdrawal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Reporting of Adverse Drug Reactions with Parenteral Drugs for the On-Demand Treatment of Hereditary Angioedema Attacks – Analysis of the FAERS Database 2009 to 2022 (AAAAI 2023) - "This analysis suggests the real-world reporting rates of ADRs generally correspond to those included in the labels of parenteral HAE drugs. Significantly increased risk for hypersensitivity was found for ecallantide. Reporting rates of injection site reactions were significantly increased for pdC1-INH, and showed a trend for icatibant and rhC1-INH."

Adverse drug reaction • Cardiovascular • Complement-mediated Rare Disorders • Gastrointestinal Disorder • Hereditary Angioedema • Immunology • Pain

Safety of Medications for Hereditary Angioedema During Pregnancy and Lactation. (PubMed, Expert Opin Drug Saf) - "Additional research is needed to increase safe access to other therapy options. We are hoping that future clinical studies, registries, and databases will shed additional light on this subject."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

ANGIOEDEMA PREVENTING EXTUBATION IN A CASE OF ACQUIRED C-1 ESTERASE DEFICIENCY (SCCM 2023) - "Epinephrine and Solumedrol were administered, however the neck swelling worsened and the patient was intubated for airway protection...Glucocorticoids were ineffective as the patient had a reported allergy to Prednisone, therefore were further avoided...If Berinert is ineffective, some immunologists and allergists have seen favorable outcomes and recommend treatment with the kallikrein inhibitor, ecallantide and the bradykinin B2 antagonist icatibant. To date, therapies targeted at prevention of angioedema in acquired cases have not been as successful as in hereditary forms, therefore, treatment is directed at the underlying condition, such as immunotherapy or chemotherapy for CLL."

Clinical • Allergy • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology

Protein-activated and FRET enhanced excited-state intermolecular proton transfer fluorescent probes for high-resolution imaging of cilia and tunneling nanotubes in live cells. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "The expressed proteins Ecallantide and MarTX were selected as the models to light up the inter-ESPT fluorescence of the probes and revealed that the inter-ESPT process can be triggered by the specific probe-protein recognition events. In the use of the super-bright inter-ESPT fluorescence, not only the proteins, but also the protein-based cilia and tunneling nanotubes (TNTs) can be specifically visualized in living cancer cells. Furthermore, such recognition-driven strategy allows us to construct a unique inter-ESPT probe to track and image specific endogenous proteins in live cells, highlighting the potential of inter-ESPT fluorogens as novel intelligent biomaterials."

Journal • Oncology

Benefit Package of Universal Coverage Scheme for Hereditary Angioedema (HAE) Caused By C1 Esterase Inhibitor Deficiency (C1-INH) (ISPOR-EU 2022) - "From current trials, first-line therapy such as Plasma-derived C1 inhibitor, Recombinant C1 inhibitor Conestat alfa, Icatibant, and Ecallantide showed benefits over placebo. HAE may affect the budget of Thailand if patients do not receive appropriate treatment. Thus, screening, diagnosis, and effective medication for treating acute attacks are essential measures to decrease the overall HAE-related healthcare cost. However, full economic evaluation studies of first-line therapy in Thailand are needed."

Cardiovascular • Complement-mediated Rare Disorders • Gastrointestinal Disorder • Genetic Disorders • Hereditary Angioedema

Real-World Treatment Burden Associated with Parenteral On-Demand Therapies for Hereditary Angioedema (ACAAI 2022) - "Method : We searched FAERS data from 10/01/2009 to 3/31/2021 for human C1-inhibitor (H-C1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (R-C1-INH). ADR rates are not exposure-adjusted and are based on spontaneous reporting. These real-world descriptive results suggest that patients experience significant treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks."

Clinical • HEOR • Real-world evidence • Cardiovascular • Complement-mediated Rare Disorders • Dermatology • Hereditary Angioedema • Pain

Long-term Prophylaxis with Androgens in the management of Hereditary Angioedema (HAE) in emerging countries. (PubMed, Orphanet J Rare Dis) - "In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries."

Journal • Review • Acne Vulgaris • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Depression • Dyslipidemia • Genetic Disorders • Hereditary Angioedema • Hypertension • Metabolic Disorders • Mood Disorders • Musculoskeletal Pain • Pain • Psychiatry • Pulmonary Arterial Hypertension

Treatment of hereditary angioedema-single or multiple pathways to the rescue. (PubMed, Front Allergy) - "Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • Rare Diseases