RESUMO
Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1. C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.
Assuntos
Angioedemas Hereditários , Proteína Inibidora do Complemento C1 , Transplante de Fígado , Humanos , Proteína Inibidora do Complemento C1/uso terapêutico , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/complicações , Angioedemas Hereditários/genética , Lactente , Masculino , FemininoRESUMO
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 ß -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.
Assuntos
Angioedemas Hereditários , População Rural , Humanos , Masculino , Feminino , Estudos Transversais , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/terapia , Criança , Adulto , Adolescente , Pré-Escolar , População Urbana , Adulto Jovem , Proteína Inibidora do Complemento C1/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.
Assuntos
Angioedemas Hereditários , Bradicinina , Humanos , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/terapia , Angioedemas Hereditários/tratamento farmacológico , Bradicinina/metabolismo , Bradicinina/análogos & derivados , Mastócitos/imunologia , Mastócitos/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , AnimaisRESUMO
Hereditary angioedema is a rare autosomal dominant condition characterized by episodes of swelling of the upper airway, intestines, and skin. The disorder is characterized by deficiency in C1 esterase inhibitor (C1-INH) or a decrease in functional C1-INH. Treatment options include on demand therapy (treatment of acute attacks), long-term prophylaxis, and short-term prophylaxis. Corticosteroids, epinephrine, and antihistamines are not effective for this form of angioedema. The high mortality in patients undiagnosed underscores a need for broader physician awareness to identify these patients and initiate therapy.
Assuntos
Angioedemas Hereditários , Humanos , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/terapia , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Médicos de Atenção Primária , Atenção Primária à SaúdeRESUMO
PURPOSE OF REVIEW: The aim of this review is to provide an account of the focus of therapeutic strategies for hereditary angioedema (HAE), give a brief overview of those used in the past and set aside and toughly discuss those currently available as first line. Further research is ongoing and the future therapeutic approaches that are still in different phases of study will be reviewed as well. RECENT FINDINGS: In the last two decades, major research advancements on HAE pathophysiology and management were made and numerous novel therapeutic options are now available. Compared to the past, drugs available nowadays are more effective, well tolerated, and possibly have a more convenient administration route. Moreover, numerous other drugs with innovative mechanisms of action are under development. SUMMARY: HAE is a rare genetic disease that if not promptly treated, it can lead to death from asphyxiation. Furthermore, due to its disfiguring and painful manifestations, HAE implies an important burden on the quality of life. Recently, following great research progresses on HAE therapy, evidence-based guidelines on HAE management were released. The therapeutic landscape of HAE is still under florid development, and it is possible novel treatments will remarkably revolutionize HAE management in the future.
Assuntos
Angioedemas Hereditários , Humanos , Angioedemas Hereditários/terapia , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Qualidade de Vida , Proteína Inibidora do Complemento C1/uso terapêutico , Proteína Inibidora do Complemento C1/genéticaAssuntos
Proteína Inibidora do Complemento C1 , Angioedema Hereditário Tipos I e II , Humanos , Proteína Inibidora do Complemento C1/uso terapêutico , Angioedema Hereditário Tipos I e II/tratamento farmacológico , Angioedema Hereditário Tipos I e II/genética , Angioedema Hereditário Tipos I e II/diagnóstico , Anticorpos Monoclonais Humanizados/uso terapêutico , Angioedemas Hereditários/tratamento farmacológicoRESUMO
Background: A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging and pharmacologic management is not well defined. Objective: The objective was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and/or address select challenges. Methods: This was a narrative review. Results: Symptoms of HAE-nl-C1-INH overlap with HAE types I and II; the heterogeneity of presentation and symptom burden are diagnostic challenges. A patient history, with particular attention to whether urticaria or other symptoms of mast cell mediator release are present, is important because such symptoms would strongly suggest a mast cell-mediated pathway. A family history of angioedema is informative but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations; most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell-targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines. Response to medications approved for HAE types I/II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE. Conclusion: Key unmet needs in HAE-nl-C1-INH include lack of confirmatory biomarker(s) for diagnosis and lack of prospective controlled clinical studies of pharmacologic products in this patient population.
Assuntos
Angioedemas Hereditários , Proteína Inibidora do Complemento C1 , Humanos , Proteína Inibidora do Complemento C1/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Diagnóstico Diferencial , FemininoAssuntos
Angioedemas Hereditários , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Humanos , Angioedemas Hereditários/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Metanálise em Rede , Proteína Inibidora do Complemento C1/uso terapêutico , Metanálise como AssuntoRESUMO
Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.
Assuntos
Angioedemas Hereditários , Consenso , Técnica Delphi , Humanos , Angioedemas Hereditários/prevenção & controle , Angioedemas Hereditários/tratamento farmacológico , Reino Unido , Proteína Inibidora do Complemento C1/uso terapêuticoRESUMO
BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swelling in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. OBJECTIVE: Our aim was to assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. METHODS: A 2-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, 4 consecutive angioedema attacks were treated with 3 doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant, 20 mg, or placebo was administered twice daily for 2 treatment periods of 8 weeks. RESULTS: Three patients were enrolled; of those 3 patients, 1 completed both study parts and 2 completed only Part 2. In Part 1, a reduction in attack severity was observed in the 3 attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6, and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events and 1 self-limiting treatment-emergent adverse event (abdominal pain). CONCLUSIONS: Deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.
Assuntos
Angioedema , Estudos Cross-Over , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Angioedema/tratamento farmacológico , Método Duplo-Cego , Idoso , Proteína Inibidora do Complemento C1/uso terapêutico , Adulto , Resultado do Tratamento , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/uso terapêuticoRESUMO
INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent edema and predominantly caused by the dysregulation of the kinin-kallikrein system. AREAS COVERED: This manuscript presents the results of preclinical and early clinical trials of newer drugs targeting the dysregulated kinin-kallikrein system. ATN-249 is an oral drug that has shown promising results in preclinical and Phase I studies, and good tolerability in the prophylactic treatment of attacks. KVD900 is also an oral agent developed for the on-demand treatment of HAE attacks. It has shown positive results in Phase I/II studies, with rapid absorption. The third drug, IONIS-PKKRx, is an antisense oligonucleotide targeting plasma prekallikrein mRNA. It has shown a dose-dependent reduction of plasma prekallikrein levels and proenzyme activation in Phase I/II studies, and has shown promising results. STAR-0215 is a long acting anti-activated kallikrein monoclonal antibody. A Phase 1a single ascending dose trial evaluated its safety, pharmacokinetics, and pharmacodynamics. Lastly, NTLA-2002 is an investigational gene-editing therapy. EXPERT OPINION: The targeted treatment of the dysregulated kinin-kallikrein system with specific inhibitors is promising for the prevention of angioedema attacks. Ongoing phase III studies will provide further insight into the efficacy and long-term safety of these novel therapies, potentially expanding treatment options for HAE treatment.
Assuntos
Angioedema , Angioedemas Hereditários , Calicreínas , Humanos , Angioedema/tratamento farmacológico , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Calicreínas/antagonistas & inibidores , Cininas , Pré-Calicreína , Pirazóis , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
BACKGROUND: Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease with similar phenotype to HAE-C1-INH but different genetic background. Currently, 6 subtypes are recognized, based on the underlying mutations. Several aspects need further clarification. OBJECTIVE: To assess clinical features of patients with genetically characterized HAE-nC1-INH from the North of Portugal. METHODS: Retrospective assessment of clinical data from all patients with HAE-nC1-INH followed at a HAE Reference Center. RESULTS: A total of 41 patients were identified, 4 with no family history. The FXII mutation Thr328Lys (38 carriers) was the most prevalent. There were 3 new potentially disease-causing variants linked to HAE-nC1-INH identified (c.529+4A>G:FXII; Cys248*:Kininogen-1; and Arg261His:Plasminogen). The HAE-FXII cohort included 82% females and 71.8% symptomatic patients. Penetrance rate was significantly higher in females (81.3% vs 28.6%; P = .012). A hormonal influence was observed in 96.2% of the symptomatic females, although 62.5% remained symptomatic after oral estrogen withdrawal. Trauma and dental procedures were frequent triggers (82.6% and 45.5%, respectively). Main locations were facial (described by 96%), lips (82.1%), and eyelids (64.3%). One patient reported erythema marginatum as prodrome. Plasma-derived C1-INH was effective as short-term prophylaxis in all treated patients, but only in 80% as on-demand treatment. Icatibant was effectively used on demand in 9 patients, but with relapses in 5 (57%). CONCLUSION: We described a large Portuguese series of patients with HAE-nC1-INH genetically characterized. Differences with others may contribute to improve current unmet needs and raise awareness of this rare disease. We highlighted the identification of 3 new variants (additional molecular studies are ongoing) and the report of erythema marginatum in HAE-nC1-INH.
Assuntos
Angioedemas Hereditários , Proteína Inibidora do Complemento C1 , Humanos , Feminino , Masculino , Portugal/epidemiologia , Adulto , Proteína Inibidora do Complemento C1/genética , Proteína Inibidora do Complemento C1/uso terapêutico , Estudos Retrospectivos , Angioedemas Hereditários/genética , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/diagnóstico , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Criança , Mutação , Idoso , Fator XII/genética , FenótipoRESUMO
A 16-year-old female presented to an outpatient clinic with a 13-year history of recurrent episodes of abdominal pain, vomiting and mild cutaneous swelling, either spontaneously or following minor trauma. The episodes occurred every 1-2 months. There was no family history of a similar complaint or hereditary angio-oedema (HAE). At the age of 16, evaluation confirmed the diagnosis of HAE type II, characterised by low C4 levels and reduced C1 esterase inhibitor function. The patient was prescribed tranexamic acid 1 g twice daily as well as C1 esterase inhibitor used as rescue medication during symptomatic episodes. This case report emphasises the importance of considering a diagnosis of HAE in patients with recurrent, unexplained abdominal pain, even in the absence of a positive family history of HAE.Abbreviations: ANA Antinuclear antibodies; C1-INH C1-inhibitor; CBC Complete blood count; FMF Familial Mediterranean fever; HAE Hereditary angioedema; IBD Inflammatory bowel diseases; SDP Solvent detergent-treated plasma; SLE Lupus erythematosus.
Assuntos
Angioedemas Hereditários , Lúpus Eritematoso Sistêmico , Adolescente , Feminino , Humanos , Dor Abdominal/etiologia , Dor Abdominal/tratamento farmacológico , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/genética , Proteína Inibidora do Complemento C1/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , PlasmaRESUMO
PURPOSE: Orolingual angioedema (OA) secondary to administration of thrombolytic therapy is a rare, but serious, known adverse effect. Despite the lack of robust evidence for their use, C1 esterase inhibitors are recommended by guidelines for the treatment of refractory thrombolytic-associated OA. This report highlights the use of a C1 esterase inhibitor in a patient with tenecteplase-associated OA unresolved by antihistamine and corticosteroid therapy. SUMMARY: A 67-year-old white male with a history of hypertension managed with lisinopril presented to the emergency department with acute onset of slurred speech and left-sided hemiparesis. Following workup, an outside hospital's neurology stroke team suspected an acute infarct and determined the patient to be a candidate for tenecteplase. Approximately 1 hour after tenecteplase administration, the patient began complaining of dyspnea and mild oral angioedema. Immediate interventions for OA management included intravenous therapy with dexamethasone 10 mg, diphenhydramine 25 mg, and famotidine 20 mg. After an additional 30 minutes, the patient's OA symptoms continued to progress and a C1 esterase inhibitor (Berinert) was administered. Shortly after administration of the C1 esterase inhibitor, the patient's symptoms continued to worsen, ultimately leading to endotracheal intubation. Following intubation, symptom improvement was noted, and the patient was safely extubated after 30 hours. CONCLUSION: Although rare, OA is a potentially life-threatening complication of tenecteplase therapy and requires prompt pharmacological intervention to optimize patient outcomes. Currently, no single agent or treatment algorithm exists that has shown significant efficacy or safety in the setting of thrombolytic-associated OA. Until data are available for C1 esterase inhibitors in this application, these inhibitors should only be considered if there is continued symptom progression after intravenous administration of corticosteroids and antihistamines.
Assuntos
Angioedema , Proteína Inibidora do Complemento C1 , Humanos , Masculino , Idoso , Tenecteplase/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Complemento C1s , Angioedema/induzido quimicamente , Angioedema/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversosRESUMO
PURPOSE: To describe a rare case of vision loss due to bilateral edema of the optic nerve in a patient with Hereditary Angioedema, treated with prophylactic C1-esterase inhibitor. METHODS: A 60-year-old Caucasian male affected by Hereditary Angioedema with unknown genetic defect (HAE- UNK) was admitted to our hospital presenting bilateral vision loss (best corrected visual acuity of 20/32 in the right eye and hand motion in the left eye) during an HAE attack. Intravenous administration of C1- esterase inhibitor (C1-INH, 1500 IU, Berinert, CSL Behring) determined the resolution of facial and periorbital swelling, however visual impairment persisted, in contrast with previous attacks experienced by the patient. Fundus examination revealed a vital optic disc without papilledema in both eyes. Magnetic resonance imaging (MRI) of the head and orbits showed bilateral edema of the optic nerve sheath. Treatment with intravenous and oral steroids was ineffective. Subsequently, a prophylactic treatment strategy with subcutaneous C1-esterase inhibitor was started (7000 IU every four days). RESULTS: Complete regression of edema of the optic nerves was observed by imaging at two months of follow-up after chronic treatment with C1-esterase inhibitor (7000 IU every four days). Complete restoration of visual acuity was achieved (BCVA 20/20 in both eyes) and multimodal imaging of the optic nerves demonstrated the absence of anatomical and functional damage. CONCLUSION: Patients affected by HAE may show atypical presentation with edema of the optic nerves without involvement of the optic nerve head. They may significantly benefit from prophylactic and chronic treatment with C1-esterase inhibitor.
Assuntos
Proteína Inibidora do Complemento C1 , Imageamento por Ressonância Magnética , Papiledema , Acuidade Visual , Humanos , Masculino , Pessoa de Meia-Idade , Papiledema/diagnóstico , Papiledema/tratamento farmacológico , Papiledema/etiologia , Acuidade Visual/fisiologia , Proteína Inibidora do Complemento C1/uso terapêutico , Cegueira/diagnóstico , Cegueira/etiologia , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/complicações , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/fisiopatologia , Nervo Óptico/diagnóstico por imagemRESUMO
Lanadelumab, a recombinant human anti-kallikrein monoclonal antibody, is recommended as the first-line option for long-term prophylaxis (LTP) in hereditary angioedema (HAE). However, the efficacy of lanadelumab and its effects on the quality of life (QoL) in Japanese HAE patients using real-world data have not been reported. Herein, we report the outcomes of five HAE patients who were treated with lanadelumab at two Japanese institutions. We retrospectively collected data on attack frequency and on-demand treatment frequency using an angioedema quality of life (AE-QoL) questionnaire. Our data corresponded to five Japanese HAE patients who started lanadelumab treatment: four with HAE due to C1-inhibitor deficiency (HAE-1) and one with HAE with a normal C1-inhibitor (HAE-nC1-INH). Two HAE-1 patients showed a reduction in both attacks and number of on-demand treatments. The other HAE-1 patients had an increase in the number of on-demand treatments, although there was no apparent reduction in attacks. The HAE-nC1-INH patient showed a slight increase in both attacks and number of on-demand treatments. Only one HAE-1 patient discontinued treatment after 1 month owing to side effects, including dizziness and headache. All four who continued treatment showed improved AE-QoL total and domain scores. Therefore, in this study, using real-world data, we demonstrated that lanadelumab reduced attack frequency and improved QoL in Japanese HAE patients.
Assuntos
Angioedemas Hereditários , Anticorpos Monoclonais Humanizados , Qualidade de Vida , Humanos , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Adulto , Estudos Retrospectivos , Angioedemas Hereditários/tratamento farmacológico , Pessoa de Meia-Idade , Japão , Resultado do Tratamento , Proteína Inibidora do Complemento C1/administração & dosagem , Proteína Inibidora do Complemento C1/uso terapêutico , Inquéritos e Questionários , População do Leste AsiáticoRESUMO
BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).
Assuntos
Angioedemas Hereditários , Sistemas CRISPR-Cas , Edição de Genes , Adulto , Humanos , Angioedema , Angioedemas Hereditários/sangue , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1/uso terapêutico , Relação Dose-Resposta a Droga , Edição de Genes/métodos , Calicreína Plasmática/genética , Resultado do TratamentoRESUMO
Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc3-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc3-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.
Assuntos
Angioedemas Hereditários , Humanos , Angioedemas Hereditários/genética , Angioedemas Hereditários/prevenção & controle , Bradicinina/uso terapêutico , Bradicinina/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , Fígado/metabolismo , Pré-CalicreínaRESUMO
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.