RESUMEN
Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.
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Anticoagulantes , Interacciones Farmacológicas , Piridinas , Rivaroxabán , Humanos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Estudios Retrospectivos , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/farmacocinética , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anilidas/administración & dosificación , Anilidas/efectos adversos , Anilidas/farmacocinética , Hemorragia/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Trombosis/inducido químicamente , Trombosis/etiología , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Administración Oral , AncianoAsunto(s)
Aminofenoles , Benzodioxoles , Fibrosis Quística , Combinación de Medicamentos , Indoles , Genio Irritable , Pirazoles , Quinolonas , Humanos , Fibrosis Quística/tratamiento farmacológico , Benzodioxoles/efectos adversos , Aminofenoles/efectos adversos , Aminofenoles/uso terapéutico , Indoles/efectos adversos , Indoles/administración & dosificación , Genio Irritable/efectos de los fármacos , Pirazoles/efectos adversos , Quinolonas/efectos adversos , Quinolonas/administración & dosificación , Piridinas/efectos adversos , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Femenino , Adulto , Masculino , Agonistas de los Canales de Cloruro/uso terapéutico , Tiofenos/efectos adversos , Tiofenos/administración & dosificación , Pirroles/efectos adversosRESUMEN
BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.
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Supervivientes de Cáncer , Neoplasias , Medición de Resultados Informados por el Paciente , Piridinas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Supervivientes de Cáncer/psicología , Neoplasias/tratamiento farmacológico , Anciano , Adulto , Encuestas y Cuestionarios , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Depresión/inducido químicamente , Satisfacción del Paciente , Calidad de VidaRESUMEN
BACKGROUND: Hypertensive crisis is an acute increase in blood pressure >180/120 mm Hg. A titratable antihypertensive agent is preferred to lower blood pressure acutely in a controlled way and prevent an abrupt overcorrection. Nicardipine and clevidipine are both dihydropyridine calcium channel blockers that provide unique benefits for blood pressure control. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of nicardipine or clevidipine for blood pressure control in the setting of hypertensive crisis. METHODS: This was a single-center, retrospective cohort study. Eligible patients received either nicardipine or clevidipine for the treatment of hypertensive crisis. The primary outcome was achievement of 25% reduction in mean arterial pressure at 1 h. The secondary outcome was achievement of a systolic blood pressure (SBP) of <160 mm Hg at 2-6 h from the start of the infusion. RESULTS: This study included a total of 156 patients, 74 in the nicardipine group and 82 in the clevidipine group. The SBP on admission and at the start of the infusion were similar between groups. There was no difference between groups in achieving a 25% reduction in mean arterial pressure at 1 h. Nicardipine achieved an SBP goal of <160 mm Hg at 2-6 h significantly more often than the clevidipine group (89.2% vs. 73.2%; p = 0.011). CONCLUSIONS: There is no difference between agents for initial blood pressure control in the treatment of hypertensive crisis. Nicardipine showed more sustained SBP control, with a lower risk of rebound hypertension and a significant cost savings compared with clevidipine.
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Antihipertensivos , Presión Sanguínea , Hipertensión , Nicardipino , Piridinas , Humanos , Nicardipino/uso terapéutico , Nicardipino/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Piridinas/uso terapéutico , Piridinas/farmacología , Piridinas/efectos adversos , Presión Sanguínea/efectos de los fármacos , Anciano , Bloqueadores de los Canales de Calcio/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacología , Resultado del Tratamiento , Estudios de Cohortes , Crisis HipertensivaRESUMEN
ABSTRACT: Targeted immunotherapy became the most advanced approach for cancer treatment. Programmed death-1 (PD-1) expressed on activated T cells can reverse immune suppression and cause T-cell activation. Nivolumab, a PD-1 immune checkpoint inhibitor antibody that is a fully human immunoglobulin G4, blocks PD-1 and promotes antitumor immunity. Cabozantinib (tyrosine kinase inhibitor) inhibits the tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3. As a result of enhancing immune response in normal tissues, immune-related adverse events can occur. Thyroid dysfunction is a common form of immune-related adverse event and seen on 18 F-FDG PET/CT scans post therapy.
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Anilidas , Carcinoma de Células Renales , Fluorodesoxiglucosa F18 , Inmunoterapia , Neoplasias Renales , Nivolumab , Tomografía Computarizada por Tomografía de Emisión de Positrones , Piridinas , Humanos , Nivolumab/efectos adversos , Anilidas/efectos adversos , Piridinas/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/diagnóstico por imagen , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/diagnóstico por imagen , Inmunoterapia/efectos adversos , Masculino , Enfermedades de la Tiroides/diagnóstico por imagen , Enfermedades de la Tiroides/inducido químicamente , Persona de Mediana EdadRESUMEN
BACKGROUND: Filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis. AIMS: The aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long-term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535). METHODS: In this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double-blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non-responders received open-label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health-related quality of life (HRQoL). We compared safety and efficacy between achievers and non-achievers of a multi-component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements. RESULTS: Data for completers (n = 250) and non-responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as-observed proportion of FIL200-treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non-responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid-free pMCS remission than non-achievers, up to LTE week 96. CONCLUSIONS: Filgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long-term benefit-risk profile. FIL200-treated CDC achievers had better long-term outcomes than non-achievers.
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Colitis Ulcerosa , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Método Doble Ciego , Resultado del Tratamiento , Estudios de Seguimiento , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.
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Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Piperazinas , Purinas , Piridinas , Receptor ErbB-2 , Receptores de Estrógenos , Humanos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Femenino , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Aminopiridinas/efectos adversos , Purinas/administración & dosificación , Purinas/efectos adversos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios Retrospectivos , Tailandia/epidemiología , Anciano , Receptor ErbB-2/metabolismo , Adulto , Receptores de Estrógenos/metabolismo , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/uso terapéutico , Receptores de Progesterona/metabolismo , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC). OBJECTIVE: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies. DESIGN, SETTING AND PARTICIPANTS: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany. INTERVENTIONS: Cabozantinib was administered as a standard of care. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized. RESULTS AND LIMITATIONS: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study. CONCLUSIONS: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.
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Anilidas , Carcinoma de Células Renales , Neoplasias Renales , Piridinas , Humanos , Anilidas/efectos adversos , Anilidas/administración & dosificación , Anilidas/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Masculino , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Femenino , Anciano , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Estudios Retrospectivos , Persona de Mediana Edad , Alemania/epidemiología , Anciano de 80 o más Años , Supervivencia sin Progresión , Adulto , Resultado del Tratamiento , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib. METHODS: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia. RESULTS: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed. CONCLUSION: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.
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Anilidas , Carcinoma de Células Renales , Glucuronosiltransferasa , Hiperbilirrubinemia , Indazoles , Neoplasias Renales , Piridinas , Pirimidinas , Sulfonamidas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Glucuronosiltransferasa/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Femenino , Persona de Mediana Edad , Hiperbilirrubinemia/inducido químicamente , Hiperbilirrubinemia/genética , Piridinas/uso terapéutico , Piridinas/efectos adversos , Anilidas/uso terapéutico , Anilidas/efectos adversos , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Indazoles/uso terapéutico , Anciano , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Axitinib/uso terapéutico , Axitinib/efectos adversos , Axitinib/administración & dosificación , Bilirrubina/sangre , Genotipo , Adulto , Polimorfismo Genético , Anciano de 80 o más AñosRESUMEN
Importance: Direct oral anticoagulants (DOACs), comprising apixaban, rivaroxaban, edoxaban, and dabigatran, are commonly used medications to treat patients with atrial fibrillation and venous thromboembolism. Decisions about how to manage DOACs in patients undergoing a surgical or nonsurgical procedure are important to decrease the risks of bleeding and thromboembolism. Observations: For elective surgical or nonsurgical procedures, a standardized approach to perioperative DOAC management involves classifying the risk of procedure-related bleeding as minimal (eg, minor dental or skin procedures), low to moderate (eg, cholecystectomy, inguinal hernia repair), or high risk (eg, major cancer or joint replacement procedures). For patients undergoing minimal bleeding risk procedures, DOACs may be continued, or if there is concern about excessive bleeding, DOACs may be discontinued on the day of the procedure. Patients undergoing a low to moderate bleeding risk procedure should typically discontinue DOACs 1 day before the operation and restart DOACs 1 day after. Patients undergoing a high bleeding risk procedure should stop DOACs 2 days prior to the operation and restart DOACs 2 days after. With this perioperative DOAC management strategy, rates of thromboembolism (0.2%-0.4%) and major bleeding (1%-2%) are low and delays or cancellations of surgical and nonsurgical procedures are infrequent. Patients taking DOACs who need emergent (<6 hours after presentation) or urgent surgical procedures (6-24 hours after presentation) experience bleeding rates up to 23% and thromboembolism as high as 11%. Laboratory testing to measure preoperative DOAC levels may be useful to determine whether patients should receive a DOAC reversal agent (eg, prothrombin complex concentrates, idarucizumab, or andexanet-α) prior to an emergent or urgent procedure. Conclusions and Relevance: When patients who are taking a DOAC require an elective surgical or nonsurgical procedure, standardized management protocols can be applied that do not require testing DOAC levels or heparin bridging. When patients taking a DOAC require an emergent, urgent, or semiurgent surgical procedure, anticoagulant reversal agents may be appropriate when DOAC levels are elevated or not available.
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Anticoagulantes , Reversión de la Anticoagulación , Pérdida de Sangre Quirúrgica , Atención Perioperativa , Hemorragia Posoperatoria , Humanos , Administración Oral , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/sangre , Fibrilación Atrial/tratamiento farmacológico , Atención Perioperativa/métodos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/sangre , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/sangre , Tromboembolia Venosa/tratamiento farmacológico , Dabigatrán/administración & dosificación , Dabigatrán/efectos adversos , Dabigatrán/sangre , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/sangre , Pérdida de Sangre Quirúrgica/prevención & control , Hemorragia Posoperatoria/inducido químicamente , Hemorragia Posoperatoria/epidemiología , Hemorragia Posoperatoria/prevención & control , Procedimientos Quirúrgicos Electivos/efectos adversos , Reversión de la Anticoagulación/métodosRESUMEN
Global epidemiological data show that the incidence of invasive fungal disease (IFD) has increased in recent decades, with the rising frequency of infections caused by Aspergillus and Mucorales order species. The number and variety of patients at risk of IFD has also expanded, owing in part to advances in the treatment of hematologic malignancies and other serious diseases, including hematopoietic stem cell transplantation (HCT) and other therapies causing immune suppression. Isavuconazonium sulfate (active moiety: isavuconazole) is an advanced-generation triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis that has demonstrated activity against a variety of yeasts, moulds, and dimorphic fungi. While real-world clinical experience with isavuconazole is sparse in some geographic regions, it has been shown to be effective and well tolerated in diverse patient populations, including those with multiple comorbidities who may have failed to respond to prior triazole antifungal therapy. Isavuconazole may be suitable for patients with IFD receiving concurrent QTc-prolonging therapy, as well as those on venetoclax or ruxolitinib. Data from clinical trials are not available to support the use of isavuconazole prophylactically for the prevention of IFD or for the treatment of endemic IFD, such as those caused by Histoplasma spp., but real-world evidence from case studies suggests that it has clinical utility in these settings. Isavuconazole is an option for patients at risk of IFD, particularly when the use of alternative antifungal therapies is not possible because of toxicities, pharmacokinetics, or drug interactions.
This article summarizes the epidemiology and risk factors for IFD, before focusing on the effectiveness and safety of the antifungal agent isavuconazole for treatment of invasive aspergillosis and mucormycosis, and its potential to prevent IFD in specific patient populations.
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Antifúngicos , Infecciones Fúngicas Invasoras , Nitrilos , Piridinas , Triazoles , Humanos , Nitrilos/uso terapéutico , Nitrilos/farmacología , Nitrilos/efectos adversos , Triazoles/uso terapéutico , Piridinas/uso terapéutico , Piridinas/efectos adversos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/prevención & control , Infecciones Fúngicas Invasoras/epidemiología , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Mucormicosis/tratamiento farmacológico , Mucormicosis/epidemiología , Salud Global , Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Aspergillus/efectos de los fármacos , Mucorales/efectos de los fármacosRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. CONCLUSION: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.
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Aminopiridinas , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Piperazinas , Inhibidores de Proteínas Quinasas , Purinas , Piridinas , Femenino , Humanos , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Aminopiridinas/efectos adversos , Antineoplásicos/efectos adversos , Bencimidazoles/efectos adversos , Estudios de Casos y Controles , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Farmacovigilancia , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Purinas/efectos adversos , Piridinas/efectos adversos , Estados Unidos/epidemiología , United States Food and Drug AdministrationRESUMEN
BACKGROUND: When considering changing hypnotic pharmacotherapy, lemborexant has attracted attention as a candidate due to its effectiveness and safety profile. However, few studies have investigated switching patterns in clinical practice. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using a nationwide claims database. Patients prescribed a single hypnotic who either subsequently switched to (switching cohort) or were additionally prescribed (add-on cohort) lemborexant between July 2020 and December 2021 were identified. Proportion of successful switching was defined as remaining on lemborexant alone or without any hypnotic at 6 months after lemborexant initiation. RESULTS: The success proportion was 70.1% in the switching cohort (n = 4,861) and 38.6% in the add-on cohort (n = 9,423). In the add-on cohort, the success proportion was lower in patients with a hypnotic history of ≥180 days (31.4%) and in patients whose prescribed hypnotic was a benzodiazepine or non-benzodiazepine (31.5% and 37.6%, respectively). CONCLUSION: The proportion of successful switching was higher in patients who switched to lemborexant than in those who added lemborexant as a concomitant treatment. The lower success proportion in the add-on cohort might be related to clinically more severe insomnia, and/or a concomitant prescription of benzodiazepine or non-benzodiazepine, from which discontinuation may be challenging.
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Bases de Datos Factuales , Hipnóticos y Sedantes , Pautas de la Práctica en Medicina , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Hipnóticos y Sedantes/uso terapéutico , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/efectos adversos , Anciano , Japón , Adulto , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Estudios de Cohortes , Quimioterapia Combinada , Sustitución de Medicamentos/estadística & datos numéricos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Adulto Joven , PirimidinasRESUMEN
BACKGROUNDS: Programmed death receptor 1 (PD-1) monoclonal antibody has been approved for the first and second-line treatments of hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of tislelizumab + regorafenib as a second-line treatment option for advanced HCC. METHODS: Treatment-related adverse events (TRAEs) were the primary endpoints in this clinical trial comprising 28 patients with advanced HCC. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). RESULTS: According to the mRECIST 1.1 evaluation criteria, the ORR was 28.6%. Complete and partial response were observed in 3 and 5 patients, respectively; stable disease was observed in 12 patients (DCR, 71.4%). The median PFS was 6.4 months. The incidence of grade 1-2 and 3-4 TRAEs was 57.1% and 39.3%, respectively. CONCLUSION: This study suggests that tislelizumab + regorafenib can be used as a second-line treatment for advanced HCC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Neoplasias Hepáticas , Compuestos de Fenilurea , Piridinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Estudios Prospectivos , Adulto , Resultado del TratamientoRESUMEN
OBJECTIVE: Elexacaftor/tezacaftor/ivacaftor (E/T/I) has provided life-changing pharmacotherapy for many people with cystic fibrosis (CF), but conflicting literature exists regarding the effect on mental health. While some reports suggest E/T/I may induce adverse psychiatric symptoms, others report improvements in mental health symptoms. To add to this growing body of knowledge, we retrospectively analyzed depression and anxiety symptoms before and after E/T/I initiation in adults with CF at a single large US CF center. METHOD: Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scores recorded in a database were studied. Patients with scores collected before and after E/T/I initiation were included. Regression analyses described associations between score changes and age, race, ethnicity, sex, CFTR variant, and prior depression and/or anxiety diagnoses. Secondary analyses examined possible confounding effects of the COVID-19 pandemic. RESULTS: There was no change in mean GAD-7 (0.5 ± 5.3, p = 0.41) or PHQ-9 (-0.02 ± 6.0, p = 0.97) scores following initiation of E/T/I (N = 86). A trend between a prior diagnosis of depression and worsening in PHQ-9 post-E/T/I was observed (OR 3.58; p = 0.054). CONCLUSIONS: Treatment with E/T/I does not lead to changes in depression or anxiety symptoms at the population level in this single center cohort study. A prior diagnosis of depression trended towards an increased odds of worsening PHQ-9 scores after E/T/I initiation.
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Aminofenoles , Ansiedad , Benzodioxoles , Fibrosis Quística , Depresión , Combinación de Medicamentos , Indoles , Pirazoles , Piridinas , Quinolonas , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/psicología , Masculino , Femenino , Benzodioxoles/uso terapéutico , Benzodioxoles/efectos adversos , Adulto , Estudios Retrospectivos , Aminofenoles/uso terapéutico , Quinolonas/uso terapéutico , Quinolonas/efectos adversos , Depresión/epidemiología , Depresión/psicología , Depresión/diagnóstico , Indoles/uso terapéutico , Indoles/efectos adversos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Ansiedad/epidemiología , Adulto Joven , Pirrolidinas/uso terapéutico , Pirrolidinas/efectos adversos , Agonistas de los Canales de Cloruro/uso terapéutico , SARS-CoV-2RESUMEN
BACKGROUND: The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC). METHODS: We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability. RESULTS: We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures. CONCLUSIONS: Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Metaanálisis en Red , Piridinas , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Piridinas/uso terapéutico , Piridinas/efectos adversos , Anilidas/uso terapéutico , Anilidas/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Ramucirumab , Resultado del Tratamiento , Supervivencia sin Progresión , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
PURPOSE: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with regorafenib (hereafter, TACE-regorafenib) or camrelizumab (hereafter, TACE-camrelizumab) for treating hepatocellular carcinoma (HCC) with untreatable progression after TACE and sorafenib therapy. METHODS: The medical records of patients with HCC who received TACE-regorafenib or TACE-camrelizumab between September 2018 and December 2023 were retrospectively evaluated. Therapeutic response, overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared between the two groups. RESULTS: A total of 76 patients were enrolled in this study, with 41 and 35 patients in the TACE-regorafenib and TACE-camrelizumab groups, respectively. The objective response rates in the TACE-regorafenib and TACE-camrelizumab groups were 9.8% and 8.6%, respectively, with no statistically significant difference between the two groups (P = 0.859). Similarly, there was no statistically significant difference in disease control rates between the two groups (61.0% vs 68.6%, P = 0.838). The median OS was 11 months in the TACE-regorafenib group and 10 months in the TACE-camrelizumab group, with no significant difference between the two groups (P = 0.348). The TACE-regorafenib group had a median PFS of 7 months, which was significantly longer than that of the TACE-camrelizumab group (4 months, P = 0.004). There was no significant difference in the incidence of AEs between the two groups (P = 0.544). CONCLUSIONS: TACE-regorafenib was safe, well-tolerated, and showed promising efficacy in patients with sorafenib-refractory advanced HCC, whereas TACE-camrelizumab demonstrated similar survival benefits.
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Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Compuestos de Fenilurea , Piridinas , Sorafenib , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Quimioembolización Terapéutica/métodos , Quimioembolización Terapéutica/efectos adversos , Sorafenib/uso terapéutico , Sorafenib/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Estudios Retrospectivos , Estudios de Casos y Controles , Anciano , Terapia Combinada , Progresión de la Enfermedad , Resultado del Tratamiento , AdultoRESUMEN
BACKGROUND: The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines. METHODS: Patients with CRC in the Optum's de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group. RESULTS: 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% (n = 66/310) to 45% (n = 178/393), the proportion who received standard dosing decreased from 79% (n = 244/310) to 55% (n = 215/393), the proportion who initiated their third treatment cycle increased from 36% (n = 113/310) to 46% (n = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1). CONCLUSIONS: Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib.
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Neoplasias Colorrectales , Compuestos de Fenilurea , Piridinas , Humanos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Anciano , Estados Unidos , Metástasis de la Neoplasia , Resultado del Tratamiento , Relación Dosis-Respuesta a Droga , AdultoRESUMEN
PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
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Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Ipilimumab , Nivolumab , Piridinas , Neoplasias Urogenitales , Humanos , Masculino , Anilidas/uso terapéutico , Anilidas/efectos adversos , Ipilimumab/uso terapéutico , Ipilimumab/efectos adversos , Ipilimumab/administración & dosificación , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Persona de Mediana Edad , Anciano , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Neoplasias Urogenitales/tratamiento farmacológico , Neoplasias Urogenitales/patología , Anciano de 80 o más Años , Supervivencia sin ProgresiónRESUMEN
INTRODUCTION: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disease caused by aberrant DUX4 expression, leading to progressive muscle weakness. No effective pharmaceutical treatment is available. Losmapimod, a small molecule selective inhibitor of p38 α/ß MAPK, showed promising results in a phase 1 trial for the treatment of FSHD, prompting additional studies. We report the findings of an open-label phase 2 trial (NCT04004000) investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of losmapimod in participants with FSHD1. METHODS: This study was conducted at a single site in the Netherlands from August 2019 to March 2021, with an optional, ongoing open-label extension. Participants aged 18 to 65 years with FSHD1 took 15 mg of losmapimod twice daily for 52 weeks. Primary endpoints were measures of losmapimod safety and tolerability. Secondary endpoints were assessments of losmapimod pharmacokinetics and pharmacodynamics. RESULTS: Fourteen participants were enrolled. No deaths, serious treatment-emergent adverse events (TEAEs), or discontinuations due to TEAEs were reported. Losmapimod achieved blood concentrations and target engagements that were previously associated with decreased DUX4 expression in vitro. Clinical outcome measures showed a trend toward stabilization or improvement. CONCLUSIONS: Losmapimod was well tolerated and may be a promising new treatment for FSHD; a larger phase 3 study is ongoing.