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BACKGROUND: Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking. METHODS: We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed. RESULTS: In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation. CONCLUSIONS: Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).
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Apolipoproteína L1 , Glomerulosclerose Segmentar e Focal , Proteinúria , Animais , Humanos , Camundongos , Apolipoproteína L1/antagonistas & inibidores , Apolipoproteína L1/genética , Apolipoproteínas/genética , Negro ou Afro-Americano , Creatinina/urina , Mutação com Ganho de Função , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/genética , Células HEK293 , Proteinúria/tratamento farmacológico , Proteinúria/genéticaRESUMO
BACKGROUND: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. OBJECTIVE: To evaluate infections over 6 years in alemtuzumab-treated patients. METHODS: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 µg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. RESULTS: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. CONCLUSION: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.
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Alemtuzumab/efeitos adversos , Alemtuzumab/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Suscetibilidade a Doenças , Feminino , Humanos , Infecções , Interferon beta-1a/administração & dosagem , Masculino , Recidiva , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. METHODS: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. RESULTS: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. CONCLUSION: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. CLINICALTRIALSGOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553.
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OBJECTIVES: This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (alpha-LNA), safely reduced symptom severity in youth with bipolar disorder. METHODS: Children and adolescents aged 6-17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg alpha-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses. RESULTS: There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician-rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: %alpha-LNA (r = -0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = -0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for alpha-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for alpha-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms. CONCLUSIONS: Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n-6 levels, individual variations in conversion of alpha-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone.
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Transtorno Bipolar/tratamento farmacológico , Óleo de Semente do Linho/metabolismo , Óleo de Semente do Linho/uso terapêutico , Ácido alfa-Linolênico/uso terapêutico , Adolescente , Ácido Araquidônico/sangue , Transtorno Bipolar/psicologia , Criança , Depressão/tratamento farmacológico , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Insaturados/sangue , Feminino , Humanos , Óleo de Semente do Linho/efeitos adversos , Masculino , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Ácido alfa-Linolênico/efeitos adversosRESUMO
OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy. METHODS: In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed. RESULTS: Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, -0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter. CONCLUSIONS: Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Alemtuzumab , Anticorpos Monoclonais Humanizados/efeitos adversos , Atrofia/diagnóstico por imagem , Atrofia/prevenção & controle , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Avaliação da Deficiência , Seguimentos , Humanos , Fatores Imunológicos/efeitos adversos , Estimativa de Kaplan-Meier , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Tamanho do Órgão , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Pediatric obesity (body mass index [BMI] > or = 95th percentile for sex and age) and overweight (BMI > or = 85th percentile < 95% percentile) are priority public health targets for the prevention of diabetes and cardiovascular disease. We examined the prevalence and risk of overweight and obesity in adolescents with serious mental disorders. METHOD: Height, weight, demographic, diagnostic, and treatment data were reviewed for 114 adolescents attending a partial hospitalization program over 18 consecutive months between January 2003 and July 2004. Sample data were compared to normative National Health and Nutrition Examination Survey data and regional county data for BMI. Unadjusted odds ratios and their 95% CIs were calculated for each categorical risk factor using the chi-squared test. A logistic regression model was conducted to detect the effects of these risk factors on the occurrence of overweight and obesity. RESULTS: The combined prevalence of overweight and obesity was 55.4% (n = 63); the prevalence for obesity alone was 30% (n = 34), approximately double the rate in national and county norms. Lack of private insurance, smoking, and antidepressant and antipsychotic treatment were associated with overweight and obese status. CONCLUSIONS: Adolescents with severe mental illness are at increased risk for overweight and obesity. Identification of elevated BMI, associated risk factors, and efforts to prevent weight gain should begin at initiation of mental health treatment.