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1.
N Engl J Med ; 382(3): 244-255, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31893580

RESUMO

BACKGROUND: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS: APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Lipoproteína(a)/sangue , Oligonucleotídeos/administração & dosagem , Adulto , Idoso , Doenças Cardiovasculares/sangue , Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Fatores de Risco
2.
N Engl J Med ; 381(6): 531-542, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31390500

RESUMO

BACKGROUND: Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. METHODS: We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. RESULTS: Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began. CONCLUSIONS: Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Hiperlipoproteinemia Tipo I/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , RNA Mensageiro/antagonistas & inibidores , Trombocitopenia/induzido quimicamente , Triglicerídeos/sangue , Adulto , Idoso , Análise de Variância , Apolipoproteína C-III/sangue , Apolipoproteína C-III/genética , Método Duplo-Cego , Feminino , Humanos , Hiperlipoproteinemia Tipo I/sangue , Injeções Subcutâneas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Contagem de Plaquetas , Adulto Jovem
3.
Expert Rev Clin Pharmacol ; 12(8): 701-711, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268366

RESUMO

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Polineuropatias/tratamento farmacológico , Adulto , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Animais , Humanos , Mutação , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Polineuropatias/etiologia , Pré-Albumina/genética , Qualidade de Vida
4.
Drugs ; 79(12): 1349-1354, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31301033

RESUMO

Volanesorsen (Waylivra®), an antisense oligonucleotide inhibitor of apolipoprotein CIII (apoCIII) mRNA, is being developed by Ionis Pharmaceuticals through its subsidiary company, Akcea Therapeutics, to treat familial chylomicronemia syndrome (FCS), hypertriglyceridemia and familial partial lipodystrophy (FPL). In May 2019, volanesorsen was approved in the EU for the treatment of adult patients with FCS based on positive results from the multinational, phase III APPROACH and COMPASS studies. Other clinical trials are ongoing to assess its utility in hypertriglyceridemia, FPL and partial lipodystrophy. This article summarizes the milestones in the development of volanesorsen leading to this first approval as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Apolipoproteína C-III/genética , Apolipoproteína C-III/metabolismo , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Europa (Continente) , Humanos , Hiperlipoproteinemia Tipo I/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Lipodistrofia Parcial Familiar/tratamento farmacológico , Lipodistrofia Parcial Familiar/genética , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos
6.
Drugs ; 79(7): 751-766, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989634

RESUMO

AIM: Our aim was to assess the efficacy and safety of mipomersen through a systematic review of the literature and a meta-analysis of the available clinical studies. METHODS: A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to January 20, 2019, in order to identify clinical trials assessing the effect of mipomersen on lipoproteins, and the safety profile of mipomersen. Effect sizes for lipid changes were expressed as weighted mean differences (WMD) and 95% confidence intervals (CI). For safety analysis, odd ratios (OR) and 95% CI were calculated using the Mantel-Haenszel method. Data were pooled from 13 clinical studies comprising 49 arms, which included 1053 subjects overall, with 729 in the active-treated arm and 324 in the control arm. RESULTS: Meta-analysis of data suggested that mipomersen significantly reduced low-density lipoprotein cholesterol (WMD - 1.52, 95% CI - 1.85 to - 1.19; p < 0.001), total cholesterol (WMD - 1.55, 95% CI - 1.97 to - 1.13; p < 0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (WMD - 1.66, 95% CI - 2.06 to - 1.27; p < 0.001), lipoprotein(a) (WMD - 0.99, 95% CI - 1.37 to - 0.62; p < 0.001), apolipoprotein B (WMD - 1.66, 95% CI - 2.04 to - 1.27; p < 0.001), triglycerides (WMD -0.61, 95% CI - 0.76 to - 0.46, p < 0.001), very-low-density lipoprotein cholesterol (WMD - 0.58, 95% CI - 0.73 to - 0.43; p < 0.001) and apolipoprotein A-I (WMD - 0.25, 95% CI - 0.51 to - 0.001; p = 0.049) without affecting HDL-C levels (WMD 0.11, 95% CI - 0.03 to 0.26; p = 0.124). However, treatment with mipomersen was positively associated with an increased risk of discontinuation of treatment (OR 3.02, 95% CI 1.96-4.65; p < 0.001), injection-site reaction (OR 11.41, 95% CI 7.88-16.52; p < 0.001), hepatic steatosis (OR 4.96, 95% CI 1.99-12.39; p = 0.001), hepatic enzymes elevation (OR 3.61, 95% CI 2.09-6.24; p < 0.001) and flu-like symptoms (OR 2.02, 95% CI 1.45-2.81; p < 0.001). CONCLUSION: Despite favourable effects on the lipid profile, some concerns are reinforced from the safety profile. As a matter of fact, mipomersen therapy is more likely discontinued and associated with increased risk of injection-site reactions, hepatic steatosis, hepatic enzyme elevation, and flu-like symptoms.


Assuntos
Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/metabolismo , LDL-Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Feminino , Humanos , Lipídeos , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triglicerídeos/metabolismo
7.
Expert Opin Investig Drugs ; 28(4): 389-394, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30753100

RESUMO

INTRODUCTION: Despite the substantial reduction in cardiovascular morbidity and mortality after the management of dyslipidemia with statins, residual risk remains even after achieving low-density lipoprotein cholesterol targets. This residual risk appears to be partly attributed to low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides (TG). Apolipoprotein C3 (APOC3) is a key regulator of TG metabolism and its targeting may reduce TG levels and cardiovascular risk. AREAS COVERED: We discuss APOC3-targeted experimental treatments for dyslipidemia. There is an emphasis on volanesorsen because it the agent in the most advanced stage of development. M580, a retinoic acid receptor-α specific agonist, an agent in early-stage development is briefly covered. Preclinical data suggest that this agent decreases APOC3 mRNA levels and reduces total cholesterol, TG levels and hepatic lipid accumulation. EXPERT OPINION: The effects of this novel therapeutic approach on cardiovascular morbidity and mortality should be determined in randomized controlled trials. The cost of volanesorsen, the unfavorable safety profile and the need for subcutaneous administration present barriers to long-term use. AM580 may hold promise in the management of hypertriglyceridemia but further investigations are necessary to evaluate safety and efficacy.


Assuntos
Apolipoproteína C-III/metabolismo , Hiperlipidemias/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Animais , Apolipoproteína C-III/genética , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/fisiopatologia , Humanos , Hiperlipidemias/fisiopatologia , Lipídeos/sangue , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , RNA Mensageiro/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos/sangue
8.
Neurol Sci ; 40(2): 327-332, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30430317

RESUMO

Nusinsersen is now available in Italy for all SMA types. We describe the experience with intrathecal treatment with nusinersen in 50 patients with SMA at the NEMO Center (NEuroMuscular Omniservice Clinical Center) in Milan, a neuromuscular patient-centered clinic hosted within Niguarda Hospital, a National Public General Hospital. Our results indicate that the pathway of care described outweighs the burden due to the repeated intrathecal injections. Irrespective of age and severity, the treatment is feasible, accessible, and replicable provided that there is a multidisciplinary team having experience and training in SMA.


Assuntos
Prestação Integrada de Cuidados de Saúde , Atrofia Muscular Espinal/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Oligonucleotídeos/administração & dosagem , Adolescente , Criança , Pré-Escolar , Prestação Integrada de Cuidados de Saúde/métodos , Família , Geografia Médica , Humanos , Lactente , Injeções Espinhais , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/diagnóstico , Fármacos Neuroprotetores/efeitos adversos , Oligonucleotídeos/efeitos adversos , Equipe de Assistência ao Paciente , Pacientes Desistentes do Tratamento , Escoliose/complicações , Escoliose/diagnóstico por imagem , Punção Espinal , Coluna Vertebral/diagnóstico por imagem
9.
Eur J Pediatr ; 178(2): 253-258, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30448867

RESUMO

A retrospective study in which we reviewed the hospital files of a subset of 7 patients with Duchenne muscular dystrophy participating in the open-label phase I/II PRO051-02 study in Leuven. The objective of this study was to describe in detail the injection site reactions in these children treated with drisapersen (PRO-051), a 2'-O-methyl phosphorothioate RNA antisense oligonucleotide, that induces exon 51 skipping in Duchenne muscular dystrophy. Antisense oligonucleotides, restoring the reading frame by skipping of exons, have become a potential treatment of Duchenne muscular dystrophy and other monogenetic diseases. Erythema followed by hyperpigmentation, fibrosis, and calcification were seen at the injection sites in all children. Ulcerations, which were difficult to heal, occurred in 5 of 7 children. Progression still occurred after switching to intravenous administration of drisapersen or even after stopping therapy. Systemic reactions included a reversible proteinuria and α1-microglobulinuria. Moreover, hypotrichosis was a common feature.Conclusion: Subcutaneous administration of drisapersen causes severe and progressive injection site effects. What is known: • Antisense oligonucleotides offer the possibility to convert Duchenne muscular dystrophy to the less severe Becker type. This can potentially be achieved by targeting and skipping specific exons of the Duchenne muscular dystrophy gene to restore the disrupted reading frame and to induce the production of a semi functional dystrophin protein. • Drisapersen is such an antisense oligonucleotides which can be administered subcutaneously. Its use has been tested extensively in the escalating dose pilot study (PRO051-02). What is new: • This report describes the injection site reactions caused by this type of agent in detail which has never been done before. We therefore reviewed the hospital files of 7 patients with Duchenne muscular dystrophy participating in the phase I/II open-label, escalating dose pilot study (PRO051-02) with drisapersen. • Severe side effects starting with erythema, hyperpigmentation, and later fibrosis, calcification, and difficult to treat ulcerations developed in all patients, and these continued to progress even after cessation of drisapersen. We discuss some possible underlying mechanisms. The exact mechanism however is still not known.


Assuntos
Reação no Local da Injeção/epidemiologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos/efeitos adversos , Criança , Humanos , Reação no Local da Injeção/etiologia , Injeções Subcutâneas/efeitos adversos , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos Antissenso/administração & dosagem , Projetos Piloto , Estudos Retrospectivos
10.
J Neuromuscul Dis ; 6(1): 119-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30594933

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle loss. In December 2016 the FDA approved the first and only treatment drug for SMA: Spinraza (nusinersen). Despite excitement and optimism, there are no published data on the perceptions of individuals with SMA and their families about the benefits, risks, and challenges associated with treatment. OBJECTIVE: This qualitative interview study sought to characterize the perspectives of patients/families with SMA who did not want, or were unsure about, receiving this new innovative treatment for a previously untreatable and often fatal condition. METHODS: Individuals and families were recruited via advertisements on Facebook groups related to SMA and through the Stanford Neuromuscular Contact Registry. Participants completed a demographic questionnaire and participated in a semi-structured interview via voice conferencing. Interview questions focused on: 1) experiences with SMA, 2) opinions about Spinraza treatment, and 3) factors considered in decisions regarding treatment. RESULTS: Thirteen people were interviewed: ten adults with SMA (ages 27-48, nine with Type II) and three parents of minor children with SMA (one each of Types I, II and III). Qualitative content analysis identified a range of opinions about Spinraza treatment: five were uninterested (2 adults, 3 parents), four adults were still deciding whether to pursue treatment, three adults were interested or in the process of pursuing treatment, and one adult was currently receiving the drug after overcoming significant reluctance. Participants described several key factors influencing their treatment decisions, including: concerns about risk factors and side effects, high cost, insurance coverage, time involvement, and lack of data about efficacy. Participants reported learning about most of these factors through parent/patient testimonials on SMA-specific social media groups. CONCLUSIONS: Participants reported basing decisions about pursuing Spinraza on a variety of practical and value-based considerations. They described carefully weighing the perceived potential benefits and risks of treatment through the lens of their current quality of life and prognosis. These findings suggest that providers should be aware that some patients and parents, especially those with Types II-IV, may approach treatment decisions differently than parents of children with SMA I. Informed treatment decisions can be supported through: 1) the collection and dissemination of better data on Spinraza treatment in these populations; 2) clear communication about risks, side effects and eligibility; 3) improved access to payment and treatment facilities; and 4) facilitation of discussions between providers and patients/families about identity and disability in the context of goals of care and other life and support challenges.


Assuntos
Atrofia Muscular Espinal/psicologia , Atrofia Muscular Espinal/terapia , Oligonucleotídeos/uso terapêutico , Adulto , Cuidadores/psicologia , Tomada de Decisões , Feminino , Terapia Genética/economia , Terapia Genética/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/economia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/economia , Pais/psicologia , Pesquisa Qualitativa , Medição de Risco , Adulto Jovem
11.
Orphanet J Rare Dis ; 13(1): 96, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925433

RESUMO

BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. METHODS: We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). RESULTS: Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) - equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. CONCLUSIONS: Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. TRIAL REGISTRATION: NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).


Assuntos
Benzimidazóis/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Benzimidazóis/efeitos adversos , LDL-Colesterol/sangue , Ponte de Artéria Coronária , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/uso terapêutico
12.
Eur J Endocrinol ; 179(2): 97-108, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29789410

RESUMO

OBJECTIVE: ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. DESIGN: Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. METHODS: The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. RESULTS AND CONCLUSIONS: Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.


Assuntos
Oligonucleotídeos Antissenso , Oligonucleotídeos/uso terapêutico , Receptores da Somatotropina/genética , Acromegalia/tratamento farmacológico , Adulto , Idoso , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , RNA Mensageiro/antagonistas & inibidores , Receptores da Somatotropina/antagonistas & inibidores , Resultado do Tratamento
13.
Br J Cancer ; 118(11): 1434-1441, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29765151

RESUMO

BACKGROUND: A randomised study to assess the addition of apatorsen, an antisense oligonucleotide that inhibits Hsp27 expression, to docetaxel in patients with metastatic urothelial carcinoma (mUC) relapsed after prior platinum-based chemotherapy. METHODS: Multicentre, phase II study with 1:1 randomisation to apatorsen (three loading doses at 600 mg intravenous followed by weekly doses) plus docetaxel (75 mg/m2 intravenous every 21 days) (A/D) or docetaxel alone. Overall survival (OS) was the primary end point with a P value <0.1 (one-sided) being positive. Progression-free survival (PFS), objective response rate (ORR), safety, and effect of Hsp27 levels on outcomes were secondary end points. RESULTS: Patients randomised to A/D (n = 99) had improved OS compared to docetaxel alone (n = 101): HR: 0.80, 80% CI: 0.65-0.98, P = 0.0784, median 6.4 vs 5.9 months. PFS and ORR were similar in both arms. A/D had more incidence of sepsis and urinary tract infections. Patients with baseline Hsp27 levels <5.7 ng/mL had improved OS compared to those with levels ≥5.7 ng/mL. Patients with a decline or ≤20.5% increase in Hsp27 from baseline benefited more from A/D than those with >20.5% increase. CONCLUSIONS: A/D met its predefined OS end point in patients with platinum-refractory mUC in this phase II trial. This trial is hypothesis generating requiring further study before informing practice.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Docetaxel/administração & dosagem , Proteínas de Choque Térmico HSP27/metabolismo , Oligonucleotídeos/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/metabolismo , Docetaxel/efeitos adversos , Regulação para Baixo , Esquema de Medicação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Recidiva , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Urológicas/metabolismo
14.
Biomacromolecules ; 19(7): 2535-2541, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29698604

RESUMO

The recently developed synthetic oligonucleotides referred to as "click" nucleic acids (CNAs) are promising due to their relatively simple synthesis based on thiol-X reactions with numerous potential applications in biotechnology, biodetection, gene silencing, and drug delivery. Here, the cytocompatibility and cellular uptake of rhodamine tagged, PEGylated CNA copolymers (PEG-CNA-RHO) were evaluated. NIH 3T3 fibroblast cells treated for 1 h with 1, 10, or 100 µg/mL PEG-CNA-RHO maintained an average cell viability of 86%, which was not significantly different from the untreated control. Cellular uptake of PEG-CNA-RHO was detected within 30 s, and the amount internalized increased over the course of 1 h. Moreover, these copolymers were internalized within cells to a higher degree than controls consisting of either rhodamine tagged PEG or the rhodamine alone. Uptake was not affected by temperature (i.e., 4 or 37 °C), suggesting a passive uptake mechanism. Subcellular colocalization analysis failed to indicate significant correlations between the internalized PEG-CNA-RHO and the organelles examined (mitochondria, endoplasmic reticulum, endosomes and lysosomes). These results indicate that CNA copolymers are cytocompatible and are readily internalized by cells, supporting the idea that CNAs are a promising alternative to DNA in antisense therapy applications.


Assuntos
Oligonucleotídeos/química , Polietilenoglicóis/química , Células 3T3 , Animais , Endocitose , Camundongos , Oligonucleotídeos/efeitos adversos , Organelas/metabolismo
15.
N Engl J Med ; 378(7): 625-635, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29443664

RESUMO

BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. RESULTS: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .).


Assuntos
Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Idade de Início , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Injeções Espinhais , Análise dos Mínimos Quadrados , Masculino , Destreza Motora , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/efeitos adversos , Atrofias Musculares Espinais da Infância/fisiopatologia
17.
Rev Cardiovasc Med ; 19(1): 13-19, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31032598

RESUMO

Diabetic dyslipidemia in type 2 diabetes (T2DM) is characterized by elevated levels of triglycerides (TG), decreased levels of high density lipoprotein-cholesterol (HDL-C), elevated levels of low density lipoprotein-cholesterol (LDLC), and the predominance of small and dense LDL particles (sdLDL). The mechanism underlying diabetic dyslipidemia remains unclear. Insulin resistance is believed to be an important determinant. Mechanisms underlying insulin resistance-induced diabetic dyslipidemia seem to be related to apolipoprotein CIII (ApoCIII), a known inhibitor of lipoprotein lipase. The concentration of very low density lipoprotein1 (VLDL1) with a higher TG content and abundant ApoCIII was found to be significantly elevated in patients with T2DM. Recently, volanesorsen as a promising ApoIII inhibitor was shown to improve the lipid profile in patients with diabetic dyslipidemia. Herein, this paper will review recent advance in pathophysiology of diabetic dyslipidemia and the role of ApoCIII in this condition, with focus on describing a novel drug volanesorsen as potential treatment strategy.


Assuntos
Apolipoproteína C-III/sangue , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Oligonucleotídeos/uso terapêutico , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/etiologia , Humanos , Hipolipemiantes/efeitos adversos , Resistência à Insulina , Oligonucleotídeos/efeitos adversos , Resultado do Tratamento
18.
Neuromuscul Disord ; 28(1): 4-15, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29203355

RESUMO

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.


Assuntos
Distrofia Muscular de Duchenne/terapia , Oligonucleotídeos/uso terapêutico , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Masculino , Atividade Motora , Distrofia Muscular de Duchenne/sangue , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/metabolismo , Resultado do Tratamento
19.
Gastrointest Endosc ; 87(4): 1126-1131, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29122598

RESUMO

BACKGROUND AND AIMS: Carbohydrate sulfotransferase 15 (CHST15) promotes tumor growth and invasion and is considered to be an emergent therapeutic target for pancreatic cancer. The aim of this study was to evaluate the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, the double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer. METHODS: Six patients with unresectable pancreatic cancer, treated at Tokyo Metropolitan Geriatric Hospital, were used in this open-labeled, investigator-initiated trial. A total of 16 mL STNM01 (250 nM) was injected into the tumor through EUS-FNI. The study's primary endpoint was safety, with a secondary endpoint of tumor response 4 weeks after the initial injection. Some patients received a series of infusions as extensions. The local expression of CHST15 and overall survival (OS) were also evaluated. RESULTS: There were no adverse events. The mean tumor diameter changed from 30.7 to 29.3 mm 4 weeks after injection. Four patients exhibited necrosis of tumor in biopsy specimens. CHST15 was highly expressed at baseline, with 2 patients showing large reductions of CHST15 at week 4. The mean OS of these 2 patients was 15 months, whereas it was 5.7 months for the other 4 patients. CONCLUSIONS: EUS-FNI of STNM01 in pancreatic cancer is safe and feasible. The CHST15 reduction could predict tumor progression and OS. Injections of STNM01 during the beginning of treatment may reduce CHST15 and warrants further investigation.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Oligonucleotídeos/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Endossonografia , Feminino , Humanos , Injeções Intralesionais , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Necrose , Oligonucleotídeos/efeitos adversos , Sulfotransferases/antagonistas & inibidores , Sulfotransferases/metabolismo , Taxa de Sobrevida , Carga Tumoral , Ultrassonografia de Intervenção
20.
Clin Pharmacol Ther ; 104(2): 335-345, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29134633

RESUMO

Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase I clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung. In healthy volunteers, AZD1419 was found to be safe and well-tolerated. Target engagement in the lung was demonstrated at all dose levels tested. No evidence of tolerization or amplification of responses was evident on repeated dosing and 15.4 mg was defined as the maximum tolerated dose. AZD1419 clinical data supports its continued development as a potentially disease-modifying therapeutic in asthma.


Assuntos
Antiasmáticos/administração & dosagem , Interferon Tipo I/metabolismo , Pulmão/efeitos dos fármacos , Oligonucleotídeos/administração & dosagem , Células Th2/efeitos dos fármacos , Receptor Toll-Like 9/agonistas , Administração por Inalação , Adolescente , Adulto , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacocinética , Células Cultivadas , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Macaca fascicularis , Masculino , Dose Máxima Tolerável , Camundongos , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Medição de Risco , Células Th2/imunologia , Células Th2/metabolismo , Receptor Toll-Like 9/metabolismo , Regulação para Cima , Adulto Jovem
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