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1.
N Engl J Med ; 369(9): 819-29, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23984729

RESUMO

BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).


Assuntos
Neuropatias Amiloides Familiares/terapia , Pré-Albumina/genética , RNA Interferente Pequeno/uso terapêutico , Adolescente , Adulto , Neuropatias Amiloides Familiares/genética , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Lipossomos , Macaca fascicularis , Masculino , Nanocápsulas , Pré-Albumina/metabolismo , RNA Interferente Pequeno/administração & dosagem , Adulto Jovem
2.
Br J Clin Pharmacol ; 76(2): 164-72, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23438102

RESUMO

Many monoclonal antibodies (MAbs) have been studied in healthy volunteers in phase 1, but few data have been published on the safety of that practice. We aimed to review the available data, and thereby to estimate the risks of participation in phase 1trials of MAbs. We searched PubMed, the ClinicalTrials.gov database and Google, using the search terms 'monoclonal antibody', 'phase 1' and 'healthy volunteers'. We identified 70 completed trials of MAbs in healthy volunteers, but the published data were too sparse to allow confident assessment of the risks of MAbs in healthy volunteers. Our best estimate of risk of a life-threatening adverse event was between 1: 425 and 1: 1700 volunteer-trials, but all such events occurred in a single trial (of TGN1412). In a phase 1trial of a small molecule, the risk of death or a life-threatening adverse event appears to be 1: 100,000-1,000,000 volunteer-trials, which is similar to the risk of many ordinary daily activities. Most people would consider that level of risk to be 'minimal' or 'negligible' and, therefore, acceptable. On that basis, the safety record of MAbs in healthy volunteers has been ruined by the TGN1412 disaster. However, that experience is unlikely to be repeated, because of improvements in governance and practice of phase 1trials. If the experience of TGN1412 is disregarded, it seems reasonable to continue using healthy volunteers in phase 1trials of MAbs, provided that there are scientific and medical reasons to conclude that the risk is truly minimal.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Avaliação Pré-Clínica de Medicamentos/métodos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Ensaios Clínicos como Assunto , Ensaios Clínicos Fase I como Assunto , Voluntários Saudáveis , Humanos , Fatores de Risco
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