MIME-Version: 1.0 Content-Type: multipart/related; boundary="----=_NextPart_01CBA43C.3882CB80" This document is a Single File Web Page, also known as a Web Archive file. If you are seeing this message, your browser or editor doesn't support Web Archive files. Please download a browser that supports Web Archive, such as Microsoft Internet Explorer. ------=_NextPart_01CBA43C.3882CB80 Content-Location: file:///C:/71486902/Mipomersen-rus-web.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="us-ascii" Эффективнl= 6;сть и безопасносm= 0;ь мипомерсенk= 2; -

Мип&= #1086;мерсен – некоторые результаты клиническоk= 5;о изучения<= /b>

Мипl= 6;мерсен – первый представитk= 7;ль класса ингибитороk= 4; синтеза апо-В, находящийсn= 3; в настоящее время на поздней стадии развития. Он предназначk= 7;н для снижени = 03; уровней хол = 77;стерина липопротеиl= 5;ов низкой плот = 85;ости (ХСЛНП) путём предупреждk= 7;ния образованиn= 3; атерогенныm= 3; липидов. Мип= 086;мерсен действует, уменьшая продукцию апо-В, состав&#= 1083;яющих структурноk= 7; ядро всех атерогенныm= 3; липидов, переносящиm= 3; холестерин = 74; кровотоке, включая ХС ЛНП. Потенци= 072;льно способен действоватn= 0; у больных семейной гомозиготнl= 6;й гиперхолисm= 0;еринемией (рис.1)

Рис. 1.<= /p>

 

Приk= 4;одим краткое изложение доступных д = 72;нных о крупных клиническиm= 3; исследованl= 0;ях мипомерсенk= 2;.

 

Эффе= ;ктивность и безопасносm= 0;ь мипомерсенk= 2; - антисмыслоk= 4;ого (antisense) ингибитора аполипопроm= 0;еина В у людей с гиперхолесm= 0;еринемией, получающих стабильную терапию статинами. 1

&#= 1052;ипомерсен - ингибитор синтеза аполипопроm= 0;еина В - для снижен&= #1080;я концентрацl= 0;и холестеринk= 2; ЛНП у пациен= 090;ов с гомозиготнl= 6;й семейной гиперхолесm= 0;еринемией: рандомизирl= 6;ванное, двойное сле = 87;ое плацебо контролироk= 4;анное плацебо исп = 99;тание  <= !--[if supportFields]>= PAGEREF _Toc281041295 \h 2

&#= 1044;ругие испытания мипомерсенk= 2;. 5

&#= 1048;сследовани= е при тяжелой гиперхолесm= 0;еринемии. 5

&#= 1048;сследовани= е у пациентов = 089; гиперхолесm= 0;еринемией и высоким риском разв = 80;тия коронарной болезни сердца. 6

&#= 1048;сточники. 6

 

Эффект= 080;вность и безопасносm= 0;ь мипомерсенk= 2; -
антисмыслоk= 4;ого (antisense) ингибитор= а аполипопроm= 0;еина В
у людей с гиперхолесm= 0;еринемией,
получающих стабильную терапию статинами.

 

Efficacy and Safety of Mipomersen, an Antisense Inhibitor of Apolipoprotein B, in Hypercholesterolemic Subjects Receiving Stable Statin Therapy<= o:p>

Ре= ;зюме публикации [1]<= o:p>

«Цели.

Цель этого исследованl= 0;я оценить эффективноl= 9;ть и безопасносm= 0;ь мипомерсенk= 2; у людей с гиперхолесm= 0;еинемией, принимающиm= 3; получающих стабильную терапию статинами.

Пр= ;едпосылки.

Мипомерl= 9;ен - ингибитор синтеза аполипопроm= 0;еина В, вызвавший существеннl= 6;е снижение Ап = 86; В и холестеринk= 2; липопротеи&#= 1085;ов низкой плотности у здоровых добровольцk= 7;в в клиническиm= 3; испытаниях первой фазы.

Ме= ;тоды.

Рандомиk= 9;ированное контролироk= 4;анное плацебо исследованl= 0;е второй фазы = 089; повышением доз препарата было спланироваl= 5;о, чтобы оценить действие эффекты мипомерсенk= 2; у людей с гиперхолесm= 0;еринемией, получающих стабильную терапию статинами.

Пациентm= 9; (n=3D74) были последоватk= 7;льно включены в одну из 6 когорт с разными дозами в отношении 4:1 (активный препарат/пл = 72;цебо). В первых 5 когортах па = 94;иенты получили 7 доз от 30 до 400 мг в течение 5 недель. Пациенты 6-й когорты пол = 91;чили 15 доз по 200 мг в течение 13 недель. Заранее определённm= 9;ми конечными точками был = 80; изменения Апо В и холестеринk= 2; ЛНП в процен= 090;ах от исходног = 86;. Безопасносm= 0;ь оцениваласn= 0; по результатаl= 4; лабораторнm= 9;х тестов и тяжести нежелательl= 5;ых событий.

Ре= ;зультаты.

Апо В и холестерин ЛНП были снижены соответствk= 7;нно на 19-54% и 21-52% при дозах мипомерсенk= 2; 100 мг/нед и более в когортах, в которых леч = 77;ние осуществляl= 3;ось в течение 5 недель.

Эффектиk= 4;ность увеличивалk= 2;сь при лечении = 074; течение 13 недель в доз= 077; 200 мг/нед. Реакции в ме= 089;тах инъекций (от легкой до умеренной э = 88;итемы) и повышения печеночной трансаминаk= 9;ы (17%) были наиболее частыми нежелательl= 5;ыми событиями; они привели = 082; прекращениn= 2; [лечения] соответствk= 7;нно у двух и одного пациентов.

В когорт = 77; пациентов, в которой лечение осу = 97;ествлялось в течение 13 недель, у 5 из 10 человек име = 83;о место трёхк = 88;атное или более пр= 077;вышение верхней границы нормы, у 4 из ни= ;х оно сохраня = 83;ось при 2-х последоватk= 7;льных измерениях (визитах, на которых выполнялосn= 0; измерение).

За= ;ключение

Мипомерl= 9;ен может оказаться п = 77;рспективны&#= 1084; у пациентов, не достигаю = 97;их целевых уровней ХС ШЛНП на стабильной терапии ста = 90;инами. Требуется д = 72;льнейшие исследованl= 0;я механизмов = 80; клиническоk= 5;о значения изменений т = 88;ансаминаз при применении мипомерсенk= 2;». =

 

Мипоме= 088;сен - ингибитор синтеза аполипопроm= 0;еина В
- для снижения концентрацl= 0;и холестеринk= 2; ЛНП
у пациентов = 089; гомозиготнl= 6;й семейной гиперхолестерине&#= 1084;ией:
рандомизирl= 6;ванное, двойное слепое &#= 1087;лацебо контролирl= 6;ванное плацебо испытание

Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial

Резюме публикации = [2]

 

«Предпосыл = 82;а.

Гомозигl= 6;тная семейная гиперхолесm= 0;еринемия - редкое генетическl= 6;е расстройстk= 4;о, при котором дефектны об = 77; аллели рецептора к = 051;НП, что приводи = 90; к очень высоким концентрацl= 0;ям холестеринk= 2; ЛНП в плазме и преждевре = 84;енной коронарной болезни.

В этом исследованl= 0;и выяснялось, является ли антисмыслоk= 4;ой ингибитор синтеза апо = 83;ипопротеин&#= 1072; В мипомерсе = 85; эффективныl= 4; и безопасны = 84; дополнителn= 0;ным средством снижения концентрацl= 0;й холестеринk= 2; ЛНП у пациен= 090;ов с гомозиготнl= 6;й семейной ги = 87;ерхолестер&#= 1080;немией.

 

Методы.

Это рандомизирl= 6;ванное двойное слепое плац = 77;бо контролироk= 4;анное исследованl= 0;е 3-й фазы было предпринятl= 6; в девяти липидных кл = 80;никах в семи странах. Пациенты в возрасте 12 лет и старше с клиническиl= 4; диагнозом или генетич = 77;ским подтверждеl= 5;ием гомозиготнl= 6;й семейной гиперхолесm= 0;еринемии, которые уже получали максимальнm= 1;ю переносимуn= 2; дозу липид снижающего лекарства, были случайным образом рас = 87;ределены к мипомерсенm= 1; (200 мг подкожно каждую неделю) или к плацебо на 26 недель. Рандомизацl= 0;я была сгенерировk= 2;на компьютероl= 4; и стратифиц = 80;рована по весу (<50 кг и = ³<= /span>50 кг). Централи&#= 1079;ованная рандомизацl= 0;я блоками осуществляl= 3;ась с помощью ко= 084;пьтеризова&= #1085;ной интерактивl= 5;ой голосовой реагирующеl= 1; системой.

Весь клиническиl= 1; и фармацевтиm= 5;еский персонал и пациенты не были осведомленm= 9; о распределеl= 5;ии к лечению (оно было "замаскиров= ;ано"). Первичной конечной точкой было изменение концентрацl= 0;и холестеринk= 2; ЛНП в процентах о = 90; исходного. Анализ выполнялся "по намерению л = 77;чить".

Испытанl= 0;е зарегистриl= 8;овано на сайте ClinicalTrials.gov под номером NCT00607373.

Ре= ;зультаты.

К мипомерсенm= 1; были распределеl= 5;ы 34 пациента, к плацебо - 17. Проанализиl= 8;ованы данные от вс= 077;х больных.

Средние концентрацl= 0;и холестеринk= 2; ЛНП в исходн= 086;м состоянии были 11.4 ммоль/l= 3; (стандартно = 77; отклонение [СО] 3.6) в группе мипомерсенk= 2; и 10.4 ммоль/л (3.7) в группе плацебо. Среднее изменение концентрацl= 0;и холестеринk= 2; ЛНП в процентах было достоверно большим на м= 080;померсене (–24.7%, 95% доверительl= 5;ый интервал [ДИ] –31.6 до –17.7), чем нk= 2; плацебо (–3.3%, –12.1 до 5.5; p=3D0.0003) (&= #1088;ис 1 и 2).

 

Рис. 1

 

Рис.2

 

 

Наиболеk= 7; обычными нежелательl= 5;ыми явлениями б = 99;ли реакции в местах инъекций (26 [76%] пациентов в группе мипомерсенk= 2; и 4 [24%] в группе плацебо). У четырёх пациентов (12%) k= 4; группе мипомерсенk= 2;, но ни у одного в группе плацебо, произошло повышение концентрацl= 0;и аланиновой аминотрансm= 2;еразы до уровня трёх или более верхних пределов нормы.

Ин= ;терпретаци = 03;

Ингибирl= 6;вание синтеза аполипопроm= 0;еина В представляk= 7;т собой новую эффективнуn= 2; терапию, снижающую концентрацl= 0;ю холестеринk= 2; ЛНП у пациентов с гомозиготнl= 6;й семейной гиперхолесm= 0;еринемией, уже получающих = 83;ипид-снижаю&= #1097;ие лекарства, включая статины в высоких дозах».

Другие испытания мипомерсенk= 2;.

В l= 5;ачале августа 2010 года 2 компании, развивающиk= 7; мипомерсен, - <= /span>Gen= zyme Corp. и Isis Pharmaceuticals<= /span> Inc сообщили ещ = 05; о двух испытаниях 3-й фазы этого = препарата [3]. В одном из них эффективноl= 9;ть и безопасносm= 0;ь мипомерсенk= 2; изучалась у пациентов с тяжёлой гиперхолесm= 0;еринемией, в другом – с высоким риском возникновеl= 5;ия коронарной болезни сердца. В обоих условием вк = 83;ючения был приём других липи = 76;-снижающих средств в максимальнl= 6; переносимы&#= 1093; дозах.

Исслед= 086;вание при тяжелой гиперхолесm= 0;еринемии.

Дв= ;ойное слепое плацебо контролироk= 4;анное испытание н = 72; 58 пациентах с тяжелой гиперхолесm= 0;еринемией, получавших максимальнl= 6; переносимы дозы липид-снижа = 02;щих лекарств. Критерии тяжелой гиперхолесm= 0;еринемии были следующими ХСЛНП . ≥ 200 мг/д= 083; (5.18 ммоль/л) у пациентов с сердечносоl= 9;удистым заболеваниk= 7;м и  ≥300 м= 075;/дл (7.77 ммоль/л) без него. Рандомизацl= 0;я к мипомерсе = 85;у (200 мг еженедельнl= 6; в течение 26 недель) и пла&#= 1094;ебо осуществляl= 3;ась в отношении 2:1= .

Ср= ;едний ХСЛНП у рандомизирl= 6;ванных к мипомерсе = 85;у пациентов был равен перед начал = 86;м лечения 276 мг/дл (7.15 ммоль/л), в конце испытания 175 мг/дл (4.53 ммоль/л) – снижение на 101 мг/дл (36%). Это снижение произошло в дополнение = 82; достигнутоl= 4;у на максимальнm= 9;х переносимыm= 3; дозах липид снижающих лекарств. Снижение ХСЛНП сопровождаl= 3;ось достоверныl= 4;и снижениями уровней апо-В, холест&#= 1077;рина не ЛВП, и общего холестеринk= 2;. Приведенныk= 7; результаты получены пр = 80; анализе «по = 085;амерению лечить».

По= ;лностью лечение осуществлеl= 5;о у 27 из 39 и 18 из 19 пациентов, рандомизирl= 6;ванных соответствk= 7;нно к мипомерсе = 85;у и плацебо. В 8 случаях применение = 84;ипомерсена и 1 – плацебо прекращено из-за нежела= 090;ельных явлений. В испытании зарегистриl= 8;ована 1 смерть (от острого коронарногl= 6; синдрома в группе мипомерсенk= 2;). 

Ст= ;ойкие повышения (п= 086; крайней мер = 77; в 2-х последов&= #1072;тельных анализах с промежуткоl= 4; в 1 неделю) АЛТ в 3 и более раза превышавшиk= 7; верхнюю границу нормы (ВГН) отмечены у 15% пациентов, н= 086; это не сопровождаl= 3;ось изменениямl= 0; других лабораторнm= 9;х тестов, которые указывали б = 99; на клиничес = 82;и значимую дисфункцию печени.

Исслед= 086;вание у пациентов = 089; гиперхолесm= 0;еринемией и высоким риском развития коронарной болезни сердца.

Дв= ;ойное слепое, плацебо контролироk= 4;анное испытание н = 72; 158 пациентах с гиперхолесm= 0;еринемией (ХС ЛНП ≥ 100 мг/д= 083;) с высоким риском развития коронарной болезни сердца (КБС), принимавшиm= 3; статины в ма= 082;симально переносимыm= 3; дозах. Они были рандом = 80;зированы в отношении 2:1 к получению мипомерсенk= 2; (200 мг) или плацебо еженедельнl= 6; на протяжен = 80;и 26 недель. Испытание проводилосn= 0; в 43 центрах СШ= А и Канады. Оно было первым, в котором оценивалосn= 0; действие мипомерсенk= 2; у больных ди= 072;бетом (в этом исследованl= 0;и диабет типа 2 имел место более чем у 50% пациентов).

Ср= ;едний ХСЛНП у пациентов, леченных мипомерсенl= 6;м, был в исходном состоянии 123 мг/дл (3.19 ммоль/= 083;),  в конце испытания – 75 мг/дл (1.9 ммоль/л), сред&= #1085;ее снижение составило 37% (48 мг/дл). У полов= ины леченных мипомерсенl= 6;м был достигнут у = 88;овень ХСЛНП менее 70 мг/дл (1.8 ммоль/ = 83;) – признанны = 81; целевой уро = 74;ень для пациентов высокого риска. Такие снижения ХСЛНП произошли в дополнение = 82; уже достигнутыl= 4; у этих пациентов н = 72; максимальнl= 6; переносимыm= 3; дозах статинов. В испытании также произошло статистичеl= 9;ки значимое снижение апо-В, холестеринk= 2; не липопрот = 77;инов высокой плотности (non= -HDL-cho= lesterol – не относящегоl= 9;я к ЛВП), и общего холестеринk= 2;. Эти результаты получены пр = 80; анализе «по намерению лечить».

Од= ;нако из 105 пациентов, у которых был = 86; начато лечение мипомерсенl= 6;м, закончили его только 60, тогда как в группе плацебо лечение был = 86; полностью осуществлеl= 5;о у 44 из 53 пациентов. Прекращениk= 7; приёма мипо = 84;ерсена у 26 пациентов было связан = 86; с нежелател = 00;ными явлениями, в общем схожими с на= 073;людавшимис&= #1103; в исследованl= 0;ях по семейной гиперхолесm= 0;еринемии. В группе плацебо из-з= 072; нежелательl= 5;ых явлений прекратили лечение 2 пациента.
В этом исследованl= 0;и зарегистриl= 8;ована 1 смерть (от острого инфаркта миокарда в группе плацебо).

От= ;меченные повышения АЛТ у пациентов, получавших мипомерсен, также были близкими к н= 072;блюдавшимс&= #1103; в других исследованl= 0;ях. Стойкое (в ≥2-х последоватk= 7;льных анализах с промежуткоl= 4; в 1 неделю) пов= ышение АЛТ ≥ 3 ВГН во время лечения произошло у 10% пациентов. П= 086; данным магнитно резонансноl= 1; визуализацl= 0;и повышения АЛТ во многи= 093; случаях ассоциировk= 2;лись с повышенны = 84; содержаниеl= 4; жира в печени. Но ни у одного из пациентов н = 77; отмечено изменений лабораторнm= 9;х показателеl= 1;, который указывали б = 99; на клинически значимую дисфункцию печени.

Источн= 080;ки.

1.      = Raal F.J., Santos R.D., Blom D.J., Marais A.D., Charng M.-J., Cromwell W.C ., Lac= hmann R= .H., Gaudet <= span lang=3DEN-US style=3D'mso-ansi-language:EN-US'>D., Tan J.L., Chasan-T= aber S= ., Tribble D.L., Flaim J.D., Crooke S.T. Mipomersen, an a= polipoprotein B= s= ynthesis i= nhibitor, for lowering of= LDL cholesterol concentrations i= n p= atients w= ith h= omozygous f= amilial h= ypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 998–1006. =

2.      = Akdim F., Stroes <= span lang=3DEN-US style=3D'mso-ansi-language:EN-US'>E.S.G., Sijb= rands E= .J.G., Tribble D.L., Trip= M= .D., Jukema <= span lang=3DEN-US style=3D'mso-ansi-language:EN-US'>J. W., Flaim J.D., Su= J., Yu R., Baker B.F., Wedel M.K., Kastelein. J.J.P.&n= bsp; Efficacy and Safety of Mipomersen, an Antisense Inhibitor of Apolipoprotein B, in Hypercholesterolemic Subjects Receiving Stable Statin Therapy. J Am Coll Cardiol, 2010; 55: 1611-1618.

3.       Genzyme and Isis Report Results of Two Phase 3 Trials of Mipomersen.
http://www.businesswire.com/portal/site/genzyme/

&nb= sp;

&nb= sp;

&nb= sp;

П&= #1086;дготовлено Н.А.Грацианс= ким

Р&= #1072;змещено 25.12.2010<= /span>

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