Антагонисты PCSK9: эффективность в клинической практике и основные направления создания новых лекарственных средств

Актуальность. Сердечно-сосудистые заболевания являются ведущей причиной смерти в мире. Дислипидемия как патофизиологическая основа атеросклероза — важнейшая причина развития сердечно-сосудистых заболеваний. В число факторов, модифицирующих эту патологию, Всемирная организация здравоохранения включает статины, которые эффективно снижают уровень холестерина. Вместе с тем приверженность лечению статинами недостаточна для достижения популяционных контрольных показателей уровня липидов. Этот факт является мощным стимулом для создания принципиально новых групп гиполипидемических средств, в частности антагонистов пропротеиновой конвертазы субтилизин/кексин типа 9 (PCSK9).

Цель. Обзор инновационных подходов к созданию нового поколения гиполипидемических средств — антагонистов PCSK9, оценка их эффективности, безопасности и перспектив применения в клинической практике.

Обсуждение. Применение антагонистов PCSK9 значительно повышает эффективность гиполипидемической терапии при комбинировании со статинами или в случае монотерапии при наличии противопоказаний для назначения статинов. Препараты моноклональных антител к PCSK9, а также препарат инклисиран характеризуются благоприятным соотношением «польза–риск». Вместе с тем высокая стоимость находящихся в гражданском обороте антагонистов PCSK9 ограничивает их применение в клинической практике. Показано, что перспективными направлениями создания новых антагонистов PCSK9 с принципиально иными механизмами действия являются аднектины, технология редактирования генома CRISPR/Cas9, малые молекулы и низкомолекулярные ингибиторы PCSK9, вакцины против PCSK9, антисмысловые олигонуклеотиды. Препараты из данных групп находятся на различных этапах доклинических и клинических исследований.

Выводы. Таким образом, разработка новых гиполипидемических средств может реализовываться как путем синтеза высокои низкомолекулярных лигандов PCSK9, так и путем воздействия на генетические механизмы синтеза этого белка. Рассмотренные в обзоре инновационные лекарственные средства отличаются высокой эффективностью, для большинства из них на дорегистрационном этапе не было отмечено проявлений токсичности.

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