초록 ▼

- 본 과제에서는 MD-2 (myeloid differentiation 2) 길항제로 도출한 유효물질을 글로벌 패혈증 약물로 개발하기 위한 Hit-to-Preclinical candidate 프로그램의 전략적 사전기획을 수립하였음.
- 패혈증 개요 및 약물개발 파이프라인; 패혈증은 감염균에 의한 전신염증반응증후군이며 중증 패혈증, 패혈증 쇼크로 질환이 심화됨. 패혈증의 병태생리, 약물시장, 특허동향을 분석하였고 약물후보들의 연구개발 파이프라인을 분석하였음.
- 약물타겟 MD-2/TLR4 및 약물후보 Eritoran; 수용

- 본 과제에서는 MD-2 (myeloid differentiation 2) 길항제로 도출한 유효물질을 글로벌 패혈증 약물로 개발하기 위한 Hit-to-Preclinical candidate 프로그램의 전략적 사전기획을 수립하였음.
- 패혈증 개요 및 약물개발 파이프라인; 패혈증은 감염균에 의한 전신염증반응증후군이며 중증 패혈증, 패혈증 쇼크로 질환이 심화됨. 패혈증의 병태생리, 약물시장, 특허동향을 분석하였고 약물후보들의 연구개발 파이프라인을 분석하였음.
- 약물타겟 MD-2/TLR4 및 약물후보 Eritoran; 수용체 MD-2/TLR4의 패혈증 약물타겟으로서 가능성을 제시하였고, eritoran의 약물 작용점, 비임상 약물효능, 임상시험, DMPK/PD 등에 대한 연구개발 결과를 분석하였음.
- 유효물질 MD-2/Anta의 패혈증 신약개발; 신약개발 단계상 위치와 유효물질의 특성 및 SWOT 분석을 제시하였음. Hit-to-Lead와 Lead optimization 프로그램의 연구개발 내용 및 범위, 추진체계 및 방법에 대한 전략적 사전기획을 완성하였음.
- 본 기획사업은 패혈증 후보물질을 도출하는 신약개발 연구사업의 로드맵을 제시할 수 있을 것으로 기대함.

Abstract ▼

￭General Feature of Sepsis Disease
-Sepsis is an infection-induced systemic inflammatory response syndrome with high risk mortality according to increasing severity viasevere sepsis and septic shock.
-Pathophysiology of sepsis can be vastly simplified as an over-riding inflammatory and coagula

￭General Feature of Sepsis Disease
-Sepsis is an infection-induced systemic inflammatory response syndrome with high risk mortality according to increasing severity viasevere sepsis and septic shock.
-Pathophysiology of sepsis can be vastly simplified as an over-riding inflammatory and coagulative mechanism in the early stage followed by compensatory anti-inflammatory response and immune suppression.
-The incidence rates of sepsis are higher in infants and also in elder population aged over 65s, expecting with annual increase above 1.2-1.7% in the next 10 years (2010 to 2020). Epidemiology data represent that 30-50% of the incidents are caused by Gram-positive bacteria and 25-30% by Gram-negative bacteria.
-Xigris and antibiotics (Vancomycin, Pasil, Sivadene, and Vialebrex) are clinically used in the treatment of sepsis. Worldwide sales of Xigris were amounted to 104 million US dollars in the year of 2010.
￭Pipeline of Sepsis Drug
-Searching machine with keywords (septicH & antagonistH) has identified 518 patents from US and 305 from Korea. Annual patent applications, material properties, and the distribution of target have been analyzed.
-Expiration date of the regional patents for sepsis drug Xigris and Phase III candidate Eritoran are investigated.
-R&D pipelines of Phase III candidate TAK-242 and Phase II clinical trials (Talactoferrin alfa, CytoFab, IV alkaline phosphate, and NOX-100) have been analyzed.
￭Drug Target MD-2/TLR4
-MD-2 is absolutely required to sense the lipid A domain of bacterial LPS and to trigger TLR4-mediated signal cascade across the plasma membrane.
-Based on the X-ray structure of human MD-2, small-molecule antagonists have been classified into 4 groups; type A (occupying 60-70 % of the interior MD-2 pocket), type B (polar interaction with the entrance of MD-2 pocket), type C (covalent binding to the Cys-133 residue on MD-2), and type D (hydrophobic binding to the deep interior of MD-2 pocket).
￭Drug Candidate Eritoran Targeting MD-2
-R&D pipeline of eritoran (Phase III) has been analyzed.
-Eritoran, structurally similar to lipid A moiety of LPS, competitively antagonizes the MD-2 binding to LPS of Gram-negative bacteria.
-Eritoran inhibits endotoxin challenge-induced cytokine production, and confers a survival benefit in animal models of septic death.
-Phase I studies in healthy humans represent that eritoran ameliorates clinical symptoms in response to LPS with only notable side effect of phlebitis. Phase II study in sepsis represents that eritoran decreases the 28-day mortality rates of high risk patients. Phase III ACCESS study in high risk patients has been completed and its results are under analysis to be unsatisfactory.
-Plasma clearance of eritoran was slow without widely distributing to other body tissues, but it gradually became inactive upon binding to HDL.
￭Pharmacological Compound in New Drug Development
-A guideline for determining Hit, Lead or Candidate has been provided and that of pre-clinical pharmacology/toxicity test is also investigated.
￭Strategy of Sepsis Drug Development of Hit Compound MD-2/Anta
-Drug-discovery strategy in the Hit-to-Lead and Lead Optimization program of MD-2/Anta has been established according to the analysis data of R&D pipeline of eritoran.
-MD-2/Anta is an early Hit for sepsis drug and its SWOT is compared with eritoran.
-Key features of this study include 1) the molecular modeling-based design of MD-2/Anta derivatives which may be patentable and possess drug-like property, and 2) the strategies supporting in vitro/vivo PoC (proof of concept) and DMPK/PD.
-This study proposes an R&D team with 11 experts assigned to three groups; 1) molecular modeling-based chemical synthesis, 2) in vitro/vivo PoC, and 3) DMPK/PD and pre-toxicity.

목차 Contents

• 제 출 문 ... 1
• 보고서 요약서 ... 2
• 요 약 문 ... 3
• SUMMAY ... 6
• CONTENTS ... 9
• 목 차 ... 10
• 1. 패혈증 개요 ... 12
• 1-1) 질환의 정의 ... 12
• 1-2) 병태생리 ... 14
• 1-3) 질병역학 ... 19
• 1-4) 패혈증 약물 및 시장조사 ... 23
• 2. 패혈증 약물개발 파이프라인 ... 26
• 2-1) 특허분석 ... 26
• 2-2) 특허권 만료 ... 30
• 2-3) 임상 2-3상의 약물후보 ... 34
• 2-4) 약물타겟별 파이프라인 ... 36
• 3. 약물타겟 M D-2/TLR4 ... 39
• 3-1) 수용체 TLR ... 39
• 3-2) M D-2/TLR4 수용체의 박테리아 LPS 인식 ... 41
• 3-3) 병원성 lipid A의 M D-2 타겟 분자모델링 ... 44
• 3-4) M D-2 길항제 및 분자모델링 ... 46
• 4. M D-2 타겟 약물후보 Eritoran ... 58
• 4-1) Eritoran의 화학구조 ... 58
• 4-2) 약물 작용점 ... 60
• 4-3) 비임상 약물효능 ... 63
• 4-4) 임상시험 ... 68
• 4-5) DM PK /PD profiling ... 72
• 4-6) Eritoran의 질환 적응증 확대 ... 77
• 5. 신약개발 단계상 약효물질 ... 86
• 5-1) 유효물질 (Hit compound) ... 86
• 5-2) 선도물질 (Lead compound) ... 90
• 5-3) 개발후보물질 (Development candidate) ... 92
• 5-4) 전임상 약리/독성시험 ... 95
• 6. 유효물질 M D-2/A nta의 패혈증 신약개발 사전기획 ... 98
• 6-1) 신약개발 단계상 위치 ... 98
• 6-2) 유효물질의 특성 ... 98
• 6-3) 유효물질의 SW OT 분석 ... 106
• 6-4) 연구개발의 목표 ... 109
• 6-5) 연구개발의 내용 및 범위 ... 111
• 6-6) 연구개발의 추진전략 및 방법 ... 123
• 7. 연구개발 결과의 성과물 및 기대효과 ... 142
• 8. 참고자료 ... 143