[기본형]성공을 위한 사업계획서

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진영 미
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1 오송첨단의료산업진흥재단신약연구기획지원부 부장김종원

2 고위험, 고부가가치산업 (High risk, high return): 개발과정이길고복잡하며, 개발성공률이낮다. 막대한개발비가소요되고, 규제기관의영향력이크긴하지 만, 성공하면고수익을창출할수있는산업 R&D 비중이타산업에비해상대적으로매우높은산업 물질특허의확보가사업의핵심성공요인. 오픈이노베이션을통한분야별다양한전문가들과의협업이필요. 개발비용과상업적인이익의상관관계에대한이해가필요 규제에대한이해가반드시필요, 개발초기부터허가과정고려 환자의유익을최대한고려한신약개발이필요

3 PreIND meeting Define TPP (Target Product Profile) Animal efficacy Safety & Tox Formulation Development Clinical Need Assessment Target ID & validation Drug Screening Heat Drug Optimization Lead Non-GLP Studies Development Candidate Regulatory Preclinical GLP Clinical Trial Design Phase I Phase II Phase III Safety/Efficacy Manufacturing Formulation Stability IRB approval IND Filing First in human Dose Efficacy Reproductive tox Carcinogenicity Validation Define Drug Product or Drug Substance

4 질병표적은생화학을비롯한기초연구자들의힘든연구를통해발굴된다. 약물타겟은발현양변화 ( 증가또는감소 ), 돌연변이, 활성변화 ( 증가또는감소 ) 등이원인이되어질병을일으키는물질로단백질이대부분이며, 이물질의활성이나발현을조절하여질병을치료할수있다. 약물표적탐색 (Drug target discovery): 표적검증 (Target validation) Basic Research ( 주로생화학과유전학, 세포생물학등 ) Omics (Genomics,Proteomics, Metabolomics, Microarray, etc) Bioinformatics Gene- Knockout, Knock-in 모델활용 (Transgenic 세포나동물 ) sirna 를이용한표적유전자기능조절 (gene silencing) Neutralizing antibody 표적물질의활성을조절하는 Small molecule inhibitors 이용

약물표적에대한이해는신약개발성공에결정적인역할을담당, 약물표적과관련된유전적인변이나임상적인효능과안전성을이해하는것이매우중요함 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act, 667

5 약물표적에대한이해는신약개발성공에결정적인역할을담당, 약물표적과관련된유전적인변이나임상적인효능과안전성을이해하는것이매우중요함 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act, 667 human-genome-derived proteins targeted by drugs for human disease. 세포내표적 저분자화합물이유리 세포표면표적이나혈액순환표적 항체또는세포치료제로접근가능 Nature Reviews Drug Discovery volume16, pages19 34 (2017)

6 끝을염두에두고개발을시작하는것이중요 임상적필요, 개발전략의타당성, 개발가능성및타임라임등을객관적으로평가하는것이중요 환자중심의신약개발 : 환자가꼭필요로하는최적의신약개발 개발가능성 ( 최적화, 약효및독성평가모델, 생산성, 안정성, 물리화학적인특성분석등의시험법확보, 활용가능한실험동물모델유무 ) 과개발비용, 시장성, 허가획득가능성등을종합적으로평가 투여경로, 투여량, 투여기간, 약물투여후효능의최종목표점등을포함하여전체적인개발과정을계획하는것이중요 최종목표신약프로파일 (TPP: Target Product Profile) 만들기 신약후보물질 (Candidate) 의결정 약물효능을평가하기위한 Cell-based assay 나 Biochemical assay 디자인 효능 (nanomolar 농도에서의활성을가지는것이이상적 ), 선택성, 용해도, bioavailability, 반응기간, 혈장내반감기등약으로서의특징을대한최대한살리는최적화작업을통해높은약효, 낮은독성, 최적의약동력학 /ADME, Wide Therapeutic Window 를가지는물질을선택

7 TPP 란신약개발과정을통해만들고자하는약물 ( 치료제 ) 의최소한의특성 (ideal and acceptable range) 들을설명하는자료 프로젝트의전체적인방향을지시, 개발프로그램별로다른특성의 TTP 개발파이프라인을지나면서계속수정하고다듬어져야함 go/no go 의결정에중요, 개발될약물이가져야할최적의목표설정이중요 TPP에일반적으로포함되어야할내용 : 임상용법및의학적인필요 clinical indication and medical need 투여방법및투여빈도 route and frequency of administration 경쟁약물 current and future competition 약품가격및개발비용 cost of intended therapy 지적재산권 intellectual property position 현재요법에대한상대적인이점 all other advantages over current treatments 임상개발방법 clinical development path 허가방법 regulatory path 대사체와안전성프로파일 metabolic and safety profiles.

8 분류 약물의특성 (ideal and acceptable range) Clinical Indication(s); specify intended lead indication Indication and Usage Intended patient population Current available treatment options Product description Development candidate Preclinical work Type of agent (small molecule, peptide, mab, etc..) Proposed target Target specificity Efficacy (in vitro, cell-based, and in vivo) Animal model of disease Safety/toxicity profiles Absorption, distribution, metabolism, excretion Clinical Pharmacology Half-life in plasma or serum Pharmacodynamics (extent or target inhibition or activation) Protein binding, etc. Dosing amount, frequency, etc. Dosage and administration Route of Administration Formulation (excipients) Estimated Shelf life, required storage conditions, etc. Safety and toxicity in humans Known on-target or off-target predicted safety concerns Therapeutic window Presumed clinical path forward Regulatory considerations Eligibility for Orphan drug status. Fast Track, Subpart H, etc. Precedents set by Previous trials in indication/patient population Intellectual property Freedom to operate evaluation (competing patients, opportunities to write new patents) Desired Licensing outcome (license to company vs. start-up) Cost of goods Financial considerations Projected pricing and affordability compared to current options Cost to develop Estimated return on investment

9 1. Oral dosing (ideally once, but not more than 3 times per day) 2. Low cost of goods (~US $1 per full course of treatment) 3. Effective against drug resistant parasites (e.g., those that have developed resistance to chloroquine or sulfadoxine pyrimethamine treatment) 4. Fast acting and curative within 3 days 5. Potential for combination with other agents 6. Pediatric formulation should be available 7. Stable under tropical conditions 8. IP: requires freedom to operate; composition of matter patent would be ideal

10 1. In vitro activity in antiprotozoan screens: Plasmodium falciparum: IC50 <0.2 μg/ml: Trypansoma cruzi: IC50 <1.0 μg/ml. 2. Antihelminthic screens: Schistosoma mansoni: 100% adult worm motility reduction, IC50 <2 μg/ml, Onochocerca lienalis, O. ochengi, or O. volvulus: 100% inhibition of microfilarial motility at 1.25 x 10-5 M or 10 μg/ml. 3. Established selectivity for a molecular target or differential sensitivity between parasite and host enzymes should be > ten-fold. 4. Pre-toxicity screen in non-infected mice using up to 100 mg/kg ip or po. 5. In vivo activity in mouse or hamster models: significant reduction in parasitemia and/or increase in life span at 4 x 50 mg/kg either through ip or po route with no overt signs of toxicity. 6. Metabolic stability determined in microsomes in at least two species, including humans. 7. herg binding >10 μm. 8. Low CYP450 inhibition profile. 9. IP: should be novel and be able to file for composition of matter patent.

Clinical Needs Developability Development Candidate Disease Indication Pharmacology QTPP Safety Immunogenicity /Immunotoxicity Specificity: on/off-target interaction Risk Management Products MoA

11 Clinical Needs Developability Development Candidate Disease Indication Pharmacology QTPP Safety Immunogenicity /Immunotoxicity Specificity: on/off-target interaction Risk Management Products MoA Manufacturability Process Market Administration CQA Productivity Quality: Chemical & Physical Stability, PTMs Formulability Formulation Safety Regulatory requirements Pharmacology & Biological Activity PK/PD: Delivery, RoA, Halflife Mode of Action Efficacy Final Product Specification QTPP (Quality Target Product Profile): prospective summary of a biopharmaceutical product s quality, safety, efficacy, route of administration, dosage form, bioavailability, strength, and stability CQA (Critical Quality Attributes): physical, chemical, biological property or characteristic

12 강점과약점을정직하고솔직하게평가하여작성하는것이중요

신약개발성공확률을높이고, 신약개발기간을단축시켜국가의글로벌경쟁력을높이기위해서는다양하고방대한규모의연구 임상데이터를이해하고소통할수있는인공지능 (Artificial Intelligence, AI) 의필요성이대두됨 분야별전문가들의협업이반드시필요함

13 신약개발성공확률을높이고, 신약개발기간을단축시켜국가의글로벌경쟁력을높이기위해서는다양하고방대한규모의연구 임상데이터를이해하고소통할수있는인공지능 (Artificial Intelligence, AI) 의필요성이대두됨 분야별전문가들의협업이반드시필요함 정보탐색, 약물설계 약물최적화, 약효평가, 동물실험 인간대상임상 판매, 생산 문제점 탐색비용과다, 오랜연구기간 시행착오발생 최적의임삼시험전략, 특히, 환자군구성이힘듦 사후추적및관리에어려움이있음 AI 최적물질제시실험결과예측최적환자군제시등 추적자동화및관리자동화

14 첨단바이오의약품의개발과인공지능 (AI) 의결합에있어서는빅데이터가필수적이며, 방대한규모의의료정보, 질병정보, 의약정보, 오믹스사업등을통하여기구축된데이터확보 질병표적, 오믹스사업을통해발굴된바이오마커정보, 의료정보등의방대한데이터를처리하여신약개발에적합한 AI 환경을구축을위해고도의계산능력과고용량의저장소를가진컴퓨터시스템과더불어관련전문가들과의긴밀한협력관계를통한신약개발인공지능플랫폼구축 바이오빅데이터센터 Database Disease Biomarkers Omics Known Drug targets Clinical study Drug Data mining & Analysis AI Platform (ML/DL) Scoring Engine: Published data review and analysis (MOA/POC) learning Scoring output Experimental Validation: in vivo/in vitro Druggability (Efficacy Toxicity, etc) Developability learning Drug Candidate New Drug Development Pipeline

16 Easy to generate (hybridoma, Phage display, libraries ) Easy to tune or optimize (Fc engineering, humanization, affinity maturation ) Relatively low toxicity Relatively high success rate (~17%) Wide therapeutic platform (ScFv, Bispecific, ADC ) Very suitable for use in combination therapy (because of limited overlapping toxicity and lack of pharmacokinetic interactions)

18 Identification Peptide Mapping(amino acid sequence), SDS-PAGE(R/NR), IEF, WB, CEX, N-Glycan, binding assay 등 Purity SEC/RP-HPLC, IEC-HPLC(CEX, AEX), CE-SDS(Reduced/Non-Reduced) 등 Impurities HCP(Host cell protein), HCD (Host cell DNA), Protein A, 기타배양배지첨가물 (insulin, antifoam 등 ) 등 Contents UV (280nm)/ 흡광계수, 안정제 (Polysorbate 등 ) 등 Efficacy cell based assay(proliferation, cell death 등 ), binding assay 등 General properties ph, osmolality, endotoxin, 바이오버든 ( 무균 ), 불용성이물, 불용성미립자, 실용량등 Ref) International Conference on Harmonization (ICH) Guidelines 1. Q2 R1: Validation of Analytical Procedures 2. Q6B: Test Procedures And Acceptance Criteria For Biotechnological Biological Products

19 Binding Partner Antigen Function Binding Affinity and Specificity Binding Partner Fc receptor complement FcRn Protein A Function ADCC, ADCP CDC Long Serum Half Life Affinity Purification

20 Candidate Screening In Silico Analysis Lead Optimization Phage display, etc. Immunogenicity, Aggregation, Degradation, PTMs Antibody engineering: Fc engineering, Humanization, Codon optimization Binding Affinity? Biacore/OCTET Folding Stability Tm ( 생산성과연결 ) Soluble multimer? SEC Sequence? Intact Mass Purity? SDS-PAGE Soluble multimer? SEC Sequence? Intact Mass Charge Variants? CE-iEF Binding Affinity? Biacore/OCTET In Vitro Assessment Process Development In Vivo Assessment Efficacy, Yield, Stability, Formulability, Safety Host Development, DSP Development, Analytical Development Toxicology, Pharmacology SDS-PAGE, Intact Mass, CE-iEF, Biacore/OCTET, SEC, Reverse Phase, IEX, DLS, DSC, MFI Full Analysis package

분석법 Intact mass analysis SEC-HPLC/UPLC 분석장비 UPLC Q-Tof (Synapt G2-Si, Waters) 분석내용 분석에필요한정보 Accurate MW determination Intact mass of de-glycosylated samples Glycoprofiling of major N-linked

21 분석법 Intact mass analysis SEC-HPLC/UPLC 분석장비 UPLC Q-Tof (Synapt G2-Si, Waters) 분석내용 분석에필요한정보 Accurate MW determination Intact mass of de-glycosylated samples Glycoprofiling of major N-linked oligosaccharides (e.g., G0, G1 and G2) Assessment of truncations and major PTMs such as oxidation, N- term pyroglutamate formation and C-term Lys processing Expected amino acid sequence in Word buffer type, ph, any additives, and protein concentration Any information on solubility and/or stability of the test article UPLC/HPLC MW and soluble aggregates (multimers) assessment buffer type, any additives, and protein concentration Any information on solubility and/or stability of the test article Charge variants analysis HPLC (WCX, SCX) CE (CE-IEF) Measurement of accurate isoelectric points (pi) of each isoform Profiling of charge heterogeneity buffer type, any additives, and protein concentration Any information on solubility and/or stability of the test article

23 Considerations-Cell Therapy Product Survival/Engraftment The biocompatibility of the cell delivery device and the CT product (considerations include cell shearing, adsorption onto the walls of the catheter/syringe) The Route of Administration. The genetic relationship of the cells to the host animal (autologous/ syngeneic, allogeneic, or xenogeneic). The immune status of the host animal. The timing of cell administration relative to the onset of the disease/injury (i.e., the pathophysiologic status of the microenvironment). Distribution Various methods, such as imaging modalities used for detection of radioisotope-labeled cells, genetically modified cells (e.g., expressing green fluorescent protein), nanoparticle-labeled cells (e.g., iron-dextran nanoparticles), or the use of polymerase chain reaction (PCR) analysis and immunohistochemistry to identify cells of human origin or cells of a karyotype different than the host (e.g., gender) Differentiation and Integration Local microenvironment Tumorigenicity The differentiation status profile of cell types within the CT product (ranging from undifferentiated/embryonic to terminally differentiated/specialized). The extent of cell manipulation employed during manufacture of the product and the resulting growth kinetic profile (e.g., minimal, culture expansion only, culture expansion with/without growth factors, ex vivo differentiation, ex vivo transduction with or without cell expansion). The expressed transgene (e.g., various growth factors) of genetically modified cells. The potential to induce or enhance tumor formation from existing sub-clinical host malignant cells. The target patient population.

24 Monitoring Survival and Biodistribution Long-term survival, accurate homing of stem cells Clinical Success?? Monitoring Tumorigenicity Pluripotent stem cells: self-renewal, rapid proliferation, lack of contact inhibition, and high telomerase activity Cancer?? ipsc: transfection of reporter genes, overexpression of survival genes Cancer?? Teratoma formation? needed reporter-suicide genes (Imaging + suicide switch) Monitoring Immunogenicity abnormal gene expression T-cell mediated immune response?? Theranostics. 2012; 2(4):

25 1. Migration to non-target area 2. Interaction with concomitant therapies 3. Vector insertional mutagenesis 4. On-target/off-target toxicity 5. Previous clinical experience with similar product 6. Proof of Concept/TOX date in appropriate animal model 7. Studies using homologous cells in animal model

27 CAR-T cell therapy(chimeric Antigen Receptor): Kymriah (Novartis, 2017) Yescarta (Gilead, 2017)

29 안정적이며재현성이확보된 GMP 수준의공정시스템과빠른분석시스템개발이필요

32 CAR-T 의부작용에대해서적절한대응시스템이갖추어진검정된사이트에서임상을하는것이반드시필요함

35 획일적인개발절차의개선 규제정책의변환 : 일회성또는단편적인대응이아닌종합적개선안도출이필요 첨단바이오의약품법과생명윤리법등관련법안의합리적인개정안도출및재 개정 합리적이고도전적인벤처기업육성방안마련 : ( 참고 ) "Big Pharma appreciates innovation and respects how it happens. That's why the industry is interested in doing great deals with young companies that can move fast to solve big scientific problems," said Abbie Celniker, Ph.D., partner at Third Rock Ventures. "Sharing risk among a small team of technologists and scientists is a very different culture than being in a large pharmaceutical company that must meet requirements of stock goals. (

36 오송첨단의료산업진흥재단

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract