第 21 回安評センター学術講演会レギュラトリーサイエンス」

「ものを作る側からの 第21回安評センター学術講演会レギュラトリーサイエンス」武田薬品工業株式会社　薬剤安全性研究所　永井博文 DVM, MS, PhD, DJSTP

Agenda • Target選定から市販後までの医薬品安全性研究： • Target selection • Tox screening • Candidate selection • Tox package for IND • Tox package for NDA • Tox activities after NDA • Human relevance framework • List of withdrawn drugsdue to toxicity • What is important in toxicology

Target Therapeutic Area • Lifestyle-Related Diseases / Blockbuster • High Unmet Medicinal Needs / Orphan drugs • Neurological damage (either as a result of accident or stroke),Alzheimer’s disease, chronic heart failure, chronic obstructive pulmonary disease, many cancers, obesity, and other chronic conditions have few or no treatmentoptions. • 中枢、心不全、COPD、がん、肥満:有効性と安全性のバランスが重要 • 糖尿病、高血圧、ホルモン依存性がん、消化器領域:安全で当たり前

Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40 GPR40 expression in pancreatic beta cells FFAs increase insulin secretion in a glucose-dependent manner TAK-875/Fasiglifam: 抗糖尿病薬Ph3 NATURE 422; 173-6, 2003

The First GPR40 agonist/TAK-875/ Fasiglifam: 抗糖尿病薬Ph3 • USA： • 糖尿病薬や抗肥満薬では、第2/3相試験のメタアナリシスが申請前に必要。メタアナリシスにおける心血管系リスク比が高ければ、大規模臨床試験が必要 • Zimmermanらが提唱したHy's lawに照らした肝障害リスク評価が必要 Alogliptin has had a bumpy road, receiving two “complete response” letters before receiving FDA approval on its third try. Takeda submitted its original application Dec. 27, 2007, before the December 2008 FDA “Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” and the agency asked Takeda to submit an additional cardiovascular safety study to satisfy the guidance requirements. Takeda filed for Oseni approval Sept. 19, 2008 and filed for Kanzano approval Nov. 23, 2011. After receiving the additional data, FDA asked Takeda in 2012 for additional safety data for monotherapy and in combination with pioglitazone, which the company provided from Japanese postmarketing data and ongoing clinical trials. In total, Nesina’s approval relied on 14 clinical trials with a total of roughly 8,500 patients, according to FDA. Still, FDA has requested five postmarketing studies for the new DPP-4 inhibitor: a cardiovascular outcomes trial; an “enhanced pharmacovigilance program to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions; and three pediatric studies – a dose-finding study and two safety-efficacy studies for monotherapy and in combination with metformin. • Japan: • 24週間投与Ph3試験で有効性と安全性を評価 • 近々、申請予定

医薬品の研究開発ステージ 100~1000個もの候補化合物の毒性はどうやって評価? Nat Rev Drug Disc 6; 636-49, 2007

In Silico Toxicology 1000個:DEREK等のin silicoツールを用いた毒性回避 Super Mutagen Mutation Res 223: 73-103, 1989 J Antimicrobial Chemother33: 685-706,1994

Lead optimization 1000個:In silicoモデリングによる毒性回避 • X線結晶構造解析やNMRスペクトルから得られた生体分子の三次元情報を利用したStructure-based drug designや計算化学Computational chemistryよる副作用の回避：hERG阻害の回避例 1 of hERG subunits Binding mode of terfenadine J Med Chem52: 1630-8, 2009

In Vitro Toxicology 100個:In vitro評価による化合物選別 hERG assay Phospholipidosis Toxicol Mechanism Method 19: 477-85, 2009

Agenda • Target選定から市販後までの安全性研究： • Target selection • Tox screening • Candidate selection • Tox package for IND • Tox package for NDA • Tox activities after NDA • Human relevance framework • List of withdrawn drugsdue to toxicity • What is important in toxicology

Candidate Selection 10個:　動物を用いた候補化合物選択 In vitro sciences continue to mature and contribute to our machanistic understanding of drug-induced toxicity; however, their ability, or rather degree of validation, to predict in vivo responses is not yet ready, for most toxicities, to supplant the use of short-term in vivo models in the early evaluation of drug candidates. Expert Opin Drug Saf 7: 107-10, 2008

Candidate Selection 10個:　動物を用いた候補化合物選択 • 簡易Ames試験（遺伝毒性評価） • 静注での心循環器系評価（心電図や血圧など） • 薬効薬理試験内での毒性評価 • 単回投与TK/MTD試験（ラット・イヌ） • ラット・イヌを用いた1-2週間程度の反復投与用量設定毒性試験（検査項目は化合物やTargetの特性に応じて適宜設定） • 上記の評価及び薬効/動態試験結果等に基づき、開発制限毒性の有無を判断し、臨床開発候補化合物を選定する

Tox screening & candidate selection Chem-Biol Interact 150: 9–25, 2004

Tox Package for IND • ICH M3: Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals • The core battery of safety pharmacology studies includes the assessment of effects oncardiovascular, central nervous and respiratory systems, and should generally be conducted before human exposure, in accordance with ICH S7A and S7B • In vitro metabolic and plasma protein binding data for animals and humans andsystemic exposure data in the species used for repeated-dose toxicity studies (ICH S3A) generally should be evaluated before initiating human clinical trials. • When acute toxicity information is available from any study, separate single-dose studies are not recommended. • Repeated-dose toxicity studies in two species (one non-rodent) for a minimum duration of 2 weeks would generally support any clinical development trial up to 2 weeks in duration (ICH S4). • An assay for gene mutation is generally considered sufficient to support all single dose clinical development trials. To support multiple dose clinical development trials, an additional assessment capable of detecting chromosomal damage in a mammalian system(s) should be completed (ICH S2).

Tox Package for IND • ICH S9: Nonclinical Evaluation for AnticancerPharmaceuticals • An assessment of vital organ function, including cardiovascular, respiratory and central nervous systems, should be available before the initiation of clinical studies; such parameters could be included in general toxicology studies. Stand-alone safety pharmacology studies need not be conducted to support studies in patients with late stage cancer or advanced disease. • The evaluation of limited kinetic parameters , e.g., peak plasma levels, AUC, and half-life, in the animal species used for non-clinical studies can facilitate dose escalation during Phase I studies. • Toxicology studies should be designed to support the clinical schedule. Evaluation of reversibility and delayed toxicity should be addressed. • Genotoxicity studies are not considered essential to support clinical trials. • 抗がん剤のPhase 1試験実施には、臨床試験の投与期間をカバーし得るげっ歯類及び非げっ歯類を用いた反復投与試験（安全性薬理評価を含む）の実施のみで可 • ICH S6: Preclinical Safety Evaluation of Bio-technology-Derived Pharmaceuticals • バイオ医薬品では、サルの4w試験のみで可の場合もある

Starting Dose and Capping Dose • ICH M3: Approach 5 of Exploratory Clinical Trials • In the absence of adverse effects in the clinical trial, escalation above this AUC can be appropriate if the findings in the toxicity studies are anticipated to be monitorable, reversible, and of low severity in humans. • ICH S9: • A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose. • In general, the highest dose or exposure tested in the nonclinical studies does not limit the dose-escalation or highest dose investigated in a clinical trial in patients with cancer.

Tox Package for NDA • ICH M3: Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals • ICH S1: Carcinogenicity • ICH S5: Development & Reproductive toxicity • ICH S8: Immunotoxicity • ICH S10Draft: Phototoxicity • ICH Q3: Impurities in New Drug Substances • ICH M7 Draft: Genotoxic Impurities • ICH E2A: Expedited Reporting (15-Day Reports)

Tox Activities after NDA • ICH E2C: Periodic Benefit-Risk Evaluation Report(PBRER) • Other Regional Guidelines • Nonclinical Safety Evaluation of Drug or Biologic Combinations • Nonclinical Safety Evaluation of Pediatric Drug Products

Concordance of Toxicity in Human & Animals Nat Rev Drug Disc 3:226-36, 2004

Human relevance framework • IPCS-Mode of action of chemical carcinogenesis Sonich-Mullin et al., Regul. Toxicol. Pharmacol. 34:146-152-, 2001 • ILSI/RSI (EPA, Health Canada)- Human relevance framework for chemical carcinogens Meek et al., Crit. Rev. Toxicol. 33:591-653, 2003 • ILSI/EPA, Health Canada)- Human Relevance of mode of action and life stage information of animal toxicity data Seed et al., Crit. Rev. Toxicol, 35:663-672, 2005 • IPCS-Human relevance framework for chemical carcinogens Boobis et al., Crit. Rev. Toxicol. 36: 781-792, 2006 • IPCS- Human relevance framework for non-cancer toxicities Boobis et al., Crit. Rev. Toxicol. 38:87-96, 2008

Human relevance framework 定性的定量的 J Toxicol Pathol 23:189-211,213-34, 2010

Human relevance framework (Example) Endocrine Reproductive Climate in Aging Female Rats and Mode of Action of Bromocriptine Leading to Uterine Tumors J Toxicol Pathol 23:189-211,213-34, 2010

Human relevance framework (Example) A novel serotonin reuptake inhibitor with 5-HT1AR agonism and 5-HT3R antagonism/Lu AA21004/vortioxetine/BRINTELLIX: 市販抗うつ薬 US Label 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in which CD-1 mice and Wistar rats were given oral doses of vortioxetine up to 50 and 100 mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for male and female rats, respectively, for 2 years. The doses in the two species were approximately 12, 24, 20, and 39 times, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females at doses 39 times the MRHD, but not at 15 times the MRHD. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study. The finding did not occur in male rats at 20 times the MRHD. In mice, vortioxetine was not carcinogenic in males or females at doses up to 12 and 24 times, respectively, the MRHD.

Rodent tumors not relevant to human • Bladder tumor by sodium salts • Renal tumor by α2μglobulin or exaggerated CPN • Liver tumor by enzyme-inducers including PPARαagonists • Thyroid tumor by enzyme-inducers • Pheochromocytoma secondary to hormonal modulation • Leydig cell tumor by decreased testosterone level • Gastric carcinoid by acid blockers • Pancreatic acinar tumor by trypsin inhibitors • Ovarian smooth muscle tumor by α stimulants • Hemangioendothelial tumors by increased proliferation • Subcutaneous sarcoma by foreign materials, etc…

Framework for Determining a Mutagenic MOA for Carcinogenicity 遺伝毒性の有無 No-Threshold Mode of Action; TTC approach 1.5μg Threshold Mode of Action; PDE approach EPA 120/R-07/002-A, Sep 2007

Human relevance framework (Example) Consensus Diagnoses and Mode of Action for the Formationof Gastric Tumors in Rats Treated with the Chloroacetanilide Herbicides Alachlor and Butachlor. (Toxicol Pathol 2014, in press) Both compounds were positive for Ames assay but… Conclusion: Chloroacetanilide-induced gastric neoplasia develops via a nongenotoxic MOA, which is subject to a threshold for ECL cell carcinogenicity, and under conditions that are not relevant to humans at known or anticipated levels of exposure

Framework for Determining a Mutagenic MOA for Carcinogenicity 遺伝毒性の有無遺伝毒性陽性でもPDE approachが可能な場合がある EPA 120/R-07/002-A, Sep 2007

Human relevance framework(Example) Ethyl methanesulfonate (EMS) toxicity in Viracept – a comprehensive human risk assessment based on threshold data for genotoxicity. Toxicol Lett 190:317-29, 2009 Fig. 1 Dose based comparison of genotoxicity data: graphical presentation of the dose–response relations in the MNT and MutaMouse studies.The relative increase of the genotoxic effect over incidences recorded in the negative control (normalized to 1) animals is plotted as a function of the daily dose.

List of withdrawn drugsdue to toxicity From Wikipedia

What is important in toxicology • Benefit/Risk Balance　くすり／リスク Sponsor evaluates benefits/risks for what?

Better Health, Brighter Future

第 21 回安評センター学術講演会 レギュラトリーサイエンス 」