Transcript Tox Package for NDA

第21回安評センター学術講演会
「ものを作る側からの
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 List of withdrawn drugs due to toxicity
 What is important in toxicology
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 List of withdrawn drugs due to toxicity
 What is important in toxicology
Target Therapeutic Area
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Lifestyle-Related Diseases / Blockbuster
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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
High Unmet Medicinal Needs / Orphan drugs
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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 treatment options.
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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
Free fatty acids regulate insulin secretion
from pancreatic beta cells through GPR40
GPR40 expression in pancreatic beta cells
FFAs increase insulin secretion in a glucosedependent 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
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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.
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Japan:
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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
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 drugs due to toxicity
 What is important in toxicology
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
1000個: DEREK等のin silicoツールを用いた毒性回避
In Silico Toxicology
Super Mutagen
Mutation Res 223: 73-103, 1989
J Antimicrobial Chemother
33: 685-706,1994
1000個: In silicoモデリングによる毒性回避
Lead optimization
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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 Chem 52: 1630-8, 2009
100個: In vitro評価による化合物選別
In Vitro Toxicology
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 drugs due to toxicity
 What is important in toxicology
10個: 動物を用いた候補化合物選択
Candidate Selection
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
10個: 動物を用いた候補化合物選択
Candidate Selection
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
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 drugs due to toxicity
 What is important in toxicology
Tox Package for IND
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ICH M3: Guidance on Non-Clinical Safety Studies for the
Conduct of Human Clinical Trials and Marketing Authorization for
Pharmaceuticals
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The core battery of safety pharmacology studies includes the assessment of effects on
cardiovascular, central nervous and respiratory systems, and should generally be conducted
before human exposure, in accordance with ICH S7A and S7B
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In vitro metabolic and plasma protein binding data for animals and humans and systemic
exposure data in the species used for repeated-dose toxicity studies (ICH S3A) generally
should be evaluated before initiating human clinical trials.
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When acute toxicity information is available from any study, separate single-dose studies
are not recommended.
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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).
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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
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ICH S9: Nonclinical Evaluation for Anticancer
Pharmaceuticals
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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. Standalone safety pharmacology studies need not be conducted to support studies in patients with late stage cancer or
advanced disease.
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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.
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Toxicology studies should be designed to support the clinical schedule. Evaluation of reversibility and delayed toxicity
should be addressed.
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Genotoxicity studies are not considered essential to support clinical trials.
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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-technologyDerived Pharmaceuticals
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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
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ICH M3: Approach 5 of Exploratory Clinical Trials
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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:
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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.
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 drugs due to toxicity
 What is important in toxicology
Tox Package for NDA
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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 S10 Draft: Phototoxicity
ICH Q3: Impurities in New Drug Substances
ICH M7 Draft: Genotoxic Impurities
ICH E2A: Expedited Reporting (15-Day Reports)
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 drugs due to toxicity
 What is important in toxicology
Tox Activities after NDA
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ICH E2C: Periodic Benefit-Risk Evaluation Report (PBRER)
Other Regional Guidelines
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Nonclinical Safety Evaluation of Drug or Biologic Combinations
Nonclinical Safety Evaluation of Pediatric Drug Products
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 drugs due to toxicity
 What is important in toxicology
Concordance of Toxicity in
Human & Animals
Nat Rev Drug Disc 3:226-36, 2004
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
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ILSI/RSI (EPA, Health Canada)- Human relevance framework
for chemical carcinogens
Meek et al., Crit. Rev.Toxicol. 33:591-653, 2003
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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
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IPCS-Human relevance framework for chemical carcinogens
Boobis et al., Crit. Rev. Toxicol. 36: 781-792, 2006
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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
Control aging rats
Bromocriptine-treated aging rats
Pituitary Low LH
High prolactin
(in rats but human)
Low LH
Decreased prolactin
Ovary
→ Persisting corpora
lutea
→ High progesterone
Estrogen normal
→ Persisting corpora lutea
→ Low progesterone due to low prolactin
(prolactin is necessary for maintaining LH
receptors in corpora lutea of rats but human)
Estrogen normal
Uterus
Progesterone dominance
→ Pseudopregnancy with
prolonged diestrus
Estrogen dominance
(increased estrogen/progesterone ratio)
→ Squamous metaplasia, pyometra, neoplasia
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
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Bladder tumor by sodium salts
Renal tumor by α2μ globulin or exaggerated CPN
Liver tumor by enzyme-inducers including PPARα agonists
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
Threshold Mode of Action;
PDE approach
No-Threshold Mode of Action;
TTC approach 1.5μg
EPA 120/R-07/002-A, Sep 2007
Human relevance framework (Example)
Consensus Diagnoses and Mode of Action for the Formation of 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: Chloroacetanilideinduced 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.
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 drugs due to toxicity
 What is important in toxicology
From Wikipedia
List of withdrawn drugs due to toxicity
Drug name
Withdrawn Remarks
1950s–
Withdrawn because of risk of teratogenicity; returned to market for
Thalidomide
1960s
use in leprosy and multiple myeloma under FDA orphan drug rules
Fen-phen (fenfluramine
Phentermine remains on the market, dexfenfluramine and
1997
and phentermine)
fenfluramine – later withdrawn as caused heart valve disorder
Withdrawn because of risk of hepatotoxicity; superseded by
Troglitazone (Rezulin) 2000
pioglitazone and rosiglitazone
Cisapride (Propulsid)
2000s
Withdrawn in many countries because of risk of cardiac arrhythmias
Cerivastatin (Baycol,
2001
Withdrawn because of risk of rhabdomyolysis
Lipobay)
Rofecoxib (Vioxx)
2004
Withdrawn because of risk of myocardial infarction
Voluntarily withdrawn from U.S. market because of risk of
2005–
Natalizumab (Tysabri)
Progressive multifocal leukoencephalopathy (PML). Returned to
2006
market July, 2006.
Withdrawn around the world because of risk of severe depression
Rimonabant (Acomplia) 2008
and suicide
Sibutramine
Withdrawn in Europe, Australasia, Canada, and the U.S. because of
2010
(Reductil/Meridia)
increased cardiovascular risk
Withdrawn in Europe because of increased risk of heart attacks and
Rosiglitazone (Avandia) 2010
death. A post-hoc analysis revealed Avandia had no increased risk of
heart attacks.
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 drugs due to toxicity
 What is important in toxicology
What is important in toxicology

Benefit/Risk Balance くすり／リスク
Sponsor
evaluates
benefits/risks
for what?
Better Health, Brighter Future