Nonclinical Data for Pediatrics

1. Nonclinical Data for Pediatrics Karen Davis Bruno CDER/OND Associate Director Pharmacology & Toxicology Pediatric Clinical Investigator Training Workshop February 28, 2019

2. Adequate Nonclinical studies support FIH & Provide: • Understanding of MOA • Establish exposure (dose) response relationship • Relationship to duration & extent of systemic exposure • Identification of target organs & characterization of toxic effects • Assess potential reversibility of toxic effects • Extrapolate to potential human risk • Estimate safe starting dose/regimen, route for trials including FIH • Identify parameters for clinical safety monitoring & guide patient eligibility • Assist in management of risk

3. Supportive Nonclinical Studies •Pharmacology/Safety pharmacology •Repeat dose toxicity (rodent, non-rodent) –Test species based on human PD/PK similarity •Genotoxicity (in vitro, in vivo) •Carcinogenicity •Developmental & Reproductive (DART) –Fertility –Embryo-fetal developmental –Pre-/Post-natal development -Juvenile animal study (JAS)

4. JAS: Bridging the Data Gap Direct Dosing Juvenile animal studies Repro Seg III Repeat dose studies Adult ~PND60 Birth Weaning PND 21 Indirect exposure

5. Why Juvenile Animal Studies (JAS)? • Address pediatric safety concerns not addressed by clinical or standard tox due to developmental differences compared to adults • Assess safety concerns cannot be studied in peds trials • Adequate/Safe/Ethical trials- irreversible AE • Provide info for adequate clinical monitoring • Provide prospect of efficacy (POC) • JAS are considered on a case-by-case basis • Scientific justification should support the need for JAS

6. Application of the WoE approach in JAS in ICH S11: Nonclinical Safety Testing in Support of Development of Pediatric Medicines

7. JAS Linaclotide (Linzess) • MOA: 14aa guanylate cyclase-C agonist, acts locally on the luminal surface of the intestinal epithelium. • Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). • Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. • NME for IBS-C 290 mcg orally once daily (5 mcg/kg/day) & for CIC 145 mcg orally once daily (2.4 mcg/kg/day) • JAS requested based on indication in relatively young pediatric population (< 4 years of age) • Resulted in mortality in neonatal mice on PND 7, 14, and 21, although the lethal dose increased with age. Well tolerated when dosing began on PND 35. • Mortality due to severe dehydration as a result of increased fluid secretion into the intestinal lumen. • Subsequently determined that severe dehydration corresponds to increased intestinal expression of GC-C in neonatal mice, which decreases with age. • From the label: LINZESS is contraindicated in patients less than 6 years of age; in neonatal mice, linaclotide caused deaths due to dehydration. Avoid use of LINZESS in patients 6 years to less than 18 years of age. • The Division required a study to measure GC-C mRNA levels in duodenal and colonic tissue obtained from children ages 0 to 6 years of age to inform the potential risk of linaclotide administration in this pediatric population.

8. JAS: CDER’s Experience • An internal CDER archival data base (DARRTS) was searched for Agency/Applicant correspondence & reviews between 2009 and 2016 related to the conduct of JAS in support of pediatric clinical trials. • All JAS-related documents were then retrieved and relevant information was used to populate an excel database. The following key criteria were captured: • Study required or not required – including rationale • Study completed or not completed • Study design characteristics when available (e.g. species, age, endpoints) – including rationale • JAS results • Regulatory impact We asked the following questions: • What is the rationale when a JAS is performed or not needed? • What are the common JAS design elements? • Do JAS show unique safety signals? • If so, what design elements had the biggest impact? • What impacts does JAS data have on the regulatory decision making process?

9. CDER’s JAS Database Results • 85% JAS have toxicity findings (110/130) • 76%JAS with toxicity findings identified a new toxicity or increased sensitivity relative to adult toxicology studies (84/110) • In 76% of these studies a toxicity not identified in adult nonclinical toxicology studies was observed (64/84). • New toxicities (43) were identified from endpoints not routinely captured in adult studies and/or specific to the developing animal (e.g. bone, growth, learning and memory) • 37 JAS w/new tox findings & PPND data- no correlation (59%; 22/37) • 59 JAS w/new tox findings & pharmacology data- correlation (68%; 40/59) • In 24% of these studies an increased sensitivity (same toxicity observed at a lower dose) was observed (20 out of 84) • Exposure data from JAS were ≤ adult animal exposure in (69%) toxicity studies • Suggests that increased drug exposure in the JAS does not explain the identification of a new toxicity

10. JAS: CDER’s Experience – Regulatory Impact Unacceptable Risk To Pediatric Subjects

11. JAS: CDER’s Experience – Negative Studies • 130 of the required studies were completed and reviewed • 110 had toxicity findings (85%) • 14 had no toxicity findings (11%) • 6 were considered inadequate to assess toxicity due to design flaws (5%) • Of the 14 studies with no toxicity findings the rationale to conduct the studies were: • Unknown Risk – n = 10 (57%) • Target in Developmentally Sensitive System – n = 2 (14%) • Pediatric Population ≤ 6 – n = 2

12. JAS: CDER’s Experience –Conclusions • JAS provide value in that they are a tool to generate data bridging the gap between adult and pediatric subjects. • JAS capable of identifying important new toxicities not previously identified in adult toxicity studies. • Age of pediatric subjects (< 6 y.o.) to be studied is a major driver of JAS requests and design. • Findings from adult nonclinical studies or the presence of the target in a developing organ/system are additional drivers of JAS requests and design. • Increased sensitivity/unique toxicity cannot be explained by differences in TK. • May be able to predict whether a study will be positive based on available data; however, cannot predict what the toxicity profile will be. • New toxicities or increased sensitivity led to regulatory decisions

13. Acknowledgements • PTCC Pediatric Subcommittee Co-chairs: Tim McGovern, Darren Fegley • Jason Aungst Elizabeth Hausner • Gerri Baer Belinda Hayes • Federica Basso David Joseph • Carmen Booker Imran Khan • Paul Brown April Kluever • Emily Place Grace Lee • Olayinka Dina Ikram Elayan Peyton Myers Parvaneh Espandiari Ed Fisher Ravi Ravindran • Andrew Goodwin Melissa Tassinari • Wafa Harrouk Claudia Wrzesinski