Evaluation of Developmental Repro

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Evaluation of Developmental Repro Juvenile
Animal Toxicity

• Karen Davis-Bruno
• CDER/OND/DMEP

BioSafe/FDA Leadership Meeting Washington DC
Feb. 26, 2007
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Overview

• Developmental reprotoxicity case studies
• MAb NHP early embryo-fetal dev.
• rh-peptide reprotox std. battery
• Immunized rabbit model
• Test anti-rh-peptide antibody response
• Juvenile animal toxicity

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Case Study 1 Developmental Reprotox

• Fully humanized MAb
• Targets mediator of resorptive phase of bone
  remodeling
• Indications PMO, bone loss, RA, bone
  metastasis, multiple myeloma
• Relevant species NHP based on MAb recognition
  of monkey analogue
• Chronic tox 12 month cyno monkey
• Segment 2 cyno monkey

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NHP Embryo-Fetal Developmental (Seg 2) Study

• Cyno monkey 16/group
• Dose 0, 2.5, 5, 12.5 mg/kg/week, SC
• Organogenesis GD 21, 28, 35, 42, 49
• Cesarean GD 100
• Evaluation
• Maternal Wt, FC, Ab titer, pregnancy, TK
• Fetal Wt (body, placenta, organ), length,
  external/visceral/skeletal exam, limited
  histopath (thymus, spleen, Peyers patches)
• Note target organ ID from knockout mice N/E

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Case 1 Results

• No maternal tox or adverse effects on pregnancy
• No teratogenicity
• ?Fetal spleen, ovarian wt
• ?Fetal body, adrenal, heart wt
• Incomplete bone ossification, vestigial/malformed
  cervical ribs
• Anti-MAb antibodies
• Maternal incidence 80, 69, 50
• Fetal incidence 53, 40, 6
• Neutralizing Ab 2/16 dams and 0/16 fetuses

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Limitations

• Inadequate histopath limits interpretation of
  developmental risk
• Known effects of MAb target in lactation signal
  transduction related to pro-inflammatory response
  may lead to peri-natal adverse effects not
  evaluated

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Case 2 Background

• rh-peptide osteoblast differentiation factor,
  promotes osteoinduction
• Indication fracture healing
• PD conserved x-species
• ratgtdogsgtNHP
• IV, IM tox rat, dog
• IV Rat, Rb embryo-fetal development
• Decreased female fetuses
• Decreased ossif. skull, pubic ischial,vertebrae,
  sternebrae
• Rabbit increased abortions at HD

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Developmental Safety Concern

• Literature indicates rh-peptide is involved in
  skeletal development
• Abs to this peptide are associated with atypical
  skeletal development
• KO mouse gene for peptide is embryonic lethal
  (cardiac defect)
• Effect of anti-rh-peptide Abs tested in immunized
  rabbits

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Developmental Study Immunized Rabbits

• Rh-peptide IM prior to mating
• Confirmed anti-peptide titers
• Relevant model
• Maternal to fetal Ab transfer as human
• High titers-no effect on repro/preg function
• Sm. inc. delayed ossif. of skull bones
• Litter variation in vascular organization from
  immunized dams

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Case 2Juvenile Animal Study

• Determine effect of treating bone defects in
  growing juvenile rabbits with active growth
  plates
• Concern metaphyseal fx w/ active physis can
  result in premature closure of the growth plate
  potential angular/rotational/length defect in
  limb
• Rabbit skeletal growth complete _at_ 28 weeks
• Rabbit growth plate fusion 25-28 weeks
• To support pediatric use of rh-peptide for fx
  healing

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Juvenile Rabbit Bone Lesion

• Unilateral mid-diaphyseal ulna osteotomy in 2 3
  month old rabbits
• Rh-peptide given SD implant
• Study duration 4 weeks
• Weekly evaluations
• ulna length
• growth rate/plate morph
• radiography of fx site
• healing time
• surgical control contralateral ulna

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Results Juvenile Rabbit Bone Lesion

• Decrease in growth plate thickness in rh-peptide
  trt limbs vs. surgical control
• Radiographic ulna growth rate reduced week 4 in
  rh-peptide vs. surgical control in 3 mo. Rbs
• Differences in ulna length depends on Rb age _at_
  treatment
• 2-month old rabbits -0.6 mm ulna length
• 3-month old rabbits -0.3 mm ulna length
• Accelerated time to bone healing w/trt
• Adult Rbs 75 trt lesions bridged 2wks vs. 33 SX
  CX
• But fx gap still _at_ 4 weeks complete _at_ 6weeks
• 40 2-month old 70 3-month old Rbs. bridged _at_
  1wk. vs (17) SX CX.
• Like adult bridging _at_ 2 wks.
• Lesion healing 80 in trt young Rbs vs. 40 in
  SX CX

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Limitations

• 4-weeks sufficient for Rb healing may not be
  analogous to that in children
• Model doesnt address the overgrowth phenomena
  seen in healing pediatric fractures
• ulna, radius, femur
• Long-term effect of ? g.plate thickness?
• Bone quality of bridge uncertain
• Untrt controls were from a different supply and
  had larger initial bone lengths
• Difference in bone size and growth plate
  comparison difficult
• Comparison to the surgical controls valid

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What have we learned?

• Experience with traditional biologics (MAb,
  peptides) helpful
• One size fits all development plan doesnt work
• New hybrid molecules pose new challenges
• Case by case with emphasis on science based study
  designs based on knowledge of the molecule
• Standard study designs may need modification to
  address concerns

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Pediatric initiatives ID data gaps

• Unnecessary exposure to ineffective therapies
• Many examples e.g. therapies for depression
• Ineffective dosing overdosing of effective
  drugs
• Effects on metabolism/clearance
• Most pediatric trials are short duration focus
  on PK
• New pediatric adverse events (AEs)
• Increased depression, suicide (human, no model)
• Effects on growth behavior

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Addressing data gaps

• Juvenile animal studies may provide added hazard
  ID adequate clinical monitoring in trial
• Guidance to Industry Non-clinical Safety
  Evaluation of Pediatric Drugs (Feb.2006)
• Juvenile animals may be useful to assess safety
  concerns not adequate, ethical or safely studied
  in pediatrics

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Application of Juvenile Animal Data to Clinical
Risk Assessment

• Assure adequate clinical monitoring
• Identification of safety risk
• Correlate juvenile animal adverse effect to
  exposure/duration
• Identification of irreversible/non-monitorable
  toxicity
• Assess delayed toxicity following acute exposure
• Pediatric trials are short duration treatment
• Apply biomarkers/methods identified to limit risk
  to trial design
• Label considerations
• Inclusion of relevant non-clinical findings
• Identification of use/non-use at specific ages

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Pediatric PK/PD Differences Exist

• Developmental /or sensitivity differences may
  result in altered PK/PD in pediatrics
• Development (structure/function) is continuous
• Role of developmental vs. chronologic age-matched
  animal/kids
• Consider cross-species postnatal maturation
• Organ System Maturation
• Neurologic Adolescent-Adult
• Reproductive Adolescent/Puberty
• Pulmonary (alveoli) Infant (1-2 years)
• Renal function Infant (1 year)
• Skeletal Adolescent-Adult
• Immune (IgG, IgA) Infant-Child (5, 12 years)

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Utility Of Juvenile Animal Models

• Juvenile animals may be appropriate for
  predicting postnatal developmental toxicities in
  children when...
• Likely use of the drug in pediatrics
• Safety data unavailable from toxicity testing or
  clinic
• Pre/postnatal studies indicate target organ
  toxicity
• Possible effects on growth/development
• Particular concern for long term exposure in
  relation to critical human postnatal
  developmental stages
• Most PK pediatric clinical trials are lt 6 months
  duration
• Consider the developmental age of animal relative
  to indicated pediatric population
• Timing duration of dosing relative to growth
  development in kids juvenile animals
• Type of study design Screening vs. focused
  study
• Not every pediatric product requires juvenile
  studies
• Case by case basis Depends on available info
  safety concern

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Conclusions

• Juvenile animal studies are useful, especially
  when performed to address a concern
• Juvenile animal studies are not prohibitively
  challenging to conduct
• However current data base is limited