PowerPoint Presentation€¦ · Clinical ethics drives minimising pre-clinical toxicology Early...
Transcript of PowerPoint Presentation€¦ · Clinical ethics drives minimising pre-clinical toxicology Early...
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March 2018
ELLEGAARD EXHIBITOR HOSTED SESSION
ANTICANCER DRUG DEVELOPMENTCOMPARISON OF TOXICITY IN MINIPIG AND
MOUSE
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Increasingly Cancer
Touches
All of Our Lives
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Increased Survival Driven by Animal Research
Cancer Survival has Doubled in the Last 40 Years
Animal Research Critical to this Progress
Continued Animal Work Vital to Save More Lives
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Cancer will affect1 in 2
Aspiration> 75% survival
Source – www.cancerresearchuk.org
Aspiration to Improve Survival
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of promising small molecule anticancer agents have been developed
Few shown to be safe and efficacious in humans
Considerable impact in Development and Human Cost
Improved Pre-Clinical Assessment of candidates needed
Anticancer Drug Development
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Clinical ethics drives minimising pre-clinical toxicology
Early stage clinical trials in cancer patients are often initiated with limited toxicology data
A clinical trial at a dose < efficacious is undesirable
A clinical trial producing unexpected severe toxicity is even worse
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Anticancer Drug Development
Most Commonly Used Model
Similar to Human
Genome
Historically the Only Pre-Clinical Species
Extensive Background Data
Variety ofGenetic Models
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Not always reliable – drugs work well at preclinical stage but ineffective in clinical trials – e.g. 9-aminocamtothecin
Mouse bone marrow potentially less sensitive than human
Fundamental challenge for clinical cancer drug development
Mouse
Predictivity Non-Clinical to Clinical
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Other Species
NHP
• Likely similar bone marrow sensitivity to man
• Expensive
• Ethical concerns
• Disease status (immunosuppression)
Dog
• Possibly similar bone marrow sensitivity to man
• Prone to emesis
• Ethical concerns (charities)
Minipig
• Possibly similar bone marrow sensitivity to man
• Less prone to emesis
• High throughput –cost effective
• Reduced ethical concern
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Alternative species
Similar to Human
Genome
Increasing #Genetic Models
Extensive Background Data
Growing use – well accepted non-rodent species
Regulatory pressure to use two species
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STUDY DATA COMPARISON
Mouse versus Minipig
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Preliminary and 14 Day Study in the Mouse
- MTD and Range Finder in the Minipig
- 28 Day Minipig with a 28 Day Treatment-Free Period
Test Item : Novel Oral Anti-cancer drug (non-solid tumours)
Non-Clinical Studies conducted
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Mouse – Preliminary and 14 Day Study
Study Design
Click to add text
GroupDose level
(mg/kg bid)
Number of animalsDuration of dosing
Males FemalesPreliminary phase
5 150 2 2 7 days
6 225 2 2 up to 7 days
7 100 2 2 7 days8 125 2 2 7 days
Dose range finding phase
1 75 12 12 14 days
2 125 12 12 12 days
3 75 3 3 14 days
4 125 3 3 13 days
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Minipig – MTD and Range-Finding Study
Group Animal
Dose level (mg/kg bid) on
Days
1 - 4 5 - 11 12 - 25 26 - 32 33 34 - 37
1Male 95 0 6 ND 9 ND 12 Necropsy (Day 34)
Female 98 0 6 ND 9 ND 12 Necropsy (Day 37)
Study Design - Phase 1
Study Design – Phase 2
GroupAnimal Numbers Dose (mg/kg bid)
Males Females
2 97 99 6
3 101 100 9
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Minipig – 28 Day Study with 28 Day Treatment- Free Period
Study Design
Group
Number of animals Animal ID numbers Dose level
(mg/kg bid)
Dose
concentration
(mg/mL bid)Males Females Males Females
1 5 5 33 - 3751 - 53,
57, 58Control 0
2 3 3 38 - 40 46 - 48 3 0.6
3 5 5 41 - 4549, 50, 54
- 566 1.2
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Dose Level Comparison
Mouse Minipig
Dose Level mg/kg BID
Low 75 3
High 125 6
Minipig dose levels more in line with human dose levels
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Measured Study Endpoints
Mouse MinipigClinical Observations post-dose and daily post-dose and daily
Body weights twice weekly, daily weekly
Food consumption twice weekly
Ophthalmoscopy acclimatisation and end of study
Electrocardiograms acclimatisation and end of study
Haematology end of study acclimatisation and end of study (additional 0.1 mL taken twice
weekly)
Blood Chemistry end of study acclimatisation and end of study
Urinalysis at necropsy, by cystocentesis
Proof of Absorption/TK
end of study Day 1 and Day 28
Organ weights
Pathology
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Plasma and Liver concentrations
Proof of Absorption - Mouse
0
2000
4000
6000
8000
10000
12000
Mouse - plasma Mouse - liver
End of study
Male Low dose Male high dose Female Low dose Female High dose
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TK Data - Minipig
Mean Plasma Profiles
Day 1 Day 28
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Plasma concentrations – end of study (1 hour)
Proof of Absorption comparison
0
1000
2000
3000
4000
5000
6000
7000
Mouse - plasma
Mouse
Male Low dose Male high dose
Female Low dose Female High dose
0
200
400
600
800
1000
1200
Minipig plasma (Day 28)
Minipig
Male Low dose Male high doseFemale Low dose
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Clinical Observations - Similarities to Human
Mouse
Piloerection
Pale Extremities
Decreased Activity
Hunched Posture
Minipig
Tremors
Vomiting
Subdued Behaviour
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In-Life Findings – Body weights
Mouse
30.5
31
31.5
32
32.5
33
33.5
34
34.5
35
35.5
36
Day 1 Day 4 Day 8 Day 11 Day 15
Males
Low dose High dose
23.5
24
24.5
25
25.5
26
26.5
27
27.5
Day 1 Day 4 Day 8 Day 11 Day 15
Females
Low dose High dose
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In-Life Findings – Body weights
Minipig
9
9.5
10
10.5
11
11.5
12
12.5
13
Week -2 Week -1 Week 1 Week 2 Week 3
Females – High dose
Female 1 Female 2 Female 3 Female 4 Female 5
9
9.5
10
10.5
11
11.5
12
12.5
13
Week -2Week -1 Week 1 Week 2 Week 3 Week 4 Week 5
Males – High dose
Male 1 Male 2 Male 3 Male 4 Male 5
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Clinical Pathology Results - Males
0
0.5
1
1.5
2
2.5
3
Mouse -low dose Mouse High dose Minipig - Control Minipig - Low dose Minipig - High dose
Neutrophil counts 103uL
Background/Pre-dose End of treatment
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Clinical Pathology Results - Males
0
1
2
3
4
5
6
7
8
Mouse -low dose Mouse High dose Minipig - Control Minipig - Low dose Minipig - High dose
Neutrophil counts 103uL
Background/Pre-dose End of treatment End of treatment-free
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Clinical Pathology Results - Females
0
0.5
1
1.5
2
2.5
3
Mouse -low dose Mouse High dose Minipig - Control Minipig - Low dose Minipig - High dose
Neutrophil counts 103uL
Background/Pre-dose End of treatment
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Clinical Pathology Results - Females
0
0.5
1
1.5
2
2.5
3
3.5
4
Mouse -low dose Mouse High dose Minipig - Control Minipig - Low dose Minipig - High dose
Neutrophil counts 103uL
Background/Pre-dose End of treatment End of treatment-free
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Bone Marrow Smear
Control High Dose
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MinipigBone Marrow Smear Depletion
Control Low Dose
High Dose Early decedent
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Mouse Pathology
Pathology
Treated mouse - duodenum
Control mouse- duodenum
Crypt cells, nicely basophilic
Villi protruding into centre region
Very little basophilia
No/limited replenishment of cells
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Mouse Pathology
Pathology
Treated mouse – duodenum
Apoptopic bodies
Crypt region knocked out
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Mouse PathologyPathology
Treated mouse – ileum
Control mouse- ileum
Abnormally shaped nuclei and abnormal cell turnover
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Minipig Pathology
Pathology - Minipig
Caecum Colon
Surface focal erosions
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Longer duration repeat dose toxicity study
Animals closely monitored (haematology) and taken off dose when necessary
Clinical signs and pathology similar to man
Haematology: reduction in total white cell count (neutropenia, lymphocytopenia)
changes fully reversible
Main pathology: bone marrow and intestines
There were non-responders on the study!
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Clinical use in humans
Expected dose levels similar to those selected for minipigs, mice > 10x higher
Main pathology in humans:
Haematology and bone marrow
Responders and non-responders (man and minipig)
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Pros and Cons
Pros Cons
Minipig Mouse Minipig Mouse
Pre-clinical cost √ √
Additional Haematology
monitoring√ √
Similarity to humans :-
Clinical signs √ √
Haematology effects √ √
Bone marrow effects √ √
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Overall Conclusions
most frequently used model for anticancer drugs.
frequent disappointments when moving into clinical trials.
high cost in both financial and human terms of clinical failures.
better preclinical model is called for.
offers a viable non-rodent species or alternative to commonly
used rodent models.
monitor parameters throughout the study.
although the initial cost is higher
outweighed by improved prediction of clinical efficacy.
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Acknowledgements
Ellegaard
Client for allowing me to share the data
Sequani Personnel
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Thank you for your Attention
Easy Questions ????