Handling of PK data from ADA positive animals

Daniela Stoellneron behalf of the EBF TT-63

EBF 9th Open Symposium16-18 November 2016

Barcelona

Anti-drug antibodies (ADA) may leadto altered pharmacokinetics (PK) by

Ø Impacting the clearance of drugØ Interfering with the drug assay

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Sailstad et al. «A White Paper—Consensus and Recommendations of a Global Harmonization Team on Assessing the Impact of Immunogenicity on Pharmacokinetic Measurements» The AAPS Journal, Vol. 16, No. 3, May 2014

PK profiles in presence of ADA

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0

2

4

6

8

10

12

14

16

18

20

1.0

10.0

100.0

1000.0

0 14 28 42 56 70 84

Tite

r

drug

con

c (n

M)

time (d)

total drugfree drugIG titer

No impact

Increased clearance / interference in drug assay

Decreased clearance / higher exposure to

active drug

ADA neg

ADA pos

How should mean PK/TK concentrations + mean PK/TK parameters be calculated and reported if animals appear to be ADA positive in tox studies?

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Consider purpose of TK data

ØShow validity of tox study à proveexposure at start and end of dosing periodbased on mean concentration data

ØHuman dose prediction commonly basedon Day 1 data

ØSafety margin based on initial/steady-stateAUC and Cmax

ØEstablish PK-PD relationship based on individual PK-PD data

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A. Exclude all PK/TK data including timepoints before onset of immunogenicity from mean calculations regardless of the impact on the PK profile

B. Exclude PK data only if impact on PK profile

C. Include all PK data in mean calculations regardless of ADA status

D. Case-by-case based on scientific judgement

E. Full analysis with and without ADA positive animals to understand impact

Survey conducted within EBF-IGM community in 2015

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E: 46%B: 18%

C: 9%

D: 27%

Reporting of PK/TK summary statistics

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Survey conducted within EBF-IGM community in 2015Have you described your approaches in a SOP?

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No SOP7Yes

1

Answer skipped

3

No SOP but formal guideline «No SOP provides flexibility, but may introduceinconsistency»

When can a PK/TK profile be consideredas abnormal?

ØComparison between profiles of ADA negative and ADA positive animals

ØComparison of profiles within dosing phase to profiles after initial dose

Is the impact quantifiable?Can we define a threshold?

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Review of case studies

Case study 1

ØStudy design: SC administration of drug or vehicle once weekly for 4 weeks followed by a recovery period of 6 weeks

Ø 3/6 animals of low and mid dose group and 2/10 animals of the high dose group developed ADA during dosing phase

ØSome animals exhibited clear impact on PK profiles while others were less obvious

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Case study 1: excluding ADA positive animals was based on meanaccumulation ratio

Ø Ctrough concentrations at Day 8, Day 15, Day 22 and Day 29 were assessed

Ø Mean accumulation ratio (AR) from first to last dose (Ctrough Day 29 to Ctrough Day 8 ratio) was calculated from animals not determined to have PK impacted by ADA

Ø 1 standard deviation of the mean was calculated and animals with an AR less than this value were excluded from the analysis

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Case study 2

ØStudy design: SC administration of drug or vehicle once weekly for 8 weeks followed by a recovery period of 4 weeks

ØMajority of animals (8/10 animals of low andmid dose group and 7/10 animals of thehigh dose group) developed ADA duringdosing phase

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Case study 2: excluding ADA positive animals was based on mean accumulation ratio

Ø AUCt Day 57/Day 1 (AR) calculated

Ø AR >1.89 excluded

Ø AR <1.89 were included in TK parameter even if ADA+ve

conc

entra

tion

time

Case study 3

Ø IV administration of drug or vehicle once weekly for 13 weeks followed by a recovery period of 18 weeks

Ø 4/6 animals of low and 2/6 of mid dose group developed ADA during dosing phase with clear impact on PK profiles (rapid clearance). No ADA in high dose group (NOAEL)

ØMean of all animals calculated. ADA positive animals NOT excluded

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ConclusionØStandardization of reporting of PK/TK data

from ADA positive difficult:Each biotherapeutics program can be considered as unique– Different drug constructs and target biology– Different PK behaviour– Study designs may differ significantly

ØEBF recommends most applied approach: PK/TK summary statistics with all animals and with ADA positive animals excluded (where possible)

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AcknowledgementsTeam members:

Daniela Stoellner (Novartis, TT lead)Dragomir Draganov (Roche)James Lawrence (Envigo)Jasja Wolthoorn (Triskelion)Jo Goodman (MedImmune)Marie-Helene Pascual (Sanofi)Pascal Delrat (Servier)Per Holse Mygind (Novo Nordisk)Robert Nelson (Novimmune)Susanne Pihl (Ascendis Pharma)

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