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TRANSCRIPT
Translational Pharmaceutics®: a unique platform
to accelerate early oncology development
Lisa Clarke-Lens, Associate Director, Oncology Services
Quotient Clinical
Clinical Operations in Oncology Trials East Coast
15th July 2015, Boston, MA
Agenda
• Translational Pharmaceutics – what is it? What benefits does it deliver?
• How Translational Pharmaceutics can help overcome the challenges in
early oncology development
• Applications in early clinical trials with oncology molecules:
• First in Human case study (Enabled-FIH)
• Drug product optimization case study (RapidFACT)
• Human mass balance case study (OncoADME)
2
Translational Pharmaceutics
Healthy volunteers studies
Patients studies
Industry configured in siloes
3
Vertically integrated
supply chains
Make
Clinical trial
supplies
Pharmaceutical
development
API synthesis
Commercial
manufacture
Test
Patients
Laboratories
Healthy
volunteers
Commercial
development
Contract Development &
Manufacture OrganisationsContract Research Organisations
Translational Pharmaceutics
4
Horizontal
integration
Formulation development
Pharmaceutical analysis
Real time GMP manufacturing
Translational
Pharmaceutics
Make
Clinical trial
supplies
Pharmaceutical
development
API synthesis
Commercial
manufacture
Test
Patients
Laboratories
Healthy
volunteers
Commercial
development
Clinical Pharmacology Unit
Regulatory affairs
Data analysis & reporting
Real-time adaptive manufacturing
5
• Full GMP manufacture, with scalable
technologies and processes
• Fit-for-Phase drug product strategy:
• Batch size typically <250 units, with
capability to rapidly scale to >10,000 units
• Shelf-life typically 7 days, with potential
extension to >6 months
• 7-14 day make-test cycles
• Pre-approved design space(s) increase
program formulation flexibility
GMP
Manufacturing
GCP
Clinical Testing
7-14-day make-test cycle time
MHRA
Pre-approved
design space
Translational Pharmaceutics: proven advantages
6
Reduce development timelines by >6months
Precise dose and formulation selection driven by emerging clinical data
API consumption reduced by >85%
Simplified supply chain, all via Quotient Clinical
Translational Pharmaceutics services
7
Enabled-FIH: Enabled First-In-Human
RapidFACT: Rapid Formulation development And Clinical Testing
Enabled-FIH®
RapidFACT®
Early
development
Full
developmentMarketResearch PoC
Enabled-FIH®
Human ADME
Benefits of early trials in healthy volunteers
• Recruitment is more straightforward
• Cohorts can be dosed in full
• Less risk from co-medications
• Less variability in clinical data
• Studies are therefore quicker to conduct
• Benefits are magnified where the molecule has challenging
physicochemical or biopharmaceutic properties and there is a risk to
achieving adequate oral bioavailability
8
Enabled FIH case study:
Assessment of safety, tolerability, PK and identification of a
solid oral dosage form for patient studies
9
Pi3k / mTOR inhibitors
NFkB pathway inhibitors
Met kinase inhibitors
Background and objectives
• Background
• Small molecule, tyrosine kinase inhibitor
• First-in-Human (FIH) study required
• Differences in PK seen in preclinical studies in different species
• Program objective
• Conduct successful SAD/MAD study
• Move straight into Phase II with a solid oral
• Case study published at AACR 2015
10
Dosage form selection within the FIH program
11
SAD
Dose 1(Dose form 1)
SAD
Dose 2(Dose form 1)
SAD
Dose 3(Dose form 1)
SAD
Dose 4(Selected form)
SAD
Dose 5(Selected form)
SAD
Dose 6(Selected form)
SAD
Dose 3(Dose form 2)
SAD
Dose 3(Dose form 3)
Drug product
selection
• Single protocol and regulatory submission
• Typical MHRA approval time <20days
• Overall timeline <10mths
• Program budget: <$2m
• Drug product selected for Phase 2
Single clinical protocol
MAD(Selected form)
SAD
Dose 5(Selected form)
POC/Patients(Selected form)
RapidFACT case study:
Improvement in exposure and reduction in PK variability for
CO-1686
12
Tyrosine kinase inhibitors
FAK and Pyk2 kinase inhibitors
Receptor antagonists
Janus kinase inhibitors
ER antagonists
Background and objectives
• Background
• CO-1686, a tyrosine kinase inhibitor, in patient trials as a free base
• Variable PK observed
• Program objective
• Switch from free-base to new salt form and identify dose
• Screen immediate release (IR) formulation prototypes
• Further evaluate selected formulation for:
• Dose linearity
• Food effect
• Multiple dosing
13
Study design and outcomes
• 2-3 fold increase in bioavailability compared to same dose of free base
• >50% reduction in variability
• Overall program timeline: <8mths
• Selected formulation transitioned directly back into patient trials
14
Period 1
Free base at 150mg
current formulation
Period 2
Salt at 50mg
Formulation 1
Period 3
Salt at 150mg
Formulation 1
Period 4
Salt at 150mg
Formulation 2
Period 5
Salt at 150mg
Formulation 3
0
200
400
600
800
1000
0 4 8 12 16 20 24Me
an
pla
sm
a c
on
c (
ng
/mL
)
Time post dose (hours)
PK profile CO-1686
150mg free base
0
200
400
600
800
1000
0 4 8 12 16 20 24Me
an
pla
sm
a c
on
c (
ng
/mL
)
Time post dose (hours)
PK profile CO-1686
150mg free base 50mg HBr
0
200
400
600
800
1000
0 4 8 12 16 20 24Me
an
pla
sm
a c
on
c (
ng
/mL
)
Time post dose (hours)
PK profile CO-1686
150mg free base 50mg HBr 150mg HBr
Interim analysis after each period,
followed by real time small scale
manufacture
Human ADME studies
Evaluation of the mass balance, routes and rates of
elimination and drug metabolism in the body
15
Options for ADME in oncology
16
Tyrosine kinase inhibitors
Pi3k / mTOR inhibitors
MEK inhibitors
HSP-90 inhibitors
AR inhibitors
Human ADME
Anti-metabolite pyrimidine analogue
Microdose
Topoisomerase inhibitors
PARP inhibitors
DNA methylation inhibitors
OncoADME
Healthy volunteers Oncology patientsHealthy volunteers
Overview
17
Healthy volunteers
• Therapeutic / sub therapeutic dose
• Fast recruitment
• Single dosing period
• Single site
• Single 14C drug product manufacture
Oncology patients
• Therapeutic dose
• Slow recruitment
• Multiple dosing periods
• Per patient 14C drug product manufacture upon patient initiation
• Advantages of using Quotient
• Significant knowledge and expertise in performing these studies
• 14C drug product development and manufacture, QP released product
• Most efficient use of 14C API
• Time and cost savings
OncoADME case study:
Provision of personalized 14C sterile drug product directly to
oncology patients
18
Background and objectives
• Background
• Cytotoxic molecule, under going Phase III trials
• Human ADME study required in Oncology patients with solid tumors
• N=6 patients required, Intravenous drug product
• Expected recruitment rate of 12-18 months
• Objectives
• Obtain clinical data needed for regulatory application
• Perform the study as quickly and efficiently as possible
• Minimise cost input for 14C labelled drug substance and drug product
19
Development program and clinical supply
• Formulation developed for per patient manufacture
• 7 days stability data
• Regulatory data package available in 6 weeks
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14C drug product developed
(IV or oral)
Regulatory data collected incl short
term stability
IMPD preparation and regulatory submissions
Notification of patient enrolment
14C drug Product manufactured
Product shipped to clinic, fully QC
releasedPatient dosed
• Personalised patient manufacture on demand
• Most efficient use of 14C material utilised
7 days
5 days
Real-time adaptive manufacture for patient/POC studies
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• > 600 clinical trial manufactures and shipments performed
• > 12 countries shipped incl. US, Europe, Australia (multiple clinical sites)
• 99% success rate of meeting required dosing date
• All product provided within 1-3 weeks of notification
• Personalised product
• Patient weight
• Body surface area
• Genotype screen
• Patient packs
• Flexible bulk supplies
Summary
• Translational Pharmaceutics has had a positive impact on the drug
development process
• Proven to reduce timelines and cost
• Increased R&D productivity
• The case studies presented show how the platform is applied to different
study types for early oncology programs and has been demonstrated to
add benefits to healthy volunteers and patient supply studies
• Looking to extend our real-time adaptive manufacture and supply
approach for broader oncology patient studies
Clinical ADME studies
• First in patient studies
• Managing formulation changes/optimization
22
To transform drug development with science and innovation
Speed Quality Passion
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www.quotientclinical.com