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

20

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

21

• > 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

lisa.clarke-lens@quotientclinical.com

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www.quotientclinical.com