Translational Pharmaceutics : a unique platform to accelerate early oncology development

Transcription

1 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

2 Agenda Translational Pharmaceutics what is it? What benefits does it deliver? How Translational Pharmaceutics can help overcome the challenges in early oncology development Translational Pharmaceutics Healthy volunteers studies Patients studies 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

3 Industry configured in siloes Vertically integrated supply chains Make Test API synthesis Laboratories Pharmaceutical development Clinical trial supplies Healthy volunteers Patients Commercial manufacture Commercial development Contract Development & Manufacture Organisations Contract Research Organisations 3

4 Translational Pharmaceutics Make Test API synthesis Laboratories Formulation development Pharmaceutical analysis Real time GMP manufacturing Pharmaceutical development Clinical trial supplies Translational Pharmaceutics Healthy volunteers Patients Clinical Pharmacology Unit Regulatory affairs Data analysis & reporting Commercial manufacture Horizontal integration Commercial development 4

5 Real-time adaptive manufacturing Full GMP manufacture, with scalable technologies and processes 7-14-day make-test cycle time 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 GMP Manufacturing GCP Clinical Testing 7-14 day make-test cycles Pre-approved design space(s) increase program formulation flexibility MHRA Pre-approved design space 5

6 Translational Pharmaceutics: proven advantages 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 6

7 Translational Pharmaceutics services Research Early development PoC Full development Market Enabled-FIH Enabled-FIH RapidFACT Human ADME Enabled-FIH: Enabled First-In-Human RapidFACT: Rapid Formulation development And Clinical Testing 7

8 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

9 Enabled FIH case study: Assessment of safety, tolerability, PK and identification of a solid oral dosage form for patient studies Pi3k / mtor inhibitors NFkB pathway inhibitors Met kinase inhibitors 9

10 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

11 Dosage form selection within the FIH program Single clinical protocol Drug product selection 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) Single protocol and regulatory submission Typical MHRA approval time <20days Overall timeline <10mths Program budget: <$2m Drug product selected for Phase 2 MAD (Selected form) SAD POC/Patients Dose 5 (Selected form) (Selected form) 11

12 RapidFACT case study: Improvement in exposure and reduction in PK variability for CO-1686 Tyrosine kinase inhibitors FAK and Pyk2 kinase inhibitors Receptor antagonists Janus kinase inhibitors ER antagonists 12

13 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

14 Mean plasma conc (ng/ml) Study design and outcomes 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 PK profile CO mg free 150mg base free 150mg base 50mg free base HBr50mg HBr 150mg HBr Interim analysis after each period, followed by real time small scale manufacture Time post dose (hours) 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

15 Human ADME studies Evaluation of the mass balance, routes and rates of elimination and drug metabolism in the body 15

16 Options for ADME in oncology Healthy volunteers Healthy volunteers Oncology patients Human ADME Tyrosine kinase inhibitors Pi3k / mtor inhibitors MEK inhibitors HSP-90 inhibitors AR inhibitors Microdose Anti-metabolite pyrimidine analogue OncoADME Topoisomerase inhibitors PARP inhibitors DNA methylation inhibitors 16

17 Overview Healthy volunteers Therapeutic / sub therapeutic dose Fast recruitment Single dosing period Single site Single 14 C drug product manufacture Oncology patients Therapeutic dose Slow recruitment Multiple dosing periods Per patient 14 C drug product manufacture upon patient initiation Advantages of using Quotient 17 Significant knowledge and expertise in performing these studies 14 C drug product development and manufacture, QP released product Most efficient use of 14 C API Time and cost savings

18 OncoADME case study: Provision of personalized 14 C sterile drug product directly to oncology patients 18

19 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 months Objectives Obtain clinical data needed for regulatory application Perform the study as quickly and efficiently as possible Minimise cost input for 14 C labelled drug substance and drug product 19

20 Development program and clinical supply 14 C drug product developed (IV or oral) Regulatory data collected incl short term stability IMPD preparation and regulatory submissions Formulation developed for per patient manufacture 7 days stability data Regulatory data package available in 6 weeks Notification of patient enrolment 14 C drug Product manufactured Product shipped to clinic, fully QC released Patient dosed 7 days 5 days Personalised patient manufacture on demand Most efficient use of 14 C material utilised 20

21 Real-time adaptive manufacture for patient/poc studies Personalised product Patient weight Body surface area Genotype screen Patient packs Flexible bulk supplies > 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 21

22 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

23 To transform drug development with science and innovation Speed Quality Passion 23