RapidFACT: Accelerated Formulation Development for Poorly Soluble Drugs and Modified Release Products

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1 RapidFACT: Accelerated Formulation Development for Poorly Soluble Drugs and Modified Release Products Kevin Kane, Scientific Director, BCP 7 th Annual Global Drug Delivery & Formulation Summit 28 th August 2017 Boston, MA USA

2 Presentation outline What do we mean by optimization? How do we develop formulations today? Introduction to Translational Pharmaceutics Overview of RapidFACT Formulations to address poor drug solubility Development of modified release products Summary 2

3 What do we mean by optimization? Early development Late development/ Commercial Formulation Optimization Drug delivery Marketable Scale Stability 3

4 Drug and formulation performance are rarely ideal Half-life Variability Proportionality Increasing dose Blood Level of Drug Blood Level of Drug Blood Level of Drug 0 24 Time (Hours) 0 24 Time (Hours) 0 24 Time (Hours) Invariably there is a need to address formulation during drug development to either Promote drug solubility to achieve efficacy, or Modify the shape of the PK profile to sustain the therapeutic effect 4

5 Conventional formulation development Drug substance Stability studies Storage at Clinic Formulation & analytical development Engineering Batch (Repeat Preclin?) Dose and study conduct Preclinical evaluation Clinical manufacture & release, Ship Reporting Process development File and Await approval Next step is..? Grass and Sinko, DDT Vol.6, No. 12(Suppl.), 2001 Confirmed by Musther et al Eur.J.Pharm.Sci 2013 Drawbacks of this approach include: Time and cost (12-18 months, outsource cost $1.5M to $2.5M) Selection decisions based on in vitro and pre-clinical data Clinical testing restricted to a pre-defined, pre-approved selection of prototypes 5

6 The Local Maximum Problem 6 View of true objective is obscured Every optimization step feels downhill Other potential routes forgotten or left behind

Translational Pharmaceutics Make Test API synthesis Laboratories Formulation development Pharmaceutical analysis Real time GMP manufacturing Pharmaceutical

Commercial manufacture Horizontal integration Commercial development Integration of Development, GMP, and GCP capabilities enables: Full-service formulation

7 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 Integration of Development, GMP, and GCP capabilities enables: Full-service formulation development or transfer and optimization Real-time manufacturing and dosing to volunteers within days Flexibility within CMC and clinical domains to respond to arising PK/PD data 7

8 Real-time adaptive manufacturing Full GMP manufacture 7-14-day make-test cycle time Fit-for-Phase drug product strategy: Shelf-life typically 7 days Batch size typically 250 units GMP Manufacturing GCP Clinical Testing 7-14 day make-test cycles Pre-approved prototypes or design space increase program formulation flexibility Developable and scalable for downstream development Shelf life extension to >6 months Rapid scale up to >10,000 units MHRA Pre-approved prototypes or design space 8

9 RapidFACT: real-time formulation screening Rapid Formulation development And Clinical Testing Drug substance Manufacturing methods Analytical methods Pharmaceutical development program Regulatory application Tablets Capsules Multiparticulates Granulation Clinical Make-Test cycle Real time, adaptive manufacture Clinical dosing Spray drying Coating Particle size reduction Lipids Parenterals Non-oral delivery 9

10 Composition variable #2 Formulation design space to enhance flexibility FP1 FP2 Freedom to adjust formulation to optimize performance Formulation design space No requirement for regulatory amendments FP4 FP3 Parameters investigated Drug dose/concentration Functional excipient content Processing parameters Composition variable #1 10

11 Breadth of experience 11 Over 125 RapidFACT programs and 400 formulations

Case study: Spray dried dispersion development Background Poorly soluble NCE Spray dispersion used for First-inhuman studies Administered as

12 Case study: Spray dried dispersion development Background Poorly soluble NCE Spray dispersion used for First-inhuman studies Administered as Powder-in-bottle Goals: Transition to solid oral dosage form and maintain drug exposure Scale-up and supply Phase II product Avoid critical path impact on program 12

13 SDD tablet development program design Clinical Part 1 Reference (powder in bottle) Formulation & analytical development CMC batches for regulatory filings Lead tablet system (X mg) * Lead tablet system (Y mg) * Lead tablet system (Y mg fed) Clinical Part 2 Multiple dosing SDD development Dry granulated IR tablet 1-D Design space QC methods Biorelevant dissolution Batch release data 1 week stability data 1 month extension plan 4 period crossover 12 healthy volunteers Subjects on-site to 48h post dose 10 days BID dosing 8 active: 2 placebo Single protocol, one approval 13

14 RapidFACT program outcomes Program timeline: Labwork Initiation* Regulatory submission FSFD Draft CSR Pharmaceutical development program CTA prep Ethics & MHRA Vol scr Part 1 Part 2 Reporting 16 wks 3 wks 4 wks 3 wks 6 wks 4 wks 10 wks SDD tablet established in 16 weeks FSFD in 26 weeks and LSLD in 34 weeks Relative bioavailability of 100% vs suspension (fasted state) Production scale up and supply to PoC studies underway 14

Optimization of SDD tablet composition BCS II molecule Transition to IR tablet required Multiple solubility enhancement technologies screened in vitro and in preclinical species

15 Optimization of SDD tablet composition BCS II molecule Transition to IR tablet required Multiple solubility enhancement technologies screened in vitro and in preclinical species - data did not correlate No reliable animal model to evaluate formulation prototypes 2 x SDDs developed each with a 2d design space for excipients affecting in vitro dissolution 15

16 Clinical outcomes Cohort 1 Cohort 2 Reference Reference 10 different SDD tablets rapidly screened in clinic P1 high surfactant P1 high surfactant + acid Test treatment #A1 Test treatment #A2 Test treatment #A3 P2 high surfactant P2 high surfactant + acid Test treatment #B1 Test treatment #B2 Test treatment #B3 Extra-granular excipients critical to maximize exposure P1 = 39 to 98% F rel P2 = 22 to 30% F rel Best performing P1 tablet selected for Phase II Discriminatory in vitro dissolution methodology confirmed = Interim data review 6 month time saving 16

17 Classical evaluation of modified release formulations Reference 4hr release 8hr release 16hr release Typically screen slow, medium and fast release formulation at fixed dose Extension on T max Reduction in C max Some increase in C trough Further cycle of development typically required to optimise PK 17

18 Case study: Extended release development Background SLX2101 PDE5 inhibitor being developed for hypertension IR product used for early development C max driven AE profile, C min below PD threshold over 24hr period Program objective Develop a controlled release formulation Eliminate C max related adverse events Ensure 24hr coverage to support once-a-day dosing 18

19 Release (mg) Dose Design space configuration FP1 FP2 Erosion-controlled matrix tablet Design space defined by 4 prototypes Ability to change dose at fixed release rates Ability to change release rate at fixed dose Regulatory approval for real-time dosing of any drug product within the design space Formulation design space FP4 FP3 Polymer content (%w/w) Dissolution space Time (hrs) FP1 FP3

20 Concentration Concentration Concentration Optimization process Reduced C max Raised overall profile Raised C min Time (h) Time (h) Time (h) IR profile Delay release to reduce peak:trough Adjust dose to raise C max and C min Formulation selection driven by interim PK and safety data

21 Program results - clinical data highlights Reference FP-X FP-Y FP-Y FP-Y fed Optimized drug product selected within 3 study periods Final period used to confirm absence of food effect Program timeline 28 weeks, start to finish 21

22 Summary Translational Pharmaceutics delivers horizontal integration of GMP and GCP providing flexibility and efficiency in early development RapidFACT allows the development team to exploit these benefits Convention RapidFACT Timeline savings None Typically save >6 months Flexibility Fixed compositions Adaptive within protocol Formulation decisions Based on pre-clinical data Based on clinical data API consumption Standard Up to 85% reduced CMC/CTM savings None Typically > 500,000 Supply chain Typically >4 vendors Quotient Clinical 22

23 Optimizing for the Global Maximum with RapidFACT RapidFACT Optimal Conventional Sub-optimal Starting point 23

24 To transform drug development with science and innovation Speed Quality Passion 24

25 Case study selection Company Objectives Category Transition CO-1686 to healthy volunteers and switch salt form Development of a new inhaled bronchodilator therapy Once daily product development for an obesity compound Improve bioavailability of the protein kinase inhibitor nilotinib Development and clinical evaluation of enabled formulations of IDX-719 Development of a once daily formulation to increase C24 and reduce Cmax Optimise drug release profile of LY MR tablets through scintigraphic imaging Reformulation of an IV therapy for subcutaneous delivery PD assessment of three ophthalmic formulations to reduce intraocular pressure Solubilisation Non-oral Modified release Solubilisation Solubilisation Modified release Modified release Route switch Non-oral Not for profit Development of an age-independent formulation for BCS Class 2 compound Solubilisation Salt form change and pharmacodynamics assessment of GI tolerability Evaluating of Novel enabled formulations of RHUDEX Salt form Solubilisation Biotech Pharmacokinetic Properties of Various Modified Release Tablet Formulations for IVIVC Modified release Gastro-Retentive controlled release technology to enable once-daily dosing Modified release 25

Bioavailability and Bioequivalence Studies

Bioavailability and Bioequivalence Studies Standard Approach Part I: Design and Conduct H. Rettig, Ph.D. LLC www.ivivc.com Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98