The Impact of Drug Delivery on Modern Medicines

1. The Impact of Drug Delivery on Modern Medicines Waseem Malick Ph.D. Roche, Nutley, New Jersey ISPE Meeting & Annual Student Poster Competition, Roche, Nutley, April 21, 2011

2. Drug Delivery “The Promise” Drug Delivery Technologies can increase the likelihood of getting the right medicine for the right patient at the right place and at the right time A. D. Roses, Lancet (2000)

3. Transformation of a Molecule to a Medicinevia Creation of a Dosage Form Delivery Technology Excipient Manufacturing Process Drug Product Molecule / Compound Drug Delivery makes the difference between a great molecule and a great medicine

4. Drug Delivery Sophistication Emerging New Technology 3rd Technology 2nd Technology 1st Technology Past Present Future Advancements in Drug Delivery SystemsBreakthrough Research in Industry and Academia

5. Small Molecules Solubility Oral Bioavailability Peptides Solubility Stability Proteins Stability Aggregation MAb Solubility / Viscosity Aggregation Oligonucleotides Targeting Stability Modern Medicines “ Wide Variety of Molecules”Diversity of disease targets lead to diversity of molecular formats Different Molecular Formats Present Unique Delivery Challenges

6. Modern Drug MoleculesDesired Attributes of New Molecules • Mechanism Based • Novel biological targets (Discovery) • Thorough biological understanding • Known disease markers • Personalized health care • Highly Potent • Specific for the disease target • Wide therapeutic index • Well tolerated Drug Delivery Contribution • “Druggable” • Desirable PK/PD characteristics • Desirable physiochemical properties • Transformation to dosage form achievable

7. Desired Attributes of a Dosage FormEnable development of efficacious, safe, and quality products Efficacious • Differentiated Product • Patient Compliance • Drivers • Molecule Specific Delivery Needs • Clinical Advantage • Patient Compliance • Novel Technology • Intellectual Property • Stable • Shelf-life • Transport • Manufacturable • Robust Process • Cost effective

8. Material Sciences Biology Clinical Sciences Pharmaceutical Sciences Bioinformatics Engineering Chemistry Pharmaco-kinetics Safety Biochemistry Interdisciplinary Approach is Critical to Successful Drug Delivery A flexible interdisciplinary approach is critical to the future drug delivery innovation

9. Delivery of emerging modalities • siRNA, stem cells • Oral delivery of solubility limited molecules • BCS Class II and IV • Alternate delivery routes for proteins and peptides • Pulmonary, nasal, oral, buccal Key Challenges and Opportunities in Drug DeliveryTransformation of Molecules into Medicines  • Injectable delivery of high dose proteins, MAb, peptides • Viscosity, Aggregation  • Parenteral sustained delivery of Protein/Peptides • Conjugation • Formulation/Depot  • Targeted delivery systems • Site specific delivery, tumor targeting

10. Oral delivery of poorly soluble molecules • BCS Class II and IV Dissolution solution necessary for absorption Precipitation Absorption  • Solubility • Permeability • Stability

11. PharmacokineticMeasurement Clinical / PDMeasurement In-VivoDissolution Permeability Solubility Gut Wall DosageForm Drug inSolution Blood Site of Action Therapeutic Effect In-VitroDissolution pH 4.5 FaSSIF Amt Dissolved (mg) Journey of Molecules from Tablet to Target TissueIn-Vitro In-Vivo Performance Impacting PK/PD Adapted From : 2007 AAPS-FDA BCS, BE, and Beyond Workshop Presentation, entitled General BA/BE Issues, Dale Conner, Division of Bioequivalence, Office of Generic Drugs, CDER, FDA

12. Biopharmaceutical Classification System (BCS)Formulation intervention required to increase bioavailability of poorly soluble compounds • Root causes for poor bioavailability • Low aqueous solubility • Poor permeability • Challenges with poor bioavailability • Insufficient exposure • Lack of dose proportional absorption • High inter- and intra-subject variability • Potential side effects for narrow TI drugs • Food effect Industry average for BCS2/4 compounds is 40-60%

13. Oral Formulations Approaches for Poorly Water Soluble CompoundsConventional to Innovative Technologies to enable Enhanced Bioavailability Conventional  Non-Conventional : Risk and complexity Salts SEDDS/SMEDDS Nanoparticles Amorphous (high dissolution rate and super saturation) ~ 100 nm Particle size reduction Complexes Crystalline Solid Dispersion ~ 10 µm Need for novel formulations has increased significantly

14. /////////// /////////// /////////// Crystalline API Amorphous (Glass) API /////////// /////////// /////////// /////////// API + Stabilized Amorphous Formulation Polymer Design of Amorphous FormulationsPolymer selection critical to stablization and improving solubility • Higher chemical potential results in higher dissolution rate and solubilitybut also makes them thermodynamically unstable • API, without protection from matrix, may revert back to crystalline state • Polymer matrix can make amorphous system more stable, if properly selected • Selection of polymer and process are crucial

15. Amorphous Solid DispersionsStabilized amorphous form of the drug Amorphous drug uniformly embedded in a polymer matrix Amorphous Drug Stabilizing Polymer

16. API + Polymer + Solvent Washing With water Filter Acidified Cold Water Drying Filter • Spray Drying (SDD) • Solvent evaporation • Acceptable solubility of drug in low boiling solvent required • Hot Melt Extrusion (HME) • Temp. and shear • Non-solvent • MP < 200 °C required • Microprecipitation (MBP) • Antisolvent process • Allows use of high BP solvent • Stability in antisolvent critical Processing Technologies for Amorphous FormulationsChoice of technology depends on physico-chemical properties of molecule

17. …. Transformation of a highly efficacious but challenging molecule to a medicine using an innovative bioavailable formulation Story of Compound “X”

18. Form II characteristic signal Capsules Lot 07 - 0029 and 07 - 0045 show unmistakable level of Form II in them Form II Form II Phase 1 Capsule 07 - 0029, 300 mg, 5/2007 07 - 0045, 100 mg, 7/2007 07 - 0020, 100 mg, clinical 2000 3/2007 Lin (Counts) 07 - 0020, 100 mg, stability 1000 3/2007 Capsule Dissolution 07 - 0046, 300 mg, 7/2007 USP App-2, 75 rpm, FASSIF(500 mL) Capsules with Metastable Form I – Converted to Form II ( as seen by precipitation/ loss of solubility during dissolution 0 40.0 1 10 20 40 30 2-Theta - Scale 35.0 30.0 25.0 20.0 Mg dissolved 15.0 10.0 5.0 0.0 0 50 100 150 200 % Time (minutes) 07-0020 100 mg 3 capsules 07-0020 100 mg 1 capsule 07-0029 300 mg capsule Formulation Challenges of Compound “X”Bioavailable formulation was critical for the success of the efficacious molecule • Poor Solubility (crystalline API) >>>>> Poor Bioavailability • Prone to polymorphic transformation (metastable Form I to stable Form II) >>>> Loss of systemic exposure • High Dose >>>> Patient Dosing Convenience (Number of tablets per dose) Polymorphic conversion detected by Dissolution and pXRD MBP based amorphous formulation was invented based on physico-chemical properties of the molecule

19. Crystalline drug Polymer SDD & HME technologies unsuitable • Very high melting point • Poor solubility in organic solvents Polymer + Drugdissolved in organic solvent Cold Acidified Water Controlled precipitation Advantages of MBP • High Bioavailability • Unique stabilizing polymer offers innovative approach Filtration MBP Drying Washing MBP based high dose tablet formulation invented Suitable downstream process developed ensuring amorphous form stability Micropreciptated Bulk Powder (MBP) Roche invented and patented technology

20. Crystalline API Formulation MBP formulation MBP formulation AUC 0-24h 3000 1120 BID 3000 4000 3500 AUC 3000 960 BID 2000 2000 AUC 0-24 hr (uM*hr) AUC 0-24 hr (uM*hr) 2500 720 BID 2000 Mean Drug Exposure (uM*hr) 1500 1000 1000 1000 ………………….............................. Target AUC for regression 500 ………………….............................. PK Bridging Target AUC for stasis 0 0 200 400 600 800 1000 1200 160 240 360 720 1120 960 100 200 400 800 1600 Dose (mg BID) Daily BID Dose (mg) Daily BID Dose (mg) MBP Formulation delivered desired exposure in the ClinicCompound “X” Dose-Proportionality of Plasma AUC Dose Escalation in clinic • MBP formulation provided 8-10x higher exposure than crystalline formulation • The MBP formulation was dose proportional • Target exposures were achieved N. Engl. J. Med. 363: 809 (2010)

21. Day 0 Day15 MBP Formulation Enabled Efficacy in the Clinic for Compound “X”Highly bioavailable formulation with reduced pill burden Melanoma patient PET scan at baseline and day +15; 720 mg BID Reference: New England J. Medicine 2010

22. MBP Formulation Enabled Efficacy in the Clinic for Compound “X”Highly bioavailable formulation with reduced pill burden Melanoma patient PET scan at baseline and day +15; 720 mg BID Reference: Nature 467, 596-599 (7 September 2010)

23. Injectable delivery of high dose proteins, MAb, peptides • Viscosity, Aggregation  • Subcutaneous parental delivery limited to ~ 1.0 mL • High viscosity of concentrated solutions (Syringability)

24. IV Infusion versus Subcutaneous AdministrationPatient Convenience is a key driver in design of delivery systems Subcutaneous Injection Intravenous Infusion Subcutaneous parenteral delivery limited to ~ 1.0 mL

25. Injectable Delivery of High Dose Monoclonal Antibody (MAb)Challenges – SC Delivery High Dose Requiring high concentration (50 -200 mg/mL) Challenges • Risk of aggregation • Physical stability • High viscosity • Processing /manufacturing challenges • Administration challenges

26. sc lyo sc liquid im lyo iv lyo iv liquid 150 mg/mL 125 mg/mL 100 mg/mL 50 mg/mL 1mg/mL 1 mg/mL MAb / Peptides viscosity increases with concentrationViscosity and Aggregation mitigation is critical „Landscape“ of marketed MAb formulations IgG Kanai, Del Terzo, Wurth, Roche 2008 S. Kanai et al., J Pharm Sci 97 (2008) 4219-4227

27. Novel Technology to Enable Subcutaneous Injection of > 1 mL Injection Enzyme based Technology

28.  Hyaluronidase temporarily opens SC tissue Subcutaneous Administration of volumes >1 mLAllowing administration of larger volumes – paradigm shift Challenges of SC Delivery without EnhanzeTM • Low BA after SC injection (50%-70%) • Strong hyaluronan network hinders injection and tissue distribution of administered drugs • Limitation of small volume administration to avoid pain and patient discomfort • Tissue backpressure • Injection pain • Blebs after injection 15 mg/kg MAb SC in Göttingen minipigs (mean ± SD)

29. Administration of larger volumes (>1 mL) Halozyme EnhanzeTM Technology • Temporary breakdown of hyaluronan fibers by use of rHuPH20, a human soluble hyaluronidase (pores in subcutis) • Decreases tissue back-pressure and injection pain • Faster drug distribution, larger administration volumes, higher BA for biologics

30. Administration of larger volumes (>1 mL) Halozyme EnhanzeTM Technology • Technology being applied to several Medicines • Well tolerated • Clinical programs ongoing Technology allows subcutaneous delivery of intravenous medicines Halozyme Therapeutics Website

31. Parenteral sustained delivery of Protein/Peptides • Conjugation • Formulation/Depot  Interferon Alfa-2a to PEG Interferon “Conjugation Approach”

32. Advances in Formulation Development “Evolution” of Interferon Dosage Forms 1986 2004 Albumin containing lyophilizate Albumin containing solution Albumin free solution Specialized delivery devices (PFS, pen, NFI) Chemically Modified Interferons (Pegylation) Improved safety, efficacy and compliance

33. Synthesis of Pegylated InterferonSelection of suitable size of peg moiety was critical to achieve sustained exposure Interferon alfa-2a Branched 40 kD PEG • PEGASYS created with a 40-kDa polyethylene glycol (PEG) strand (Lys linkage) • Allows stable therapeutic serum levels up to a full week with a single dose

34. Interferon Short half-life Rapid absorption Sharp rise and decline High peak of systemic IFN Deep troughs Pegasys Sustained exposure - 72-96 h Reduced clearance Longer half-life - 168 h Steady state drug levels 5-8 wks Pegasys vs. Interferon Human PK StudiesAchieved sustained exposure Pegylation enabled once-a week dosing Ref. S. Zeuzem et. al. EASL, Rotterdam 2000

35. Conclusions

36. Optimized Protein & Peptide Formul. • Solubilization • Stabilization • High conc. SC Form. • Improve Tolera-bility/Efficacy • Parenteral Form. • (Including SR) • Enhance Oral • Absorption • Increase BA • Reduce Food Effect Improved Therapeutic Outcome Alternate Delivery for Proteins and Peptides Nasal, Pulmonary, Buccal, Oral Delivery of Oligonucleotides For Gene Silencing • Enhanced PatientCompliance • Oral Modified Release • Pediatric / Geriatric • Needle-Free Inj. • Brain Delivery • BBB Transport • Targeted Delivery • Parenteral Delivery (Micelles) • Bioadhesion • Tumor targetting • Colon Targeting Drug Delivery/Formulation Innovation “Drug Delivery System can make or break a drug”

37. Prescription Drug Sales ($Bn) US Drug Approvals from 2002–‘06 Information from www.fda.gov Drug delivery intervention accounts for > 2/3 of FDA product approvals US Ethical Drug Market - Strategies for Sustained Growth - BCC Res Drug Delivery ImpactSubstantial Market Value for innovative drug delivery products

38. Emerging Drug Delivery Landscape Intracelluar Delivery Nanomachines Nanochips Nanoshells Oligonucleo. Delivery Multifunct. Nanoparticles On-demand Release Bio MEMs Tumor targetting BBB Delivery Biomaterials Oral Protein/ Peptide Delivery

39. My Belief • Drug Delivery is becoming more interdisciplinary • Innovation is happening at interfaces of diverse disciplines • Cross training in multiple areas is emerging as a key success factor in delivery research • Universities providing multidisciplinary education are making an invaluable contribution to future drug delivery science • Pharmaceutical Researchers must reach out to other industries for finding innovative solutions to complex delivery challenges

40. We Innovate Healthcare