Lonza Group Ag · SIX:LONN
Lonza — Technical Presentation (February 2022)
48 slides from Lonza's technical presentation, Feb 23, 2022
Slide 1: Improving solubility and accelerating drug development through integrated programs
Enabling a Healthier World LONZGa Improving solubility and accelerating _e drug development through integrated programs David Lyon, Ph.D., Senior Fellow, Global R&D Peter Scholes, Ph.D., Chief Scientific Officer at Quotient Sciences Public Peter Timmins, Ph.D., Visiting Professor in the Department o
Slide 2: Amorphous Solid Dispersions, and Accelerating Drug Development
Amorphous Solid Dispersions, and Accelerating Drug Development Introductory Remarks * Drivers for the utilization of spray dried amorphous dispersions * Drivers for accelerated drug product development - addressing key questions early * Drivers for an integrated approach 23rd February 2022 | Webinar
Slide 3: Rapid Development of Amorphous Solid Dispersions (ASDs) for Improved Bioavailability
Rapid Development of Amorphous Solid Dispersions (ASDs) for Improved Bioavailability David Lyon, Ph.D. Senior Fellow, Global R&D, at Lonza 23rd February 2022 | Webinar with Pharmaceutical Technology
Slide 4: Small Molecule Technologies
Small Molecule Technologies LONZQa Flexible model across the product development cycle ‘Small Molecules VW Drug Substances & DESIGN Small / Lab-Scale (non-GMP) feasibility full range of API inclusive of GMP intermediates, HPAPI, cytotoxic payloads for ADC’s Cron Particle-Engineering AN > 350Projects
Slide 5: SimpliFiH Solutions - Rapid First-In-Human Services
SimpliFiH® Solutions - Rapid First-In-Human Services LONZa Designed for poorly soluble molecules and accelerated development ‘Small Molecules Solid State Characterization Technology Selection + Salt screening * Technology Review Board * Polymorph screen oversight * Chemical / physicochemical Selecti
Slide 6: Our Global Footprint in Small Molecules
Our Global Footprint in Small Molecules... LONZa Small Molecules e) 7 Sites Bend, USA Particle engineering / solid == dispersions Drug product Visp, Switzerland development & manufacturing Drug Substance development and manufacturing HPAPI and ADC capabilities Tampa, USA Drug product development and
Slide 7: Our Track Record — Small Molecule Programs
Our Track Record — Small Molecule Programs LONZa Best practices developed across our service offerings to meet a myriad of ‘Small Molecules customer needs K >350 > Therapies in clinical development in 2019* S&S >270 >» Commercial APIs and Intermediates in 2019* Lonza Pharma & Biotech supported 3 O%
Slide 8: Outline
Outline LONZa Small Molecules Drug & polymer B properties Problem statement Many oral oncology drugs are poorly soluble and show pH- dependent absorption 23rd February 2022 | Webinar with Pharmaceutical Technology Gl physiology Py) In vitro tools Case study Acalabrutinib amorphous solid dispersion (
Slide 9: Total approved drugs 2010-2019 by disease area
Total approved drugs 2010-2019 by disease area European licensed oral oncolytics, 2016 Brown & Wobst, J Med Chem, 2021 Sawicki, Cancer Treat. Rev., 2016
Slide 10: Weak Base Drugs Show Reduced Performance at High Gastric pH
Weak Base Drugs (e.g. oncolytics) Show Reduced Performance at LONZGa High Gastric pH Small Molecules Gastric PH - Gastric pH — B Gastric acid reducing agents (ARAs) e.g. proton pump fasting on ARAs = inhibitors (PPls) increase gastric pH 100000 e 40000 Increased pH results in reduced solubility of p
Slide 11: Calquence (Crystalline Acalabrutinib) Shows Reduced Performance with ARAs
Calquence® (Crystalline Acalabrutinib) Shows Reduced LOnNZa Performance with ARAs Small Molecules @ Bruton tyrosine kinase inhibitor indicated for ‘YU oncology (acalabruti nib) 100 mg capsules Crystalline free base in gelatin capsule Plasma AUC reduced by 43% when taken with proton pump inhibitor (P
Slide 12: Amorphous Solid Dispersion (ASD) to Overcome pH Effect
Amorphous Solid Dispersion (ASD) to Overcome pH Effect LONZa Small Molecules Bi scs2 BE St Pei 5.4 X 104 cm/s* Ba pK, 3.5, 5.8 (basic)* BI Melting point: 214° c# intrinsic sol.: 48 pg/mi* BE Glass transition: 133° C# 10 ASD (Measured) \ t 2, NH Solubility (mg/ml) Crystalline (Pepin et al.*) wa 0.01
Slide 13: In Vitro - In Silico ASD Development Strategy
In Vitro - In Silico ASD Development Strategy LONZa Small Molecules Tablet dissolution In silico prediction In vivo study Streamlined approach based upon drug, polymer, & physiological properties Mudie et al. Pharmaceutics 2021, 13, 1257 23rd February 2022 | Webinar with Pharmaceutical Technology Pu
Slide 14: HPMCAS-H and -M Polymers Provide Longest Supersaturation Sustainment
HPMCAS-H and -M Polymers Provide Longest Supersaturation Sustainment LONZa Small Molecules Solvent-shift UV assay Medium = pH 6.5 phosphate with 6.5mM bile salts (“SIF”) Measured concentration Drug Concentration Added concentration Time Mudie et al. Pharmaceutics 2021, 13, 1257 23rd February 2022 |
Slide 15: Create HPMCAS ASDs via Spray Drying
Create HPMCAS ASDs via Spray Drying LONZQa Small Molecules Drug loading (%) Dispersion polymer 1 25 HPMCAS-H 2 25 HPMCAS-M 3 25 HPMCAS-L 4 50 HPMCAS-H 5 50 HPMCAS-M 6 50 HPMCAS-L Dissolves > pH: ~5.7 (-H), ~5.2 (-M), ~4.8 (-L) Mudie et al. Pharmaceutics 2021, 13, 1257 23rd February 2022 | Webinar wi
Slide 16: ASD Intermediate Dissolution at Elevated and Low Gastric pH
ASD Intermediate Dissolution at Elevated (i.e. PPI) and Low Gastric pH LONZa Small Molecules Pion pDiss Profiler™ >| Dose concentration = 2 mg/ml > 1 mg/ml “non-sink’ in intestinal medium (WRT crystalline & amorphous sol.) Add concentrated FaSSIF solution at t= 30 min 10 ml pH2 or pHE Stir/monitor f
Slide 17: HPMCAS-H ASDs Show the Highest Enhancements Over Crystalline Drug
HPMCAS-H ASDs Show the Highest Enhancements Over Crystalline Drug LONZG Small Molecules 8 7 74 ce. 64 Ef 5] as sf 44 iS} YQ z= 24 M - 14 L 04 Bf AILASDs achieved higher BE HPMCAS-H ASDs achieved 50% drug loading HPEMCAS-H intestinal AUCs than the highest AUC ASD chosen as lead to crystalline acalabr
Slide 18: Immediate Release ASD Tablets - 60% Smaller Than Calquence
Immediate Release ASD Tablets - 60% Smaller Than Calquence LONZa Small Molecules Good tablet attributes } Function | Inaredint Tablet Fraction wt) Tablets 60% smaller than Calquence Good compression properties > 2 MPa tensile strength & 0.8 solid fraction compressed at 78 MPa Rapid disintegration ti
Slide 19: ASD Tablets Overcome pH Effect In Vitro
ASD Tablets Overcome pH Effect In Vitro LONZa Small Molecules Gastric compartment pH 2or6 100 mg dose (1mg/ml dose conc.) Intestinal compartment pH 6.5 + ‘SIF’ Waste compartment Mudie et al. Pharmaceutics 2024, 13(4), 557 23rd February 2022 | Webinar with Pharmaceutical Technology Gastric Compartmen
Slide 20: In Silico Predictions - Gain Confidence in Formulation
In Silico Predictions - Gain Confidence in Formulation Identified from LONZa In Vitro Testing Small Molecules fad eee Bottom - up predictions ia GastroPlus® v9.8 - = (Simulations Plus, Inc.) No optimization Gastric pH adjusted to reflect pentagastrin (bulk PH ~2) or famotidine pretreatments (bulk pH
Slide 21: 𝒅𝑴 𝑫𝒆𝒇𝒇 = ∙ 𝑨𝒔 (𝒕) ∙ 𝐶𝑠 − 𝐶𝑏 𝑡 𝒅𝒕 𝑹 ʄ
𝒅𝑴 𝑫𝒆𝒇𝒇 = ∙ 𝑨𝒔 (𝒕) ∙ 𝐶𝑠 − 𝐶𝑏 𝑡 𝒅𝒕 𝑹 ʄ ʄ
Slide 22: Acalabrutinib (µg/mL)
2/3 𝑑𝑀 𝑀𝑢,𝑡 3∙𝐷 = 𝑧 ∙ 𝑀𝑢,𝑜 𝐶𝑠 − 𝐶𝑏 𝑧= 𝑑𝑇 𝑀𝑢,𝑜 𝜌 ∙ 𝑟2 200 ASD Tablet Acalabrutinib (µg/mL) 100 Calquence Capsule 0 0 30 Time (min) 60 90
Slide 23: In Silico Predictions Suggest ASD Tablets Will Overcome pH Effect in Dogs
In Silico Predictions Suggest ASD Tablets Will Overcome pH Effect in Dogs LONZa Small Molecules 5,000 2 cae ° ° 3S 3S ro) ro) i) [o) fo) oO Q fo} fo} Acalabrutinib concentration (ng/ml) 100 mg dose ASD tablet, low pH i\\ \\ASD tablet, high pH 1 I \ ! I 12 \\ Calquence capsule, low pH i Seo 4 Vo | X
Slide 24: In Vivo Outcome Matches Bottom-Up In Silico Predictions
In Vivo Outcome Matches Bottom - Up In Silico Predictions LONZa Small Molecules Absolute average AUCo ing (ng h/mL) fold error (AAFE) 100 mg dose 5,000 Overnight fast, n = 6, crossover study, 1 — wk washout C, vs. AUC o int time 4,000 ASD tablet, low pH* ASD tablet, low 3,000 pH 8161 9766 1.2 13 ASD
Slide 25: ASD Tablets Overcame Acalabrutinib pH Effect On The First Try
ASD Tablets Overcame Acalabrutinib pH Effect On The First Try LONZa Using In Vitro - In Silico Development Approach Small Molecules Drug & polymer B Gl physiology Py) In vitro tools In silico tools properties a In Vivo Success \4= Methods can be applied to ASDs of other weak base drugs for mitigatin
Slide 26: References
References LONZa Small Molecules Mudie DM, Stewart AM, Rosales JA, Biswas N, Adam MS, Smith A, Craig CD, Morgen MM, Vodak DT. Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs. Pharmaceutics. 2021 Apr 15;13(4):557. doi: 10.3390/pharmaceutics13040557. Mudie, D.M.; Stewart, A
Slide 27: Line-of-Sight to Commercial: Spray Drying Equipment Scales at Lonza-Bend
Line-of-Sight to Commercial: Spray Drying Equipment Scales at Lonza-Bend LONZa Pre-clinical to commercial scales in place for phase-appropriate & rapid development Small Molecules Science of scale s ed to design PSD equipment , which ensures that you can achieve rapid scale-up and minimized API requ
Slide 28: Integrated development strategies to accelerate solubility enhancement
Integrated development strategies to accelerate solubility enhancement Peter Scholes, Chief Scientific Officer
Slide 29: Who we are and the difference we make
Who we are and the difference we make 29
Slide 30: How we work with our customers
How we work with our customers Integrated Programs Tailored services Turnkey solutions for shortening development times Individual services to meet customer needs Candidate Development Selecting the right molecules for development Formulation Clinical Trial Commercial Drug Development Manufacturing
Slide 31: Our locations
Our locations Delivering bespoke programs to address molecule need and customer preference ~1300 employees integrated across two continents 31
Slide 32: Overview
Overview • Challenges in predicting clinical outcomes from surrogate data • Translational Pharmaceutics and the benefits of integrating drug product manufacturing and clinical testing • Using human data to inform SDD formulation decisions • Case studies • Formulation assessments within a FIH study •
Slide 33: Preclinical to clinical translation is not straightforward
Preclinical to clinical translation is not straightforward Grass and Sinko, DDT Vol. 6, No12(suppl) 2001 Musther et al Eur.J.Pharm.Sci 2014 33
Slide 34: Biopharmaceutics toolbox
Biopharmaceutics toolbox BCS I BCS II BCS & DCS Good solubility Poor solubility Good permeability Good permeability assessment Specialized Biorelevant models characterization BCS III BCS IV Good solubility Poor solubility Poor permeability Poor permeability Lead Candidate Identification In silico pr
Slide 35: Data driven approach to formulation selection
Data driven approach to formulation selection Challenge and Complexity DCS Classification Formulation Technology Class I Class IIa Class IIb Class III Class IV API only Micronization Nanomilling Dissolution enhancers Amorphous dispersions Lipidic systems Complexation Efflux inhibitors Permeation enh
Slide 36: Best practice?
Best practice? Formulation strategy Integrated Approach to Formulation Strategy & Design & design ✓ Definition of Target Product Profile (TPP) ✓ Physiochemical testing to characterize your API Formulation & analytical Method development ✓ Development strategy based on DCS category ✓ Formulation scre
Slide 37: Translational Pharmaceutics: Our flagship platform for accelerating drug development
Translational Pharmaceutics® Our flagship platform for accelerating drug development Unique platform developed in 2008 Used by global pharma and biotech >400 drug programs completed Rapid ‘Make- Test’ Cycles (14d) Timeline acceleration of >12 months Significant reduction in R&D spend Better decision
Slide 38: Formulation design spaces
Formulation design spaces Creating greater real-time flexibility • Demonstration data generated on corner points, compositions bracketing the entire design space • Any formulation within the design space may be manufactured and dosed • No regulatory amendments or notifications • Compositions selecte
Slide 39: Translational Pharmaceutics and SDD development
Translational Pharmaceutics and SDD development • Review of most recent SDD programs (n=38) • 95% oral, 5% inhaled • Applications across development life-cycle • ~30% FIH, ~65% formulation optimization, ~5% life cycle (route switch) • Design space utilized in ~60% of programs • 1 or 2 variables • Do
Slide 40: Case study: Formulation screening during FIH study
Case study 1 Formulation screening during FIH study Background • R552 in development for the treatment of autoimmune and inflammatory disorders • Physicochemical and nonclinical PK data suggest poor solubility • Enhanced formulations to be evaluated in FIH study to achieve desired exposure levels Pr
Slide 41: Integrated program design: Formulation screen & bridge to solid dose in FIH
Integrated program design Formulation screen & bridge to solid dose in FIH • CMC development SAD Dose 6 (Dose form 2) • Dose form #1 - lipid solution SAD Dose 5 • Dose varied via concentration (Dose form 2) Formulation • Dose forms #2 & #3 SDDs as PiB selection SAD Dose 4 • Fixed drug loading (Dose
Slide 42: Clinical results
Clinical results • Linear and dose-proportional PK observed over the evaluated dose range • Steady state attained at 4 to 6 days after multiple once-daily doses • Inter-subject variability associated with exposure was low (range 6.0% to 42.7%) • Both SDD suspensions the SDD tablet formulation showed
Slide 43: Program outcomes
Program outcomes • Primary objectives of safety, tolerability and PK assessed • Flexibility to assess alternative formulations as part of SAD allowed human PK data to inform technology selection • Continued progression / conclusion of SAD and MAD with lead system • Parallel development of SDD solid
Slide 44: Case study: Identification of optimal SDD tablet formulation composition
Case study 2 Identification of optimal SDD tablet formulation composition Background • US Biotech company developed BCS Class 2 molecule, plan to move from FIH oral suspension to solid oral dosage • Multiple solubility enhancement technologies screened in vitro and in preclinical species - data did
Slide 45: Integrated program design: Formulation design space and clinical dosing
Integrated program design Formulation design space and clinical dosing • Two-dimensional design space defined for both Spray Dried Dispersions (P1 and P2), • Excipient concentrations adjusted to alter in vitro dissolution profile • Two cohorts, each n=10 subjects • Regulatory submission contained 7
Slide 46: Project outcomes
Project outcomes • Extra-granular tablet excipients critical in maximizing oral bioavailability • P1 SDD exposures in the range 39-98% versus oral suspension • P2 SDD exposures of 22-30% versus oral suspension • Real-time manufacturing enabled effective decision making based on human data • Expedite
Slide 47: Summary
Summary • Integration of drug product manufacturing and clinical testing empowers and de-risks decision making on formulation technologies and compositions • Translational Pharmaceutics has been used extensively in the development and optimization of SDD systems across the development life-cycle • P
Slide 48: Speaker Contact Details
Speaker Contact Details: Speaker Contact Details: David Lyon, Ph.D. Peter Scholes, Ph.D. Senior Fellow, Global R&D Chief Scientific Officer David.Lyon@lonza.com Peter.Scholes@quotientsciences.com