• Drug Delivery Experts
• Sustained Release Gel Formulations
• Modifying Biologics Properties with Salts
• Injection Site Reaction Model
• Oral Delivery Innovations
02/26
TECHNOLOGY FORUM DISCUSSION
• Specialists in combination drug product development
• Complex formulation design and device integration
• Extensive experience in biologics drug development
• Highly-qualified Ph.D. scientists
• 6,000 sq. ft. R&D lab, including process suite for clean fill
02/26
CENTER OF EXCELLENCE
Drug Product Development• Formulation design • Drug product development• Analytical methods
Leveraging a deep understanding of molecular properties, formulation, and deviceIntegrating delivery system R&D projects into your development program
Optimizing target product profile to enhance value proposition
Discovery Support• Lead molecule profiling• Clinical candidate evaluation• Biologic half-life extension
Device Selection• Device identification• Integration with formulation• Combination product development
DELIVERY SYSTEMS
08/26
Analytical Research
Development Assessment
AnalyticalDevelopment
Preformulation
Delivery System Feasibility
Formulation PK Screening
Formulation Development
Technology Transfer
GMP Mfg.
Lead Molecule Selection
Delivery System Selection
Drug Product Development
Molecule DesignPeptide/Protein VariantsConjugates for Half-Life
Delivery System DesignAqueous or Non-Aqueous VehicleSustained Release FormulationTriggered or Targeted Systems
Drug Product DesignPen/Auto-InjectorPre-Filled Syringe
Nasal/Ocular Drops/Spray
Lead Molecule Design
Development Stability
Process Development
Scale Up
Analytical Methods
Qualification
Device Selection and Development
LAB CAPABILITIES
LEADERSHIP
CASE STUDY #1: SUSTAINED RELEASE GEL FORMULATION
Monday, July 23, 2018 8Confidential
SUSTAINED RELEASE GEL FORMULATION
Monday, July 23, 2018 9Confidential
SUSTAINED RELEASE GEL FORMULATION
Monday, July 23, 2018 10Confidential
SUSTAINED RELEASE GEL FORMULATION
CASE STUDY #2: PEPTIDE SALT SCREENING & SELECTION
Monday, July 23, 2018 12Confidential
PEPTIDE SALT SCREENING & SELECTION
Monday, July 23, 2018 13Confidential
PEPTIDE SALT SCREENING & SELECTION
Monday, July 23, 2018 14Confidential
PEPTIDE SALT SCREENING & SELECTION
Salts can be used to decrease solubility and slow dissolution
for sustained release PK profiles
CASE STUDY #3: INJECTION SITE REACTION
Monday, July 23, 2018 16Confidential
INJECTION SITE REACTION MODEL
Monday, July 23, 2018 17Confidential
INJECTION SITE REACTION ASSESSMENT
Monday, July 23, 2018 18Confidential
INJECTION SITE REACTION RESULTS
In vitro precipitation model is correlated to injection site reaction score and exposure
INNOVATIONS IN ORAL DRUG DELIVERY
Monday, July 23, 2018 20Confidential
PEPTIDE AND ORAL DELIVERY TECHNOLOGY EVOLUTION
Semaglutide - Long-acting Peptide and
Permeation Enhancer&
Linaclotide - Stable Peptide for Local Oral
Delivery
Microneedles and Long-Acting Peptides
Others???
Salmon Calcitonin Octreotide, CR845
in Permeation Enhancing Systems
Microneedle Advances Applied to Oral Delivery
(Rani, MIT)
Impr
ovem
ents
in P
eptid
e St
ruct
ure
New Delivery Approaches
Monday, July 23, 2018 21Confidential
PEPTIDE ORAL DELIVERY 40 YEARS ON
Challenges of oral peptide delivery
• Low permeability across epithelial membranes
• Low bioavailability impact on cost and manufacturing scale
• Poor stability of peptide in standard oral formulations
Technology Solutions• Standard enteric coated tablet or capsule• Permeation enhancing excipients• Summary: BA << 5% vs SC injection
Monday, July 23, 2018 22Confidential
SCT ORAL FORMULATION PROGRAMTARSA THERAPEUTICS (ENTERIS / UNIGENE)
• Originally supported by Novartis to phase 3• Unigene and Novartis developed oral tablet
formulation• Bioavailability ~ 1% vs SC• Phase 3 study: 200 microgram• Phase 3 results published• FDA accepted for review Oct 2015• Initiated development 1990 or so• Citric acid, lauryl carnitine
MW 3431.85 g/mole
[1] A Phase 3 Trial of the Efficacy and Safety of Oral Recombinant Calcitonin: The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) Trial, N Binkley, M Bolognese, A Sidorowicz-Bialynicka , T Vally, R Trout, C Miller, C E Buben, J P Gilligan, and DS Krause, Journal of Bone and Mineral Research, DOI: 10.1002/jbmr.1602 (p. 1821-1829)
Monday, July 23, 2018 23Confidential
SEMAGLUTIDE FOR ORAL DELIVERYNOVO OPTIMIZED GLP-1 ANALOGUE
• Bioavailability ~ 0.25% vs SC injection• Phase 3 study doses: 3, 7,14 mg orally vs 0.5 mg SC• 2019 NDA submission likely• Standard permeation enhancing technologies (Emis SNAC)• Likely to experience food effect – may not be as important• Novo relying on ability to manufacture recombinant GLP-1 cost
effectively (North Carolina manufacturing plant)• Structure is similar to Liraglutide with some important changes
Monday, July 23, 2018 24Confidential
ORAL DELIVERY INNOVATIONDEVICE ENGINEERING APPROACH
• Greatest leap forward is from engineers• Microneedle as an approach for oral delivery
• Rani Therapeutics (dissolving microneedles)• Bob Langer and MIT group (metal microneedles)
• Risks• Technology risk – very early exploratory studies, limited PK data• No safety data – safety of regularly penetrating lumen of gut• Drug loading, device complexity, manufacturing complexity
Monday, July 23, 2018 25Confidential
RANI THERAPEUTICSDISSOLVING MICRONEEDLE APPROACH
www.ranitherapeutics.com
Rani Therapeutics comes from Mir Imran’s Incube Labs
• Solid microneedle (stability)• Enteric coated capsule• Bioavailability >50% vs SC• Microneedle and capsule
release mechanism are new• Large biologics possible• Long half-life opportunity• Phase 1 late 2018
Monday, July 23, 2018 26Confidential
MIT GROUPMETAL MICRONEEDLES
MIT Group:Bob Langer, Daniel Blankschtein, Daniel Anderson, Avraham Schroeder, Carlo Traverso, Baris Polat, Carl Schoellhammer
Ref: Traverso et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:362–367, 2015
• Microneedle is solid or hollow• Novo collaboration
Monday, July 23, 2018 27Confidential
ORAL BIOLOGICS DELIVERY SUMMARY
• Permeation enhancers are still primary approach• Bioavailability still quite limited (e.g. 2% sCT)• Risks well characterized• Formulations and manufacturing well understood
• Promise of devices for oral delivery• Gut penetration approach is significant• Risk profile still to be defined• New manufacturing systems needed
Monday, July 23, 2018 28Confidential
I am fortunate to work with a really strong team!
Thanks to our collaborators, clients, colleagues, friends, and advisors!
Monday, July 23, 2018 30Confidential
SEMAGLUTIDE STRUCTURAL DIFFERENCES TO LIRAGLUTIDE (ONCE DAILY GLP-1)
2. Fatty acid side chainoptimized for enhanced albumin binding affinity
3. Linker optimized move the albumin bound fraction (99%) away from albumin to enhance activity
1. C-terminus histidinechanged to AIBN for enhanced DPPIV stability