• 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