A Year in Review on the Drug Delivery Pipeline Kurt R. Sedo

Vice President, Operations PharmaCircle LLC

Miami, FL

A Year in Review on the Drug Delivery Pipeline

• Products/Pipeline Overview

• Current State and Trends – Injection, Oral, Ophthalmic, Inhalation, Nasal, Topical, Transdermal

• Current Innovative Drug Delivery Pipeline

• Venture Capital Investments

• Conclusions

Overview: Innovator Products and Pipeline

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Route: Marketed vs Pipeline

Marketed

Pipeline

DD 38% Non-DD

62%

Marketed Products

DD 37%

Non-DD 63%

Pipeline Programs

Drug Delivery Pipeline Analysis

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DD Pipeline by Phase/Route

Phase 3

Phase 2

Phase 1

Preclinical

Research

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DD Pipeline Moved to Clinic 2017 - Sept 2018

2017

2018

Overview/Trends: Injectables

• Injectables Taking Over Pipeline

• Devices, Devices, Devices… – Multiple device strategies incorporated

into first approvals (e.g. Repatha)

• Delivery of High Volume and/or Viscous Biologics

• Trending Formulation Approaches – Biologic Formulation Stabilization

– Controlled Release SC/IM (e.g. Depot)

– Controlled Release IV (e.g. PEG)

– Targeted (ADC, Nanoparticles)

– Nucleic Acid Delivery

– Local Delivery

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160

Injection Device Approvals Since 2012

Innovative Pipeline: Injectables

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50

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150

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Injectable Nanoparticles by Phase

Marketed

Approved

Registration

Phase 3

Phase 2

Phase 1

Preclinical

Research

Innovative Pipeline: Injectables

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100

200

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Drug Conjugates by Phase

Marketed

Approved

Registration

Phase 3

Phase 2

Phase 1

Preclinical

Research

Innovative Pipeline: Injectables Program Technology Innovation

Adocia Pramlintide Insulin Combo

BioChaperone® technology enables the solubilization and stabilization of pramlintide in a ready-to-use co-formulation with insulin. Positive first clinical results reported in September 2018.

(Image Source : Adocia Website)

PharmaCyte ifosfamide

Cell-in-a-Box® is a cellulose base technology that encapsulates genetically modified cells that covert cancer drug (e.g. ifosfamide) at local site (e.g. pancreas) which reduces dose/toxicity. In Phase 2 for Pancreatic Cancer. Also planned to be used to produce insulin (Pre Clinical).

(Image Source : PharmaCyte Website)

Beta Bionics Ilet Bionic Pancreas

Pocket-size fully integrated wearable system that autonomously measure glucose levels every five min and then releases the needed insulin and/or glucagon automatically. The iLet learns over time from its performance and can change its dosing if blood sugars are running consistently high or low. In home clinical trials started July 2018.

(Image Source : Beta Bionics Website)

Overview/Trends: Oral • Mature Space

– Generic companies have capability to develop complex formulations

– Product development transitioning to CDMO’s

• Area Growth/Interest – Rapidly Disintegrating Formulations (ODT/ODF)

• Pediatric and geriatric patients

– Oral Macromolecule

• Moving Beyond Insulin

– Targeted Local/Colonic Delivery

– Abuse Resistant

• Beyond Formulation Approaches

– Oral Oncology

Oral Modified Release

46% Rapidly

Disintegrating Formulations

18%

Oral Enhanced BA

15%

Chewable 6%

Abuse Resistant

5%

Dispersible 4% Taste

Masking 4%

Other 2%

Oral DD Approvals Since 2012

Innovative Pipeline: Oral • Oral Protein – Novo Nordisk: Positive Phase 3 trial results oral semaglutide reported 2018 – Chiasma: Octreotide Phase 3 trial enrollment completed July 2018 – Entera Bio: EB612 (PTH 1-34) completed first part PK/PD trial in 2018 – Oramed: IND cleared for ORMD-0901 (GLP-1 analog). Oral Insulin program moving forward

• Abuse Resistant – KemPharm: LAT™ (Ligand Activated Therapy) prodrug that releases active in GI Tract via metabolic processes

• Apadza (benzhydrocodone hydrochloride, acetaminophen) approved US in February 2018 • Phase 3: KP415 (serdexmethylphenidate) for ADHD • Phase 1: KP484 (methylphenidate), KP511 (asalhydromorphone)

– Ensysce Biosciences: BIO-MD prodrugs activated only when administered orally (Clinical) MPAR includes an inhibitor to each BioMD which blocks activation when not taken as prescribed (Preclinical)

• Phase 1: PF329 (hydromorphone, ensysce), PF614 (hydromorphone, ensysce)

• Local GI Delivery (Colonic) – Intract: Phloral dual action mechanism releases drug in colon. Soteria variant being explored in oral protein.

• Registration: Tillots Next Generation Asacol (mesalazine)

Overview/Trends: Inhalation • Approvals since 2012 With Same Platform

– GSK Ellipta (DPI): Trelegy (2017) , Incruse (2014), Arnuity (2014), Anoro (2013), Breo (2013),

– Novartis Breezehaler (DPI): Ultibro (2013), Seebri (2012), other prior to 2012

– Almirall Genuair (DPI): Brimica/Duaklir (2014), Eklira (2012), others prior to 2012

– BI Respimat (Nebulizer): Stiolta (2015), Striverdi (2013), others prior to 2012

– Pari eFlow (Nebulizer): Arikayce (2018) , Longhala (2017), Quinsair (2015), Vantobra (2015), other prior to 2012

– Teva RespiClick/Spiromax (DPI): ArmonAir (2017), AirDuo (2016), ProAir (2015), Biresp (2014),

– Orion EasyHaler (DPI): Aerion (2018 ), Bufomix (2013), others prior 2012

– Sandoz Forspira (DPI): Airbufo (2018 ), AirFlusal (2013)

• Inhaled combination products especially difficult to develop as a generic

DPI 54%

MDI 19%

Nebulizer 27%

Inhalation Approvals Since 2012 by Technology Category

Innovative Pipeline: Inhalation

Program Technology Innovation

Liquidia LIQ861

PRINT technology combines particle molding technology with a modular, roll-to-roll manufacturing process. Phase 1 results with treprostinil reported in Jan. 2018. After consultation with FDA, initiated pivotal Phase 3 trial with results expected 1H2019. Platform particle technology showing success in Inhalation, Injectable and Ophthalmic space.

(Image Source : Liquidia Website)

Pulmatrix Pulmazole, PUR0200

iSPERSE particle technology utilizes spray drying to manufacture high dose load particles for delivery of small molecules and biologics. Suitable for multi-drug combinations as well. Positive PK results reported in July 2018. Maximum sputum itraconazole concentrations were approximately 50-fold higher following inhalation dosing of 20 mg of Pulmazole compared to oral Sporanox dosing of 200 mg.

(Image Source : Pulmatrix Website)

Innovative Pipeline: Inhalation Program Technology Innovation

3M 3M™ Intelligent Control Inhaler

A fully-integrated, breath actuated pMDI with connectivity that visually instructs patients how to use it correctly (claimed to be the first of its kind). It delivers optimum flow rate, regardless of how forcefully patients inhale and removes breath-profile variability and user-operation variability without the need for training. 3M is currently producing clinical supplies.

(Image Source : 3M Website)

Senzer Candex Cannafen

SiDD is a novel non-electronic, breath-activated inhaler (pressure based). Senzer licensed inhaler technology from Kind. Kind markets device in smoking cessation market in UK. Current pipeline is being developed for cannabinoids. US partner Insys announced positive Phase 1 results for dronabinol in September 2018. Senzer Pharmaceuticals has UK specials license and plans to launch Canafen (cannabidiol ) in 2018 and Candex (dronabinol ) in 2019.

(Image Source : Senzer Website)

Senzer technology highlights trend to use DD Technology in non-Rx space.

Overview/Trends: Ophthalmic

• Topical Most Common

• Continued Expanded Interest – Program/technology advancement

– Funding, deals…

• Unmet Needs – Back of the eye delivery

– Convenient administration

• Easy to use application device

• Reduced dosing frequency – Implants, Particulates, Half-life

Extension

Topical 85%

Devices/Dispensers 7%

Implants/Rods 6%

Other 1%

Photodynamic 1%

Iontophoresis <1%

Products/Pipeline by Technology Category

Innovative Pipeline: Ophthalmic

Program Technology Innovation

Forsight Vision 4 Genentech Lucentis PDS ranibizumab

Refillable eye implant slightly longer than a grain of rice. PDS is implanted during a surgical procedure. It is refilled using a customized needle in a minimally invasive office-based procedure. Positive Phase 2 results reported in July 2018.

(Image Source : ForSight)

Graybug Vision GB-102 sunitinib

Drug encapsulated in biodegradable polymers forms implant in-situ. High drug loading with up to 6 month drug release. Undisturbed visual axis post IVT injection with 27 G needle. Phase 1 dosing initiated September 2018

(Image Source : Graybug Vision Website)

Eyenovia EYN PG21 latnaprost

Piezo-print technology to deliver microdose medications topically to the eye reducing delivered dose and improving accuracy/deliverability. Positive POC data reported August 2018.

(Image Source : Eyenovia Website)

Innovative Pipeline: Ophthalmic

Program Technology Innovation

Clearside Biomedical CLS-TA

Hollow microneedle technology which delivers drugs (via controlled infusion) directly to the suprachoroidal space. First of two Phase 3 trials completed enrollment June 2018

(Image Source : Clearside Biomedical Website)

Polyactivia latanaprost

Drug-polymer conjugate in form of implant is placed into the eye with a novel applicator in ophthalmologist office. Up to 90 day release profile. Applicable to other site specific release applications. Phase 1 trial initiated for latanaprost in August 2018.

(Image Source : Polyactivia Website)

Kodiak Sciences KSI 301 Anti-VEGF

Antibody Biopolymer Conjugate Platform provides longer half life in ocular tissues. Novel monospecific and bispecific antibody proteins and biopolymer conjugates. Phase 1 enrollment August 2018

(Image Source : Kodiak Website)

Overview/Trends: Nasal, Topical, Transdermal

• Nasal – Applicable to fast acting (i.e. migraine, overdose) and macromolecules

– Recent device/product approvals

– Revived interest in route for right application/indication

• Topical – Slow and steady as there is always a need for these products

– Used when it makes sense

• Transdermal – Limited NDA approvals since 2012

– Modest progress in technologies such as microneedles, macromolecule…

Innovative Pipeline: Nasal Program Technology Innovation

Impel Neuropharma INP104 DHE INP103 levodopa INP105 olanzapine INP102 insulin

POD pressurized inhaler delivers drug to upper nasal cavity Phase 3 INP-104 initiated August 2018 Phase 1 INP-103 initiated May 2018 Phase 1 INP-105 initiated August 2018

Image Source : (Impel Website)

Insys Epinephrine Nasal Spray

• Positive Phase 1 reported June 2018 (similar BA to Epipen) • FDA Fast Track designation August 2018

FluGen RedeeFlu

• Strain of seasonal influenza virus (H3N2) that has been genetically designed to replicate only once in the body could protect against drifted influenza strains • Positive First In Human data (adults) presented October 2018 • Pediatric trial (9-17 yr) began enrollment September 2018

DD Venture Capital Funding Since 2010

Injection 45%

Oral 29%

Skin 8%

Ophthalmic 4%

Other 5% Inhalation

3%

Transmucosal 3%

Medical Devices

3%

Venture Capital Funding by DD Category

USA 74%

UK 6%

Germany 3%

France 2% Switzerland

2%

Canada 2%

China 2%

Israel 1%

Netherlands 1%

Belgium 1%

Europe, Other

4%

Japan, Asia,

Oceania 2%

Venture Capital Funding By Region

Closing Observations/Comments • Drug Delivery Applied Across Products/Pipeline

– ~40% apply DD technology (> trend)

• Injectables becoming majority of pipeline/focus – Injection based devices and delivery of biologics

• CDMO’s Becoming Centers for Technology/Product Development • Advances in Ophthalmic Technologies and Pipeline • Drug Delivery and Compliance Devices

– Continued development of devices across routes not just injection

• Needs Based Approach to DD Technology/Product Development – Right technology/route for right product – Opportunities exist outside biologics!!!

Acknowledgements

• PharmaCircle Drug Delivery Team – Tugrul Karali, PhD, MBA

– Esay Okutgen, PhD

– Guniz Iskender, PhD

– Omer Sarioglu, PhD