Parenteral Drug Delivery Market Trends

Kurt R. Sedo Vice President, Operations PharmaCircle LLC Sunny Isles Beach, FL

Parenteral Drug Delivery Market Trends

• Pipeline/Products Overview • Device Based Technology Trends – Autoinjectors, pens, prefilled syringes, patch pumps… • Formulation Based Technology Trends – Targeted Delivery, Drug Conjugates, Injectable Depot • Other Technologies – Concentrated/Viscous, Stability, Injection Site Absorption Enhancers • Key Approvals in Last 5 years • Drug Delivery – Technologies, Deals, Analysis • Venture Capital Investments • Conclusions

Overview: Innovator Products and Pipeline

Route: Marketed vs Pipeline Marketed Products 14000

12000 DD Non-DD 38% 10000 62%

8000

6000 Marketed 4000 Pipeline Pipeline Programs 2000

0 DD 37% Non-DD 63% Drug Delivery Pipeline Analysis

DD Pipeline by Phase/Route 4000 3500 DD Pipeline Moved to Clinic 3000 2017 - 2018 2500 900 Phase 3 2000 800 1500 Phase 2 700 600 1000 Phase 1 500 500 Preclinical 400 0 300 Research 200 2017 100 2018 0 Trends: 2017 Innovator Approvals 2017 Innovator Approvals by Route

70

60

50

40

30

20 FDA EMA 10

0 Trends: 2017 Innovator Approvals

2017 Innovator Approvals Injection Dosage Forms 70

60

50

40

30 FDA

20 EMA

10

0 Injection Injection Solution Injection Injection Injection Injection Lyophilized Lyophilized Suspension Emulsion Powder for Powder for Solution Suspension

Key Product Sales: 2003, 2010, 2017

Blue highlight cells are injectable. Blue italics have injectable formulation available in franchise in that year. Overview/Trends: Injectables

• Injectables Taking Over Pipeline Injection Device Approvals 2012-2018 • Devices, Devices, Devices… 180 – Multiple device strategies incorporated 160 140 into first approvals (e.g. Repatha, 120 Aimovig) 100 80 • Delivery of High Volume and/or 60 Viscous Biologics 40 20 • Trending Formulation Approaches 0 – Biologic Formulation Stabilization – Controlled Release SC/IM (e.g. Depot) – Controlled Release IV (e.g. PEG, Fc) – Targeted (ADC, Nanoparticles) – Nucleic Acid Delivery – Cell Therapy – Local Delivery Injectable Marketed Product Analysis

Marketed Injectables by Indication 2500 2000 Marketed Injectables by Molecule Type 1500 carbohydrate Other antibody 5% 2% 1000 peptide 5% 500 7% 0 protein small 17% molecule 64% Injectable Marketed Product Analysis

Marketed Injectables by Route Marketed Injectables by DD Category Infusion SC 8000 Intraarticular 1% 1% 7000 Intradermal Other 2% 6000 6% Infusion IV 5000 Injectable IV 28% 20% 4000 3000 Injectable IM Injectable SC 22% 2000 20% 1000 0

Injectable Pipeline Analysis

Injectable Pipeline by Indication 6000

5000 Injectable Pipeline by Molecule Type

4000 other RNA oligo 2% 3000 gene 2% 3% 7% 2000 peptide 10% antibody 1000 32% 0 cell based 13% small molecule protein 18% 13%

Injectable Pipeline Analysis

Injectable Pipeline by Route

Intravitreal 2% Injectable Pipeline by DD Category Other Intradermal 9000 11% 4% Infusion IV 8000 Injectable IM 34% 7000 10% 6000 5000 Injectable IV 4000 17% Injectable SC 3000 22% 2000 1000 0 Injectable Pipeline/Product Analysis

Injectable Pipeline Dosage Form

Emulsion Other 4% 2% Injectable Marketed Dosage Form Emulsion Lyo/Powder Suspension Other 1% 19% 8% 2% Solution Suspension 59% 16% Lyo/Powder 23% Solution 66% Evolution of Device Development Enbrel Present: Multiple Devices at Launch and Compressed LCM Repatha

1998 2004 2006 2017 Past: Devices as LCM Strategy

2015 2016 Injectable Nanoparticles

Injectable Nanoparticles by Phase 400 350 300 250 Marketed 200 Approved 150 Registration 100 Phase 3 50 Phase 2 0 Phase 1 Preclinical Research Drug Conjugates

Drug Conjugates by Phase 800 700 600 500 Marketed 400 Approved 300 Registration 200 Phase 3 100 Phase 2 0 Phase 1 Preclinical Research Injectable Depot

Injectable Depot Products/Pipeline 250

200

150 Marketed 100 Reg/Approved Phase 3 50 Phase 2 0 Phase 1 Research/Pre Injectable Depot

Injectable Depot Indications 250

200

150

100

50

0 LCM Case Study: Risperidone

Product Approval LCM Risperdal Franchise (US) 5000 4500 Risperdal 1993 4000 Oral Tablet 3500 Risperdal 1996 3000 Risperdal Total Oral Solution 2500 Risperdal Injectable 2000 Risperdal Oral Risperdal M-Tab 2003 Sales WorldMil $ 1500 ODT 1000 500 Risperdal Consta 2003 Injectable (1 x 2 weeks) 0

Risperdal Consta utilizes MedisorbTM PLGA depot technology LCM Case Study: Paliperidone

Product Approval LCM Paliperidone Franchise (US) 3500

Invega ER 2006 3000 Oral Tablet

2500 Invega Sustenna 2009 2000 Injectable (1 x month) Invega Total 1500 Invega Oral

Invega Trinza 2015 World sales sales World$ Mil Invega Injectable Injectable (1 x 3 months) 1000

500 Paliperidone is active component of risperidone Invega ER utilizes OROSTM technology 0 Sustenna/Trinza utilize NanoCrystalTM Technology LCM Case Study: Risperidone Product Approval LCM Risperidone Franchise (US) 5000 Risperdal 1993 4500 Oral Tablet 4000 Risperdal 1996

Oral Solution 3500 Risperdal M-Tab 2003 3000 Franchise Total ODT 2500 Risperdal Total Risperdal Consta 2003 2000 Invega Total Injectable Sales WorldMil $ 1500

Invega ER 2006 1000 Oral Tablet 500

Invega Sustenna 2009 0 Injectable Invega Trinza 2015 Injectable Janssen: Risperdal/Invega Franchise

Risperdal Tablet 1993 Risperdal Oral Solution 1996 Risperdal M-Tab 2003 Risperdal Consta 2003

Invega ER 2006

Invega Sustenna 2009 Invega Trinza 2015 Injectable High Concentration/Viscosity

• Concentration/dose of injectable biologics (e.g. Mabs) is increasing resulting in need to deliver viscous/concentration solutions and suspensions.

350

300 250 200 Non-Cancer Cancer 150

100

50

0 <50 mg 50-100 mg 100-250 mg 250-500 mg >500 mg 1047 Mabs from Phase 1 to Market Notable Approvals: 2014 Product Notable

HyQvia Injection Solution A novel formulation approach incorporating a proprietary (immunoglobulin G) enzyme to digest hyaluronic acid and permit a product normally administered by slow IV infusion to be delivered SC. Can be administered at home with portable

infusion pumps.

Other products approved with Halozyme’s Enhanze technology (Rituxan, Hercpetin). Neulasta OnPro The dose is administered over an extended period (empegfilgrastim) for improved tolerability. Compliance and convenience is also improved. Wearable/On body injector space very active.

Notable Approvals: 2014

Product Notable

Plegridy More oral treatments available for MS. (peginterferon beta-1a) Moves to dosing every 2 weeks. Available in patient friendly PFS and pen formats.

Alprolix Protein-immunoglobulin fusions represent a next generation (eftrenonacog alfa) prodrug approach that blurs the line between protein engineering and traditional formulation.

Notable Approvals: 2014

Product Notable Bydureon Dual Bydureon Dual provides incremental injectable delivery format/device (exenatide) convenience improvements that should translate into better compliance and therapeutic outcomes. New improved device approved in 2017.

Evzio Effectively a multimedia delivery device, Evzio provides (naloxone) printed and audio dosing instructions to allow untrained individuals to quickly and effectively administer the dose. Reportedly easier to administer without training than nasal Narcan. Good press coverage but not necessarily translating into sales. Notable Approvals: 2014 Product Notable

Xultophy Pen Combination product incorporates the latest generation Novo (insulin degludec, liraglutide) Nordisk dose-adjustable prefilled insulin syringe system providing easier use and greater accuracy. 1 X day dosing.

Trulicity Pen Fc fused proteins in a patient friendly injection system intended (dulaglutide) to provide an extended duration of action (1 X week dosing) while encouraging patient compliance.

Notable Approvals: 2014 Product Notable

Copaxone Concentrated A simple lifecycle management high-dose formulation () that enhances convenience and promises to extend the

commercial prospects of the Copaxone franchise.

Eloctate An Fc fusion protein for the treatment of hemophilia (efmoroctocog alfa) permitting an extended dosing interval of every four

days for prophylaxis.

Notable Approvals: 2015 Product Notable

Adynovate PEG enabled product with twice weekly dosing versus 3-5 times (rurioctocog alfa pegol) a week.

Onivyde Formulation may realize promise of liposomes and irinotecan in (irinotecan hydrochloride) a challenging indication. Notable Approvals: 2015 Product Notable

Invega Trinza Logical lifecycle follow-on three month IM NanoCrystal (paliperidone palmitate) formulation to complement oral Invega ER Tablets (2006) and Invega Sustenna (2009) one month IM products for treatment of schizophrenia

Aristada Prodrug approach to provide extended circulating levels of well (aripiprazole lauroxil) known drug aripiprazole. Dosing once every 4, 6, 8 weeks. Aristada Initio with NanoCrystalTM technology approved 2018 provides alternative regimen to initiate patients onto any dose of ARISTADA. Notable Approvals: 2015

Product Notable

Duodopa Infuses a gel of levodopa/carbidopa into the jejenum via a (levodopa, carbidopa) percutaneous endoscopic gastrostomy with an outer transabdominal tube and an inner intestinal tube. $430 million sales in 2018. Repatha Autoinjector and PFS solutions for high cholesterol (evolocumab) management. Multi-device approval and launch. Wearable injector approved 2016. Notable Approvals: 2015 Product Notable

Praluent In same space as Repatha but with a single injection once (alirocumab) every two weeks. Multi-device approval (PFS, Pen/Autoinjector). New device to deliver 300 mg dose, 1X monthly in one injection in Phase 3.

Toujeo SOLOSTAR Successor to Lantus SOLOSTAR. Offers better night time (insulin glargine) hypoglycemia control with lower volume of injection. Lifecycle enhancement product that brings additional patient benefits. Notable Approvals: 2016

Product Notable

Strimvelis (Europe) CD 34+ cells transfected with the ADA gene. Approach promises long term, possibly life long treatment and suggests opportunities in other genetic diseases currently treated with replacement protein therapies. Issue is very high $$$.

Sustol Other anti-emetics have a duration of action up to 48 hours. (granisetron) Sustol depot offers 5 days of protection. Notable Approvals: 2016 Product Notable

Zalmoxis (Europe) Adjunctive therapy to stem cell transplantation represents one of the future directions for drug delivery, the incorporation of a cellular “factory” in transplanted cells

Repatha SmartDose Third device in franchise. Wearable/On Body (evolocumab) injector provides much more convenient dosing for large volume injection (3.5 mL) Notable Approvals: 2017 Product Notable

Luxturna It seems to be an ideal indication for early gene therapy to (voretigene neparvovec) explore; a clear mechanism of action, localized condition and one time therapy. Limited potential for life threatening adverse event.

Zilretta Logical therapeutic option for intra-articular injection of (triamcinolone acetonide) corticosteroids. PLGA based technology provides 4 fold extension of half-life. Notable Approvals: 2017 Product Notable

Sublocade Faced with branded and generic competitors to their sublingual (buprenorphine) buprenorphine franchise, Indivor has added a long action depot formulation (up to six months) in PFS with safety needle. Analysts project sales reaching $800 million by 2023.

Oncaspar Oncapsar has been mainstay of pediatric ALL treatment for (pegaspargase) almost 3 decades. More stable lyophilized formulation will reduce availability issues seen with other formulations. Notable Approvals: 2017 Product Notable

Enbrel Mini Cartridge Designed as follow on to PFS and Pen presentations. The new (etanercept) single use injector is intended to ensure more consistent dosing by limiting the potential points of patient confusion.

Bydureon Bcise The new autoinjector provides significant patient-use (exenatide) improvements over previous dual chamber injector. Diabetes device space is very competitive Once a week dosing is not enough without easy-to-use device. Notable Approvals: 2017 Product Notable

Ozempic Once/twice weekly dosing in FlexTouch injection pen. (semaglutide) Potential for additional oral therapy of semaglutide as well (Phase 3)

Vyxeos Combination liposome that provides molar ratios of drugs in (daunorubicin, cytarabine) a synergistic fashion. Analyst sales projection of $300 million by 2022. Notable Approvals: 2017 Product Notable

Yescarta Patient T-cells are transected ex-vivo with a retroviral construct (axicabtagene ciloleucel) coding the specific CD-19 targeted antigen. Analyst sales projection of $2 billion by 2022.

Kymriah CART-T from Novartis. Analyst sales projection (tisagenlecleucel) of $1 billion by 2022 mostly in Europe Notable Approvals: 2018 Product Notable

Onpattro First commercialized RNAi therapy. (patisiran) 2021 sales projected to be $1.1 billion.

Dexycu Single administration (intracameral/intraocular injection) of a (dexamethasone) corticosteroid post cataract surgery eliminates non-compliance Notable Approvals: 2018 Product Notable

Lumoxiti CD22-directed immuno/cytotoxin ADC. First-in-class (moxetumomab pasudotox- treatment in the US for adult patients with relapsed or tdfk) refractory hairy cell leukemia (HCL)

Xyosted Once weekly male testosterone treatment in an easy to use (testosterone enantate) device. Notable Approvals: 2018 Product Notable

Buvidal First long acting treatment for opioid dependence approved (buprenorphine) in EU. Launched in January 2019 as once weekly and once monthly. Tentative US approval in December 2018 (Brixadi). Liquid lipid formulation.

Perseris Once a month delivery of well established schizophrenic drug (risperidone) risperidone. Atrigel PLGA technology. Peak net revenues expected to be $200 to $300 million.

Notable Approvals: 2018 Other Notables Multiple Device Based Novo FlexPen insulins Tegsedi PFS (inotersen sodium) Actemra Auto-Injector (tocilizumab) Xolair PFS (omalizumab) Makena SC Auto-injector (7 alpha-hydroxyprogesterone caproate) Emgality PFS/Autoinjector (galcanezumab-gnlm) Toujeo Max SoloSTAR (insulin glargine) Aimovig PFS/Autoinjector (erenumab-aooe)

Biosimilar Devices Fulphila PFS (pegfilgristam-jmdb) Hyrimoz PFS/Pen (adalimumab-adaz) Udencya PFS (-cbqv) Nivestym PFS (-aafi) Ilumya PFS (tildrakizumab-asmn)

Notable Approvals: 2018 Other Notables Multiple Peg Jivi (damoctocog alfa pegol) Revcovi (elapegademase-lvlr) Palynziq PFS (pegvaliase-pqpz)

Multiple Depot Perseris (risperidone) Buvidal (buprenorphine) Aristada Initio (aripiprazole lauroxil)

Note: All supplied in PFS

Innovative Pipeline: Injectables Program Technology Innovation BioChaperone® technology enables the solubilization Adocia Pramlintide Insulin and stabilization of pramlintide in a ready-to-use co- formulation with insulin. Positive first clinical results Combo reported in September 2018. (Image Source : Adocia Website) Cell-in-a-Box® is a cellulose base technology that PharmaCyte ifosfamide 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) Pocket-size fully integrated wearable system that Beta Bionics Ilet Bionic Pancreas 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. Additional trial January 2019 (Image Source : Beta Bionics Website) Drug Delivery Technologies Technology Count by Injectable DD Technologies DD Category

3500 Conc/Viscous Injectable Absorption 3000 4% Water Insoluble Enhancers 2% <1% 2500 2000 Depot Injectable 1500 10% 1000 Targeted Conjugates 39% 500 14% 0 Injection Systems 31% Drug Delivery Deals

Drug Delivery Related Deals 2010-2018 Drug Delivery Technology Deals 2010-2018

Inhalation Ophthalmic Otic Inhalation Otic 6% 4% <1% 6% Ophthalmic <1% 4% Transmucosal Transmucosal 9% Injection 6% Other 41% Other Injection 11% 18% 46% Skin Skin 12% Oral 7% 17% Oral 13% Injectable Drug Delivery Deals

Injectable Drug Delivery Related Deals 2010-2018 Injectable DD Technology Deals 2010-2018

Conc/Viscous Injectable Conc/Viscous Absorption Injectable 3% Water Insoluble 6% Absorption Enhancers Water 3% Enhancers Other 1% Insoluble 1% Injectable Other Injectable 6% 2% Depot Depot 1% 8% 8% Injectable Targeted Injectable Injection 42% Injection Targeted Systems Systems 44% 16% 19% Conjugates Conjugates 19% 21% DD Venture Capital Funding Since 2010

Netherlands Belgium Venture Capital Funding by DD Category China 1% 2% 1% Transmucosal Medical Japan, Other 3% Devices Canada Israel Europe, Asia, 5% Inhalation 3% 2% Other Oceania Ophthalmic France 1% 3% 4% 2% 4% 2% Switzerland 2%

Skin Injection Germany 8% 45% 3% UK 6% Oral 29% USA 74%

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

Acknowledgements • PharmaCircle Drug Delivery Team – Tugrul Kararli, PhD, MBA – Esay Okutgen, PhD – Guniz Iskender, PhD – Omer Sarioglu, PhD – Selda Candan, MS