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 (glatiramer acetate) 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