IMPROVEMENT OF RECOMBINANT PROTEIN S COST OF GOODS & AFFORDABILITY

Transcription

1 IMPROVEMENT OF RECOMBINANT PROTEIN S COST OF GOODS & AFFORDABILITY Li How Chen PhD Senior Director, revo Biologics Inc. USA Sami CHTOUROU PhD Senior Vice President Innovation & Scientific Affairs LFB Biotechnologies France

2 Focus Biotherapeutics medicines Recombinant plasma proteins mabs 2

3 US Healthcare Perspectives US Healthcare spending by 2015 forecast 15% GDP ( $ 4 T) Prescription pharmaceuticals in 2015 forecast $ 446 B (> 11% total healthcare expenses) Biologic drugs expenditure Already accounts for > 14 % pharmaceutical spending CAGR of biologics bill >> than for small molecules 33 % of all drugs in development These trends are clearly unsustainable 3

4 The Economic Perspectives 1. Current situation developed countries Social security systems under pressure Slow down of Economy situation in the EU 2. Future trend Co-payment systems Payments by individuals What is expected: Higher pressure on treatment and manufacturing cost of Biotherapeutics Cheaper copy version of innovator products: Biosimilars More potent products: Biobetter (more potent version of well known products) 4

5 Monoclonal Antibodies Market and Perspectives 1. The major contribution mabs have made to medicine is evidenced by their vigorous and continuing growth: the global mabs market is now valued at $45B, 1. By the end of 2012, there were 40 monoclonal antibodies & derivatives approved and marketed for therapeutic use. 2. This Class of product is now approaching maturity, the first products having been put on the market more than ten years ago 3. However monoclonal antibodies are set to continue increasing in importance because of the ubiquity of antigen-antibody interactions in human health and disease. 5

6 mabs Market 1. Highly concentrated market: the Roche group accounted for >40% of total therapeutic monoclonal antibody sales in therapeutic antibodies of the 40 marketed achieved blockbuster sales of more than US$ 1B. 3. Cost of therapies with mabs are typically much higher than small molecules ($30K - $400K / year; $5K - >$20K / g). 4. Cost pressures will increase as the current original brands approach patent term expiration: creating an opportunity for biosimilars. 6

7 Geographic Breakdown of mabs Markets The USA is the largest regional market representing almost half the global total. Differences between developed and emerging economies are greatest for mabs and therapeutic proteins because of their premium prices. Innovator biologics are typically associated with treatment costs that are well above what can be afforded by the majority of patients in emerging economies 7

8 Non-mAbs Biologics Market Dynamics

9 How to Improve Recombinant Protein CoGs and Affordability 1. Use of an improved expression cell line combined with improved cell (see for more details Antibody Technology Companies 2010, La Merie Business Intelligence on November 1, 2010) 2. Use of an alternative expression system with capacity to reduce the Capex and Opex as the production in the milk of transgenic animals 3. Improve the functionality of the mabs: obtain the same therapeutic effects with less product (enhanced ADCC, enhanced CDC; longer half-life) 9

10 LFB s Approach: 3 Different Platforms EMABLING: High ADCC antibodies by natural glycosylation improvement HuMabFc: effector function modification ADCC, CDC, half-life by Mutagenesis rpro Technology: Biosimilar and Biobetter mabs, recombinant plasma proteins 10

11 ADCC % lysis Glyco-engineered mabs: High ADCC Human Abs glycosylation 40 Target : B-CLL R603-LFB Rituximab n= ng/ml 20 > 5000 ng/ml Mab ng/ml (LOG) EMABling (Strong IP position) Natural glycosylation pattern: - Cell line with low Fuc (EB66, YB2/0) - Tg animal (rabbit) Glycosylation pathway modification : KO/Kin (CHO, Yeast, plant, moss) Silencing (CHO, plant) Use of fucosylation inhibitors during production (Kifunensine) or selection of non fucosylated Mabs during purification 11 11

12 ratio/ ratio/ Fc - WT C Fc Sequence Engineering All Fc mediated functions can be modulated: ADCC/ADPC, CDC and half-life Fc mutagenesis can be immunogenic best situation is with human like sequence or close ADCC /ADPC modulation (FcgR binding) CDC modulation (C1q binding) C half-life modulation (FcRn binding) Random mutagenesis + phage display (No limits in the options) MS2 on FcRn : ratio/wt from 2 to 28 Fc - Phages Anti - M13 HRP ratio/ Fc WT FcRn - p Current Opinion in Biotechnology 2009, 20:

13 rpro Technology 13

14 Our mabs USP Production Units A bioreactor that eats hay 14

15 rpro Technology How it Works Separation Filtration Purification Viral eradication Polishing Fill and finish Packaging Utuximab Utuxin Separation Filtration Purification Viral eradication Polishing Fill and finish Packaging

16 CAPEX & OPEX Considerations $500 million mabs manufacturing plant $25 million Tg mabs manufacturing plant Considerations Significant investment Must be made early in development cycle Additional volumes require New plant (=money) Revalidation (=time and risk) Decision must be made years in advance (=money and risk) Considerations No new capital investment req d Virtually unlimited production capacity Unparalleled flexibility for scale-up No additional costs Short timeframes to add capacity No revalidation (no risk) Validated with US and EU regulatory authority product approval 16

17 Lower Cost & Time Saving of Scaling Up the Production Traditional cell-based protein production vs. Transgenic protein production S U P P L Y Pilot plant Plant #1 Plant #2 Plant #3 S U P P L Y 17

18 rpro Technology s Expected Benefits What are the expected benefits for human healthcare? Providing abundant and cost effective therapeutic recombinant products Contributing in healthcare cost reduction in developed countries Improving access to therapeutic products (availability and affordability) for developing countries

19 Broad Utility for rpro Technology rpro Technology Can Be Harnessed to Produce High Yield Recombinant Versions of a Wide Range of Traditionally Plasma-Derived Proteins Protein Indications Antithrombin ATryn FDA, EMA approved) Hereditary Antithrombin Deficiency Pulmonary Embolism Disseminated Intravascular Coagulation C1 Esterase Inh Ruconest (EMA approved) Hereditary Angioedema Factor VIIa Alpha-Fetoprotein Alpha-1 Antitrypsin Fibrinogen Factor IX Butyrylcholinesterase Albumin Prothrombin Hemophilia Myasthenia Gravis Multiple Sclerosis Alpha-1 Antitrypsin Deficiency Fibrin Glue Hemophilia B Organophosphate Poisoning Volume Replacement Hemostasis

20 ATryn Recombinant Antithrombin Single chain complex glycoprotein - Plays fundamental role in suppression of coagulation - Principal inhibitor of thrombin and factor Xa - Binding of heparin causes a conformation change and 1000 fold increase in inhibitory activity Difficult to express cost-effectively in cell culture (large doses are often required) Anticoagulant and anti-inflammatory properties Hereditary and acquired deficiencies: Hereditary Deficiency (HD, approved ATryn indication) Acquired Deficiency (e.g. DIC, preeclampsia, extra-corporeal circulation, trauma, burns etc Non approved) Regulatory Approvals in 2006 (EMA) and 2009 (FDA) Currently commercialized; ongoing clinical development for acquired deficiency indications.

21 Human FVIIa Development Goal To provide to the global Hemophiliac population an affordable, highly-active rh-fviia therapy for the treatment of Hemophiliac A or B with inhibitors by leveraging our proprietary, highyield, low cost manufacturing technology.

22 Characterization of LFB-rFVIIa Extensive analytical characterization performed and compared to NovoSeven Physiochemical Structural properties Functional Characterization Structural - Comparable γ-carboxylation, Hydroxylation and O-glycosylation - Differences in N-glycosylation - No immunogenic structure Gal-Gal detected. In-Vitro Functional tests performed: * Capacity to bind rstf * Capacity to bind phospholipids * Capacity to activate Factor X * Capacity to generate thrombin *FVII assays : antigen, chronometric & chromogenic In-Vivo PK studies in rabbit with similar half-life Warfarin treated rats similar bleeding times

23 FVIIa activity (ng/ml) FVIIa activity (ng/ml) FVIIa Phase 1b Preliminary PK/PD mcg/kg Time (h) mcg/kg Time (h) 23 23

24 Transgenic Expression of mabs 24

25 Tg Expression Advantage Cell Culture Best Commercial now 1-2 g/l after 14 days, 23X/yr Claim of 10 g/l (DSM) Uncertain achievement in practice Likely significant additional license burden Likely achievable range 1 2, perhaps 5 g/l Expect commercial lines of 2 g/l 2013, up to 5 g/l 2017 GTC Transgenics average ~ 5 g/l Varied Expressions from ~ 1 up to 50 g/l Confident achievement of 3 10 g/l 25

26 Adalimumab Binds to TNFα preventing activation of TNF receptors Important in down-regulating the inflammation associated with autoimmune diseases Third TNF inhibitor to be approved in US after infliximab (Remicade) and etanercept (Enbrel) Abbott Labs Humira approved by FDA in 2002 #1 global biologics therapy: $9.2B in 2012 revo generated transgenic goat lines in 2010 Expression ~20 g/l

27 Arthritic Score Histopathology Score Average Body Weight Adalimumab - Arthritis Model CHO-adalimumab Tg goat-adalimumab Dose of anti-tnf antibody (mg/kg) 1 CHO-adalimumab Tg goat-adalimumab Dose of anti-tnf antibody (mg/kg) 15 CHO-adalimumab Tg goat-adalimumab Dose of anti-tnf antibody (mg/kg) ED 50 (mg/kg) CHO Transgenic Arthritis Score Histopathology Score Source: Kaymakcalan et al. (2002) Poster presented at FOCIS 2002

28 % Lysis % IL-2 Induction Tg anti CD20: A Biobetter anti-cd20 mab ADCC (Antibody Dependent Cellular Cytotoxicity) Key mechanism by which MAbs kill tumor cells enhanced efficacy decreased dosing IL-2 Induction Transgenic-goat MAbs have naturally enhanced ADCC 100 B-CLL Patients B cells Rituxan 0 Rituxan TG20 TG20 (anti-cd20 MAb) TG20 (anti-cd20 MAb) TG20 TG20 (vs. Rituxan) has: significantly enhanced ADCC similar target affinity similar CDC [MAb] (ng/ml) (Log) Anti-CD20 MAb market >$6B Licensed to TG Therapeutics (TGTX) 28

29 Trastuzumab Humanized antibody that binds selectively to the HER2 protein Cancers usually develop resistance to trastuzumab Combination of trastuzumab with chemotherapy has been shown to increase both survival and response rate Treatment cost up to $100,000 per year Sales: >$6.4B in Transgenic production: Transgenic goats: 50 g/l Equivalent binding to Her2 Equivalent ADCC CDC under evaluation

30 Cetuximab Chimeric antibody that binds selectively to the EGFR (epidermal growth factor receptor) Indicated for the treatment of metastatic K-RAS wild-type colorectal as well as for head and neck (squamous cell carcinoma) cancers. Typical treatment cost: ~$80,000 (~$10,000 per month) Worldwide Sales: ~$2 Billion in 2012 Transgenic goats: 10 g/l Equivalent binding to EGFR ADCC and CDC under evaluation Transgenically-derived product is free of a 1-3 Gal residues which cause anaphylaxis observed with Erbitux

31 Three Key Take-aways g/l = Operational Advantages Expression Advantage 5 vs 2 g/l FLEXIBLE SCALE - KG Global Cost Advantages Upstream Capex 10x Total Capex 2x COGS ~= 50-60%, incl royalties LOWER CAPEX HIGHER AVERAGE UTIL% 31

32 Thanks for your attention IMPROVEMENT OF RECOMBINANT PROTEIN S COST OF GOODS & AFFORDABILITY Li How Chen PhD Senior Director, revo Biologics Inc. USA Sami CHTOUROU PhD Senior Vice President Innovation & Scientific Affairs LFB Biotechnologies France