On the Verge of a Biologics Golden Age David Meininger Executive - PowerPoint PPT Presentation

On the Verge of a Biologics Golden Age David Meininger Executive Director, Molecular Discovery Department of Protein Sciences, Merck & Co., Inc. Biologics: Bringing Innovation to Merck

From Virgil’s Fourth Eclogue Novus ordo seclorum Now comes the final era of the Sibyl’s song; The great order of the ages is born afresh. And now justice returns, honored rules return; Now a new lineage is sent down from high heaven. D. Meininger LakePharma Symposium 4 October 2013 2

Drug Industry Productivity Source: http://www.forbes.com/sites/matthewherper/2011/08/03/the- best-drug-companies-of-the-decade/ D. Meininger LakePharma Symposium 4 October 2013 3

Pharma R&D Spend D. Meininger LakePharma Symposium 4 October 2013 4

Small vs. Large Molecule: 1999 – 2009 NPV & IRR Nature Rev Drug Disc (2009) 8 , 609 D. Meininger LakePharma Symposium 4 October 2013 5

Development Success Rates for Large and Small Molecule Therapeutics D. Meininger LakePharma Symposium 4 October 2013 6

An Industry Trend Toward Biologics Top 10 Drugs: 2012 Top 10 Drugs: 2018 Predicted* 1. Humira (arthritis) $ 9.6 1. Humira (arthritis) $ 12.8 2. Enbrel (arthritis) $ 8.5 2. Januvia/Janumet (diabetes) $ 10.1 3. Advair (asthma/COPD) $ 8.1 3. Enbrel (arthritis) $ 8.7 4. Remicade (arthritis) $ 7.6 4. Lantus (diabetes) $ 8.1 5. Rituxan (cancer) $ 7.2 5. Avastin (cancer) $ 7.7 6. Crestor (cholesterol) $ 6.8 6. Sofosbuvir (hepatitis C) $ 7.4 7. Lantus (diabetes) $ 6.4 7. Remicade (arthritis) $ 7.2 8. Herceptin (cancer) $ 6.3 8. Rituxan (cancer) $ 6.8 9. Januvia/Janumet (diabetes) $ 6.2 9. Revlimid (cancer) $ 6.6 10.Avastin (cancer) $ 6.0 10.Herceptin (cancer) $ 6.2 7 of the top 10 drugs in 2018 predicted to be Biologics *EvaluatePharma, June 2013: World Preview 2013, Outlook to 2018 D. Meininger LakePharma Symposium 4 October 2013 7

An Industry Trend Toward Biologics D. Meininger LakePharma Symposium 4 October 2013 8

Biopharma Pipeline NPV D. Meininger LakePharma Symposium 4 October 2013 9

Growth by Therapeutic Area D. Meininger LakePharma Symposium 4 October 2013 10

Total Disclosed Pre-Clinical & Clinical Antibodies by Enabling Discovery Technology Source data: Tabs database accessed September 23, 2013 D. Meininger LakePharma Symposium 4 October 2013 11

Total Disclosed Clinical Antibodies by Enabling Discovery Technology Source data: Tabs database accessed September 23, 2013 D. Meininger LakePharma Symposium 4 October 2013 12

Percentage Disclosed Clinical Antibodies by Enabling Discovery Technology Source data: Tabs database accessed September 23, 2013 D. Meininger LakePharma Symposium 4 October 2013 13

HuCAL GOLD mAb MK-X 2D-Gel Analysis D. Meininger LakePharma Symposium 4 October 2013 14

Not all mAbs from Mice Have Good CMC Properties SEC-MALS Analysis BioSep-SEC-S 3000 Size 300x7.8mm with 5 micron particle size, PBS + 200mM NaCl pH7.4 0.5mL/min, 30 min, 10 ug Main peak Shoulder peak Superdex 200 PBS+ 200mM NaCL pH 7.4 0.5mL/min, 60 min, 40 ug Abscissca Position Rh (nm) Dt Mw (min) 5.62 ± 0.36 (4.45 ± 0.29) e-7 cm²/sec 162700 ± 0.6% Main Peak 19.779 5.67 ± 0.65 (4.40 ± 0.5) e-7 cm²/sec 170200 ± 0.8% Shoulder Peak 18.675 Ipilimumab (Medarex/BMS) runs as two peaks << 150 kDa by SEC, but split peak  150 kDa by SEC-MALS D. Meininger LakePharma Symposium 4 October 2013 15

CMC Engineering Thermal Stability Viscosity/Solubility Protein Eng Des Sel (2010) 23 , 643 Protein Eng Des Sel (2010) 23 , 549 D. Meininger LakePharma Symposium 4 October 2013 16

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Bispecifics: Zymeworks D. Meininger LakePharma Symposium 4 October 2013 19

ADCs: Ambrx DNA encoding mAb 1 of interest and Ambrx O-tRNA & O-tRNA Synthetase 2 Orthogonal Conjugation Chemistry • Site-specific modification of mAbs • Versatile: multiple functionalities possible • Rapid: recombinant-based technology O O Ambrx Amino Acid mAb of Interest w/ Ambrx Amino Acid + Optimized Antibody Proprietary Conj. & Rational design to Conjugate O Linker Chemistry preserve ADCC and O N NH 2 H HCl compliment binding 4 3 Site-Specific Conjugation D. Meininger LakePharma Symposium 4 October 2013 20

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Conclusions • Therapeutic Antibodies continue to provide attractive ROI although the market is maturing • Phage display has underperformed as a de novo lead generation platform in comparison to fully human leads from transgenics and humanized leads from normal mice with this trend expected to persist • CMC properties of therapeutic antibodies must be carefully selected for and/or engineered to bias for clinical and commercial maximum success • Bispecifics and ADCs represent compelling growth opportunities • Immunotherapy looks extremely promising in the clinic and will usher in a biologics “golden age” D. Meininger LakePharma Symposium 4 October 2013 26

Acknowledgements Merck Biologics Discovery Merck External Scientific Affairs Merck Corporate Licensing Zymeworks Ambrx D. Meininger LakePharma Symposium 4 October 2013 27