12. November 2013 Jan Endell. From library to bedside: Potential of the anti-cd38 antibody MOR202 in combination therapy of multiple myeloma

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1 12. November 2013 Jan Endell From library to bedside: Potential of the anti-cd38 antibody MOR202 in combination therapy of multiple myeloma

2 The MorphoSys Pipeline 21 Clinical Programs, 82 Total Program Partner Target Indication Discovery Preclinic Phase 1 Phase 2 Phase 3 Bimagrumab (BYM338) Novartis ActRIIB Musculoskeletal Gantenerumab Roche Amyloid-ß Alzheimer s Disease BHQ880 Novartis DKK-1 Cancer CNTO3157 Janssen/J&J - Asthma CNTO6785 Janssen/J&J - Rheumatoid Arthritis Guselkumab (CNTO1959) (2 programs) Janssen/J&J IL23p19 Psoriasis Rheumatoid Arthritis LFG316 Novartis C5 Ophthalmology MOR103 (2 programs) GSK GM-CSF Rheumatoid Arthritis Multiple Sclerosis MOR208 - CD19 CLL, NHL, ALL NOV 3 Novartis - not discl. OMP-59R5 OncoMed/GSK Notch 2 Cancer VAY736 Novartis BAFF-R Inflammation BAY Bayer Healthcare Mesothelin (ADC) Cancer BI 1 BI - not discl. LJM716 Novartis HER3 Cancer MOR202 Celgene/MOR CD38 Multiple Myeloma NOV - 7 Novartis - Ophthalmology PFE 1 Pfizer - Cancer Vantictumab (OMP-18R5) OncoMed/Bayer Fzd 7 Cancer 22 Programs Various Partners - Various Indications 39 Programs Various Partners 3 MOR Programs - Various Indications 75 Partnered Programs 7 MOR Programs MorphoSys - Oktober 2013

3 CD38 An Ideal Target for Hematologic Diseases What is CD38? Type II-transmembrane glycoprotein Belongs to family of ectoenzymes/receptors involved in catabolism of extracellular nucleotides Function ADP-Ribosyl-cyclase/cADPR-hydrolase Ca2+-mobilization involved in hormone release Low-moderate expression on normal cells B/T lymphocytes, monocytes/macrophages, NK cells $ Highly and uniformly expressed on MM cells sources: medscape.com, medlibes.com, trialx.com hematologyatlas.com MM selected as primary indication

4 Multiple Myeloma Pathophysiology Malignant plasma cells in bone marrow Immune deficiency Anemia, thrombocytopenia Ca 2+ Bone lesions Renal failure M-Protein Neuropathy

5 MOR202 Shows High ADCC and ADCP Activity as Single Agent fully human HuCAL IgG1 binds to human CD38 with low nanomolar affinity induces potent immune effector mechanisms at picomolar levels: Antibody-Dependent Cellular Cytotoxicity (ADCC) Antibody-Dependent Cellular Pagocytosis (ADCP)

6 MOR202 Induces ADCC and ADCP Mediated Killing of Multiple Myeloma Cells at Picomolar Range Killing of primary MM cells via ADCC Killing of MM cell line via ADCP (example, 5 patient samples total) EC 50 : ~ pm EC 50 : ~ pm

7 Potential of MOR202 in Combination Therapy of MM In Vitro Not all combination therapies make sense Your therapy will be a combination of drugs and clowns

8 Possible Therapeutic Outcomes for Drug-Drug Combinations Additivity Antagonism Synergy Potentiation MorphoSys 8 AG

9 MOR202 and Lenalidomide Functional Interplay of Key Mode of Actions

10 Lenalidomide (LEN) on Effector Cells: Enhanced ADCC Via NK Cell Activation NCI-H929 (CD38 high, lenalidomide cytotoxicity sensitive) AMO-1 (CD38 low, lenalidomide cytotoxicity insensitive) MOR202 [log nm] MOR202 [log nm] LEN-induced effector cell activation

11 Killing Via ADCC is Dependent on CD38 Expression ADCC in CD38 low vs. high cell lines CD38 upregulation CD38 high CD38 low ADCC efficiency is dependent on CD38 expression levels on target cells Lenalidomide increases CD38 expression on target cells Increase in CD38 lenalidomide induced effector cell activation enhanced MOR202 ADCC / ADCP?

12 Lenalidomide on Effector and Target Cells: Enhanced ADCC Via NK Cell Activation & CD38 Upregulation NCI-H929 (CD38 high, lenalidomide cytotoxicity sensitive) AMO-1 (CD38 low, lenalidomide cytotoxicity insensitive) Lenalidomide added to effector cells and MM cell line MOR202 added to effector cells and MM cell line MOR202 [log nm] LEN-induced effector cell activation LEN-induced CD38 upregulation LEN-induced cytotoxic effect on target cells

13 Combination of Lenalidomide and MOR202 Shows Synergy in ADCC Assays NCI-H929 (CD38 high, lenalidomide cytotoxicity sensitive) AMO-1 (CD38 low, lenalidomide cytotoxicity insensitive) normalised specific killing MOR202 LEN MOR202 + LEN (theoretical) Synergy MOR202 + LEN (experimental) normalised specific killing MOR202 LEN MOR202 + LEN (theoretical) Synergy MOR202 + LEN (experimental) 13

14 Lenalidomide on Target Cells: Enhanced ADCP via CD38 Upregulation Primary Plasma Cell Leukemia (CD38 low, lenalidomide cytotoxicity sensitive) OPM-2 (CD38 low, lenalidomide cytotoxicity insensitive) 60 MOR202/DMSO Specific killing activity [%] MOR202/LEN Isotype ctrl/dmso Isotype ctrl/len MOR202 [nm] MOR202 [log nm] LEN-induced CD38 upregulation LEN-induced cytotoxic effect on target cells

15 Combination of Lenalidomide and MOR202 in ADCP Primary Plasma Cell Leukemia (CD38 low, lenalidomide cytotoxicity sensitive) OPM-2 (CD38 low, lenalidomide cytotoxicity insensitive) Additivity Synergy 15

16 Potential Combination Partner: Bortezomib

17 Combination of Bortezomib (BOR) and MOR202: Additive Activity in Vitro NCI-H929 (CD38 high expression) LP-1 (CD38 medium expression) Additivity Additivity

18 Potential of MOR202 in Combination Therapy of MM In Vivo

19 MOR202 Significantly Reduces Bone Lysis in a Physiological Mouse Model of Multiple Myeloma MOR202 monotherapy ELISA of M protein serum levels Bone lysis [%] Orthotopic Bone Lysis Model shows hallmarks of Multiple Myeloma Bone lysis M protein gradient For detail refer to Poster presented at ASCO 2011 Abstract #8078

20 MOR202 Shows Synergistic Activity with Lenalidomide In Vivo (Bone Lysis Model) Bone lysis M-Protein Bone lysis [%]

21 MOR202 Shows Synergistic Activity with Bortezomib In Vivo (Bone Lysis Model) Bone lysis M-Protein Bone lysis [%]

22 MOR202 Shows Synergistic Activity with Melphalan In Vivo (Bone Lysis Model) Bone lysis M-Protein Week 4 Week 6 * p<0.001 MOR202 + melphalan significantly reduces both bone lysis and M Protein promising potential therapeutic approach for heavily pretreated / salvage MM patients

23 MOR202 Combination Significantly Prolongs Survival in a Ramos in Vivo Mouse Model MOR202 + lenalidomide MOR202 + bortezomib

24 High Efficacy of MOR202 in Combination with Standard-of-Care drugs in In Vivo Models Survival model Bone lysis model MOR202 MOR lenalidomide bortezomib lenalidomide bortezomib melphalan ImiD proteasome inhibitor ImiD proteasome inhibitor alkylating agent = = = = = Potentiation Potentiation Synergy Synergy Synergy

25 And now?

26 Outlook: MOR202 as Monotherapy and in Combination with Standard Therapy in MM The clinical phase I/IIa trial is actively recruiting Study Design Phase I/IIa multicentre, open-label, dose escalation study Recruitment Target: 82 patients; 2 European countries (Germany, Austria) Patient population Patients with relapsed/refractory myeloma (failure of 2 or more prior therapies) Objectives Investigate maximum tolerated dose, safety and tolerability of MOR202 as monotherapy and in combination with lenalidomide and bortezomib (adaptions possible) Pharmacokinetics and immunogenicity Assess preliminary anti-myeloma activity Evaluate potential of exploratory biomarkers Page 26

27 Thank You