Innate Immunity-based Therapeutic Strategies Actualized through Affimed s ROCK Platform

Transcription

1 Innate Immunity-based Therapeutic Strategies Actualized through Affimed s ROCK Platform Dr. Martin Treder CSO Affimed GmbH Innate Killer Summit, San Diego, US March 19-21, 2019

2 Forward-Looking Statements / Safe Harbor This presentation and the accompanying oral commentary contain forward-looking statements that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this presentation and the accompanying oral commentary, including statements regarding our future financial condition, business strategy and plans and objectives of management for future operations, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as believe, will, may, estimate, continue, anticipate, intend, should, plan, might, approximately, expect, predict, could, potentially or the negative of these terms or other similar expressions. Forward-looking statements appear in a number of places throughout this presentation and the accompanying oral commentary and include statements regarding our intentions, beliefs, projections, outlook, analyses and current expectations concerning, among other things, the value of our ROCK platform, the safety and efficacy of our product candidates, our ongoing and planned preclinical development and clinical trials, our collaborations and development of our products in combination with other therapies, the timing of and our ability to make regulatory filings and obtain and maintain regulatory approvals for our product candidates our intellectual property position, our collaboration activities, our ability to develop commercial functions, expectations regarding clinical trial data, our results of operations, cash needs, financial condition, liquidity, prospects, future transactions, growth and strategies, the industry in which we operate, the trends that may affect the industry or us and the risks uncertainties and other factors described under the heading Risk Factors in Affimed s filings with the Securities and Exchange Commission. Forward-looking statements involve known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Forward-looking statements represent our management s beliefs and assumptions only as of the date of this presentation. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future. 2

3 Affimed Brings a New Approach to Counter Tumor Immune Evasion Through the Innate Immune System Current Treatments Advanced I-O agents demonstrate it is possible to activate the immune system to trigger tumor killing Despite these advances, a cure remains elusive and more options are needed to truly help patients Most current therapeutic options focus on adaptive immunity, not leveraging the potential of innate immunity Affimed Affimed is committed to improving patient outcomes through the power of the innate immune system Affimed s clinically validated ROCK platform creates medicines that enable the body s innate immune cells, NK cells and macrophages, to recognize and kill tumor cells (basis for the Genentech collaboration) 3

4 Affimed s Innate Cell Engagers Can Give Patients Back their Innate Ability to Fight Cancer Cancer Patient s Innate Immune System Affimed s unique approach activates innate cells through proprietary CD16A targeting Tumor recognition X Innate Cell Engagers Tumor lysis (ADCC through CD16A) Increase binding of CD16A X Increase NK cell activation Increase cytotoxicity (ADCC) Increase phagocytosis (ADCP) NK cell Tumor cell Macrophage 4

5 Innate Cell Engagers Differentiated and Versatile Innate Cell Engagers Target Hematological and Solid Tumors AFM13 Disease Target CD30 Immune Cell Target CD16A Hodgkin lymphoma + PD-1 Phase 1 (Collaboration) Hodgkin lymphoma Phase 2 (IST) Hodgkin lymphoma + adoptive NK cells Pre-IND (Collaboration) CD30-positive lymphoma Phase 2 Additional clinical studies In preparation In preparation AFM24 Disease Target EGFR Immune Cell Target CD16A Solid tumors Pre-IND AFM26 Disease Target BCMA Immune Cell Target CD16A Multiple Myeloma Pre-IND Affimed Programs Partnered Programs Licensed Programs 5

6 CD16A target ROCK Platform Fit-for-Purpose tumor target 6

7 Fit-for-Purpose ROCK Platform Allows Innate Cell Engagers to be Designed for Specific Indications ROCK Platform is Affimed s proprietary technology to generate in-house innate cell engagers Versatile Platform Tailor tetravalent, bispecific innate cell engagers with high avidity and affinity, and variable PK profiles Strong Engineering Proven record in building potent and stable molecules in a short time Proprietary Target Specific CD16A-targeting addresses major hurdles required for potent activation Generate novel IP to broaden leadership in innate immunity Elegant predictability for powerful medicines The right approach to unlock innate immunity 7

8 ROCK Platform Offers Unique Modularity and Versatility for Customizable Antibody Generation ROCK generates antibodies that address shortcomings of other technologies: Customization with ROCK (Protected by a broad IP portfolio) Tumor Targeting Target different tumor-associated antigens Cell killing even with low target expression Use the avidity effect Immune Cell Engagement Recruit innate immune cells through anti-cd16aspecific epitopes CD16A engagers: activation of NK cells and evidence of tumor infiltration of NK cells; no non-specific activation of innate immune cells CD16A target Tumor target Therapeutic Window Offer different PK profiles Possess long cell retention time Innate cell engager PK, pharmacokinetics; TAA, tumor-associated antigen 8

9 % remaining antibody Tetravalent, Bispecific Engagement of NK Cells Results in More Effective Tumor Cell Lysis Efficacy of target cell lysis in vitro Cell surface retention on human NK cells AFM13 Tetravalent, bispecific Fc-enhanced IgG Native IgG T e tr a v a le n t b is p e c ific F c -e n h a n c e d Ig G n a tiv e Ig G B iv a le n t b is p e c ifc (d ia b o d y ) Incubation at 37 C (min) Long cell retention on NK cells mediated by high affinity binding creates an armed NK cell and a pharmacodynamic advantage Reusch et al., MAbs,

10 CD11b fo ld in d u c tio n v s. w /o a n tib o d y c o n tro l fo ld in d u c tio n v s. w /o a n tib o d y c o n tro l Innate Cell Engagers Induce Antibody-dependent Cellular Phagocytosis (ADCP) ADCP induced by ROCK innate cell engagers ADCP of EGFR-positive target cells induced by AFM A n tib o d y c o n c e n tra tio n A n tib o d y c o n µ g /m L 0.1 µ g /m L w /o a n tib o d y 1 0 µ g /m 0.1 µ g /m w /o a n t Flow cytometric assessment of ADCP w/o antibody +0.1µg/mL AFM24 +10µg/mL AFM w /o a n tib o d y 0 AF M 2 4 R S V / C D 1 6 A/ w /o AF M 2 4 R S V / E G F R R S V a n tib o d y E G F R C D 1 6 A/ R S V CMFDA Wingert et al, ASH Annual Meeting, 2018, Abstract

11 CD16A target Innate Cell Engagers in Hematologic Tumors Treatment with AFM13 CD30 target 11

12 In Clinical Studies, AFM13 Monotherapy Has Shown Promising Efficacy in Patients With CD30 Positive Lymphoma CD30-Positive Lymphoma Trial: Investigator-sponsored*, translational study to evaluate immunological effects and preliminary efficacy of AFM13 monotherapy in R/R CD30+ lymphoma with cutaneous presentation 9 patients treated in 3 dose cohorts Results R/R Hodgkin Lymphoma Overview**: AFM13 monotherapy is active post-brentuximab vedotin failure Biomarker data: possible correlation between response and tumor NK cell infiltration pre-therapy 44% ORR including 1 CR and 3 PRs *Principal Investigator: Ahmed Sawas, MD, Columbia University Medical Center, New York, NY. **Sawas et al., ASH Annual Meeting 2018, Abstract CR, complete response; MTD, maximum-tolerated dose; ORR, objective response rate; PR, partial response; R/R, relapsed/refractory; T-MF, transformed mycosis fungoides 12

13 Treatment with AFM13 Followed by Allogeneic Stem Cell Transplant Demonstrated Durable Response in a Patient with T-MF Response: Skin lesions (leg) Pre Study Cycle 1 Week 11 Post Cycle 2 Response: Lymph nodes (PET-CT) PRE Study R/R Hodgkin Lymphoma Lymph node First Assessment Lymph node * Tumor tissue Tumor tissue Efficacy in T-MF: Responses were observed in lymph nodes, skin and the peripheral blood *Imaging response for same leg in left photographs. T-MF, transformed mycosis fungoides 13

14 Activation of the Innate Immune System for Tumor Recognition and Killing Also Initiates an Adaptive Immune Response Innate Immunity, First Line of Defense Tumor cell Affimed (innate cell engagers) NK cell CD16A receptor Adaptive Immunity, Second Line of Defense Current therapies (e.g., anti-pd-1/l1) Dendritic cell T cell CD16A receptor Initiation of adaptive response Macrophage Tumor cell Tumor killing Tumor killing 14

15 Preclinical Data Demonstrated Efficacy of AFM13 in Combination with αpd-1 Decrease in tumor volume observed with AFM13 + αpd-1 (PDX model) Tumor sections (8X8 mm) from newly diagnosed patients with CD30+ HL were engrafted and grown over 28 days Autologous PBMCs infused at 2x10 6 PBMCs/mouse i.p. at baseline αpd-1 and AFM13 given at 5 mg/kg every week Treder et al, ASCO Annual Meeting 2016, Abstract #e

16 Fold Change vs. IgG Fold Change vs. IgG AFM13 Induces Tumor Infiltration by Immune Cells, Strongly Enhancing the Effect of αpd-1 Monotherapy Tumor infiltration, day 2 post-treatment start* Tumor infiltration, day 30 post-treatment start* C D 8 + T -c e lls N K -c e lls C D 8 + T -c e lls N K -c e lls AFM13 AFM13 + αpd AFM13 AFM13 + αpd Ig G A F M 2 2 a n ti-p D -1 A F M a n ti-p D -1 A F M 1 3 A F M a n ti-p D Ig G A F M 2 2 a n ti-p D -1 A F M a n ti-p D -1 A F M 1 3 A F M a n ti-p D Ig G A FIg MG 2 2 a na ti-p F MD2 2-1 aan Fti-P M 1D 3-1 A F M 1 3 A F M a n ti-p D -1 + a n ti-p D Ig G A FIg MG 2 2 a An ti-p F M 2D 2-1 a na ti-p F M 1D 3-1 A F M 1 3 A F M a n ti-p D -1 + a n ti-p D -1 *Tumor sections (8x8 mm) from newly diagnosed CD30+ HL were engrafted and grown over 28 days, autologous PBMCs infused at 2x106 PBMCs/mouse i.p. at baseline, CPIs and AFM13 given at 5mg/kg every week. AFM13 induces rapid NK cell infiltration, followed by T cell infiltration in tumors Effect is >doubled for the AFM13/αPD-1 combination Treder et al, ASCO Annual Meeting 2016, Abstract #e

17 Addition of AFM13 to Pembrolizumab Results in Doubling of the Complete Response Rate in Patients With R/R HL R/R Hodgkin Lymphoma Trial: AFM13 in combination with Merck s Keytruda (pembrolizumab) Total of 30 patients treated to date MTD not reached in dose escalation study; highest dose employed in an extension study (24 patients evaluable) Results 88% ORR, 42%/46% CR rate (local/central read) Best Response, Tumor Volume Outcome: Durable responses: 77% estimated 6-month PFS rate Deepening of responses over time in multiple patients Patients previously transplant ineligible transitioned to transplant after achieving an objective response Bartlett et al., ASH Annual Meeting 2018, Abstract CR, complete response; MTD, maximum-tolerated dose; ORR, objective response rate; PR, partial response; R/R, relapsed/refractory. 17

18 Potential to Enhance Efficacy of Adoptive NK Cell Transfer by Combination With Innate Cell Engagers (e.g. AFM13) Adoptive NK cell transfer has demonstrated ability to induce remissions in patients with AML Studies across several tumor indications suggest that prevalence of NK cells is associated with beneficial outcomes Limitations of adoptive NK cell transfer include limited persistence and lack of re-direction A combination approach of adoptively transferred NK cells with innate cell engagers may overcome these hurdles Collaboration with MDACC investigates AFM13 in combination with CB-NK cells + AFM13 Koehl et al., Oncoimmunology, 2015; Bachanova et al., Blood, 2014; Curti et al., Blood, 2014; Rubnitz et al., J. Clin. Oncol., 2010; Miller et al., Blood, 2005; Romee et al., Sci. Transl. Med., CB-NK = cord blood-derived NK cells 18

19 Features Combination of AFM13 with Adoptive NK Cell Transfer to Generate a Potent, Pre-loaded and Re-directed Therapy Innate cell engager e.g. AFM13 CB-NK cells AFM13 pre-loaded CB-NK cells + CD16A receptor = High affinity High potency CD16- specific Allogeneic Off-the-shelf Re-direction High efficacy Better persistence 19

20 30 AFM13-loaded CB-NK Cells Demonstrated Enhanced Efficacy in vitro AFM13-loaded cbnk cells kill CD30+ cells 0 AFM13-loaded cbnk cells demonstrate an activated phenotype % Positive CD56+ CD CD107a INFg TNFa * AFM13 loaded CB-NK CB-NK cells + AFM ug/ml vs Karpas Unloaded CB-NK CB-NK vs Karpas % Positive CD56+ CD * CD107a * INFg TNFa * Kerbauy et al, Oral Presentation, ASH Annual Meeting 2018, Abstract 341. CB-NK cells + AFM ug/ml vs Karpas 20

21 Combination of AFM13 and CB-NK Cells Decreased Tumor Growth and Increased Survival in vivo AFM13-loaded CB-NK cells demonstrate a reduction in tumor volume AFM13-loaded CB-NK cells lead to increased survival Karpas Karpas + unloaded NK cells Karpas + AFM13 loaded NK cells Unloaded CB-NK AFM13 loaded CB-NK AFM13 Kerbauy et al, Oral Presentation, ASH Annual Meeting 2018, Abstract

22 Multiple Clinical Development Opportunities With AFM13 Initial registration path AFM13 monotherapy in PTCL - Potential for accelerated approval Confirmatory study for PTCL Affimed-sponsored study Next registration path AFM13 monotherapy in CTCL (TMF) AFM13 + Anti-PD-1/PD-L1 in R/R HL Affimed-sponsored study Planned study Exploratory opportunities AFM13 + CB-NK in CD30 lymphomas Collaboration with MDACC 22

23 AFM13 in CD30+ Lymphomas Summary AFM13 is able to activate tumor lysis through both NK cells and macrophages AFM13 has demonstrated clinical efficacy as both monotherapy and combination therapy with apd-1 in patients with CD30+ lymphomas AFM13 monotherapy in patients with r/r T cell lymphomas: ORR of up to 44%, including 1 CR and 3 PRs AFM13 in combination with apd-1 in patients with r/r HL: Doubling of ORR and complete response, 88% ORR, 42%/46% CR rate (local/central read) Clinical studies of AFM13 observed a well-tolerated safety profile as monotherapy or in combination with apd-1 antibodies AFM13 has preclinically demonstrated synergy with cytokines (e.g. IL-2, IL-15) in relevant in vitro models* Differentiated combination approach with adoptive NK cell transfer to form a pre-loaded, re-directed therapy Decreased tumor growth and increased survival were reported in vivo studies * Pahl Publication 23

24 CD16A target Innate Cell Engagers in Solid Tumors Treatment with AFM24 EGFR target 24

25 New Approaches Are Needed to Overcome The Limitations Of Current Therapies Unmet Need in EGFR-expressing tumors New technological approaches are needed to address limitations of: Lack of efficacy (mabs, Fc-enhanced mabs) Narrow therapeutic window, benefit/risk profile (e.g., ADC, BiTE) EGFR is overexpressed in several tumors (e.g. CRC, NSCLC, HNSCC, GBM, TNBC) EGFR-mediated signaling is frequently affected by mutations in various tumors leading to increased tumor growth Current therapies rely on inhibition of EGFR signal transduction and may be limited by: Associated toxicities Acquired resistance Limited antitumor immune response Affimed s solution: ROCK based AFM24 (CD16A/EGFR) The ROCK platform enables development of innate engagers that Address targets where other approaches showed limitations based on safety or efficacy Address targets identified on the basis of expression, clinical experience, tumor immune cell infiltration Novel mode of action addressing safety of SOC and SOC-resistant patient population Innate cell engager bridging NK cells and macrophages to EGFR expressing tumors An influx of TILs and NK cells is associated with a beneficial prognosis in EGFR tumors TIL, tumor infiltrating lymphocytes 25

26 % Specific lysis fo ld in d u c tio n v s. w /o a n tib o d y c o n tro l AFM24 s Innate Mechanism Demonstrates Potent Tumor Cell Killing through Activation of NK Cells and Macrophages AFM24 demonstrates potent killing of EGFR + target cells through NK cells as effector cells (ADCC) AFM24 elicits macrophage-induced killing of EGFR + target cells (ADCP) Cytotoxicity assay with A-431 targets and NK cells as effector cells In vitro Phagocytosis assay with DK-MG targets and macrophages as effector cells In vitro 100 AFM24_I cetuximab anti-cd16a control antibody w/o antibody A ntibody concentration 10 µg/m L 0.1 µg/m L w /o antibody w/o w /o a n tib o d y AF M 2 4 R S V / E G F R C D 1 6 A/ R S V Antibody concentration [pm] 26

27 Tumor volume [mm3] AFM24 Demonstrated Potent in vivo Tumor Cell Killing and Improved Safety AFM24 demonstrates dose-dependent tumor growth inhibition in an in vivo mouse model AFM24 shows favorable safety profile in a dose range finding toxicity study in cynomolgus monkeys Vehicle AFM24_I (5mg/kg) AFM24_I (15mg/kg) AFM24_I (45mg/kg) In vivo All animals were clinically well throughout the study without notable changes in body temperature, clinical hematology, or clinical chemistry Macroscopic and microscopic assessment of tissues showed no findings of toxicities (e.g., skin toxicity) AFM24 is markedly more tolerable vs. published safety data for cetuximab in cynomolgus monkeys The half-life of AFM24 is comparable to the half-lives of cetuximab and panitumumab in cynomolgus monkeys Time [days] 27

28 AFM24, a New Mode of Action Activating Innate Immunity in EGFR+ Solid Tumors Summary and Next Steps AFM24 demonstrated potent cell killing capabilities through activation of ADCC & ADCP Preclinical studies have indicated that AFM24 can inhibit tumor growth and has a favorable safety profile Dose-dependent tumor growth inhibition in an in vivo model Differentiating safety profile observed in cynomolgus toxicology study Potential for improved efficacy in tumor types with EGFR mutations/resistance Combination therapies that leverage innate and adaptive immunity may enhance efficacy in solid tumor types Next steps: Planned IND filing by mid-2019 Phase 1 study: All-comer study with focus on mcrc, SCCHN and NSCLC, with clinical data possible in

29 Affimed s Innate Cell Engagers Offer Novel Therapeutic Strategies for the Treatment of Hematologic and Solid Tumors Affimed offers a differentiated and versatile fit-for-purpose ROCK platform that generates innate cell engagers with high affinity binding and potent innate immune cell killing (ADCC/ADCP) These medicines/therapies may address the limitations of efficacy or safety observed with other approaches, thereby addressing the unmet needs in both hematologic and solid tumors The lead engager AFM13 (CD30/CD16A) demonstrated efficacy in monotherapy and in combination with pembrolizumab (TCL, HL) with a tolerable safety profile Adoptive NK cell transfer in combination with AFM13 is an attractive opportunity to further enhance clinical efficacy in CD30+ lymphoma patients AFM24 has the potential to be efficacious where current SOC therapies have limitations due to resistance (mutations) or safety (skin toxicity) 29

30 Acknowledgments Wolfgang Fischer Erich Rajkovic Thorsten Ross Michael Tesar Michael Kluge Joachim Koch Ivica Fucek Kristina Ellwanger Michael Weichel Uwe Reusch Stefan Knackmuss Ute Schniegler-Mattox Thomas Müller Torsten Haneke Susanne Wingert Vera Molkenthin Volker Lang Lucila Nassif Kerbauy Elizabeth J Shpall Katy Rezvani Adelheid Cerwenka Jens Pahl Ulrike Köhl Stefan Klöss 30

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