Immuno-Oncology Clinical Trials Update: Antibody-Drug Conjugates (ADCs) Issue 6 March 2017

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1 Delivering Competitive Intelligence Advantage Immuno-Oncology Clinical Trials Update: Antibody-Drug Conjugates (ADCs) Issue 6 March 2017

2 Immuno-Oncology CLINICAL TRIALS UPDATE The goal of this MONTHLY series is to provide: A regularly updated database of CLINICAL TRIALS in the key areas of the evolving immuno-oncology (I-O) market This service is COMPLIMENTARY. It is based on clinical trials from We recognize that the information in this database is not 100% accurate as timing and registration details for specific trials may be out of date. In addition, it is not required for Phase 1 drug and biologic trials to be recorded. However, in aggregate, this information provides value due to the large number of clinical trials analyzed. This service lists all relevant clinical trials in the following areas of the I-O market, together with overall top-line analysis. Each area will be covered and updated around twice a year: 1. CAR cells (chimeric antigen receptor cells, or genetically-engineered immune cells) Oct Bispecific antibodies Nov Checkpoint inhibitors Anti-PD-1/PD-L1 Dec Checkpoint inhibitors Others Jan Oncolytic viruses Feb ADCs (antibody-drug conjugates) March Immune activators or stimulators and therapeutic vaccines This series is produced by EMC Analytics Group. We are specialists in competitive strategy and help clients understand the competitive forces impacting either their product development or commercial plans. If you would like ADDITIONAL DETAILS on any area of the I-O market, or other drug markets, please feel free to contact: Mike Ratcliffe EMC Managing Director mratcliffe@emcanalytics.com +1 (508) Issue 6, March

3 ADCs are a growing class of anti-cancer treatments Antibody-drug conjugates (ADCs) are an exciting class of the I-O market with approximately 70 candidates in active Phase 1 through 3 clinical trials and 2 approvals: Adcetris (brentuximab vedotin) jointly developed and marketed by Seattle Genetics and Takeda Oncology (Millennium Pharma) was initially approved in 2011; currently indicated for: Classical Hodgkin s lymphoma after failure of autologous hematopoietic stem cell transplantation or at least two prior chemotherapy regimens in patients who are not transplantation candidates or at high risk of relapse/progression post-transplantation Systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen 2016 global sales around $250 million Kadcyla (ado-trastuzumab emtansine) from Genentech was first approved in 2013; currently indicated for: Patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination 2016 global sales around $830 million Some ADCs appear to promote anti-cancer T-cell responses and are a potential synergistic combination with checkpoint inhibitors Kadcyla has elicited antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) Kadcyla has been shown to sensitize drug-resistant breast cancer to PD-1 and CTLA-4 blockade in preclinical models There is a growing variety of drug payloads being used At least over 10 currently DM1, DM4, doxorubicin, duocarmycin, MMAE, MMAF, calicheamicin, amberstatin269, PBD, SN-38, auristatin-based, azonafides Novel payloads such as azonafides induce immunogenic cell death (ICD), resulting in cytotoxic T-cell proliferation and CTL infiltration of the tumor microenvironment and could improve durability of targeted therapies Linker variety is also increasing Novel structures are being developed to improve ADC stability, homogeneity, and payload site-specificity Also growing is the number of cancer antigens being targeted There are over 25 targets currently Issue 6, March

4 Major focus on lymphomas ADCs are heavily focused on lymphomas B-cell, Burkitt, Follicular, Gray zone, Diffuse large B-cell, Mantle cell, Non-Hodgkin s, T-cell, and Waldenstrom macroglobulinemia As with other I-O therapies, a wide range of solid tumors are being investigated, with the major focus on breast cancer Industry sponsors are often focusing more on specific cancer types: AbbVie small cell lung cancer, glioblastoma Genentech/Roche breast, non-hodgkin s, NSCLC Novartis breast cancer Pfizer leukemias Seattle Genetics Hodgkin s lymphoma, AML AbbVie (Stemcentrx) small cell lung cancer Takeda Oncology Hodgkin s lymphoma Issue 6, March

5 Many candidates have progressed to Phase 2 or 3 Roughly 40% of all trials have progressed to Phase 2 or Phase 3, a significantly higher percentage than other I-O technologies Industry sponsors dominate this area of the I-O market, either running the trial themselves or partnering with other industry sponsors Seattle Genetics is the major player running over 10% of all trials itself, and if its partnership trials with Agensys/Astellas, Bristol- Myers Squibb (BMS), Takeda Oncology are included, it is involved in some 15% of all trials 12 candidate compounds actively in clinical development Genentech/Roche is also an major investor in this technology running over 10% of all trials 8 candidate compounds actively in clinical development 65% of all trial are through U.S. sponsors Nearly all major biopharma companies in both the U.S. and Europe are involved in researching ADCs AbbVie, Amgen, Bayer, BMS, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Novartis, Pfizer, and Sanofi Issue 6, March

6 Company Drug Target Comment Company Drug Target Comment AbbVie ABBV-085 LRRC15 GSK (Seattle Genetics) GSK BCMA AbbVie (Seattle Genetics) ABBV-221 EGFR ImmunoGen IMGN529 CD37 AbbVie (Seattle Genetics) ABBV-399 c-met ImmunoGen Lorvotuzumab Mertansine (IMGN901) CD56 AbbVie (Seattle Genetics) ABBV-838 SLAMF7 ImmunoGen Mirvetuximab Soravtansine (IMGN853) FRα AbbVie (Seattle Genetics) ABT-414 EGFR ImmunoGen XMT-1522 HER2 Trial terminated AbbVie (Stemcentrx) Rovalpituzumab Tesirine (SC16LD6.5) DLL3 Immunomedics Labetuzumab-SN-38 (IMMU 130) CEACAM5 AbGenomics AbGn-107 Undisclosed Immunomedics Milatuzumab-DOX (IMMU-110) CD74 ADC Therapeutics ADCT-301 CD25 Immunomedics Sacituzumab Govitecan (IMMU-132) CD22 ADC Therapeutics ADCT-402 CD19 Mersana Therapeutics XMT-1522 HER2 Trial terminated Agensys Seattle Genetics Astellas ASG-15ME SLITRK6 Novartis HKT288 CDH6 Astellas (Seattle Genetics) AGS-16C3F ENPP3 Novartis LOP628 ckit Trial terminated Agensys Seattle Genetics Astellas AGS-16M8F ENPP3 Nothing since 2012 Novartis (ImmunoGen) PCA-062 p-cadherin Agensys Astellas (Ambrex) AGS62P1 FLT3 Pfizer PF ST4 Trial terminated Agensys Seattle Genetics Astellas AGS67E CD37 Pfizer PF PTK7 Agensys Seattle Genetics Astellas ASG-22CE Nectin-4 Pfizer PF EFNA4 Astellas (Seattle Genetics) Enfortumab vedotin (ASG-22ME) Nectin-4 Pfizer (UCB) Inotuzumab Ozogamicin (CMC-544) CD22 Astellas (Seattle Genetics) ASG-5ME Nothing since 2013 Pfizer (UCB) Mylotarg (Gemtuzumab Ozogamicin) Amgen AMG-172 CD27L Progenics (Seattle Genetics) PSMA-ADC PSMA Amgen AMG-595 EGFRvIII RemeGen RC48-ADC HER2 Aspyrian RM-1929 EGFR Sanofi (immunogen) Coltuximab Ravtansine (SAR3419) CD19 Bayer (ImmunoGen) Anetumab Ravtansine (BAY ) mesothelin Sanofi (immunogen) SAR CEACAM5 Bayer (Seattle Genetics) BAY C4.4a Sanofi (immunogen) SAR LAMP1 Bayer BAY FGFR2 Trial terminated Sanofi (immunogen) SAR CA6 BioTest AG (ImmunoGen) BT-062 CD138 receptor Sanofi (Stemcentrx) SC-002 Undisclosed BMS BMS mesothelin Sanofi (Stemcentrx) SC-003 Undisclosed Celldex (Seattle Genetics) Glembatumumab Vedotin (CDX-011) gpnmb Seattle Genetics Denintuzumab Mafodotin (SGN-CD19A) CD19 Celldex (Seattle Genetics) CDX-014 TIM-1 Seattle Genetics SGN-2FF CD19 Daiichi Sankyo DS-8201a HER2 Seattle Genetics SGN-75 CD70 Trial terminated Daiichi Sankyo U HER3 Seattle Genetics SGN-CD123A CD123 Eli Lilly LY FGFR-3 Seattle Genetics SGN-CD19B CD19 Genentech Kadcyla (Trastuzumab Emtansine, T-DM1) HER2 Seattle Genetics SGN-CD352A CD352 Genentech (Seattle Genetics) Lifastuzumab Vedotin (RG-7599) NaPi2B Seattle Genetics SGN-CD70A CD70 Genentech (Seattle Genetics) Polatuzumab Vedotin (RG-7596) CD79b Seattle Genetics SGN-LIV1A LIV-1 Genentech (Seattle Genetics) Vandortuzumab Vedotin (DSTP3086S, RG-7450) STEAP1 Seattle Genetics Vadastuximab Talirine (SGN-CD33A) CD33 Genentech (Seattle Genetics) DMUC 4064A (RG-7882) MUC16 Synthon Trastuzumab vc-seco-duba (SYD985) HER2 Genentech (Seattle Genetics) DCDS0780A (RG-7986) Undisclosed Takeda Oncology (Millenium) MLN-0264 guanylyl cyclase C Genentech (Seattle Genetics) DSTA4637S (RG-7861) S. aureus Takeda Oncology (Seattle Genetics) Adcetris (Brentuximab Vedotin, SGN-35) CD30 Genentech (Seattle Genetics) DLYE5953A (RG-7841) Ly6E Zhejiang Medicine Ambrx ARX788 HER2 Genmab (Seattle Genetics) Tisotumab Vedotin (HuMax-TF-ADC) TF Genmab (Seattle Genetics) HuMax-AXL-ADC AXL Issue 6, March

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13 Antibody-Drug Conjugate (ADC) Backgrounder ADCs consist of highly toxic drugs covalently bound to an antibody by a linker The monoclonal antibody is highly specific for a tumor-associated antigen Ideally, the linker is stable in blood circulation, but releases the toxin once the ADC is internalized by cancer cell The highly toxic drug is designed to kill the cancer cell once internalized Because the tumor-associated antigen has little to no expression on healthy cells, drugs that otherwise would be too toxic to administered systemically can be used to kill cancer cells while limiting damage to healthy ones The success of an ADC depends on the target antigen, the antibody, the linker, and the drug Challenges: Increase stability of the linker to prevent spontaneous release of the highly toxic drug into systemic circulation Reduce heterogeneity of the ADC product, controlling the number of toxins attached per antibody and their location on the antibody Develop bioanalytical methods to assess the multiple ADC species in a product, identify them in the systemic circulation, and correlate them with efficacy and safety/toxicity Issue 6, March