Immuno-Oncology Clinical Trials Update: Checkpoint Inhibitors Others (not Anti-PD-L1/PD-1) Issue 4 January 2017

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1 Delivering a Competitive Intelligence Advantage Immuno-Oncology Clinical Trials Update: Checkpoint Inhibitors Others (not Anti-PD-L1/PD-1) Issue 4 January 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the information in this database is not 100% accurate as timing and registration details for specific trials may be out of date.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 6. ADCs (antibody-drug conjugates) 7. 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 4, January

3 Anti-CTLA-4 was the first checkpoint inhibitor class to make it to market The only checkpoint inhibitor that is launched and that is not an anti-pd-l1/pd-1 inhibitor is the anti-ctla-4 drug Yervoy (ipilimumab) from Bristol-Myers Squibb (BMS) In 2011, it was launched as a monotherapy for late-stage melanoma By 2013 had reached $1 billion in global sales As of 2016, it has gained FDA accelerated approval for unresectable or metastatic melanoma, in combination with Opdivo (nivolumab), also from BMS Yervoy is showing impressive results in melanoma, but with high toxicity rates About 1 in 5 patients treated with Yervoy monotherapy have survived 10 years Median PFS mono vs. combo: 2.9 vs months Response rate mono vs. combo: 19% vs. 58% Grade 3-4 AE rate: ~20% vs. 57%, most of which are manageable with immunosuppressors In NSCLC, anti-ctla-4 inhibitors have also shown encouraging trial results in combos with anti-pd-l1/pd-1 drugs Opdivo + Yervoy combo has doubled the efficacy over Opdivo monotherapy Durvalumab (PD-L1) + tremelimumab (CTLA-4) combo, both from AstraZeneca (MedImmune), has also resulted in strong antitumor activity in an early study Besides anti-ctla-4 molecules, several other checkpoint inhibitors exist that could be targeted Seven additional checkpoint inhibitor molecules are in clinical development (see next slide) Drugs targeting an additional five checkpoint inhibitor molecules have not yet reached clinical development as per clinicaltrials.gov: B7-H4, BTLA, CD160, CD244, TIGIT Issue 4, January

4 Multiple molecules have reached early clinical testing Key to abbreviations: see slide 11 Issue 4, January

5 U.S. sponsors dominate the clinical market 94% of all trials are in Phase 1 and 2 and only a handful in Phase 3 There are only nine trials in Phase 2/3 or Phase 3 out of 156 trials Non-industry sponsor involvement is significant and accounts for half of all trials, with partnerships between industry and nonindustry accounting for roughly 20%, leaving 30% for industry sponsorship The National Cancer Institute (NCI) in the U.S. is involved in 50 trials, or one third of all reported trials and nearly all with no industry involvement Two anti-ctla-4 therapies dominate these trials: Yervoy from BMS accounting for 50% of all trials tremelimumab from AstraZeneca (MedImmune) accounting for 20% Breakdown by Phase (156 trials) Breakdown by Type of Sponsor (156 trials) Industry Industry/Other Other P1 P1/2 P2 P2/3 + P3 U.S. sponsors, whether major pharma or non-industry hospitals/academic centers, account for nearly three quarters of all trials BMS is the major U.S. sponsor with the greatest number of trials In Europe, AstraZeneca (MedImmune) by far is the largest sponsor Breakdown by Location of Sponsor HQ (156 trials) USA Europe RoW Issue 4, January

6 Melanoma and blood-born cancers are the key focus The greatest focus of these trials is on melanoma Around one third of all trials includes this indication Many trials include minor oncology indications not covered by other areas of immuno-oncology therapies Most of these are still in Phase 1 and so only at the early exploratory stages of investigation This is especially true for many of the NCI trials The majority of these trials are combinations of an anti-pd-l1/pd-1 drug with either Opdivo (nivolumab) from BMS durvalumab from AstraZeneca (MedImmune) Often these anti-pd-l1/pd-1 combo trials also include a monotherapy arm Most of these trials will be reading out over the next two years ( ) This will be an exciting time to see if these novel therapies can deliver results as good as the highly successful anti-pd-l1/pd-1 drugs reported out in our previous report, or can improve their efficacy as combos Breakdown by Cancer Type (156 trials) number of trials Melanoma Lymphoma Leukemia Lung Prostate Breast MDS CRC Ovarian RCC Brain Bladder Pancreas Gastric H&N Myeloma Cervical Liver Espoph Other Solid Cancers Issue 4, January

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12 Backgrounder Checkpoint inhibitors in oncology Checkpoints are molecules on the surface of cancer killing cells such as cytotoxic T cells that suppress their killing activity when engaged by the corresponding ligands on the surface of cancer cells and other regulatory cells Checkpoint inhibitors are antagonistic antibodies, decoy proteins, or small molecules that bind checkpoint molecules By blocking the checkpoint molecules, checkpoint inhibitors break the suppressive signals unleashing the full killing power of anti-cancer cells A wide range of combination regimens are now being tested in an attempt to increase the number of patients responding to these remarkable novel drugs The idea of these combinations is to increase the activation of T cells, prevent the non-responsiveness of other anti-cancer effectors such as NK cells, block the suppressive tumor microenvironment, expand the levels of anticancer cells, and even generate/liberate new tumor antigens A challenge developing checkpoint inhibitors is maximizing efficacy and minimizing toxicity, particularly in combinations Issue 4, January 2017 EMC Analytics Group, LLC