Immuno-Oncology Clinical Trials Update: Therapeutic Anti-Cancer Vaccines Issue 7 April 2017

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1 Delivering a Competitive Intelligence Advantage Immuno-Oncology Clinical Trials Update: Therapeutic Anti-Cancer Vaccines Issue 7 April 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the information in this database is not 100% accurate as timing and registration details for specific trials may be out of date.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 Therapeutic vaccines April Immune activators or co-stimulators 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 7, April

3 Limited success to date After PD-L1 checkpoint inhibitors, therapeutic vaccines is one of the most active areas of the I-O market in terms of number of active trials There are nearly 400 active trials with a very heavy involvement of non-industry sponsors In total there are some 80 industry and 150 non-industry sponsors involved in trying to successfully develop vaccines for the oncology market Major spopnsors are the U.S.A. s NCI, the Sidney Kimmel Cancer Center in Baltimore, MD, the Washington University School of Medicine in St. Louis, MO and the Moffitt Cancer Center in Tampa, FL Rather than a summary table listing these sponsors, please see the detailed clinical trial slides, as many only have one trial and one vaccine they are testing The success of therapeutic vaccines has been limited to date They have not worked well due in part to up-regulation of checkpoint molecules on activated anti-cancer immune cells and the activation of immunosuppressive cells It is therefore expected that combinations of vaccines with checkpoint inhibitors, immune co-stimulators and agents blocking immunosuppressive cells will lead to better anti-cancer immune responses Only one therapeutic anti-cancer vaccine has been approved: Provenge (sipuleucel-t) Provenge was developed by Dendreon and bought by Valeant in 2015 for $495m after Dendreon went bankrupt; in Jan 2017, Valeant announced it was selling Provenge to the China s Sanpower Group for $820m as senior management decided that urological oncology did not fit into Valeant s core long-term strategy Provenge consists of autologous peripheral blood monocytes incubated with a fusion protein encoding GM-CSF and PAP for activation Approved in 2010 for asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer Based on a median survival increment of 4.1 months [22% increase] from 21.7 to 25.8 months Provenge s high cost $95,000 for three (3) vaccinations and manufacturing complexity have limited its adoption *Note: Imlygic (talimogene laherparepvec) is in-market and may be considered a vaccine, but we covered it under oncolytic viruses in a separate issue Issue 7, April

4 The rebirth of therapeutic anti-cancer vaccines Therapeutic vaccines have shown low clinical efficacy as monotherapies 70% of tumors on average lack CD8+ tumor infiltrating lymphocytes (TILs), avoiding cancer-killing T-cells Vaccines can help increase TILs, but have resulted in low efficacy and/or un-sustained responses Best responses have been with whole cell lysates and mrna vaccines as cancer antigen sources The goal is to exploit the entire repertoire of available cancer-specific antigens in a patient (potentially tens to thousands) RNA vaccines stimulate both innate and cellular responses, increase migration and activation of dendritic cells to present cancer antigens Response rates of autologous whole tumor vs. defined antigen vaccines have been 8-12% vs. 4-6% There has been a need to increase the strength and to sustain the anti-cancer responses of therapeutic vaccines The requirement of initial testing of new drugs in metastatic diseases when the immune system is most suppressed has likely contributed to low responses Newer therapeutic modalities are being combined with anti-cancer vaccines to enhance their efficacy Checkpoint inhibitors and immune activators or co-stimulators can increase potency of anti-cancer vaccines and sustain their responses Preclinical and clinical research has shown that inhibitory receptors such as CTLA-4, PD-1, LAG-3, and TIM-3 are induced on vaccine activated T-cells Checkpoint inhibitors have enhanced activation of vaccine-induced tumor-specific T-cells and responses synergistically in animal models Immune activators targeting co-stimulatory receptors such as CD40L, OX40 and GITR expressed on activated T-cells have also synergize cancer vaccines Blocking suppressive cells within the tumor microenvironment will also help potentiate anti-cancer responses from therapeutic vaccines Treg cells, which are increased in cancer patients, can inhibit both the priming and the function of antitumor effector T-cells after vaccine administration Issue 7, April

5 Large number of parties are involved in developing vaccines With nearly 400 clinical trials, therapeutic anti-cancer vaccines is one of the most active areas in the I-O market However, only some 20 trials are in Phase 3 with the majority in early clinical phases A significant number of trials are combos with other anti-cancer therapies such as Avastin (bevacizumab), Imfinzi (durvalumab), Yervoy (ipilimumab), Opdivo (nivolumab), Keytruda (pembrolizumab), Rituxan (rituximab) Industry sponsors account for only 25% of all current trials with involvement in non-industry sponsored trials another 25% 75% of trials have some involvement by non-industry sponsors or interested parties, in particular U.S. universities and hospitals with large academic research groups as well as the National Cancer Institute (NCI) The NCI is involved in over 80, or some 20%, of all of these trials U.S. sponsors dominate accounting for 75% of all clinical trials The vast majority of non-industry sponsors are U.S-based through the heavy involvement of U.S. academic institutions Issue 7, April

6 Focus has been on solid tumors Research on solid tumors dominates this technology Industry sponsors are focused on a wide range of types, for example Aduro Biotech (CA, USA) brain, pancreatic Advantagene (MA, USA) prostate, lung Advaxis (NJ, USA) cervical Dendreon (WA, USA) prostate Gradalis (TX, USA) Ewing s Sarcoma, melanoma, ovarian Immunovative Therapies (Israel) hepatocellular carcinoma, head & neck, colorectal Major industry sponsors are involved in combo trials Bristol-Myers Squibb Opdivo (nivolumab) and Yervoy (ipilimumab) in brain, lung, and melanoma Merck Keytruda (pembrolizumab) in bladder, follicular lymphoma, and pancreatic Roche Tecentriq (atezolizumab) in bladder Issue 7, April

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15 Therapeutic anti-cancer vaccines backgrounder Therapeutic anti-cancer vaccines induce cancer-specific immune responses: Step 1: cancer-specific molecules are delivered to dendritic cells (DCs) in a way that activates the DCs concurrently Step 2: DCs process the cancer-specific molecules and present pieces of them [antigens] to T-cells [priming phase] DCs traffic to local lymph nodes Antigens are presented within the context of MHC class I and II molecules to prime CD8 and CD4 T-cells, respectively Step 3: T-cells get activated, proliferate, traffic to tumor sites, extravasate into tumor, recognize antigens on cancer cells and kills them [effector phase] Sources of cancer-specific antigen: mrna, DNA, peptides, tumor lysate, whole tumor cell, anti-idiotype Anti-cancer vaccine challenges: Delivery to reach DCs and activate enough T-cells for priming and/or enhancing existing immunity Vaccination regimens and methods to activate DCs effectively via inflammatory signals or innate immunity activation such as attenuated vaccinia/pox viruses, adjuvants, cytokines, danger molecules [pathogen molecules and cell-damage molecules] Engage multiple cancer-specific antigens required to prevent tumor immune escape, induce enough DCs, decreasing the effects of immunosuppressive cells and the barriers of the tumor microenvironment in solid tumors Personalized-based approaches may be best for efficacy but particularly hard/cumbersome to manufacture and not as scalable Challenges include generating multiple cancer-specific neoantigens from each patient and using fresh tumors or establishing autologous tumor cell lines as sources of cancer antigens Issue 7, April