Immuno-Oncology Clinical Trials Update: Oncolytic Viruses Issue 5 February 2017

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1 Delivering a Competitive Intelligence Advantage Immuno-Oncology Clinical Trials Update: Oncolytic Viruses Issue 5 February 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the information in this database is not 100% accurate as timing and registration details for specific trials may be out of date.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) 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)

3 Oncolytic viruses are an emerging modality for combination treatments Imlygic (talimogene laherparepvec or T-VEC) from Amgen is the first approved oncolytic viral therapy in the U.S. FDA approved Imlygic in October 2015 for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after surgery Average price of $65,000 per treatment course OPTiMtrial in advanced [Stage IIIB-IV] melanoma showed higher efficacy for Imlygic vs subcutaneous GM-CSF: Overall response rate of 26.4% vs. 5.7% Durable response rate of 16.3% vs. 2.1% However, the median overall survival increase [23.3. vs months] was not considered significant Imlygic showed low toxicity: the only grade > 3 adverse event was cellulitis in just 2.1% of patients Despite modest clinical efficacy as monotherapies, oncolytic viruses (OVs) induce anti-cancer immune cells and several combination tests with other agents are ongoing Checkpoint inhibitors Combination has shown increased efficacy compared to virus or checkpoint inhibitor alone in animal models Adding checkpoint inhibitors makes sense to prevent exhaustion and expand the newly generated tumor killer cells Chemos and radiotherapy Induces immunogenic cell death, leading to release of new tumor antigens and enhanced tumor immune responses The combination has shown synergy in in vitro and in vivo models Given the very low toxicity of oncolytic viruses, no new adverse events are expected Although Imlygic and several other current OVs are delivered loco-regionally, future OVs may be designed for systemic delivery to enable them to reach all sites of tumor growth in metastatic disease Challenges: For clinical translation, manufacturing processes, development and regulatory approval paths will need to be individualized for each OV Development of toxicity models, increase of viral yields, commercial scale purification, long-term stability formulations, bioavailability, tumor resistance to the virus, and the host immune response against the OV are challenges to overcome OV combination therapies are promising in terms of efficacy and likely to be increasingly tested in the near future, but challenges include selection of virus, tumor type, combination agent[s], regimen, and cost 3

4 Oncolytic Viruses in Clinical Trials Sponsor/Collaborators Therapy Base Virus Commercial Amgen Imlygic (talimogene laherparepvec,t-vec, OncoVex GM-CSF ) herpes simplex virus 1 (HSV-1) Cold Genesys CG0070 adenovirus DNAtrix DNX2401 adenovirus serotype 5 Genelux GL-ONC1 vaccinia virus (Lister strain) Hadassah Medical Org MTH-68H Newcastle disease virus Institut Catal d'oncologia ICOVIR-5 adenovirus Lokon Pharma LOAd703 adenovirus MediGene G207 herpes simplex virus (HSV-1) Oncolys Telomelysin (OBP-301) adenovirus Oncolytics Reolysin reovirus Oryx H-1PV parvovirus PsiOxus Therapeutics Enadenotucirev adenovirus Shanghai Sunway Biotech H101 adenovirus SillaJen (Jennerex) Transgene Pexa-Vec (JX-594) vaccina virus Takara Bio TBI-1401 (HF10) herpes simplex virus (HSV-1) Targovax (Oncos Therapeutics) ONCOS-102 (CGTG-102) adenovirus Tocagen Toca 511 (vocimagene amiretrorepvec) nonlytic retroviral replicating vector Turnstone Biologics Chiltern International Ad-MAGEA3 MG1-MAGEA3 Maraba virus VCN Biosciences VCN-01 adenovirus Viralytics CAVATAK (Coxsackievirus A21, CVA21) coxsackie virus Virttu Biologics HSV1716 herpes simplex virus (HSV-1) Academic Benjamin Movsas, M.D. Henry Ford Health System Ad5-yCD/mutTKSR39rep-ADP adenovirus Darell D. Bigner, MD Solving Kids Cancer Duke Univ PVSRIPO recombinant polio/rhinovirus Erasmus MC VU Univ Medical Center delta-24-rgd adenovirus adenovirus Jenny C. Chang, MD Merck Methodist Hos System (Ark Therapeutics) ADV/HSV-tk adenovirus Mayo Clinic MV-NIS measles virus (Edmonston strain) Univ of AK MV-NIS measles virus (Edmonston strain) NewGenPharm Theragene, Ad5-yCD/mutTKSR39rep-ADP adenovirus 4

5 Major focus in brain cancer Unlike other I-O therapies, research on oncolytic viruses has a strong focus on brain cancer Brain cancer, glioma, glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma As with other I-O therapies, a wide range of solid tumors are being investigated, but fewer trials with blood-based tumors are seen with OVs compared to other I-O technologies Industry sponsors are focusing more on specific cancer types: Amgen melanoma and to a less extent breast cancer Tocagen brain cancers Viralytics bladder, brain, and NSCLC The NCI, often in partnership with the Mayo Clinic, is researching OVs in a wide range of solid tumors Breakdown by Cancer Type (# = 159) (includes counts of multiple indications in the same trial) Brain Melanoma Lung Sancoma Bladder Pancreas Breast Ovarian Carcinoma Lymphoma CRC H&N Meso HCC Fallopian CNS Solid tumors - general Other - specific cancers number of trials 5

6 U.S. industry sponsors dominate the clinical market Roughly 10% of all trials has progressed to Phase 2/3 or Phase 3 (6 trials) with half still in Phase 1 Industry sponsors dominate this area of the I-O market, either running the trial themselves or partnering with academia Amgen has over 20% of the trials and is by far the largest industry sponsor All are with Imlygic The NCI also has nearly 20% of the trials and is by far the largest non-industry sponsor It is partnering with the Mayo Clinic for roughly half of its trials and its oncolytic measles virus Breakdown by Phase (# = 82) P1 P1/2 P2 P3 Breakdown by Type of Sponsor (# = 82) Industry Industry/Other Other Nearly three quarters of all trial are through U.S. sponsors Amgen is the major U.S. industry sponsor with Imlygic Viralytics (Australia) is the major non-u.s. industry sponsor with CAVATAK, a oncolytic common cold virus All but one non-industry sponsored trial is U.S.-based Breakdown by Location of Sponsor (# = 82) USA Europe RoW 6

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10 Backgrounder Oncolytic viruses in cancer treatment Oncolytic viruses (Ovs) are viruses that selectively replicate in and kill cancer cells by lysing them Because the antiviral defense pathways are impaired in tumor cells, OVs selectively replicate in such cells, sparing healthy cells In addition to lysing tumor cells, OVs liberate tumor antigens and induce immune responses against cancer cells OVs can be genetically engineered to Improve tumor selectivity and safety Tumor killing activity and efficacy Express immunostimulatory proteins, which may increase the systemic killing of OV-uninfected tumor cells The incidence of severe [Grade> 3] side effects caused by OVs is generally very low In addition to inducing anti cancer immune cells, OVs can decrease the immunosuppression of the tumor microenvironment by blocking or depleting regulatory T cells (T-regs) or myeloid-derived suppressor cells (MDSCs), and can lyse cancer stem cells thereby constituting a promising approach against cancer drug resistance and relapse 10