Emergence of Novel Immune - Mediated Therapies

1. Life Sciences & Healthcare Research and Analytics Services WHITEPAPER Emergence of Novel Immune - Mediated Therapies An SGA Perspective

2. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective Relevance Immunotherapy has emerged as a promising treatment for cancer, with immune checkpoint inhibitors (ICIs) dominating the market. Among the ICIs, the Anti-programmed Cell Death/ Programmed Cell Death Ligand-1 (PD-1/PD-L1) segment has shown the highest growth. Numerous CAR-T therapies are currently in development, with hematology emerging as the primary focus. Beyond oncology, immunotherapies are also under investigation for applications in primary immunodeficiencies, demyelinating polyneuropathy, and diverse bacterial and viral infections. Upcoming immune therapies will be the majority for oncology indications, followed by infectious and autoimmune indications. The market is projected to grow due to the rise in the prevalence of diseases, the increase in the adoption of combination therapies, the surge in the funding for new therapies, and the approval of innovative therapies. Introduction Immunotherapy is a treatment that uses the body’s immune system to fight against diseases, especially cancer. The first immune checkpoint inhibitor antibody that the Food and Drug administration (FDA) approved was the anti-CTLA-4 mAb, Yervoy (Ipilimumab) for treating metastatic melanoma. The market is categorized according to the type of immune therapies: Immune Checkpoint Inhibitors (ICI), Adoptive Cell Therapies, Cancer Vaccines, Immune Stimulants, and Oncolytic Viruses. The immune checkpoint inhibitors (ICIs) segment dominates the market due to the availability of blockbuster products such as Keytruda and OPDIVO. 2

3. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective Overview of approved therapies and classes Immune checkpoint blockade:The checkpoints function as switches that must be activated (or deactivated) to initiate an immune response. In this approach, molecules mainly target these switches that block the stop signals, allowing them to destroy cancer cells. PD-1 inhibitors: • Keytrude (pembrolizumab) • Opdivo (nivolumab) PD-L1 inhibitors: • Tecentriq (atezolizumab) • Bravencio (avelumab) • Imfinzi (durvalumab) • Libtayo (cemiplimab) • Zynyz (retifanlimab) CTLA-4 inhibitor: • Yervoy (lpilimumab) LAG-3 inhibitor: • Opdualag • imjudo (tremelimumab) TF inhibitor: • Tivdak (tisotumab vedotin-tftv) Adoptive cell therapy:The patient’s T-cells are taken (tumor/blood) into the laboratory, where their ability to destroy cancer cells is enhanced. These enhanced T cells are then given to the patient. • The first CAR-T therapy that the FDA approved was Kymriah (tisagenlecleucel) by Novartis for treating patients up to 25 years with B-cell precursor acute lymphoblastic leukemia. As of April 2023, 6 CAR-T cell therapies were approved in B-cell malignancies and multiple myeloma.1 CAR-T cell therapy has been groundbreaking, yielding remarkably effective and long-lasting clinical responses. The one-time infusion of CAR-T therapy has shown promising clinical outcomes, with rates of lasting survival benefits of 45–51% and a full recovery of up to 92% of patients with hematological malignancies.2 Immune stimulation: Drugs are used to advance immune response to attack cancer cells. These can be Interleukins, Interferons, and Immunomodulators like Revlimid (lenalidomide) and Pomalyst (pomalidomide). Cancer vaccines: Cancer cells are exposed to the body’s immune system so that the patient’s immune system will launch a successful attack against the cancer cells in the body. Vaccines for cancer prevention are Cervarix, Gardasil, and Gardasil-9. Vaccines for cancer treatment are Provenge, T-VEC, and BCG Oncolytic viruses: These viruses can infect and destroy cancer cells, without harming healthy cells. In 2015, the FDA approved Amgen’s Imlygic (talimogene laherparepvec) as the first oncolytic viral therapy in the US for the local treatment of recurrent melanoma after the initial surgery. 3

4. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective Relative Comparative Market Size Cancer Vaccines Immune Stimulation Adoptive Cell Therapies ICI ICI Adoptive Cell Therapies Cancer Vaccines Immune Stimulation Note: SGA Analysis (based on 2022 revenues) Immune Checkpoint Inhibitors ICIs contribute a major share, with PD-1/PDL-1 inhibitors form the highest-growing segment. Currently, ICIs dominate the market. PD-1/PDL-1 inhibitors CTLA-4 inhibitor LAG-3 inhibitor TF inhibitor Note: SGA Analysis 4

5. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective Epidemiology surge in the incidence of cancer and infectious disease patients Cancer is the second most frequent cause of morbidity and mortality in the Americas, after cardiovascular disease.4 Prostate cancer in males and breast cancer in females are expected to be the most common cancers. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the US3. In the US, an estimated 41 out of 100 men and 39 out of 100 women will develop cancer during their lifetime. Approximately 238,340 adults (117,550 men and 120,790 women) in the US will be diagnosed with lung cancer in 2023.7 Beyond oncology, immunotherapies are also being studied in primary immunodeficiencies, for which the overall incidence is around 1:10,000 and is more prevalent in children.8 Growth of approved therapies Forecasts for Anti-PD-1/PDL-1 5,455 742 4,774 474 7,215 3,919 505 3,570 465 6,896 14,508 6,413 13,174 5,279 12,116 11,033 13,177 11,945 10,930 9,887 31,284 27,398 25,348 23,087 2023 2024 2025 2026 Keytruda Opdivo Libtayo Tecentriq Bavencio Imfinzi Note: Figures from Refinitiv Forecast for CAR-T Therapies 1,515 1,088 845 556 1,516 1,379 1,659 1,162 485 538 424 410 1,034 792 1,317 563 168 145 129 153 2,381 2,335 2,247 1,976 2023 2024 2025 2026 Yescarta Imjudo Abecma Tecartus Carvykti Breyanzi Note: Figures from Refinitiv 5

6. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective Reimbursement landscape Immune therapies offer a great source of hope for patients but are typically expensive, substantially contributing to the rising healthcare costs. Global and US drug prices have substantially increased over the last two decades. Cellular and gene therapies are among the most expensive therapies on the market. The price of Kymriah in R/R ALL for $543,828 and Yescarta for R/R DLBCL is $424,000 (listed price as of March 2023) in the US.5 CAR-T has had a limited market uptake in Europe due to the difficulties in obtaining reimbursement in European countries. Companies are open to collaborating with payers to establish reimbursement suggesting options encompassing outcome-based agreements (OBRs), price-volume agreements, value- based discounts, and indication-specific pricing. agreements, Key deals Many M&As were signed in 2023, including trial collaborations, product licensing, and R&D agreements. Recently, NAYA Biosciences acquired two clinical-stage immune therapies-bispecific antibody assets for treating hepatocellular carcinoma and multiple myeloma. Moderna and Immatics announced a strategic multi- platform collaboration to develop TCR-based therapies with a potential deal value of $1.82B. Type of Deals Involving Immune-mediated Therapies in 2023 Product purchase R&D and marketing licensing Trial collaborations Includes Royalty Note: SGA Analysis, October 2023 Bristol-Myers Squibb (BMS) acquired Mirati Therapeutics for up to $5.8B. Through the acquisition, BMS will gain the FDA-approved lung cancer drug Krazati and its combination with PD-1 inhibitors. The deal is expected to close by the first half of 2024. Current challenges with immune therapies • Reimbursement of cell therapies • Logistic challenges for CAR-T therapies: A need for an appropriate infrastructure to handle all logistics in the CAR-T therapy process. • Side-effects and toxicities: Life-threatening CAR-T- cell-associated toxicities, limited efficacy against solid tumors, inhibition and resistance in B cell malignancies, antigen escape, poor trafficking, tumor infiltration, limited persistence, and the immunosuppressive microenvironment • High R&D costs • Market access: The ability of HTA bodies to evaluate the value of oncology immunotherapies. 6

7. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective Analysis of the near-term pipeline Novel targets are being studied for ICIs. Izuralimab (with PD1 X ICOS) is being developed for sarcoma, malignant melanoma, and solid tumors. CI-8993, the first-in- class antagonist of VISTA, and CA-170, an oral, small molecule VISTA/PD-L1 antagonist, are being developed by Curis9. Anti-TIM3 are also under development – Sabatolimab by Novartis for myelodysplastic syndromes and chronic myelomonocytic leukemia, and cobolimab by AnaptysBio/GSK for NSCLC. Immune Checkpoint Inhibitors (Indications under Investigation in Phase III) Renal Prostrate Ovarian NSCLC Melanoma Breast Liver Others Gastric Esophageal CRC Bladder cancer PD-1 CTLA-4 LAG-3 TIGIT Note: SGA analysis; LCM drugs are also considered CAR-T Therapies: Groundbreaking immunotherapy treatment Currently, numerous CAR-T therapies are in development, with hematology emerging as the primary focus. Indications for CAT-T under development Autoimmune Infectious Hematology Solid tumors Note: SGA analysis; Phase II considered Cancer vaccines: Many cancer vaccines are under investigation in Phase II for Colorectal cancer (CRC), brain cancer, gastric cancer, and pancreatic cancer. Currently, in Phase II clinical trials, the GCC vaccine is designed to elicit immune responses against colorectal, pancreatic, gastric, and esophageal cancers. In 2022, Polynoma reached an agreement with the FDA under a Special Protocol Assessment (SPA) on a pivotal Phase III clinical study of seviprotimut-L, a melanoma cancer vaccine, for the adjuvant treatment of patients aged 60 years and younger patients with Stage IIB or IIC melanoma, following definitive surgical resection to improve recurrence-free survival. Oncolytic viruses: A few oncolytic viruses are in the Phase III stage of development. Pelareorep is a first-in-class, non-pathogenic, oncolytic virus under development by Oncolytic Biotech in breast and gastrointestinal cancers. CG Oncology is developing cretostimogene grenadenorepvec for bladder cancer and has recently secured $105M in funds. Immune stimulation: Drugs targeting 4-1BB (CD137/ ILA/TNFRSF9)6 are under investigation for solid tumor and other cancers. ATG-101 (PD-L1/4-1BB bispecific antibody) is in Phase I trials for solid tumors and non- Hodgkin Lymphoma (NHL). The drug is Antengene’s first in-house developed molecule with global rights. 7

8. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective New targets under preclinical evaluation Upcoming launches Many PDUFAs are expected in 2024 and 2025. Regeneron’s odronextamab is under review, and if approved, it would be the first and only bispecific antibody approved for both Follicular lymphoma (FL) and Diffuse large B cell lymphoma (DLBCL). The exploration of novel targets, such as 4-1BB, has attracted significant attention as a promising avenue for therapeutic intervention within the realm of treating cancer. Other novel targets under evaluation are CD112R, BTLA, GITR, and NKG2A. Immune Therapies under Registration Autoimmune/immunology oncology Infectious Note: SGA analysis; as of Oct 2023 Outlook Numerous opportunities within the realm of immune therapies exist, considering the increasing prevalence of several diseases. Multiple clinical trials are actively underway, examining the potential synergistic benefits of combining immunotherapy with other treatment modalities. Moreover, there is a notable upswing in funding for developing innovative therapies and a rising trend in novel immunotherapies approval. References: 1. 2. 3. Siegel, R. L., Miller, K. D., Wagle, N. S., & Jemal, A. (2023b). Cancer statistics, 2023. CA: A Cancer Journal for Clinicians, 73(1), 17–48. 4. World Cancer Day 2023: Close the care gap. (accessed on 2023, October 20) 5. Cliff, E. R. S., Kelkar, A. H., RusslerGermain, D. A., Tessema, F. A., Raymakers, A., Feldman, W. B., & Kesselheim, A. S. (2023). High cost of chimeric antigen receptor T-cells: Challenges and solutions. American Society of Clinical Oncology Educational Book, 43. 6. Kim, A. M. J., Nemeth, M. R., & Lim, S. (2022). 4-1BB: A promising target for cancer immunotherapy. Frontiers in Oncology, 12. 7. Lung cancer - non-small cell - statistics. (2023, March 20). Cancer.Net. 8. Primary immunodeficiencies worldwide. (accessed on 2023, October 20). Frontiers. 9. Curis, Inc. (2023, July 7). Pipeline Overview - Curis, Inc. 10. SGA Research CAR T cells: Engineering immune cells to treat cancer. (2022, March 10). National Cancer Institute. CAR-T Therapy Whitepaper by European Cancer Patient Coalition (accessed on 2023, October 20). 8

9. Emergence of Novel Immune-Mediated Therapies – An SGA Perspective About the Author Rajiv Kalia • Vice President, Life Sciences & Healthcare Rajiv has 18+ years of combined experience and expertise in leading teams and being a subject matter expert (SME) focused on the life sciences & healthcare industry. He has led several teams conducting strategic market assessments, opportunity evaluation (strategic and financial), project management, and qualitative and quantitative industry research. He has extensively worked with leading global clients on life sciences & healthcare research projects. He has a Master of Pharmacy, with a Pharmacology specialization, from the Manipal Academy of Higher Education and holds a PGDM in Financial Management. Shilpa Lalwani • Project Manager, Life Sciences & Healthcare Shilpa has over 8 years of experience in pharmaceutical industry research and consulting. She has a master’s in pharmacy from the National Institute of Pharmaceutical Education and Research. Having extensively worked on CI trackers and intelligence databases, she has vast experience in primary and secondary research projects in the pharmaceutical and medical device industry. Disclaimer This document makes descriptive reference to trademarks that may be owned by others. The use of such trademarks herein is not an assertion of ownership of such trademarks by SG Analytics (SGA) and is not intended to represent or get commercially benefited from it or imply the existence of an association between SGA and the lawful owners of such trademarks. Information regarding third-party products, services, and organizations was obtained from publicly available sources, and SGA cannot confirm the accuracy or reliability of such sources or information. Its inclusion does not imply an endorsement by or of any third party. Copyright © 2023 SG Analytics Pvt. Ltd. www.sganalytics.com Pune | Hyderabad | Bengaluru | London | Zurich | New York | San Francisco | Amsterdam | Toronto | Wroclaw 9 GET IN TOUCH