#1ESMO 2023 BioN Tech Data October 2023 BIONTECH#2BioN Tech at ESMO 2023 Modality Program Abstract # Type mRNA BNT116 1503 TiP TiP BNT314 1072P Poster Protein-based therapeutics DB-1305 689P Poster Cell therapies 2 Proffered paper Abstract Title A Phase 2 study of cemiplimab plus BNT116 versus cemiplimab alone in first-line treatment of patients with advanced non-small cell lung cancer with PD-L1 expression ≥50% DuoBody-EpCAM×4-1BB mediates conditional T-cell co-stimulation and promotes antitumor activity in preclinical models DB-1305 (a Trop-2 targeted antibody-drug- conjugate [ADC]) in patients with advanced solid tumors: Preliminary clinical results from the Phase 1/2a study BNT211-01: Interim results from a repeat dose escalation study of CLDN6 CAR-T cells manufactured with an automated process ± a CLDN6-encoding CAR-T cell-Amplifying RNA Vaccine (CARVac) NTC-001: A Phase I study to test safety and efficacy of BNT221, a non-engineered neoantigen-specific T cell product, in patients with advanced or metastatic melanoma Date, Time & Location • Onsite Poster display date • Monday, 23 October 2023 • Session: NSCLC. metastatic • Onsite Poster display date • Monday, 23 October 2023 Session: Investigational Immunotherapy Onsite Poster display date • Monday, 23 October 2023 • Session: Developmental Therapeutics • Mini oral session - Developmental • Monday, 23 October 2023 • 4:30-6 PM CET therapeutics Valencia Auditorium, Hall 10 O Proffered Paper session - Investigational immunotherapy Monday, 23 October 2023 • 10:15-11:40 AM CET Burgos Auditorium, Hall 3 BNT211 LBA35 Mini oral BNT221 10170 BIONTECH#31 BNT314/GEN1059 DuoBody-EpCAM x4-1 BB mediates conditional T-cell co-stimulation and promotes antitumor activity in preclinical models BIONTECH#4BNT314/GEN10591 - Designed to Boost Antitumor Immune Response Through EpCAM-Dependent 4-1BB Agonistic Activity Mechanism of action T cell tumor cell DuoBody-EpCAMX4-1BB EpCAM 4-1BB Expansion of tumor-infiltrating lymphocytes in human TIL cultures NK cells CD8+ T cells CD4+ T cells Treg cells 106- 106 106 106. TCR/CD3 complex 105- 105. MHCI/II-peptide 104- 104. T-cell activation markers (e.g. 4-1BB, CD25) 103 103 104 Cytokines ● No antibody o DuoBody-EpCAM×4-1BB (0.2 μg/mL) 105. 104 103 DuoBody-EpCAM x4-1BB (1 µg/mL) • M T-cell proliferation By cross-linking EpCAM + tumor cells with activated 4-1BB+ T cells, BNT314/GEN1059 exhibits conditional 4-1 BB agonist activity, resulting in enhanced T-cell proliferation and effector functions, such as cytokine secretion and cytotoxic activity BNT314/GEN1059 is hypothesized to boost existing antitumor immune responses and may be further exploited in combination with other immunotherapy First preclinical disclosure at ESMO 2023: DuoBody-EpCAM×4-1BB mediates conditional T-cell co-stimulation and promotes antitumor activity in preclinical models. Fellermeier-Kopf et al. Presented at ESMO 2023. #1072P 1. BNT314 (GEN1059) is partnered with Genmab based on 50/50 sharing of costs and profits EpCAM epithelial cell adhesion molecule; TCR = T cell receptor; CD = cluster of differentiation; MHC major histocompatibility complex; NK cell = natural killer cell; Treg cell regulatory T cell. 4 BIONTECH#5BNT314/GEN10591 - Designed to Boost Antitumor Immune Response Through EpCAM-Dependent 4-1BB Agonistic Activity Antitumor activity in human EpCAM-transgenic mice. Fellermeier-Kopf et al. Presented at ESMO 2023. #1072P Tumor volume (mm³) Tumor volumes over time 1,000 800 600 400 200 Percent survival Kaplan-Meier analysis of survival 100 80 60 60 10 10 20 0 0 7 14 21 28 Days after tumor inoculation B ] ** **** mbslgG2a-hEpCAM xm4-1BB Isotype control 0 0 7 14 21 28 35 42 49 Days after tumor inoculation 56 63 mbslgG2a-hEpCAM xm4-1BB Isotype control Results suggest that BNT314/GEN1059 may boost antitumor immunity in cancer patients with EpCAM + tumors. ] ** The clinical safety and preliminary antitumor activity of DuoBody-EpCAMx4-1BB will be investigated in patients with solid tumors in a first-in-human trial. 1. BNT314 (GEN1059) is partnered with Genmab based on 50/50 sharing of costs and profits.. EpCAM epithelial cell adhesion molecule 5 BIONTECH#6_2 BNT325/DB-1305 DB-1305 (a Trop-2 targeted antibody-drug-conjugate [ADC]) in patients with advanced solid tumors: Preliminary clinical results from the Phase 1/2a study BIONTECH#77 BNT325/DB-13051 - TROP2 ADC • • The three components of BNT325/DB-13051: • Humanized anti-TROP2 IgG1 mAb Proprietary DNA topoisomerase I inhibitor (P1021) Cleavable linker Y Humanized anti-TROP2 IgG1 mAb Interchain Cysteine Residue Linker-Payload Key Attributes of BNT325/DB-1305 Selectively endocytosed into the lysosome of Trop-2+ cells. Optimized drug-to-antibody ratio: ~4 • Tumor-selective cleavable linker • Stable linker-payload High potency of payload with a short systemic half-life • Payload mechanism of action: topoisomerase I inhibitor • Bystander antitumor effect 1. Partnered with Duality Bio; BIONTECH#8FIH Phase 1/2 to Evaluate Safety, Tolerability and Antitumor Activity of BNT325/DB-13051 in Patients with Advanced/Metastatic Solid Tumors Phase 1/2a study design (NCT05438329) Multicenter, non-randomized, open-label, multiple-dose, first-in-human (FIH) study, n = 235 Inclusion criteria . Advanced/unresectable, recurrent or metastatic solid tumors Relapsed or progressed on or after standard systemic treatments ECOG 0-1 Adequate organ function (©) Key endpoints Part 1: Dose Escalation Part 2a: Dose expansion progression, withdrawal DB-1305 Indications DL5 Q3W DB-1305 DL4 Q3W RP2D Q3W • Small cell lung cancer (SCLC) • HR+/HER2-neg breast cancer Disease DB-1305 DL3 Q3W DB-1305 DL2 Q3W DB-1305 DL1 Q3W Primary: Phase 1: Assessment of DLT, TEAE, SAE, MTD, RP2D. Phase 2a: TEAES, SAES, ORR Secondary: Pharmacokinetic measures (AUC, Cmax, Tmax, T1/2) • NSCLC with no EGFR- sensitizing mutation, ALK gene translocation or onco- driver gene mutations ⚫ TNBC without prior sacituzumab govite can treatment • TNBC with treatment failure on sacituzumab govitecan of consent, unacceptable toxicity 1. Partnered with DualityBio. ECOG = Eastern Cooperative Oncology Group; DL = dose level; Q3W = every three weeks; RP2D = recommended Phase 2 dose; HR = hormone receptor; HER2 = human epidermal growth factor 2 receptor; NSCLC = non-small cell lung cancer; TNBC = triple negative breast cancer; DLT = dose- limiting toxicity; TEAE = treatment emergent adverse events; SAE = serious adverse events; MTD = maximum tolerated dose; ORR = objective response rate; AUC = Area under concentration-time curve; Cmax = maximum observed plasma concentration; Tmax = time to Cmax; T1/2 = terminal elimination half-life 8 BIONTECH#9BNT325/DB-13051 in Heavily Pretreated Patients with Multiple Solid Tumors Phase 1/2a FIH study (NCT05438329): Baseline characteristics Marathe O. et al. Presented at ESMO 2023. Poster #689P. Baseline patient characteristics Age, median (range) Female, n (%) Total (n=44) 59.0 (40.0-78.0) Baseline patient characteristics Total (n=44) 26 (59.1) Median prior lines of therapy, median (range) Cancer types, n (%) 3.0 (1-6) Non-small cell lung cancer 30 (68.2) Region, n (%) United States 21 (47.7) Colorectal cancer 4 (9.1) China 23 (52.3) HR HER2-breast cancer 2 (4.5) ECOG performance status, n (%) Ovarian cancer 2 (4.5) 0 1 7 (15.9) Ampullary carcinoma 1 (2.3) 37 (84.1) Appendiceal cancer 1 (2.3) Duodenal cancer 1 (2.3) Gastric or gastroesophageal junction adenocarcinoma 1 (2.3) Primary malignant neoplasm of fallopian tube 1 (2.3) Triple negative breast cancer 1 (2.3) Prior anticancer systemic therapy, n (%) With prior immunotherapy therapy With prior platinum therapy 20 (45.5) 39 (88.6) 1. Partnered with Duality Bio.. FIH = first in human; ECOG = Eastern Cooperative Oncology Group; HR = hormone receptor; HER2 = human epidermal growth factor receptor 2; 9 BIONTECH#1010 1. Partnered with Duality Bio.. • Anti-tumor activity in heavily pretreated patients with 3 median prior lines of treatment All patients (n=23) NSCLC (n=13) BNT325/DB-13051 Demonstrated Antitumor Activity in Patients With NSCLC and Other Solid Tumors Phase 1/2a FIH study (NCT05438329): Clinical Efficacy Marathe O. et al. Presented at ESMO 2023. Poster #689P. Antitumor activity was also observed in a patient with fallopian tube cancer: 1 unconfirmed PR at 5 mg/kg: ORR, 1/1 Unconfirmed ORR, % 30.4 Unconfirmed DCR, % 87.0 46.2 92.3 Best Change from Baseline (%) FIH = first in human; ORR = objective response rate; DCR disease control rate; NSCLC = non-small cell lung cancer; CRC = colorectal cancer; TNBC = triple-negative breast cancer; GC = gastric cancer; GEJC = gastroesophageal junction cancer. -50 50 00 CRC NSCLC NSCLC CRC Best tumor response for all patients with post-baseline scans (n=23): NSCLC TNBC APPENDICEAL DUODENAL Subject name or identifer Dose level 2 mg/kg 4 mg/kg 5 mg/kg 6 mg/kg NSCLC CRC CRC GC/GEJC NSCLC BIONTECH NSCLC NSCLC NSCLC NSCLC NSCLC NSCLC NSCLC Ampullary Fallopian tube NSCLC#11BNT325/DB-13051 Was Tolerable and TRAES Were Manageable in Lower Dose Levels Phase 1/2a FIH study (NCT05438329): Safety Marathe O. et al. Presented at ESMO 2023. Poster #689P. Overall safety Summary of AEs (≥20%) and all AESI (n=44) TEAES TRAES AESI* 2 mg/kg (n=1) n (%) 4 mg/kg (n=20) n (%) 5 mg/kg (n=17) n (%) 6 mg/kg (n=6) n (%) Total Any TRAES 0 19 (95.0) 15 (88.2) 6 (100) (n=44) n (%) 40 (90.9) All grade n (%) Grade ≥3 n (%) All grade n (%) Stomatitis 33 (75.0) Grade ≥3 0 7 (35.0) 5 (29.4) 3 (50.0) 15 (34.1) Nausea 13 (29.5) 10 (22.7) 1 (2.3) 33 (75.0) Grade ≥3 n (%) 10 (22.7) All grade n (%) 33 (75.0) Grade ≥3 n (%) 10 (22.7) 12 (27.3) 1 (2.3) Serious TRAES 3 (15.0) 4 (23.5) 3 (50.0) 10 (22.7) Lymphocyte count 10 (22.7) 6 (13.6) 0 decreased Lead to dose reduction 1 (5.0) 2 (11.8) 3 (50.0) 6 (13.6) Infusion related 9 (20.5) 0 9 (20.5) 0 9 (25.0) 0 Lead to dose interruption 0 6 (30.0) 5 (29.4) 4 (66.7) 15 (34.1) reaction Lead to dose 0 1 (5.0) 0 0 1 (2.3) Decreased appetite 9 (20.5) 0 7 (15.9) 0 discontinuation Mucosal 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) Dose-limiting toxicities 0 0 0 3 (50) 3 (6.8) inflammation One patient died by suicide on day 18 after first dose and one patient experienced double pneumonia related AE on day 49. Interstitial lung disease 1 (2.3) 0 1 (2.3) 0 1 (2.3) * AESI includes interstitial lung disease/pneumonitis, infusion related reaction, diarrhea, stomatitis/mucosal inflammation, and combined elevations of aminotransferases and bilirubin. BNT325/DB-1305 was tolerable and all AEs were manageable in lower dose levels (i.e., 2 and 4 mg/kg) • Three patients dosed at 6 mg/kg experienced dose-limiting toxicities (i.e., stomatitis, febrile neutropenia, and white blood cell decreased), and the maximum tolerated dose was established as 5 mg/kg • No TEAEs led to death 1. Partnered with Duality Bio. TRAE treatment related adverse event; FIH = first in human, AESI-Adverse event of special interest, TEAE -Treatment emergent adverse event,. 11 BIONTECH#12_3 BNT211 BNT211-01: Interim results from a repeat dose escalation study of CLDN6 CAR-T cells manufactured with an automated process ± a CLDN6-encoding CAR-T cell-Amplifying RNA Vaccine (CARVac) BIONTECH#13BNT211: First-in-Class Approach for CLDN6+ Solid Tumors CLDN6 CART +1 CLDN6 CARVac αCLDN6 scvf CD8 hinge 4-1BB CD33 Highly sensitive and specific 2nd-generation CAR against CLDN6 CLDN6 is absent from healthy adult tissue, but expressed in a variety of cancers1 Clinically proven RNA-lipoplex vaccine for body-wide delivery of antigens to dendritic cells 1,2 Amplification and persistence of CAR-T cells by repeat administration 3 Full-length CLDN6 RNA Liposomes CLDN6 Claudin 6; CAR = chimeric antigen receptor. BIONTECH#14BNT211: Phase 1/2a, FIH, Open-Label, Multicenter, Dose Escalation Trial in R/R Advanced CLDN6+ Solid Tumors (NCT04503278) ESMO 2022 (n=22) ESMO 2023 (n=44) Phase I dose escalation (manual product): Completed. Phase I dose escalation with an (automated product): Ongoing Inclusion criteria Monotherapy Combination* Monotherapy Combination ≥50% tumor cells with 2+/3+ CLDN6 positivity (immunohistochemistry) Measurable disease per RECIST v1.1 or elevated tumor marker, ECOG PS 0-1 1×107 CAR-T DL3 n=0 2-5x108 CAR-T DL2 n=9 DL2 n=6 + fixed CARVac 1×108 CAR-T DL1 n=4 DL1 n=3 + fixed CARVac DL2 n=4 1×108 CAR-T DL1 n=4 1×107 CAR-T DLO n=2 DL3 n=0 + fixed CARVac DL2 n=4 + fixed CARVac DL1 n=3 + fixed CARVac * Crossover to ombination not indicated 1×106 CAR-T Key endpoints Primary: Safety and tolerability, DLTs • ORR, DCR, DOR, PFS Secondary: Immunogenicity, Dosing: Escalating doses of CLDN6 CAR-T cells ± CLDN6 CARVAC Lymphodepletion prior to CAR-T cell infusion on Day 1 (DLTs assessed for 28 days) CLDN6 CARVac fixed dose (from Day 4, 50 µg then 100 µg) Q3W × 5, then Q6W Assessments: Efficacy assessments Q6W (RECIST v1.1) & tumor marker monitoring Aim of current analysis: Determine the safety and preliminary efficacy of the automated CLDN6-CAR T product CARVac Data cut-off: 10 Sep 2023. Crossover to combination not indicated. CAR = chimeric antigen receptor; CARVac = CAR T-cell amplifying RNA vaccine; CLDN6 = claudin-6; DCR = disease control rate; DL = dose level; DLT = dose-limiting toxicity; DoR = duration of response; ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = objective response rate; PFS = progression-free survival; RECIST = response evaluation criteria in solid tumors; R/R = relapsed/refractory; QXW; every X weeks. 14 BIONTECH#15BNT211: Dose-Depend Increase in Adverse Events, Further Evaluation Ongoing to Determine RP2D Phase 1/2 FIH study (NCT04503278): Baseline characteristics and safety Haanen J. et al. Presented at ESMO 2023. Abstract #LBA35. Cohort Patient baseline characteristics DL0(n=2) DL1 (n=4) DL1+ CARVac (n=4) DL2 (n=13)1 DL2+ CARVac (n=14)² DL3 (n=7) Total (n=44) Age, years 55.5 (50-61) 54.5 (36-62) 1/1 3/1 51.0 (42-65) 2/2 45.0 (30-69) 7/6 48.0 (26-60) 50.5 (29-63) 8/6 4/3 48.0 (26-69) 25/19 Gender, male/female Indication, n Epithelial ovarian cancer (EOC) 1 1 2 6 Germ cell tumor (GCT) 1 Other indications³ 0 3 1 1 5 2 563 232 17 16 CLDN6 2+/3+ cells, % 82.5 (80-85) 97.5 (80-100) 97.5 (50-100) 95.0 (80-100) Prior treatment lines 3.0 (2-4) 4.0 (3-7) 4.0 (2-9) 4.0 (2-7) 100 (70-100) 4.0 (2-9) 80.0 (50-100) 3.5 (2-6) 11 95 (50-100) 4.0 (2-9) Treatment and safety outcome Duration of follow-up, days 321.5 (242-401) 44.5 (22-87) 90.5 (13-189) 71.5 (30-317) 120.5 (9-199) 90 (44-121) 94.5 (9-401) CARVac injections4, n ΝΑ NA 3 (1-5) ΝΑ 4 (1-7) ΝΑ 4 (1-7) Patients with TEAEs >G3 related to IMPS5, n 1 1 1 12 9 6 30 Patients with TESAES related to IMPs 6, n 1 0 0 4 4 5 14 Patients with DLTs7, n 0 0 0 1 2 1 4 Patients with CRS8, n Patients with ICANS9, n Deaths 10, n 1 0 0 2 6 9 LO 5 0 3 Data cut-off: 10 Sep 2023. 1 Cohort includes 3 patients dosed with 5x107 CAR-T. 2 Cohort includes 1 patient that did not reach full dose (2×107) and 1 patient treated that received full dose after 50% reduced lymphodepletion. 3 Other indications: 4 patients with lung cancer (different subtypes), 3 with desmoplastic round cell tumors, 2 with esophageal cancer, 1 with endometrial carcinoma and 1 with sinonasal carcinoma. 4 Crossover of patients is not indicated, as option was enabled by safety review committee decision after dose decision for monotherapy cohort without impacting efficacy read out. 5 Most TEAES 2G3 were attributed to CAR-T IMP (27/30). Most frequent TEAEs were laboratory findings (43.2%) including decreased blood cell counts, elevated liver function tests as well as levels of bilirubin and ferritin. Accordingly, cytopenia (25%) together with immune system (7%) and hepatobiliary disorders (5%) were reported frequently. 6 Most frequent non- related TESAES were infections. 7 DLTs include 2 cases of pancytopenia, 1 case of hemophagocytic lymphohistiocytosis and 1 case of liver toxicity together with sepsis. 8 CRS was limited to G1-2 for 21/23 patients with 1 G3 and 1 G4 event. 9 Neurotoxicity was mild and self-limiting in 2 patients. 10 Most patient deaths (11/12) were related to disease progression and 1 patient died from sepsis. Values given as median (range). CAR = chimeric antigen receptor; CLDN6 = claudin-6; CRS = cytokine release syndrome; DL = dose level; DLT = dose-limiting toxicity; G = Grade; ICANS immune effector cell-associated neurotoxicity syndrome; IMP investigational medicinal product; TESAE treatment-emergent (serious) adverse event. 0 2 1 2 1 4 0 0 23 2 12 BIONTECH#16BNT211 continues to show encouraging antitumor activity in patients with CLDN6-positive relapsed or refractory advanced solid tumors. Phase 1/2 FIH study (NCT04503278): Efficacy at all dose levels Haanen J. et al. Presented at ESMO 2023. Abstract #LBA35. 60 30 Change in target sum [%] 60 30 0 -90 GCT EOC Others Best response and change in target sum (all DLs) NR CLDN6 CAR-T <DL2 DL2 >DL2 Total Safety evaluable patients, n 10 27 7 44 Efficacy evaluable patients, n 9 22 7 38 Patients with PR/CR, n 1 13 3 17 Patients with SD, n 1 8 2 11 Patients with PD, n 7 1 2 10 ORR, % 11.1 59.1 42.9 44.7 DL BOR 2 2 2 2 3 2 2 2 3 2 221 222 3 2 2 2 DCR, % 22.2 95.5 71.4 73.7 1 1 2 0 3 2 2 1 1 3 2 2 1 10233 PD PD PD PD PD SD SD PD PD PR PR SD PD PD SD SD SD SD SD SD PR PR SD PR SD PR PD SD PR PR PR PR PR PR PR PR PR CR Data cut-off: 10 Sep 2023. Waterfall plot showing best percent change from baseline in sum of target lesion diameters for patients treated with CLDN6 CAR-T± CLDN6 CARVac (N = 38). One patient died prior to first assessment (NR = not reached) and BOR was defined as PD. Patients had non-measurable disease per RECIST 1.1 and BOR was assessed by tumor marker response. ** Patient achieved complete response after surgical removal of tumors. Response data was pending for 6 patients at the data cutoff. Dotted lines show standard response evaluation criteria used to determine objective tumor response for target lesions per RECIST 1.1 (CR = -100%, PR = 30 to -100%, SD = -30 to 20%, and PD = 20% or higher). Graph contains additional data from 5 patients entered manually into the database following the data cut-off date that was not available in formal outputs. BOR best overall response; CR = complete response; DCR disease control rate; DL dose level; EOC epithelial ovarian cancer; GCT = germ cell tumor; PD progressive disease; ORR = objective response rate; PR = partial response; SD = stable disease. BIONTECH#17BNT211 Demonstrates Encouraging Signs of Activity at Dose Level 2 Phase 1/2 FIH study (NCT04503278): Efficacy at all dose level 2 Haanen J. et al. Presented at ESMO 2023. Abstract #LBA35. 60 30 Change in target sum [%] 60 30 -90 Best response and change in target sum (DL2 only) ས།། Change in target sum [%] 60 40 40 20 20 O -20 -40 -60 -80 -100 0 CLDN6 CAR-T <DL2 DL2 >DL2 Total Safety evaluable patients, n 10 27 7 44 Efficacy evaluable 9 22 7 38 patients, n Patients with PR/CR, n 1 13 3 17 Patients with SD, n 1 8 2 11 Patients with PD, n 7 1 2 10 ORR, % 50 100 150 200 DCR, % Days post-infusion 11.1 59.1 42.9 44.7 22.2 95.5 71.4 73.7 GCT EOC Others Data cut-off: 10 Sep 2023. Waterfall plot showing best percent change from baseline in sum of target lesion diameters and spider plot showing percent change in target sum from baseline over time for patients treated with CLDN6 CAR-T± CLDN6 CARVac at DL2 (N = 22). Patient had non-measurable disease per RECIST 1.1 and BOR was assessed by tumor marker response. ** Patient achieved complete response after surgical removal of tumors. Response data was pending for 5 patients at the data cut-off. Dotted lines show standard response evaluation criteria used to determine objective tumor response for target lesions per RECIST 1.1 (CR -100%, PR = 30 to -100%, SD = -30 to 20%, and PD = 20% or higher). Graphs contains additional data entered manually into the database following the data cut-off date that was not available in formal outputs. BOR = best overall response; CR = complete response; DCR disease control rate; DL = dose level; EOC epithelial ovarian cancer; GCT = germ cell tumor; PD = progressive disease; ORR = objective response rate; PR = partial response; SD = stable disease. BIONTECH#18BNT211: CARVac cohort demonstrating a prolonged persistence of CAR-T cells Phase 1/2 FIH study (NCT04503278): Pharmacokinetic data Haanen J. et al. Presented at ESMO 2023. Abstract #LBA35. CLDN6 CAR -T Conc. (copies/µg) 106 105 104 103 102 101 1 x 108 (DL2) CAR-T only LLOQ 10° 0 25 GCT 50 EOC 75 100 25 Others Time (Day) 1 x 108 (DL2) CAR TCARVac LLOQ 50 50 75 100 ~D50 Conc. (copies/μg) ~D90 Conc. (copies/μg) 04 104 102 10⁰ 10-2 1 x 108 CAR-T only 1 x 108 CAR-T CARVac 104 04 102 100 10-2 1 x 108 CAR-T only 1 x 108 CAR-T CARVac Data cut-off: 1 Sep 2023. BioN Tech data on file derived from peripheral blood applying semi-quantitative PCR directed against CAR transgene. Displayed as copies of transgene per μg of DNA input of isolated PBMC. Pending data up to day 50: 2 patients each in monotherapy and combination cohort. Pending data up to day 90: 3 patients for monotherapy, and 4 patients for combination cohort. CAR = chimeric antigen receptor; CARVAC CAR T-cell amplifying RNA vaccine; DL = dose level; EOC = epithelial ovarian cancer; GCT = germ cell tumor; LLOQ = lower limit of quantification; PBMC = peripheral blood mononuclear cells. ESMO Congress 2023, Dr. John Haanen; Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. BIONTECH#19BNT211 ESMO Data: Key Takeaway Messages Safety: Toxicities at higher dose level led to further evaluation of safety via backfilling into several cohorts Efficacy: Encouraging signs of activity with 13 responses in 22 evaluable patients at DL2 (ORR 59%, DCR 95%) Pharmacokinetics: CARVac improved CAR-T persistence, leading to sustained, ongoing detection up to 100 days in several patients at DL2 Outlook: Backfilling to determine RP2D for CLDN6 CAR-T cells for a pivotal trial in GCT is currently ongoing CAR chimeric antigen receptors; CARVac = CAR T-cell amplifying RNA vaccine; CLDN6 = claudin-6; DCR disease control rate; DL dose level; GCT = germ cell tumor; ORR = objective response rate; RPD2 = recommended Phase II dose. 19 BIONTECH#20_4 BNT221 Safety and efficacy of BNT221, a non-engineered neoantigen specific T cell product for adoptive cell therapy of metastatic melanoma BIONTECH#21BNT221: A Personalized, Autologous Non-Engineered Neoantigen-Specific T Cell Product • A systematic, highly reproducible approach to expand neoantigen-specific T cells Fully personalized product • Drug product contains polyclonal neoantigen CD4+ and CD8+ T cell responses. NEO-STIM® • Potential to circumvent antigen escape PBMC starting material • Material obtained from leukapheresis Clinical opportunity MMX • Broad clinical opportunity due to targeting of personalized mutations RECON ANFORMATICS 00000 Tumor Sample DNA & RNA Bioinformatics & Processing Sequencing Personalized Peptide Manufacturing PBMC peripheral blood mononuclear cell. NEO STIM Prime Activate → Expand T cell Epitopes Leukapheresis APCs & T cells BNT221 Personalized Neoantigen T Cell Therapy BIONTECH#22Phase 1 First-in-Human Trial (NCT04625205) Evaluating BNT221 in Advanced or Metastatic Melanoma Prescreening BNT221 infusion Production Post-infusion Follow-up Expansion cohorts -20 -16 -12 -4 AD1+2+3 +6 +30 +36 +52 Week Screening/Sequencing Lympho- depletion EOT Occurs every 6 weeks Inclusion criteria Adults 18-75 yrs, unresectable or metastatic melanoma Progressive disease or intolerant to aPD-1/PD-L1 and aCTLA-4 directed therapies; ≤3 prior regimens in metastatic setting At least 1 site RECIST 1.1 measurable disease (active CNS metastasis excluded) ECOG 0-1 No active auto-immune diseases BNT221 Monotheraphy dose finding 1 x 108-1 x 109 2 x 109-1 x 1010 Combination BNT221aPD-1 Tissue collection to evaluate immune response: Blood draw Biopsy Leukapheresis Key endpoints Primary: Safety + MTD BNT221 monotherapy, + aPD-1 Secondary: ORR (RECIST 1.1), response duration, clinical benefit rate Exploratory: Immune response in peripheral blood and tumor Immunogenicity, clinical activity correlation Drug product characterization, correlation with clinical activity and safety CNS: central nervous system; MTD: minimal residual disease; ORR: overall response rate; PD: progressive disease. BIONTECH#23All patients had received anti-PD1 and anti-CTLA-4 therapy • Patients had received a median of 3 prior therapies BNT221 in Heavily Pretreated Melanoma Patients Phase 1 FIH study (NCT04625205): Baseline characteristics. Borgers J. et al. Presented at ESMO 2023. Abstract #10170. Baseline patient characteristics Median age (range) Sex M/F, n (%) ECOG 0-1, n (%) Stage IV at entry, n (%) Serum LDH increased, n (%) Tumor Burden at Prescreen median sum of TL, range (mm) Prior lines of systemic therapy median (min/max) Prior aPD-1 therapy, n (%) Total (n=9) 57 (32-72) 2 (22%) 7 (78%) 9 (100%) 9 (100%) 1 (11%) 44 (16-177) 3 (2/4) 9 (100%) 6 (67%) 4 (44%) 1 (11%) 9 (100%) 2 (22%) 2 (22%) Adjuvant Metastatic Both Prior aCTLA-4 therapy, n (%) Prior BRAF/MEK-directed therapy, n (%) Other, n (%) BRAF: V-Raf Murine Sarcoma Viral Oncogene Homolog B; ECOG: Eastern Cooperative Oncology Group; F: female, LDH: lactate dehydrogenase; M: male,; MEK: Mitogen-activated protein kinase kinase; TL: target lesion. 23 BIONTECH#24Activity Signals Observed Post Single Infusion BNT221 Monotherapy Phase 1 FIH study (NCT04625205): Clinical Efficacy Borgers J. et al. Presented at ESMO 2023. Abstract #10170. RECIST % Change in Target Lesions 50- 40- 30. 20 10- 0 -10- -20 -30 -40- -50- -60- NAC02 NAC05 NAC06 NAC04 NAC01 NAC07 NAC08 NAC03 NAC09 Patient BOR SD IPD % Change in Sum of Target Lesions BNT221 Infusion 501 40 Pre-infusion Post-infusion 30 20 10. 0 -10- -20 -30 -40- -50 -60 -25 -20 -15 -10 -5 0 5 Study Week 10 15 20 20 Tumor regressions, including prolonged SD in this aPD-1 and a CTLA4 pretreated population NAC: neoantigen cell dose received; PD: progressive disease; SD: stable disease. 25 30 30 35 Patient NAC01 NAC02 ●• NAC03 NAC04 NAC05 • NAC06 NAC07 NAC08 NAC09 BIONTECH#25BNT221: Polyclonal T-Cell Responses in Drug Product are Detectable in Peripheral Blood Post-Infusion Phase 1 FIH study (NCT04625205): T cell response Borgers J. et al. Presented at ESMO 2023. Abstract #10170. Detection of specific CD8+ T cells by 105 tetramer DP Subset of responses in drug product are detected in periphery at 3-6 weeks. O Detected in DP ● Detected in DP and periphery O Detected in DP, not tested in periphery 100 100- о Tetramer 2 104 103- 0 0 105 104 2.45% 103 104 105 Post Infusion 103- 0.075% 103 104 10% Tetramer 1 DP: drug product; NAC: neoantigen cell dose received; NVD: never dosed. % pMHC+ of CD8+ 0.01 0.001 10. NAC01 800 0 0 φο o οφ оф 0 0 o NAC02 NAC03 NAC04 NAC05 oo 0000 oo o 01.000 NAC06 NVD01 NAC07 NAC08 NAC09 NVD02 NVD03 % IFNY and/or TNFa* of CD4+ 10- 0.1 NAC01 Офо 8 o do o 00 NAC02 NAC05 NAC06 NVD01 NAC07 NAC08 NAC09 NVD02 NVD03 ⚫ Of 12 patients tested, 2 had neoantigen-specific cells detected by flow cytometry in peripheral blood prior to infusion • Of the 5 patients with available sample 3-6 weeks post-infusion, all 5 had detectable CD8+ responses and 3 had detectable CD4+ responses BIONTECH#26First-in-Human Trial Shows Promising Proof of Concept for BNT221 - a Novel Neoantigen-Focused Cell Therapy Approach Safety: BNT221 demonstrated a manageable safety profile with no DLTS. 26 Efficacy: In this aPD-1 and aCTLA-4 pretreated population, monotherapy with BNT221 resulted in tumor shrinkage for 4/9 patients Immune response: BNT221 generates a polyclonal neoantigen-specific T cell product that can be detected post-infusion Outlook: Combination of BNT221 with aPD-1 is currently being tested in the clinic. Apply translational learnings to further optimize the next-generation NEO-STIM process BIONTECH