Announcement PDF ABN 16 165 160 841 ASX RELEASE 20 January 2025 NEW DATA FOR NARMAFOTINIB PRESENTED AT INTERNATIONAL CONFERENCE HIGHLIGHTS • Additional data analysis from our Phase 1b/2a ACCENT trial in pancreatic cancer has been presented at the specialist scientific conference - the Keystone Meeting on the Tumour Microenvironment • The data analysis further confirms the promising activity of narmafotinib at the 400 mg dose • New preclinical data shows that narmafotinib enhances the activity of a drug that is used clinically to block the cancer-driving protein kRas in difficult-to-treat cancers, such as pancreatic cancer, lung cancer and colorectal cancer. Melbourne, Australia: Amplia Therapeutics Limited (ASX: ATX), (“Amplia” or the “Company”) is pleased to announce that a poster, presenting new preclinical data and updated data from the ongoing ACCENT trial in pancreatic cancer, was presented overnight at prestigious Keystone meeting ‘Tumor Microenvironment: Metastasis and the Host’ in Banff, Canada. The ACCENT trial is the company’s lead clinical program, exploring the activity of our best-in-class FAK inhibitor narmafotinib, in combination with standard-of-care chemotherapy, in advanced pancreatic cancer patients. The poster describes preclinical data for narmafotinib in models of pancreatic cancer and presents further analysis of data from the Phase 1b portion of the ACCENT trial. Data highlights from the presentation include: • Evidence from the ACCENT trial that there is a dose-dependent reduction in tumour size, as the oral dose of drug increases from 100 mg to 200 mg to 400 mg • Data showing that patients on the 400 mg dose of narmafotinib had an average treatment duration of 8.3 months, significantly better than historical data for patients receiving chemotherapy alone • Demonstration that narmafotinib has anti-fibrotic effects in a mouse model of pancreatic cancer and that narmafotinib has single-agent activity in this model • Demonstration that narmafotinib enhances the activity of chemotherapy and appears to inhibit resistance to the chemotherapy that develops over time in the mouse model In addition, the poster shows preliminary data demonstrating the beneficial effects of narmafotinib when combined with the approved drug adagrasib in mouse models of cancer. Adagrasib, marketed as Krazati®, inhibits a mutated form of the cancer causing protein kRas, which is present in a subset of pancreatic cancer patients as well as in patients with lung and colorectal cancer. A copy of the poster is attached to this announcement. Amplia’s CEO Dr Chris Burns commented: “We are delighted to present further data about our drug narmafotinib and its activity in the ACCENT clinical trial. Demonstration of the drug’s activity in cancer patients, as well as in defined animal models of cancer, helps to build a robust dataset that underpins the commercial potential of the drug.” Level 17, 350 Queen Street, Melbourne VIC 3000 Email info@ampliatx.com www.ampliatx.com This ASX announcement was approved and authorised for release by the Board of Amplia Therapeutics. About Narmafotinib Narmafotinib (AMP945) is the company’s best-in-class inhibitor of the protein FAK, a protein overexpressed in pancreatic and other cancers, and a drug target gaining increasing attention for its role in solid tumours. The drug, which is a highly potent and selective inhibitor of FAK, has shown promising data in a range of preclinical cancer studies. The drug has successfully completed a healthy volunteer study, and is currently in an open-label Phase 2a trial in pancreatic cancer where a combination of narmafotinib and the chemotherapies gemcitabine and Abraxane® is being assessed for safety, tolerability and efficacy. About the ACCENT Trial The ACCENT trial is entitled ‘A Phase 1b/2a, Multicentre, Open Label Study of the Pharmacokinetics, Safety and Efficacy of AMP945 in Combination with Nab-paclitaxel and Gemcitabine in Pancreatic Cancer Patients’. The ACCENT trial explores the use of narmafotinib in combination with standard-of-care chemotherapy of gemcitabine and Abraxane® in first-line patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. The first stage (Phase 1b), completed in November 2023, identified a 400 mg oral daily dose of narmafotinib, given in the days preceding regular chemotherapy infusion, as safe and well tolerated. The second stage (Phase 2a), of the trial is designed to assess drug efficacy in combination with gemcitabine and Abraxane. The primary endpoints are Objective Response Rate (ORR) and Duration on Trial (DOT) with secondary endpoints being Progression Free Survival (PFS) and Overall Survival (OS). Safety and tolerability will continue to be assessed. More information about the ACCENT trial, including a list of participating sites can be found via the ACCENT website, the Amplia Therapeutics website, and at ClinicalTrials.gov under the identifier NCT05355298. Investor Contact: Dr Chris Burns Chief Executive Officer chris@ampliatx.com Media Contact: H^CK Director, Haley Chartres haley@hck.digital +61 423 139 163 About Amplia Therapeutics Limited Amplia Therapeutics Limited is an Australian pharmaceutical company advancing a pipeline of Focal Adhesion Kinase (FAK) inhibitors for cancer and fibrosis. FAK is an increasingly important target in the field of cancer and Amplia has a particular development focus in fibrotic cancers such as pancreatic and ovarian cancer. FAK also plays a significant role in a number of chronic diseases, such as idiopathic pulmonary fibrosis (IPF). For more information visit www.ampliatx.com and follow Amplia on Twitter (@ampliatx) and LinkedIn. Focal Adhesion Kinase Inhibitor Narmafotinib Targets the Tumor and Microenvironment to Enhance and Sustain Sensitivity to Chemotherapy Sarah Kinkel1, Kendelle Murphy2, David Herrmann2, Paul Timpson2, Nicole Kruger1, Sumitra Ananda3, Marion Harris4, Lara Lipton5, Adnan Nagrial6, Nick Pavlakis7, Jason Lickliter1, Christopher J. Burns1, Terrie-Anne Cock1 1Amplia Therapeutics, Melbourne, Australia; 2 Garvan Institute of Medical Research, Sydney, Australia; 3Epworth Cancer Services Clinical Institute Melbourne, Australia; 4Monash Medical Centre Melbourne, Australia; 5Sunshine Hospital, Melbourne, Australia; 6Westmead Cancer Care Centre, Sydney, Australia; 7GenesisCare, Sydney, Australia. Narmafotinib treatment reduced tumor growth & proliferation Ki67 Positive Cells (%) Tumor volume (mm3) 600 400 200 ✱✱✱ 60 40 20 0 Vehicle 0.3 0.2 Vehicle Narma 500 400 300 200 100 0.1 0 5 Vehicle Narma 10 15 20 25 30 0.05 0.00 Vehicle 500 450 400 300 200 100 0 Narma 70 75 80 85 90 95 100 105 ✱ growth increase growth increase ns 6 N=10 N=10 N=3 Vehicle Narma Mean ± SD; p-values determined using Welch’s t test 300 **** 200 150 ✱✱✱✱ 100 **** 50 **** N=8 N=1 N=6 2 4 6 8 10 Treatment Day Vehicle Adagrasib 2.5mg/kg QD Dose-dependent increase in treatment duration 100mg 200mg 400mg Dose-dependent reduction in tumor burden 11 10 9 8 (non-imaging confirmed progression) 7 6 100mg 200mg 400mg 5 4 ➢ There were five confirmed partial responses (4 at 400 mg narmafotinib; 1 at 200 mg), indicating increased response with increasing dose. 100mg narmafotinib 2 (plus gemcitabine/nab-paclitaxel) 40 -20 -40 -60 -80 0 -20 -40 -60 -100 50 100 150 200 250 300 350 400 Days since screening -20 Partial response -40 -60 -100 -100 0 0 -80 -80 0 50 100 150 200 250 300 350 Days since screening 400 0 50 100 150 200 250 300 350 400 Days since screening Note: investigator read provisional analysis References 1. Lim ST, , et al. Mol Cell. 2008;29(1):9-22. 2. Sulzmaier FJ, , et al. Nat Rev Cancer. 2014;14(9):598-610. 3. Dawson JC, , et al. Nat Rev Cancer. 2021;21(5):313-324. 4. Zhang Z, , et al. Front Cell Dev Biol. 2022;10:1040311. 5. Siegel RL, , et al. Cancer statistics, 2023. CA Cancer J Clin 2023; 73, 17-48. 6. Zaghdoudi S, et al. EMBO Mol Med. 2020;12(11):e12010. 0 50 100 150 200 250 300 350 400 450 Days on study 20 Tumour burden % change from baseline 0 (plus gemcitabine/nab-paclitaxel) 40 20 Tumour burden % change from baseline 20 Tumour burden % change from baseline 400mg narmafotinib 200mg narmafotinib (plus gemcitabine/nab-paclitaxel) 40 Note: Two doseadjusted patients (400mg→100mg & 400mg→200mg) were included in safety and overall response analysis but are not shown on graphs. PD PR Withdrawn (due to chemo toxcity) 3 1 Part A (Phase 1b): patients with advanced pancreatic cancer were enrolled in a 3+3 design, with narmafotinib dose escalation (100, 200 and 400 mg), and the primary objective of determining recommended Phase 2 dose, and assessing safety and tolerability of oral narmafotinib administered prior to IV administration of gemcitabine and nab-paclitaxel. Part B (Phase 2a) is a Simon’s two-stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1.1. Mean time on study for patients receiving 100mg, 200mg or 400mg narmafotinib is indicated by bold lines on graph. 12 ➢ All participants received oral narmafotinib once daily at the selected dose on Day -8 to Day -2 (7 doses total) of a monotherapy run-in period, prior to first treatment cycle. ➢ Each 28-day treatment cycle includes IV gemcitabine and nab-paclitaxel on Days 1, 8 and 15, and oral narmafotinib priming on Days 3 to 6, 10 to 13, and 24 to 27, inclusive. 7. Jiang H, et al. Nat Med. 2016;22(8):851-860. 8. Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-703 9. Wainberg , et al. Lancet. 2023 Oct 7;402(10409):1272-1281. ➢ 6 patients on 400 mg narmafotinib had mean treatment duration of 8.3 months, with 4 of 6 patients on study for >6 months. ➢ Historical median duration of treatment for gemcitabine & nab-paclitaxel is 3.9 - 4.1 months; median time to treatment failure/duration of response is ~5 months8,9. ➢ Narmafotinib in combination SOC was generally welltolerated. 10. Zhang B, et al. Adv Sci (Weinh). 2021;8(16):e2100250. * p < 0.05 ** p < 0.01 12 14 AMP945 40mg/kg QD Adagrasib 2.5mg/kg QD + AMP945 40mg/kg QD 1400 1200 1000 ✱ 800 600 ✱ 400 200 0 0 5 10 15 20 25 30 35 40 45 Treatment Day Vehicle Adagrasib 100mg/kg QD AMP945 80mg/kg QD Adagrasib 100mg/kg QD + AMP945 80mg/kg QD Mean ± SEM; p-values determined using 2-way ANOVA with Sidak’s multiple comparison test (left panel) or unpaired t test (right panel). Preclinical KRAS G12C mutant cancer model: MIA PaCa-2 (pancreatic) and NCIH2122 (lung) subcutaneous xenograft model treated with vehicle, narmafotinib alone, adagrasib alone or narmafotinib in combination with adagrasib. 4. Clinical dose-dependent benefit of narmafotinib in combination with gemcitabine and nab-paclitaxel (Abraxane®) standard of care as first-line therapy in patients with metastatic pancreatic cancer: ACCENT trial (provisional analysis of Phase 1b) The ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and efficacy of narmafotinib in combination with gemcitabine and nabpaclitaxel (Abraxane®) standard of care (SOC), as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open-label study conducted in two stages. KRAS insensitive NCI-H2122 model 250 Mean ± SD; p-values determined using one-way ANOVA or Welch’s t test. Preclinical pancreatic cancer model: Patient-derived TKCC10lo cell line subcutaneous xenograft model treated with vehicle, narmafotinib alone, gemcitabine/nab-paclitaxel or narmafotinib in combination with gemcitabine/nab-paclitaxel. Narma KRAS sensitive MIA PaCa-2 model 0 4 2 KRAS mutations are common oncogenic drivers; KRAS G12C inhibition can hyperactivate FAK signaling, which can lead to fibrosis and reducing the effectiveness of treatment10. 0 8 0 Vehicle 50 55 60 65 Days post injection ✱✱✱✱ 10 SHG Intensity [AU] 0.10 45 ✱✱✱✱ ✱✱✱ 550 40 ✱✱✱✱ Reduced collagen crosslinking ✱✱✱✱ 600 Biref Coverage (µm3) Picrosirius Red Intensity [AU] ✱✱ 0.15 35 Narma Narmafotinib treatment reduced tumor fibrosis Reduced collagen deposition 90% of mice treated with a narmafotinib combined with gemcitabine/ nab-paclitaxel sustain sensitivity to chemotherapy 600 0.0 0 Narmafotinib + Gem/nab-PTX Gemcitabine/nab-paclitaxel (days 7 & 10) ✱✱ 0.4 Narmafotinib growth increase 80 Gem/nab-PTX 700 Reduced pFAK pFAK DAB Intensity [AU] ✱ 800 Vehicle growth increase Reduced proliferation Reduced tumor growth Narmafotinib (day1:pm-day4:am) 5. Narmafotinib increases and sustains tumor responsiveness to KRAS G12C inhibitor adagrasib Tumour volume change (%) ➢ FAK is a non-receptor tyrosine kinase that acts through numerous signaling pathways to mediate communication between cells and their environment. ➢ FAK plays a crucial role in normal cellular stress response1. ➢ Aberrant FAK signaling has been implicated in the progression of cancer, where it is involved in promoting tumor growth, adhesion, angiogenesis, invasion, and migration, as well as immunomodulation and remodeling of the fibrotic tumor microenvironment2-4. ➢ FAK is frequently overexpressed in a variety of cancers, including pancreatic ductal adenocarcinoma4, a highly fibrotic and aggressive malignancy with a poor 5-year survival rate5, in which high FAK expression correlates with poor prognosis6,7. 3. Narmafotinib improves responsiveness to gemcitabine and nab-paclitaxel; tumors showed enhanced sensitivity to chemotherapy with sustained reduction in growth Tumor Volume Change (%) 2. Narmafotinib treatment directly affects the tumor and microenvironment Tumor Volume (mm3 ) 1. Narmafotinib (AMP945) is a selective and orally bioavailable inhibitor of Focal Adhesion Kinase (FAK) *** p < 0.001 **** p < 0.0001 6. Conclusions ➢ Narmafotinib reduces tumor growth and fibrosis in a patientderived pancreatic cancer xenograft model ➢ Narmafotinib enhances sensitivity to gemcitabine/nab-paclitaxel in preclinical models to sustain tumor growth reduction and increase overall survival ➢ Preclinical analysis indicates that narmafotinib shows efficacy in combination with KRAS G12C inhibitor adagrasib ➢ In the clinic (Phase 1b), narmafotinib combined with gemcitabine/nab-paclitaxel demonstrated promising activity in a dose-dependent manner in response and duration of treatment ➢ Five confirmed partial responses (4 at 400 mg narmafotinib; 1 at 200 mg), indicating increased response with increasing dose ➢ 400 mg of narmafotinib and gemcitabine/nab-paclitaxel mean duration of treatment was 8.3 months, outperforming historical SOC ~4 months ➢ Narmafotinib in combination SOC was generally welltolerated Contact Terrie-Anne Cock PhD E: TerrieAnne@ampliatx.com W: www.ampliatx.com