DEP SN38 Results Showcased at GI Cancer Conference

ASX Announcement DEP® SN38 Results Showcased at GI Cancer Conference • Results from patients with metastatic color ectal cancer (mCRC) deemed exceptional responders in the DEP® SN38 Phase 1/2 clinical trial were presented at a specialist gastrointestinal cancer conference in Brisbane, Australia. • DEP® SN38 demonstrated promising efficacy, with sustained and durable disease control for up to 72 weeks in patients previously treated with irinotecan. • DEP® SN38 exhibited a favourable toxicity profile compared with standard irinotecan , contributing to improved quality of life experiences for these patients. • One patient with platinum-resistant ovarian cancer continues to receive DEP® SN38 treatment, having achieved prolonged disease control for more than 1.7 years. Melbourne, Australia; 21 November 2024: Starpharma (ASX: SPL, US OTC: SPHRY), an innovative biotechnology company with two decades of experience in advancing dendrimer technology from the lab to the patient , today shares a copy of a DEP® SN38 scientific poster that was presented at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in Brisbane this week. The poster presentation highlights the outcomes for five selected patients with advanced metastatic colorectal cancer (mCRC) who participated in the Phase 1/2 clinical trial of DEP® SN38 at The Kinghorn Cancer Centre at St Vincent’s Hospital and Garvan Institute of Medical Research in Sy dney. These patients were deemed exceptional responders by the study site investigators based on the ir impressive responses to DEP® SN38 treatment, particularly given their advanced disease and extensive prior treatment. These heavily pre-treated patients’ disease had progressed following prior irinotecan exposure and, in some cases, they had experienced intolerance to irinotecan. Despite these challenges, treatment with DEP® SN38 achieved sustained and durable disease control for up to 72 weeks in this group of patients. One of the patients, treated with DEP® SN38 in combination with 5-fluorouracil (5-FU) and leucovorin (LV), achieved a partial response, with a reduction in the size of their target tumour of more than 30%. Importantly, DEP® SN38 also exhibited an excell ent toxicity profile with manageable side effects , leading to improved quality of life experiences for these patients. The development and presentation of the poster was led by Dr Jordan Cohen, MBBS MMed, Medical Oncology Fellow in the team of Dr Jia (Jenny) Liu , MD PhD FRACP, Medical Oncologist and Principal Investigator of the DEP® SN38 Phase 1/2 clinical study at The Kinghorn Cancer Centre. Dr Liu commented: “The DEP® SN38 trial results are very exciting. DEP® SN38 in heavily pre -treated, advanced cancer patients demonstrated highly encouraging efficacy results in a range of tumour types, including in colorectal cancer where there is a high unmet need for more efficacious and tolerable treatments . These responses include significant and sustained tumour shrinkage and disease control in patients who have previously been treated with irinotecan. “DEP® SN38 exhibits excellent tolerability, with a distinct lack of severe gastrointestinal toxicity that is a common and problematic feature of irinotecan treatment. The treatment tolerability demonstrated by Starpharma’s DEP® SN38, combined with sustaine d disease control, has meant that many of our patients, including those who are quite young with advanced colorectal cancer, have been able to 2 receive long-term treatment and continue to work and engage socially with their peers, which is very important for their quality of life.” DEP® SN38 is a novel , water-soluble dendrimer conjugated to SN38, the topoisomerase I (TOP1) inhibitor and active metabolite of irinotecan. DEP® delivery of SN38 avoids liver metabolism normally required for activation, which helps reduce off-target toxicity that is a feature of standard irinotecan . The DEP® dendrimer nanoparticles are retained in the tumour microenvironment via enhanced permeability and retention, enabling prolonged, targeted delivery of the cytotoxic drug to tumours. The multicentre, global, Phase 1/2 clinical trial of DEP® SN38 (N=114) has shown promising efficacy in several tumour types , including mCRC and platinum -resistant ovarian cancer , along with highly favourable safety and tolerability, particularly low rates of severe gastrointestinal events and a lack of cholinergic symptoms compared to published data on conventional irinotecan. One patient with platinum-resistant ovarian cancer remains on treatment, having received 45 dose cycles of DEP® SN38 with achievement of prolonged disease control for now more than 1.7 years. Summary of the DEP® SN38 Efficacy and Safety Results in these Exceptional Responders • One patient treated with DEP® SN38 + 5 -FU/LV combination therapy achieved a partial response, with a reduction in size of their target tumour of more than 30% , and four patients exhibited stable disease, with durable disease control lasting up to 72 weeks. • Four patients showed a concomitant reduction in the levels of the CEA cancer biomarker of up to 74%. • Dose-limiting toxicities were observed in one patient , who experienced grade 3 febrile neutropenia that required a dose reduction. • Neutropenia in other patients was managed effectively with G -CSF1, and g astrointestinal events were mostly mild to moderate, with only one instance of grade 3 nausea reported, and no cases of severe diarrhoea in any patients. • Two patients continued treatment beyond progression of their disease due to clinical benefit. Summary of the Patient Characteristics • Five patients (2 male, 3 female) with mCRC and median age of 38 years. • Treatment included either monotherapy with DEP® SN38 or a combination of DEP® SN38 with 5-FU/LV (equivalent to the “FOLFIRI” regimen). • For these patients, the median number of DEP® SN38 treatment cycles administered was 24. • The median duration of treatment with DEP® SN38 was 59 weeks. Colorectal cancer is the second leading cause of cancer-related deaths globally. It is often diagnosed at advanced stages, making treatment options limited. The incidence of CRC is increasing among adults younger than 50, as reflected by the ages of the patients in this study. According to the American Cancer Society (ACS), 20% of colorectal cancer diagnoses in 2019 were in patients under the age of 55. This figure is approximately twice the rate seen in 19952 and continues to rise. Starpharma's DEP® SN38 is a priority candidate for licensing, showing promising Phase 1/2 results in mCRC and platinum-resistant ovarian cancer. Starpharma will meet with key regulators in the coming weeks to discuss potential clinical development pathways for DEP® SN3 8 aimed at achieving commercialisation. 1 G-CSF, granulocyte-colony stimulating factor, is a growth factor that stimulates the bone marrow to make more blood cells, and increases the number of some types of white blood cells in the blood 2 https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and- figures/colorectal-cancer-facts-and-figures-2023.pdf 3 About Starpharma Starpharma ASX: SPL, OTCQX: SPHRY) is an innovative biotechnology company with two decades of experience in advancing dendrimer technology from the lab to the patient. Our mission is to help patients with significant illnesses, such as cancer, achieve improved health outcomes and quality of life through the application of our unique dendrimer technology. Dendrimers are precise, synthetically manufactured, nanoscale molecules. Their unique properties—including their size, structure, high degree of branching, polyvalency, and water solubility—are advantageous in medical and pharmaceutical applications. Starpharma’s portfolio of dendrimer -based products includes three clinical -stage DEP® (dendrimer enhanced product) assets, preclinical radiopharmaceutical assets, research collaborations, and three commercially marketed over-the-counter (OTC) products. For more information about Starpharma, visit www.starpharma.com or connect with Starpharma on LinkedIn. WE Communications Hannah Howlett +61 450 648 064 WE-AUStarPharma@we- worldwide.com Starpharma Holdings Limited Cheryl Maley, Chief Executive Officer Justin Cahill, CFO and Company Secretary +61 3 8532 2704 [email protected] 4-6 Southampton Crescent Abbotsford Vic 3067 Disclosure This ASX Announcement was authorised for release by the Chair, Mr Rob Thomas. Forward-Looking Statements This document contains certain forward -looking statements, relating to Starpharma’s business, which can be identified by the use of forward -looking terminology such as “promising”, “plans”, “anticipated”, “will”, “project”, “believe”, “forecast”, “expected”, “estimated”, “targeting”, “aiming”, “set to”, “potential”, “seeking to”, “goal”, “could provide”, “intends”, “is being developed”, “could be”, “on track”, or similar expressions, or by express or implied discussions regarding potential filings or marke ting approvals, or potential future sales of product candidates. Such forward -looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any fu ture results, performance or achievements expressed or implied by such statements. There can be no assurance that any existing or future regulatory fil ings will satisfy the FDA’s and other authorities’ requirements regarding any one or more product candidates, nor can there be any assurance that such product candidates will be approved by any authorities for sale in any market or that they will reach any particular level of sales. In particular, mana gement’s expectations regarding the approval and commercialization of the product ca ndidates could be affected by, among other things, unexpected trial results, including additional analysis of existing data, and new data; unexpected regulatory actions or delays, or government regulation generally; our abi lity to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry, and general public prici ng pressures; and additional factors that involve significant risks and uncertainties about our products, product candidates, fina ncial results and business prospects. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual resu lts may vary materially from those described herein as anticipated, believed, estimated, or expected. Starpharma is providing this information as of the date of this document and does not assume any obligation to update any forward -looking statements contained in this document as a result of new information, future events or developments or otherwise. Clinical case studies and other clinical information given in this document are given for illustrative purposes only and are not necessarily a guide to product performance and no representation or warranty is made by any person as to the likelihood of achievement or reasonableness of future results. Nothing contained in this document, nor any information made available to you is, or shall be relied upon as, a promise, representation, warranty or guarantee as to the past, present or the future performance of any Starpharma product. Private and Confidential 1 Background Exceptional Responders in a Phase 1/2 Clinical Trial of Dendrimer-Enhanced (DEP) SN38 (SN38-SPL9111) for the Treatment of Metastatic Colorectal Cancer (mCRC) Jordan E. Cohen1,2, Rasha Cosman1,2,3, Anthony Rodrigues1,2,3, Anthony Joshua1,2,3, Ivan Ly1, Minh T. T. Ho1, Jeremy R.A. Paull4, Bernadette M. Jean-Francois4, Nicola J. Main4, Julia Le Meur4, Stephanie R. Edmondson4, Jia Liu1,2,3 1St Vincent’s Hospital, Sydney, NSW, Australia, 2Faculty of Medicine & Health, University of New South Wales, Sydney, Australia, 3Garvan Institute of Medical Research, Sydney, NSW, Australia, 4Starpharma Pty Ltd., Melbourne, Australia Conclusion • DEP® SN38 is a novel highly water-soluble, poly-L-lysine dendrimer nanoparticle modified with polyethylene glycol (PEG), with SN38 covalently linked via a hydrolysable linker. • SN38, the active moiety of irinotecan, is 100-1000-fold more potent than irinotecan1, but its formation requires complex liver conversion, leading to high interpatient variability in plasma levels2, which complicates optimal dosing and toxicity management. • Irinotecan, widely used in metastatic colorectal cancer (mCRC), has significant limitations due to cholinergic toxicity and life-threatening diarrhoea, both FDA “Black Box" warnings2. DEP SN38 avoids liver metabolism Linker DEP dendrimer PEG SN38 1:1 ratio SN38:PEG DEP SN38 dendrimer nanoparticle 10-15 nm diameter ACKNOWLEDGEMENTS We would like to thank the patients and their families, and caregivers, for their participation in this study. Starpharma would like to thank participating investigators and their study team for their support on this study, and their dedication to patients, particularly during the challenges attributable to the COVID-19 pandemic. Study sponsored by Starpharma Pty Ltd, Abbotsford, Australia References 1. Santi, D.V ., E.L. Schneider, and G.W. Ashley, Macromolecular prodrug that provides the irinotecan (CPT- 11) active-metabolite SN-38 with ultralong half-life, low C(max), and low glucuronide formation. J Med Chem, 2014. 57(6): p. 2303-14. 2. HIGHLIGHTS OF PRESCRIBING INFORMATION for CAMPTOSAR® (irinotecan hydrochloride) injection, FDA revised version 2022 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020571Orig1s053lbl.pdf 3. Data presented at 2024 ASCO Annual Meeting – Dendrimer-enhanced (DEP) SN38 (DEP irinotecan) in patients with advanced solid tumors: a Phase ½ trial by Jia (Jenny) Liu 4. Leonard, P ., et al., Phase II study of irinotecan with bolus and high dose infusional 5-FU and folinic acid (modified de Gramont) for first- or second-line treatment of advanced or metastatic colorectal cancer. Br J Cancer, 2002. 87(11): p. 1216-20. Results • 17 mCRC patients enrolled at the Kinghorn Cancer Centre: 8 in monotherapy, 9 in 5-FU/LV combination. • Median of 7 DEP® SN38 cycles given (range 1-25). • No routine antihistamine, H2 receptor antagonist, or paracetamol required. Majority of patients required no ongoing corticosteroids premedication, or only one day of dosing with dexamethasone. • Monotherapy: 8 mCRC evaluable with 38% Disease Control Rate (DCR). • 5-FU/LV combination: 8 mCRC evaluable 75% DCR and 25% Overall Response Rate (ORR). Methods Prior lines RECIST 1.1 Evaluable (n) DCR (n) ORR (n) Duration of response Median PFS DEP® SN38 Monotherapy Q3W/Q2W (N=38) Median = 4 (range 2-9) 31 48% (15) 0% (0) Up to 72 weeks 2.1 months DEP® SN38 + 5-FU/LV Combination Q2W (N=17) Median = 3 (range 2-6) 14 86% (12) 14% (2) Up to 59 weeks 4.2 months Evaluable: patients who received ≥ 1 dose DEP® SN38 and a CT scan at ≥ ~week 8 after first dose. ORR: Objective Response Rate (CR+PR/ORR evaluable). DCR: Disease Control Rate (CR+PR+SD/RECIST Evaluable). All mCRC patients SAFETY • Majority of TRAEs mild and moderate. • Neutropenia uneventful; managed with G-CSF. • No cholinergic symptoms, 0% vs ~47% patients irinotecan. TumourHealthy tissue Normal vasculature Leaky vasculature Free SN38 SN38 release over time DEP dendrimer drug conjugate EPR Effect • Patients ECOG 0-1 with RECIST v1.1 measurable advanced solid tumours, including mCRC and platinum resistant high-grade serous ovarian carcinoma (HGSOC)3. • Open label DEP® SN38 as monotherapy or with 5-FU (fluorouracil)/LV (leucovorin) combination. • DEP® SN38 administration: intravenous ( I V, ~60 min infusion) dosing once every 14 (Q2W) or 21 (Q3W) days; administered as mg/m2 SN38. • 5-FU/LV administration: as per modified De Gramont protocol4. • Antitumour activity assessed by RECIST v1.1; safety assessed by physical and hematological examinations, and adverse events graded according to CTCAE v5.0. Patient at Pre-cycle 12: “It’s crazy I don't get any side effects on this trial. I don't get as much nausea compared to the prior chemotherapy, …, I have no diarrhoea, and the chemotherapy doesn't affect my QoL.” Exceptional responders were young, heavily pre-treated and obtained durable control of cancer despite irinotecan pre-treatment – good QoL while on study KEY RESULTS A B C D E HISTORY Age 54 55 38 38 31 Sex F F M F M Race White Asian White Other White ECOG PS 1 0 0 0 0 Number of prior lines 6 3 5 2 5 Organs involved Liver, Lung, Node Liver, Lung, Node Bone, Liver, Node Lung Lung, Node Prior irinotecan best response PR PR PR SD but irinotecan intolerance PR Surgery / Radiotherapy Surgery & Radiotherapy Surgery Surgery & Radiotherapy Surgery & Radiotherapy ND EFFICACY Dose regimen Q3W Monotherapy 12.5 mg/m2 SN38 Q2W Monotherapy 15.0 mg/m2 SN38 Q3W Monotherapy 8.0 mg/m2 SN38 Q2W 5-FU/LV combination 12.5 mg/m2 SN38 Q2W 5-FU/LV combination 12.5 mg/m2 SN38 Number of DEP® SN38 Cycles 24 17 10 25 over 59 weeks 23 over 62 weeks Best efficacy response SD SD SD PR SD Best % reduction in Target Lesion (TL) -4.5% -22.3% -4.1% -30.8% -29.4% Duration of SD 72 weeks 37 weeks 26 weeks 35 weeks 54 weeks SAFETY Key takeaway ECOG improved to 0 from Cycle 7 until EOS DLT at Cycle 1 → reduced to 12.5 mg/m2 SN38 UGT1A1*28 homozygous mutant → 8 escalated to 12.5 mg/m2 SN38 G1 GI tox only Many breaks led to PD Treated beyond PD G1 GI tox only Longer break led to PD Treated beyond PD Gastrointestinal (GI) toxicities G3 nausea G2 nausea G1 vomiting G2 diarrhoea G1 diarrhoea G1 nausea G1 diarrhoea G1 constipation G1 nausea G1 vomiting Prophylaxis treatment Anti-emetics from C2 G-CSF from C4 G-CSF at C2-3 only following DLT None Anti-emetics from C17 G-CSF D3 each cycle G-CSF D3 each cycle Exceptional Responders of the Kinghorn Cancer Centre 12.5 mg/m2 SN38 MONOTHERAPY and 5-FU/LV COMBINATION THERAPY DEP® SN38 RECOMMENDED DOSE (RD) • Total of 55 mCRC patients across UK & Australia • 38 in monotherapy, 17 in 5-FU/LV combination • Median DEP® SN38 cycles = 4 (range 1-29) CT Scans of Lung Metastasis 31.3% reduction in target lesion BASELINE WEEK 27 38-year-old woman with Stage IV CRC All mCRC • Other exceptional mCRC responders were observed in this study, with disease control of 59 weeks and several of 53 weeks. • The favorable safety profile without corticosteroid/atropine pre-medication, reduced GI toxicity, and absence of cholinergic symptoms compared to irinotecan, along with the encouraging anti- tumor efficacy, warrant further studies with DEP® SN38 to support its promising clinical utility in mCRC. Exceptional responders Demonstrate the promising potential of DEP® SN38: • Durable anti-tumour responses (26-72 weeks) • Disease controlled with a partial response • Very well tolerated in a patient who could not tolerate conventional irinotecan • Excellent tolerability also observed in a UGT1A1*28 homozygous mutant patient who is at risk of increased systemic exposure to SN38 • Improvement of quality of life compared to prior experience of standard of care EU Clinical Trials Register EudraCT: 2019-001318-40 B D A E C -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0 50 100 150 200 250 300 350 400 450 500 550 Change from baseline % Days Tumour target lesion response Scan for more trial information from ASCO 2024 EU Clinical Trials Register EudraCT: 2019-001318-40

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