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Bicycle Therapeutics Investor Presentation • July 30th, 2026
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This presentation may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words or similar expressions that are intended to identify forward-looking statements. All statements other than statements of historical facts contained in this presentation are forward-looking statements, including statements regarding: our future financial or business performance, conditions, plans, prospects, or strategies and other financial and business matters, including expected financial runway; our current and prospective product candidates, planned regulatory interactions and submissions, the progress of and data from clinical trials and preclinical activities, current and prospective collaborations; the timing and success of our development of our current and prospective product candidates; the safety and efficacy profiles of our product candidates; the ability of our platform to identify and pursue novel targets and the timing of data related thereto, including imaging data; our ability to create an end-to-end radioisotope and radiopharmaceutical supply chain; and our ability to leverage related collaborations and partnerships in furtherance of this and other efforts; and the size and composition of the potential markets for any of our product candidates, if approved. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our preclinical and clinical results, our plans to initiate clinical trials and the designs of the planned trials and other future conditions, and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of our product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials or preclinical activities, the risk that we may not realize the intended benefits of our technology, including that we may not identify and develop additional product candidates for our pipeline, the risk that we may not maintain our current partnerships or enter into new partnerships in the future, or that we may not realize the intended benefits of these partnerships, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety and efficacy profiles that we anticipate, the risk that prior results will not be replicated or will not continue in ongoing or future studies or trials, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and potential of the markets for our product candidates will not materialize as expected, risks associated with our dependence on third parties, risks regarding the accuracy of our estimates of expenses and financial runway, risks relating to our capital requirements and needs for additional financing, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in our Quarterly Report on Form 10-Q, filed with the Securities and Exchange Commission (the “SEC”) on July 30, 2026, as well as in other filings we may make with the SEC in the future, as well as discussions of potential risks, uncertainties and other important factors in our subsequent filings with the SEC. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. This presentation does not constitute an offer to sell or a solicitation of an offer to buy securities, nor shall there be any sale of any securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. Forward-looking statements • 2
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Bicycle Therapeutics: Pioneering a new, differentiated class of innovative medicines Deeply experienced team Located in Cambridge, UK, and Lexington, MA NASDAQ: BCYC Cash and cash equivalents of $510.1 million as of June 30, 2026, with expected financial runway into 2030 Focused on oncology, with multiple clinical molecules Nuzefatide pevedotin targeting historically undruggable target with ADCs, in a Phase 2 PDAC trial Radioligand pipeline addressing novel cancer targets MT1-MMP and EphA2 Zelenectide pevedotin demonstrating differentiated safety profile and strong antitumor activity in mUC Extending use of platform into diverse range of therapeutic areas such as radioligands and non-core areas such as neurology Developing Bicycle® molecules – a novel synthetic peptide modality that can potentially deliver any payload to any target Technology based on Nobel Prize-winning science Strong intellectual property portfolio Unique Platform Internal Programs Validating Partnerships Ambitious Company • 3EphA2: Ephrin A2; MT1-MMP: Membrane type 1 matrix metalloproteinase; mUC: metastatic urothelial cancer; PDAC: pancreatic ductal adenocarcinoma; ADC: Antibody Drug Conjugate
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Bicycle® molecules are short peptides chemically constrained with a central scaffold that can induce diverse structures • 4 Scaffold Chemical modification with scaffold Short linear peptide + Bicycle® molecule
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Bicycle® platform delivers a toolkit of modular building blocks to create novel precision-guided medicines Targeting and Effector Bicycle® molecules Bicycle® Phage Display Discovery Peptide & Medicinal Chemistry Bicycle® moleculeLinear peptide Diverse Bicycle® phage libraries (>1020) Optimize Bicycle® monomers Non-natural Amino Acids Build and Optimize Therapeutic Bicycle® molecules Easy conjugation of Linkers and Payloads Natural Amino Acids Potential Bicycle® Medicines Bicycle® Drug Conjugates Multi-specific Bicycle® molecules Monomeric Bicycle® molecules • 5 Bicycle Radioligands
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• 6PK: pharmacokinetics. Better targeting Better tolerability Better combinability Better outcomesPOTENTIAL: Bicycle® molecules have optimal properties for precision- guided therapeutics
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Target Program Study Indication Pre-clinical IND enabling/ human imaging Clinical Internal oncology programs EphA2 nuzefatide pevedotin (BDC® molecule) Ph2 open label PDAC 68Ga BIA molecule Utility study Solid tumors EphA2 BRC® molecule Pre-clinical Solid tumors MT1-MMP 68Ga BIA molecule Utility study Solid tumors BT1702 (BRC® molecule, 212Pb) IND enabling Solid tumors Nectin-4 zelenectide pevedotin (BDC® molecule) Duravelo-2 Ph2 combo with pembrolizumab 1L mUC 2L mUC Additional targets Undisclosed Pre-clinical Solid tumors Partnered programs PLN ION826/AZD4063 Phase 1 Cardiometabolic disease We are building a robust pipeline of Bicycle therapeutics • 71L: 1st line; 2L+: 2nd line or later; IND: Investigational New Drug; mUC: metastatic urothelial cancer; PDAC: pancreatic ductal adenocarcinoma; BIA: Bicycle® Imaging Agent; BDC®: Bicycle® Drug Conjugate: BRC®: Bicycle® Radioconjugate; Bicycle TICA® : Bicycle tumor-targeted immune cell agonist®; PLN: phospholamban gene
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Nuzefatide pevedotin, a potential first-in-class EphA2 targeting BDC® molecule
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• 9 Highly differentiated preclinical and clinical performance: Novel, potent and selective small peptide Targets EphA2 without treatment-limiting toxicity seen with ADCs Differentiated pharmacology to deliver validated payload ADC: antibody drug conjugate; EphA2: ephrin type-A receptor 2; kDa: kilodalton; MMAE: monomethyl auristatin E CONFIDENTIALCONFIDENTIAL EphA2 background • Highly expressed in many tumor types - Pancreas, head and neck, bladder • All antibody-based approaches have failed due to severe toxicity or lack of efficacy • There are currently no approved drug conjugates targeting EphA2 Nuzefatide pevedotin Selective Bicycle® molecule to EphA2 antigen Protease cleavable linker Toxin (MMAE), shielded when bound to BDC ® molecule ~4 kDa vs ~150+ kDa for ADCs Nuzefatide pevedotin is a Bicycle® drug conjugate (BDC®) that targets EphA2, a target so far undruggable with ADCs due to severe toxicities
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Multiple antibody-based approaches to target EphA2 have been unsuccessful due to toxicity or lack of efficacy 1Annunziata et al, Invest New Drugs. 2013, 31(1): 77-84; 2Atreca Inc., press release Nov 10, 2022; 3Merrimack Pharmaceuticals Inc., press release April 4, 2019; 4Gan et al, Invest New Drugs. 2022, 40(4): 747-755; 5Shitara et al, Journal for ImmunoTherapy of Cancer. 2019, 7(1): 219-230. EphA2: ephrin type-A receptor • 10 Molecule MEDI-547 (MedImmune) ATRC-301 (Atreca) MM-310 (Merrimack) DS-8895a (Daiichi Sankyo) Format Antibody drug conjugate Antibody drug conjugate scFv antibody fragments conjugated to docetaxel-based liposomes Afucosylated antibody Development status Discontinued during phase 1 Discontinued preclinically Discontinued during phase 1 Discontinued after phase 1 “The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events”1 Non-human primate toxicology study “revealed safety signals, including bleeding”2 “Phase 1 study unable to reach optimal therapeutic index” due to “cumulative peripheral neuropathy”3 “Limited therapeutic efficacy at doses evaluated and 89Zr-DS- 8895a demonstrated low tumor uptake.”4,5 Successfully targeting EphA2 could provide new ways to address unmet need across tumor types
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Patient demographics and clinical characteristics for nuzefatide pevedotin in key dose range finding cohorts Data as of 09Feb2026 from Study BT5528-100. ECOG PS: Eastern Cooperative Oncology Group performance status; FGFR: fibroblast growth factor receptor; nivo: nivolumab; nuzefa: nuzefatide pevedotin; Q2W: once every two weeks; Q4W: once every 4 weeks Patient characteristic All patients (N=161) Nuzefa 6.5 mg/m2 Q2W (n=74) Nuzefa 8.0 mg/m2 Q2W (n=12) Nuzefa 6.5 mg/m2 Q2W + nivo 480 mg Q4W (n=14) Age, median years (range) 63 (33–83) 63 (33-78) 61 (48-74) 69 (56–83) Sex, n (%) Male Female 71 (44) 90 (56) 34 (46) 40 (54) 7 (58) 5 (42) 11 (79) 3 (21) Race, n (%) White Black or African American Other 129 (80) 5 (3) 27 (17) 55 (74) 0 19 (26) 12 (100) 0 0 13 (93) 0 1 (7) Baseline ECOG PS, n (%) 0 1 66 (41) 95 (59) 30 (40) 44 (60) 5 (42) 7 (58) 8 (57) 6 (43) Tumor type, n (%) Urothelial Non-small cell lung Head and neck Pancreas 51 (32) 14 (9) 17 (11) 9 (6) 20 (27) 9 (12) 8 (11) 1 (1) 3 (25) 0 9 (75) 0 14 (100) 0 0 0 Prior lines of therapy in the locally advanced/metastatic setting, median (range) 3 (1–13) 3 (1–13) 2 (1–5) 2 (1–6) Prior therapy, n (%) Checkpoint inhibitor Platinum Antimetabolite Antibody-drug conjugate Taxane Antineoplastic FGFR inhibitor 95 (59) 146 (91) 115 (71) 36 (22) 100 (62) 49 (30) 6 (4) 44 (60) 66 (89) 53 (72) 16 (22) 50 (68) 23 (31) 2 (3) 11 (92) 11 (92) 8 (67) 2 (17) 8 (67) 3 (25) 0 14 (100) 13 (93) 12 (86) 11 (79) 1 (7) 2 (14) 2 (14) • 11
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Nuzefatide pevedotin is generally well tolerated at clinically active doses both as a monotherapy and in combination with nivolumab Category, n (%) All patients (N=161) Nuzefa 6.5 mg/m2 Q2W (n=74) Nuzefa 8 mg/m2 Q2W (n=12) Nuzefa 6.5 mg/m2 Q2W + nivo 480 mg Q4W (n=14) TEAEs Grade ≥3 157 (98) 87 (54) 70 (95) 35 (47) 12 (100) 7 (58) 14 (100) 11 (79) TESAEs Grade ≥3 52 (32) 47 (29) 17 (23) 16 (22) 3 (25) 3 (25) 8 (57) 8 (57) TRAEs Grade ≥3 143 (89) 42 (26) 68 (92) 16 (22) 12 (100) 3 (25) Nuzefa-related Nivo-related 12 (86) 4 (29) 10 (71) 3 (21) TRSAEs Grade ≥3 14 (9) 12 (8) 6 (8) 5 (7) 0 0 1 (7) 1 (7) 2 (14) 2 (14) Dose modifications TEAEs leading to dose reduction TEAEs leading to drug interruption TEAEs leading to drug withdrawn 18 (11) 68 (42) 4 (3) 2 (3) 18 (24) 2 (3) 3 (25) 5 (42) 0 Nuzefa Nivo 2 (14) 10 (71) 0 0 6 (43) 2 (14) Data as of 09Feb2026 from Study BT5528-100. Nivo: nivolumab; nuzefa: nuzefatide pevedotin; Q2W: once every 2 weeks; Q4W: once every 4 weeks; TEAE: treatment-emergent adverse event; TESAE: treatment-emergent serious adverse event; TRAE: treatment-related adverse event; TRSAE: treatment-related serious adverse event. Very few adverse events led to the withdrawal of nuzefatide across the dose range finding cohorts • 12
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TRAEs of clinical interesta,b n (%) Nuzefatide Exposed Patients (N=161) Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Peripheral neuropathyc 31 (19.3) 20 (12.4) 11 (6.8) 0 0 0 Skin reactionsd 23 (14.3) 20 (12.4) 3 (1.9) 0 0 0 Neutropeniae 13 (8.1) 0 8 (5.0) 0 5 (3.1) 0 Eye disordersf 5 (3.1) 4 (2.5) 1 (0.6) 0 0 0 Hemorrhageg 0 0 0 0 0 0 Data as of 09Feb2026 from Study BT5528-100. aIncludes AEs related to nuzefa; bPatients can have multiple PT within a category; cBased on MedDRA SMQ [Broad] for peripheral neuropathy; dIncludes the MedDRA SMQ [broad] for Severe Cutaneous Adverse Reactions (SCAR) and MedDRA SOC of Skin and Subcutaneous Tissue disorders, excluding alopecia; ePreferred term neutropenia; fSOC of Eye disorders; gHemorrhage (excluding laboratory terms) [narrow] SMQ. 2L+: second line and beyond; ADC: antibody drug conjugate; MedDRA: Medical Dictionary for Regulatory Activities; PDAC: pancreatic ductal adenocarcinoma; PT: Preferred Term; SMQ: Standardized MedDRA Queries; SOC: system organ class; TRAE: treatment-related adverse event. Conclusion • Nuzefatide demonstrated an acceptable safety profile across dose levels as a monotherapy and in combination with nivolumab Next steps • Explore potential in 2L+ PDAC Nuzefatide shows a differentiated safety profile with no bleeding to date and few Grade 3 toxicities associated with ADCs • 13CONFIDENTIAL
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Nuzefatide pevedotin monotherapy is active across a range of EphA2+ tumor types in the late line setting • 14 Data as of 09Feb2026 from Study BT5528-100. EphA2: ephrin type-A receptor 2; GI: gastrointestinal; H&N: head and neck carcinoma; NSCLC: non-small cell lung cancer; nuzefa: nuzefatide pevedotin; Q2W: once every 2 weeks; TNBC: triple-negative breast cancer; TPS: Tumor Proportion Score EphA2 IHC status − (TPS ≤1) + (TPS >1) Waterfall plot by EphA2 status 6.5 mg/m2 nuzefa Q2W in dose expansion Efficacy evaluable analysis set No sample -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Urothelial (N=11) Ovarian (N=12) Gastric/ Upper GI (N=6) H&N (N=7) NSCLC (N=7) TNBC (N=9)
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Nuzefatide has exquisite selectivity for EphA2 over other Eph family members Membrane protein array: no binding of nuzefatide @1µM to 5,527 other proteins, including Fc receptors Nuzefatide human PK shows delivery & retention of payload in tumor, with rapid clearance from circulation • 15 Nuzefatide pevedotin binds only to EphA2, and clinically shows rapid delivery and tumor retention with limited systemic exposure ADC: antibody drug conjugate; EphA2: ephrin type-A receptor 2; Fc receptor: fragment crystallizable receptor; PK: pharmacokinetics Nuzefatide has a differentiated profile from ADCs that often bind to additional Fc receptors and proteins Ligand-binding domain Binding affinity (SPR KD nM) EphA2 1.2 EphA1 >5000 EphA3 >5000 EphA4 >5000 EphA5 >5000 EphA6 >5000 EphA7 >5000 EphB4 >5000 Nuzefatide only binds EphA2 Human PK following treatment with nuzefatide at 5 mg/kg, the estimated minimum efficacious dose (MED) Tumor 10x plasma at 24h
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EphA2 is a widely expressed tumor antigen with highest expression in pancreatic cancer 1Bicycle Therapeutics unpublished data. CRC: colorectal cancer; CST: Cell Signaling Technology; EphA2: ephrin type-A receptor 2; GEJ; gastroesophageal; HNSCC: head and neck squamous cell carcinoma; mAb; monoclonal antibody; TMA; tumor tissue microarray; TPS: Tumor Proportion Score • 16 EphA2 is expressed in a range of high value tumors including pancreas, HNSCC and urothelial Data generated internally using commercial TMA samples and CST mAb (clone D4A2), detecting the intracellular domain of EphA21 Indication % TPS ≥1 Mean H-score Pancreas 63.4% (59/93) 74.7 HNSCC 61.4% (43/70) 19.9 Bladder 50.0% (28/56) 34.8 Rectal adeno 47.3% (43/91) 44.7 Esophagus 37.1% (26/70) 38.8 Melanoma 36.7% (29/79) 88.8 GEJ 28.0% (23/82) 12.6 CRC 25.2% (35/139) 35.3 All data shown uses EphA2 CST 6997 mAb (Cell Signaling Technology) to detect the intracellular domain of EphA2 using commercially available tissue microarray (TissueArray) and whole slides (Discovery Life Science). TPS ≥ 1 (membrane and/or cytoplasmic) was used to determine positivity
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115 out of 18 patients; 68Ga: Gallium-68 radioactive positron-emitting radioisotope; EphA2: ephrin type-A receptor 2; PDAC: pancreatic ductal adenocarcinoma; PDX: patient- derived xenograft; TPS: Tumor Proportion Score EphA2 is a clinically validated target, and the Bicycle advantage can potentially apply in pancreatic cancer • 17 EphA2 PDAC expression PDAC sensitivity to MMAE Patient identification strategy Bicycle advantage in PDAC Highly expressed in PDAC TPS>1 (>60% of PDAC) Bicycle approach overcomes high intra-tumoral pressure & dense stroma 68Ga BIA5501 >80%1 EphA2 +ve in human imaging PDAC PDX models responsive to MMAE SUV values showing tracer uptake in patient with lymphonodal and hepatic metastasized pancreatic ductal adenocarcinoma
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We are exploring nuzefatide pevedotin in a Phase 2 2L+ pancreatic cancer study 1Bicycle Therapeutics unpublished data. 2L: second-line; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EphA2: ephrin type-A receptor 2; ORR: objective response rate; PDAC: pancreatic ductal adenocarcinoma; Q2W: once every 2 weeks; RECIST: Response Evaluation Criteria in Solid Tumors. BT5528-201 Schema Eligibility • Metastatic recurrent PDAC* • Failed one current line of therapy • Measurable disease on RECIST v1.1 • ECOG PS 0 or 1 • Taxane naïve • Evaluable archival or fresh tumor biopsy If ≥ 4 responses proceed to stage 2 BT5528 8 mg/m2 Q2W (n=25) Stage 2Stage 1 BT5528 8 mg/m2 Q2W (n=9) If 2 or 3 responses the study may also proceed if efficacy signal seen in an EphA2+ subgroup BT5528 8 mg/m2 Q2W (n=14 EphA2+) Prescreening required Primary Endpoint • ORR by investigator using RECIST v1.1 *Metastatic recurrent PDAC 2L+ to include any KRASi in either 1L or 2L 8 mg/m2 Q2W selected as preferred monotherapy dose based on acceptable safety profile and enhanced ability to deliver payload to tumor1 • 18
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Pancreatic cancer could provide an important opportunity for nuzefatide pevedotin to bring a first-in-class treatment to patients Considered a silent killer due to the asymptomatic nature of the disease Position of the pancreas limits clinical symptoms until tumors reach more advanced stages Poor prognosis due to lack of early diagnosis, quick dissemination to distant sites, and high resistance to current systemic therapies4,5 Stages 0-IV Annual Incidence (Stages 0-IV)1,2,3 Rank among all cancers (Incidence) 510,992 Worldwide 65,176 United States 12 Worldwide 11 United States 5-year Survival 11% / 3% Stage IV Patients diagnosed at advanced stage 80% 1Oracle Life Sciences CancerMPact, Treatment Architecture US Pancreatic Cancer, Sep 2025. Sources: Based on CancerMPact® Patient Metrics U.S., accessed Feb 2025. Ranking is based on relative incidence of 32 tumors in the US; 2World Health Organization, International Agency for Research on Cancer: Cancer Fact Sheet, Pancreas (gco.iarc.who.it) 3Li, Lancet, 2004 4NCCN Guidelines Pancreatic Adenocarcinoma, Version 2, 2025; 5Zhou, Int J Cancer, 2017. • 19 Pancreatic cancer
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The pancreatic treatment landscape is shifting rapidly, but nuzefatide pevedotin may uniquely provide benefit for patients 1L: first-line; 2L: second-line; 3L: third-line; 5-FU: fluorouracil; BSC: best supportive care; FOLFIRINOX: folinic acid (leucovorin), 5-FU, irinotecan, and oxaliplatin; FOLFOX: leucovorin, 5- FU and oxaliplatin; GnP: gemcitabine/nab-paclitaxel; NALFIRINOX: liposomal irinotecan (Onivyde), 5-FU, leucovorin, and oxaliplatin; PS: Performance Status; RASi: pan-RAS (rat sarcoma) inhibitor FOLFOX/liposomal irinotecan + 5-FU/BSC BSC Gemcitabine + nab-paclitaxel [prior Irinotecan] FOLFIRINOX/Nalirinox [PS 0-1] Liposomal irinotecan + 5-FU/FOLFOX [prior GnP] 1L metastatic pancreatic 2L metastatic pancreatic 3L metastatic pancreatic Gemcitabine + nab-paclitaxel [PS 0-2] Treatments Gemcitabine/BSC [PS 3] Pan-RASi in 2L expected by 2H 2026 Potential entry for nuzefatide • Use in patients that develop RASi resistance as treatment landscape evolves • Given rechallenge is seen to have limited benefit 1, targeted delivery of MMAE offers distinct payload • Differentiated safety profile allows opportunity for patients exposed to 1-2 lines of prior treatment Potential benefits of nuzefatide pevedotin in 2L+ setting include: 1Putnam key opinion leader insight market research conducted December 2025. • 20
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Bicycle® radioligand pipeline
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Pursue novel targets with first-in-class potential Platform proven to identify novel peptide ligands Use early imaging data to direct indication selection for BRC® and BDC® molecules and build programs in a data- driven manner Enable optimal clinical and commercial positioning of BRC® molecules Our strategy in radiopharmaceuticals is to be a next- generation player with sustainable access to all isotopes • 22 Enhanced Patient Benefit • Longer responses • Deeper/Broader responses Partner with leaders in the field Build our understanding through strategic partnerships Partner with academia to deepen our knowledgebase Build unique internal portfolio guided by KOLs Use the isotope best suited for the target Test BRC® molecules with a range of isotope payloads and select the best Establish arrangements with leading isotope suppliers & manufacturers Scale to support broad portfolio of clinical applications
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Highly selective and tumor penetrant Minimal systemic exposure Pipeline of Bicycle molecules to novel tumor antigens Selective Bicycle molecule to tumor antigen Stable linker-chelator system Chelated radioisotope Bicycle® molecule advantages for delivering cytotoxic payloads are also advantages for delivering radioisotopes • 23
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Bicycle® radioligands show selective tumor uptake and ideal PK across a range of targets and tumor models • 24 Left: HT1080 tumor model, 2h P.I. (DKFZ unpublished data) Right: HT1080 tumor model, 40 to 60 min P.I. Eder M et al. 2019. Cancer Res. 79(4):841-852 Left: MMTV-PyMT transgenic mouse model, 2h P.I. Right: Panc-1 orthotopic tumor model 1h P.I. Sharma AK et al. 2023. Cancer Res, 83(7 Suppl):2768 Left: MOLP8 tumor xenograft, 90 min P.I. Right: MOLP8 disseminated tumor model (Sharma AK et al. BioRxiv) MT1-MMP EphA2 CD38 Fibrosarcoma Pancreatic Multiple myeloma T T T T Breast T
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MT1-MMP is a novel target in the treatment of cancer • 25 Tumor Type Number of cases tested MT1-MMP positive Lung squamous 76 59% Bladder 96 56% Esophageal 66 55% Triple negative breast cancer 81 43% Ovarian cancer 82 11% Lung adenocarcinoma 69 9% MT1-MMP expression was determined using IHC performed with in house validated antibody, positive cases were defined as H-score ≥ 50 in tumor cell membrane. Membrane type 1 matrix metalloproteinase (MT1-MMP) Overexpressed in variety of cancers and associated with poor prognosis Potential first-in-class opportunity 1. Gelb T et al. 2019. Mol Cancer Ther, 18(12_Suppl):A047. 2. Eder M et al. 2019. Cancer Res. 79(4):841-852. Early MT1-MMP-targeting BIA molecules show high tumor enrichment in PET imaging studies Whole-body maximum intensity projection of 68Ga-labeled BIA molecule targeting MT1-MMP 60 min. p.i. obtained from PET/MR imaging BIA: Bicycle® Imaging Agent
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First human MT1-MMP imaging representative of data seen so far in 12 patients with various solid tumors • 26 MT1-MMP-PET/CT imaging in advanced pulmonary adenocarcinoma. Maximum intensity projections of [18F]FDG-PET/CT (A) and [68Ga]Ga-BCY25286 PET/CT at 60 mins (B) and at early time points (C) post injection. MT1-MMP-PET/CT imaging in breast and urothelial cancer. Maximum intensity projection of [68Ga]Ga-BCY25286 PET imaging (A) with representative axial PET/CT fusion slices (B-D) and corresponding immunohistochemistry staining (H&E, MT1-MMP-specific) showing the primary breast cancer (B) and bladder cancer (C) with both lymph node and bone metastases in the left sacral bone (D; white arrows). Immunohistochemistry confirmed membranous or stromal MT1-MMP expression in the primary breast cancer, bladder cancer and lymph node metastasis.
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Generation of an MT1-MMP BRC® molecule with potential theranostic applications • 27 10 -11 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 Compound Affinity (KD, M) 20 pM 1000x affinity improvement Binding properties 20 nM Binding affinities of compounds synthesized during lead optimization, as determined by surface plasmon resonance. Structurally enabled A co-crystal structure of MT1-MMP protein and bicyclic peptide was obtained and used to study molecular interactions and guide chemical optimization Kidney uptake / retention 111In SPECT images of early (left) versus optimized (right) BRC® molecules 24 hours post injection. Optimized BRC® molecule shows reduced payload levels in the kidneys and maintains high payload levels in the tumor. Lead optimization
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Our next radioligand target: EphA2, a first-in-class opportunity • 28 EphA2 overexpression associated with higher grade and/or stage in a variety of cancers1,2 Moved into human imaging in 2025 Example SPECT/CT Maximum Intensity Projection (MIP) 60 min. p.i. of 230 pmol of [111In]In labeled BRC® molecule 1. Zhou L et al. 2021. Int J Clin Exp Pathol, 14(4):484-492. 2. Cioce M and Fazio VM. 2021. Cancers (Basel), 13(4):700. High tumor uptake and low uptake in non-tumor tissues EphA2 expression was determined using IHC with pAb (RnD AF3035) on tissue microarrays. Positive cases were defined as TPS score >1 in tumor membrane or cytoplasm. For lung cancer, only samples annotated for adenocarcinoma or squamous subtype were included. TMAs included: Pancreatic - PA2081b, Bladder - BL2082a, Head and Neck - HN803f, Lung squamous – LC1921b and ATGC1118, Stomach - ST1001a, Ovarian - BC11115c, Esophageal - ES2081, TNBC - BR1301, Lung adenocarcinoma – LC706b, LC1921b, and ATGC1118. Cores with ambiguous results were removed. Top 6 indications were listed. Tumor Type Number of cases tested EphA2 positive Pancreatic 80 60% Bladder 139 58% Head and Neck 61 46% Lung squamous 88 30% Stomach 57 30% Ovarian 73 29%
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68Ga-labeled EphA2 targeted bicycle imaging agent demonstrates target expression and availability for Bicycle engagement Maximum intensity projection (left) acquired 45 minutes p.i.. Fused axial PET/CT images (right) 45 minutes p.i. showing pancreatic tumor mass (green arrow), hepatic metastases (white arrows) and lymphonodal metastases (red arrows). Patient with lymphonodal and hepatic metastasized pancreatic ductal adenocarcinoma imaged with 68Ga- labeled EphA2 targeted bicycle peptide Standardized uptake values in primary tumor, metastases and physiologic uptake • Demonstrates feasibility of payload delivery to primary and metastatic lesions in patients with PDAC through EphA2 targeting • Rapid visualization of primary tumor/metastases within 15 minutes of tracer injection • Potential diagnostic tool for EphA2-positive malignancies, facilitating personalized treatment strategies 68Ga: Gallium-68 radioactive positron-emitting radioisotope; CT: computed tomography; EphA2: ephrin type-A receptor 2; PDAC: pancreatic ductal adenocarcinoma; PET: positron emission tomography; SUV: standardized uptake values Primary Liver mets Lymph node mets Liver Muscle Blood Pool 0 5 10 15 20 SUV Tumor uptake (SUVmax) Physiological uptake (SUVmean) SUV values showing tracer uptake in patient with lymphonodal and hepatic metastasized pancreatic ductal adenocarcinoma • 29
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Radioisotope supply chain is core to our next-generation radio-oncology ambition, enabled by our strategic partners •Access to broad range of next-generation radioisotope payloads to maintain leadership opportunity •Potential world-leading radioisotope supply chain •Bespoke 212Pb generators being developed exclusively for Bicycle Therapeutics by SpectronRx, with initial quantities of 212Pb successfully produced • 30
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We are building a pipeline of next-generation radioligands to address currently intractable targets • 31FTIH: first time in humans; IND: Investigational New Drug Application; BIA: Bicycle® Imaging Agent; BRC®: Bicycle® Radioconjugate Target Molecule Preclinical Human Imaging / IND enabling Next Milestone MT1-MMP 68Ga BIA molecule BT1702 (BRC®, 212Pb) FTIH 2027 EphA2 68Ga BIA molecule BRC® molecule FTIH 2028 Additional Targets BIA molecule BRC® molecule
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Zelenectide pevedotin, a Nectin-4 targeting Bicycle® Drug Conjugate (BDC®)
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Zelenectide is designed to provide strong efficacy while reducing the significant toxicity associated with Nectin-4 drug conjugates • 33 Selective Bicycle® molecule to Nectin-4 antigen Protease cleavable linker Toxin (MMAE), shielded when bound to Bicycle® molecule Highly differentiated preclinical and clinical performance: Superior selectivity Excellent activity in multiple tumor models Reduced peripheral neuropathy, skin and eye toxicity 1Powles et al. NEJM 2024;390(10):875-888. 2PADCEV label accessed 11May2026. 3Zelenectide pevedotin Demand Study, The Link Group, Dec 2025 . 1L: first line therapy; ADC: antibody drug conjugate; BDC: Bicycle Drug Conjugate; kDa: kilodalton; MMAE: monomethyl auristatin E; mUC: metastatic urothelial cancer; SJS: Stevens Johnson Syndrome; TENS: toxic epidermal necrolysis; SOC: standard of care; IO: Immuno-oncology agent. Nectin-4 background • Highly expressed in many tumor types - Bladder, lung, breast • Nectin-4 MMAE ADC combined with IO is considered the SOC in 1L mUC • Despite strong efficacy with the SOC, high rates and grades of adverse events limit some patients with mUC from receiving or staying on the SOC1,2,3 Zelenectide pevedotin ~4 kDa vs ~150+ kDa for ADCs
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Zelenectide + pembrolizumab shows an encouraging response in 1L untreated mUC similar to published efficacy for standard of care Data as of 23Jul2025 from Study BT8009-230. aFour patients had no measurable disease at baseline per BICR and were excluded from the efficacy analysis. bThree patients had no post-baseline sum of diameter target lesion measurements. A total of 23 patients are included in the waterfall and spider plots. Asterisks denote ongoing on treatment. cSubsequent to the data cut, an additional confirmed response was observed, which would result in 62% overall response rate. The confirmed ORR at time of the data cut was 58% [95% CI 36.9-76.6]. BICR, blinded independent central review; cORR, confirmed objective response rate; CR, complete response; mUC: metastatic urothelial carcinoma; pembro, pembrolizumab; PD, progressive disease; PR, partial response; SD, stable disease; zele, zelenectide pevedotin. • 34 Responses in evaluable patients treated with zele 6 mg/m2 D1/8 + pembro by BICR (n=23)a,b • 62% cORR subsequent to data cut (n=26)a, c • Median duration of zele treatment at 6 mg/m2 was 6.3 months (range, 0.7-10.6) • 65% (15/23) of patients remained on treatment at time of analysis
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In the same data set, zelenectide plus pembrolizumab also shows a differentiated safety profile in 1L untreated mUC Data as of 23Jul2025 from Study BT8009-230. aIncludes AEs related to zele or zele + pembro of any grade that occurred in ≥20% of patients or of Grade ≥3 that occurred in ≥5% of patients in the 5 mg/m2 D1/8/15 or 6 mg/m2 D1/8 dose optimization arm. Patients with multiple AEs are counted only once by the worst NCI-CTCAE category within a preferred term. AE: adverse event; D: day; la/mUC: locally advanced/metastatic urothelial carcinoma TRAE: treatment-related adverse event; zele: zelenectide pevedotin • 35 40.0 6.7 3.3 10.0 3.3 6.7 90.0 33.3 33.3 23.3 20.0 20.0 16.7 16.7 13.3 10.0 6.7 6.7 3.3 0 20 40 60 80 100 Overall Decreased appetite Diarrhea Alopecia Anemia Nausea Neuropathy peripheral Neutropenia Asthenia Neutrophil count decreased Dysgeusia Peripheral sensory neuropathy Pneumonia AE Incidence (%) Zele-related AEs Zele 6 mg/m2 D1/8 + Pembro (N=30)a Grades 1-2 Grade ≥3 Zele + pembro at optimal dose in previously untreated la/mUC • Median relative dose intensity in patients receiving 6 mg/m2 was 97.0% • Zele-related AEs were mostly Grades 1-2 • Only 1 patient discontinued zele due to a zele-related AE • Median duration of follow-up was 7.0 months (range, 1.2-10.5)
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Conclusion • Zelenectide + pembrolizumab demonstrates similar clinical efficacy to published data for standard of care in 1L untreated mUC but does not show the same safety risk Next steps • Randomized Phase 2 data in 2H 2026 will determine most appropriate path for zelenectide Data as of 23Jul2025 from Study BT8009-230. aIncludes AEs related to zele or zele + pembro. bPatients can have multiple preferred terms within a category. cMedDRA SMQ [Broad] for peripheral neuropathy. dMedDRA SMQ [broad] for SCAR and high level terms of ‘bullous conditions,’ ‘dermatitis and eczema,’ ‘rashes, eruptions and exanthems NEC,’ ‘erythemas,’ and ‘dermatitis ascribed to specific agent.’ eSOC of eye disorders. fPreferred Term D1/8: day 1 and day 8 Zele-related AEs of clinical interest, n (%)a,b Zelenectide 6 mg/m2 D1/8 + Pembrolizumab (N=30) Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Peripheral neuropathyc 11 (36.7) 6 (20.0) 4 (13.3) 1 (3.3) 0 0 Sensory events 10 (33.3) 6 (20.0) 3 (10.0) 1 (3.3) 0 0 Motor events 1 (3.3) 0 1 (3.3) 0 0 0 Skin reactionsd 5 (16.7) 3 (10.0) 2 (6.7) 0 0 0 Eye disorderse 3 (10.0) 3 (10.0) 0 0 0 0 Hyperglycemiaf 0 0 0 0 0 0 Zelenectide + pembrolizumab has a differentiated safety profile with no severe skin toxicity and few Grade 3 toxicities observed • 36CONFIDENTIAL
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• 37 aData as of 01Aug25 from Study BT8009-100. bIncludes AEs related to zele, pembro, or zele + pembro. cPatients can have multiple preferred terms within a category. dIncludes TEAEs Related to Study Drug of Peripheral Neuropathy [Broad](SMQ). eIncludes the MedDRA SMQ [broad] for Severe Cutaneous Adverse Reactions (SCAR) and the following high-level terms (HLTs): “bullous conditions”, “dermatitis and eczema”, “rashes, eruptions and exanthems NEC”, “erythemas”, and “dermatitis ascribed to specific agent”. fPreferred term. gSOC of eye disorders. 1L: first line; AECI: adverse events of clinical interest; cis-ineligible: cisplatin-ineligible; ECOG PS: Eastern Cooperative Oncology Group performance status; mUC: metastatic urothelial carcinoma; m: months; NE: not estimable; QW: weekly; pembro: pembrolizumab; zele: zelenectide pevedotin Progression free survival for zelenectide 5 mg/m2 QW + pembrolizumab in 1L mUC cis-ineligible patients (N=22)a Median progression free survival 13m (95% CI 3.8-NE, N=22) In a Phase 1 trial, zelenectide + pembrolizumab exhibits similarly encouraging efficacy and safety results in 1L cisplatin-ineligible mUC TRAEs of clinical interest, n (%)b, c Patients (N=22) Any Gr Gr 1 Gr 2 Gr 3 Gr 4 Gr 5 Peripheral neuropathyd 14 (63.6) 5 (22.7) 6 (27.3) 3 (13.6) 0 0 Sensory events 13 (59.1) 4 (18.2) 6 (27.3) 3 (13.6) 0 0 Motor events 1 (4.5) 1 (4.5) 0 0 0 0 Skin reactionse 11 (50.0) 5 (22.7) 4 (18.2) 2 (9.1) 0 0 Hyperglycemiaf 5 (22.7) 4 (18.2) 1 (4.5) 0 0 0 Eye disordersg 4 (18.2) 3 (13.6) 1 (4.5) 0 0 0 Treatment-related AECIs in 1L mUC cis-ineligible patients treated with zelenectide 5 mg/m2 QW + pembrolizumab No Grade 4 or Grade 5 TRAE of clinical interest occurred Promising median progression free survival and safety profile seen in a frail population with advanced age, 32% with liver metastases, and 45% of patients characterized as ECOG PS 2
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In 2L mUC, zelenectide also shows promising efficacy results as monotherapy Data as of 14Jun2025 from Study BT8009-230. aFour patients were not included based on no measurable disease at baseline (n=2), not receiving zele (n=1), and a lack of adequate post-baseline target lesions (n=1). *Asterisks and grey arrows indicate patients continuing zele treatment, except patients with PD as their best overall response. bORR with confirmation (%) is defined as the proportion of participants with BOR with confirmation of CR or PR; 95% CI was calculated by using exact Clopper-Pearson method. BICR: blinded independent central review; CR: complete response; D: day; ORR: objective response rate; PD: progressive disease; PR: partial response; SD: stable disease; zele: zelenectide pevedotin. • 38 Efficacy-evaluable patients treated with zele 6 mg/m2 D1/8 by BICR (n=26)a Efficacy-evaluable patients treated with zele 6 mg/m2 D1/8 by BICR (n=26)a Confirmed ORR at the optimal dose was 30% [95% CI 13.8–50.2], with 8 patients remaining on treatment at time of analysis (n=27)b. Two additional patients had unconfirmed responses resulting in a 37% ORR regardless of confirmation.
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Zelenectide monotherapy potentially provides a well-tolerated treatment in 2L mUC Data as of 14Jun2025 from Study BT8009-230. aIncludes AEs related to zele of any grade that occurred in ≥20% of patients or of Grade ≥3 that occurred in ≥5% of patients in the 5 mg/m2 D1/8/15 or 6 mg/m2 D1/8 dose optimization arm. Patients with multiple AEs are counted only once by the worst NCI-CTCAE category within a preferred term. The safety-evaluable population treated with 6 mg / m2 zele excluded n=1 patient who did not receive zele. AE: adverse event; D: day; mUC: metastatic urothelial carcinoma; TRAE: treatment-related adverse event; zele: zelenectide pevedotin • 39 Zele monotherapy at optimal dose in previously treated mUC • Majority of TRAEs were Grade 1-2 • No Grade 4 or 5 TRAEs were reported in patients treated with 6 mg/m2 • No treatment discontinuations occurred at the optimal dose • Median duration of follow-up was 6.2 months (range, 0.1- 9.9) Zele-related AEs Zele 6 mg/m2 D1/8 (n=29)a 51.7 6.9 3.4 6.9 10.3 10.3 3.4 93.1 41.4 37.9 31.0 27.6 24.1 20.7 20.7 20.7 17.2 13.8 13.8 13.8 10.3 10.3 6.9 0 20 40 60 80 100 Overall Alopecia Nausea Anemia Diarrhea Fatigue Vomiting Rash Neuropathy peripheral Asthenia Decreased appetite Neutrophil count decreased Neutropenia Peripheral sensory neuropathy AST increased ALT increased TRAE Incidence (%) Grades 1-2 Grade ≥3
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Treatment-related adverse events of clinical interest were predominantly Grade 1 for zelenectide in 2L mUC Data as of 14Jun2025 from Study BT8009-230. aPatients can have multiple preferred terms within a category. bThe safety-evaluable population treated with 6 mg /m2 zele excluded n=1 patient who did not receive zele. cMedDRA SMQ [Broad] for peripheral neuropathy dMedDRA SMQ [broad] for SCAR and high levels terms of “bullous conditions,” “dermatitis and eczema,” “rashes, eruptions and exanthems NEC,” “erythemas,” and “dermatitis ascribed to specific agent.” . eSOC of eye disorders. fPreferred term. AE: adverse event; D: day; zele: zelenectide pevedotin • 40 Zele-related AEs of clinical interest, n (%) Zelenectide 6 mg/m2 D1/8 (n=29b) Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Peripheral neuropathyc 11 (37.9) 9 (31.0) 1 (3.4) 1 (3.4) 0 0 Sensory events 11 (37.9) 9 (31.0) 1 (3.4) 1 (3.4) 0 0 Motor events 0 0 0 0 0 0 Skin reactionsd 8 (27.6) 8 (27.6) 0 0 0 0 Eye disorderse 3 (10.3) 3 (10.3) 0 0 0 0 Hyperglycemiaf 1 (3.4) 0 0 1 (3.4) 0 0 • Majority of peripheral neuropathy was Grade 1 (82%, 9/11) • No motor events were reported • All skin reactions were Grade 1, and no patients reported severe skin reactions • Eye disorders were Grade 1 and only 1 patient experienced hyperglycemia
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Patients with mUC still need more treatments that allow them to live longer and live well One of the highest lifetime treatment costs per patient of all cancers3,4 High recurrence rate and ongoing invasive monitoring lead to economic and human toll of this disease3,4 Improved safety profiles are needed to bring the promise of innovative treatment options to mUC5 Stages 0-IV Annual Incidence (Stages 0-IV)1,2 Rank among all cancers (Incidence) 614,000 Worldwide 85,080 United States 10 Worldwide 6 United States 5-year Survival 64% / 7% Stage IV Patients developing metastatic disease 25% 1. Oracle CancerMPact, Treatment Architecture US Bladder Cancer, Dec 2025. Sources: Based on CancerMPact® Patient Metrics U.S., accessed Feb 2025. Ranking is based on relative incidence of 31 tumors; Risk factors from National Cancer Institute (cancer.gov), NCCN Guidelines Bladder Cancer v2.2025, ASCO’s patient information website (Cancer.Net), American Cancer Society (cancer.org). 2. World Health Organization, International Agency for Research on Cancer: Cancer Fact Sheet, Bladder (gco.iarc.who.it) 3. Journal of Urology, Adult Urology, Late Recurrences Following Radical Cystectomy Have Distinct Prognostic and Management Considerations, Sep2020. 4. European Urology, The Financial Burden of Localized and Metastatic Bladder Cancer, May2025. 5. Zelenectide pevedotin Demand Study, The Link Group, Dec 2025 mUC: metastatic urothelial cancer. • 41
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Primary reasons for prescribing alternative regimens in 1L mUC concerns about peripheral neuropathy1 concerns about safety profile1 general tolerability issues1 Despite having an efficacious standard of care in 1L mUC, oncologists still want improved regimens to help more patients • 42 Enhanced Patient Benefit • Longer responses • Deeper/Broader responses Variety of regimens are still used in 1L mUC instead of SOC … of patients receive regimens other than a Nectin-4 ADC1,2,3 … of oncologists believe there is still room for improvement in current treatments1 ~40% 86% 50% 43% 40% 1. Zelenectide pevedotin Demand Study, n = 115 medical oncologists, The Link Group, Dec 2025 2. IQVIA Oncology Real-World Data | Prepared for Bicycle Therapeutics | IQVIA Oncology Analytics Platform, Jan 2026. Unique Total 1L Patients: 14,438; Unique New 1L Patients: 9,063 3. Oracle CancerMPact, Treatment Architecture US Bladder Cancer, Dec 2025. 1L: 1st line treatment, mUC: metastatic urothelial cancer, SOC: standard of care, ADC: antibody drug conjugate
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• 43 DOSE SELECTION REGULATORY ENGAGEMENT DATA AVAILABILITY • Optimal dose of zelenectide 6 mg/m2 (D1/8) plus pembro demonstrates response rates comparable to published data for standard of care and a differentiated safety profile • Preliminary regulatory feedback (EMA, FDA, MHRA) indicates multiple potential pathways for the continued development and approval of zelenectide in mUC • Duravelo-2 study has been converted into a randomized Phase 2 trial and further results expected in the second half of 2026 D: day, pembro: pembrolizumab, EMA: European Medicines Agency, FDA: Food and Drug Administration, MHRA: Medicines and Healthcare products Regulatory Agency, mUC: metastatic urothelial cancer Duravelo-2 converted to a Phase 2 trial with results expected in 2H 2026
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Looking ahead
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• Strategic focus on novel targets and new payloads • Randomized Phase 2 trial data readout in 2H2026 and determine most appropriate path • Progress enrollment in Phase 2 trial in PDAC using 8 mg/m2 Q2W dose • Ongoing IND-enabling activities for BT1702 (BRC® molecule, 212Pb) and clinical start in 2027 • Progress EphA2 BRC molecule to clinical start in 2028 Strategic focus enables multiple potential value generating milestones • 45 2025 - Q1 2026 achievements ✓ Platform validation with zelenectide data ✓ Strategic portfolio reprioritization and focus on nuzefatide & radiotherapeutics ✓ Human imaging de-risks novel targets ✓ Established multiple strategic partnerships to create end-to-end radiopharmaceutical supply chain ✓ Strengthened leadership & Board 212Pb: Lead-212 radioactive alpha-emitting radioisotope; BRC: Bicycle® radioconjugate; EphA2: ephrin type-A receptor 2; PDAC: pancreatic ductal adenocarcinoma; Q2W: once every 2 weeks. ✓ Extended expected cash runway into 2030 Nuzefatide pevedotin Strategic priorities and anticipated milestones 2026 and beyond Bicycle radiotherapeutics Zelenectide pevedotin Novel targets and new payloads
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To help patients live longer and live well Our mission:
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Appendix
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• 48 • In the subset of patients with EphA2+ tumors that were MMAE-naïve, 3/3 achieved a confirmed partial response (ORR 100%) • In the subset of patients with EphA2+ tumors that were MMAE-naïve, as of 14 April ‘26, the minimum DoT was 53.9 weeks MMAE-naïve EphA2 IHC status − (TPS ≤1) + (TPS >1) Patients Percent change from baseline PD PD PD PD PD PD SD PD SD PR PR PR PRPD 100 80 60 40 20 0 −20 −40 −60 −100 −80 Waterfall plot for 6.5 mg/m2 nuzefatide Q2W + nivolumab in late line mUC (N=14) Prior treatment EV exposed Prior treatment type EV Naive Response category PD SDPR Weeks Percent change from baseline Ongoing Patients* 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 −100 80 60 40 20 0 −20 −40 − 60 −80 140 120 100 1 2 Spider plot for 6.5 mg/m2 nuzefatide Q2W + nivolumab in late line mUC (N=14) CONFIDENTIAL Data as of 09Feb2026 from Study BT5528-100. 1Patient treated beyond progression with symptomatic relief and bladder lesion clearance. 2Patient with a complete response in target lesions with persistent non-target lesions. DoT: duration of treatment; EV: enfortumab vedotin; LL: late line; MMAE: monomethyl auristatin E; mUC: metastatic urothelial cancer; PD: progressive disease; PR: partial response; Q2W: once every two weeks; SD: stable disease; TPS: Tumor Proportion Score; ORR: overall response rate. EphA2 IHC status Nuzefatide + nivolumab is active in EphA2+, MMAE-naïve LL mUC patients and exhibits a long duration of action Negative (TPS ≤1) Positive (TPS >1)
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Nuzefatide pevedotin is generally well tolerated at clinically active doses both as a monotherapy and in combination with nivolumab Nuzefa-related AEs reported in ≥10% of patientsa, n (%) All Patients (N=161) Nuzefa 6.5 mg/m2 Q2W (n=74) Nuzefa 8.0 mg/m2 Q2W (n=12) Nuzefa 6.5 mg/m2 Q2W + nivo 480 mg Q4W (n=14) All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3 Nausea 68 (42) 2 (1) 37 (50) 1 (1) 4 (33) 0 3 (21) 0 Fatigue 57 (35) 9 (6) 28 (38) 3 (4) 6 (50) 1 (8) 4 (29) 2 (14) Diarrhea 45 (28) 2 (1) 23 (31) 1 (1) 3 (25) 0 4 (29) 0 Anemia 35 (22) 9 (6) 15 (20) 3 (4) 6 (50) 1 (8) 3 (21) 1 (7) Vomiting 31 (19) 2 (1) 12 (16) 1 (1) 2 (17) 0 2 (14) 0 Alopecia 25 (16) 0 12 (16) 0 3 (25) 0 0 0 Decreased appetite 24 (15) 1 (1) 15 (20) 0 1 (8) 0 1 (7) 0 Aspartate aminotransferase increased 17 (11) 2 (1) 6 (8) 0 4 (33) 1 (8) 1 (7) 1 (7) Pyrexia 17 (11) 0 13 (18) 0 0 0 0 0 Headache 16 (10) 0 7 (10) 0 1 (8) 0 1 (7) 0 Data as of 09Feb2026 from Study BT5528-100. aIncludes nuzefa-related AEs reported in ≥10% of the All Patients population (N=161). AE: adverse event; nivo: nivolumab; nuzefa: nuzefatide pevedotin; Q2W: once every 2 weeks; Q4W: once every 4 weeks. • 49
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Preclinical evaluation of nuzefatide pevedotin suggests robust activity is achievable across a range of PDX PDAC models Panc163 0 200 400 600 800 Day 1 8 15 22 290 ^ ^ ^ ^ Tumor volume, mm3 Isotype control JH029 Tumor volume, mm3 0 100 200 300 400 Day 1 8 15 22 290 ^ ^ ^ ^ ^Dose EphA2 Isotype control EphA2 Human PDAC TMA show high EphA2 positivity (TPS ≥1) The majority of PDAC PDX models were sensitive to nuzefatide • Most (63%) samples in human pancreatic tumor microarray) EphA2 positive (TPS ≥1) • PA1921c : 93 cases, 179 cores, in a PDAC microarray • 6/14 EphA2 positive PDX showed high sensitivity to nuzefatide (TGI ≥100%) 43% of all PDX models were highly sensitive to 3mg/kg QW nuzefatide • 50EphA2: ephrin type-A receptor 2; N/A: not applicable; PDX: patient-derived xenograft, PDAC: pancreatic ductal adenocarcinoma; QW: once weekly; TGI: tumor growth inhibition; TMA: Tissue Microarray; TPS: Tumor Proportion Score
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Experts support ongoing development of new treatments in metastatic pancreatic cancer due to the high unmet need KOL views on unmet need¹ “Forty percent of patients are not eligible for chemotherapy. They just die within a short period of time. So, it would be good if you could find a drug which we could use for patients who are not fit enough for chemotherapy.” “If we continue to give people chemotherapy, the neuropathy that they get for the rest of their lives is a major quality of life issue.” “Once patients are treated, whether it’s chemotherapy or it’s inhibitors, at some point they become resistant. So, overcoming drug resistance is key.” 1FirstWord Therapy Trends. KOL Insight: Pancreatic Cancer. March 2026 (www.firstwordreports.com). Report covers insights from 6 KOLs in the US and 6 KOLs from Europe. 2L: second- line; KOL: key opinion leader • 51 ~50% of 2L patients succumb to their disease reinforcing the need for more treatments that can help patients live longer and live well
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Thank you