BT5528 / Bicycle Therap - LARVOL DELTA

Investigating the Clinical Performance of Zelenectide Pevedotin & BT5528 to Understand Class Effect Differences of Bicycle Toxin Conjugates Against Classical ADC Formats (ADC London 2025) - "Synopsis • Laying out the emerging safety profiles of zelenectide pevedotin and BT5528, and comparing toxicity characterisation against classical ADC formats • Delving into BT5528 clinical toxicity profile against EphA2 in contrast to ADCs against the same target • Rationalising preclinical and clinical differences with PKPD analysis and understanding the advantages of BTCs design and performance"

Clinical

Bicycle Therapeutics…Highlights 2025 Strategic Priorities and Milestones (Businesswire) - "2025 Strategic Priorities and Anticipated Milestones:...Advance targeted therapeutics pipeline addressing novel targets that have historically been challenging to treat: (i) Report Phase 1 combination data for BT5528 plus nivolumab in 4Q 2025; (ii) Report Phase 1 combination data for BT7480 plus nivolumab in 4Q 2025."

P1 data • Solid Tumor

Study BT5528-100 in Patients With Advanced Solid Tumors Associated With EphA2 Expression (clinicaltrials.gov) - P1/2 | N=288 | Recruiting | Sponsor: BicycleTx Limited | Trial completion date: Dec 2024 ➔ Oct 2026

Trial completion date • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer • CD4 • EPHA2

Study BT5528-100 in Patients With Advanced Solid Tumors Associated With EphA2 Expression (clinicaltrials.gov) - P1/2 | N=288 | Recruiting | Sponsor: BicycleTx Limited | Trial completion date: Oct 2026 ➔ Oct 2025

Metastases • Trial completion date • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • CD4 • EPHA2

Bicycle Therapeutics Reports Recent Business Progress and Third Quarter 2024 Financial Results (Businesswire) - "Bicycle Therapeutics is currently assessing BT5528 at 6.5 mg/m² every two weeks in combination with nivolumab, with results expected in 2025."

P1/2 data • Oncology • Solid Tumor

Peripheral neuropathy (PN) following treatment (tx) with bicycle toxin conjugates (BTCs) BT8009 or BT5528 monotherapy in patients (pts) with advanced solid tumors (ESMO 2024) - P1/2 | "Frequency and severity of TRPN were low following BT8009 or BT5528 monotherapy. Most events were mild to moderate, even in pts with baseline PN, required no withdrawals, and pts were often able to continue tx without modification."

Clinical • Metastases • Monotherapy • Biliary Tract Cancer • Oncology • Solid Tumor • EPHA2

EphA2-targeting bicycle toxin conjugate (BTC) BT5528 in patients (pts) with advanced solid tumors: A phase I/II study (ESMO 2024) - P1/2 | "BT5528 demonstrated acceptable safety with antitumor activity in pts with advanced solid tumors, particularly in UC, supporting further development of BT5528 as monotherapy and in combination with nivolumab in select tumor types. Mature data from the 5 mg/m2 QW cohort will be presented."

Clinical • Metastases • P1/2 data • Biliary Tract Cancer • Breast Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • EPHA2

Low rates of treatment-related peripheral neuropathy (TRPN) following monotherapy treatment with BTC molecules zelenectide pevedotin or BT5528. (Businesswire) - "In 149 patients treated with zelenectide pevedotin and 74 patients treated with BT5528 from ongoing Phase 1/2 studies, results showed...TRPN in 28% of patients treated with zelenectide pevedotin and 19% of patients treated with BT5528, nearly all of which were low grade (1-2). One Grade 3 event (neuralgia) was reported in a patient treated with zelenectide pevedotin following prior therapy with enfortumab vedotin. No Grade 3-4 events were observed for BT5528; Among zelenectide pevedotin-treated patients with peripheral neuropathy at baseline, 80% did not develop TRPN during treatment; TRPN resulted in few dose modifications across the overall patient populations for zelenectide pevedotin and BT5528, and no drug withdrawals were necessary for either BTC molecule...The data support the hypothesis that the antibody-drug construct may be a primary driver of peripheral neuropathy rather than MMAE toxicity as was previously believed."

Clinical data • Solid Tumor • Urothelial Cancer

Bicycle Therapeutics Presents Updated Clinical Results Across Oncology Pipeline at ESMO Congress 2024 (Businesswire) - P1/2 | N=288 | NCT04180371 | Sponsor: BicycleTx Limited | "Updated results from the ongoing Phase 1/2 trial evaluating 6.5 mg/m2 every two weeks and 5 mg/m2 weekly of BT5528 monotherapy in patients with advanced solid tumors showed...Among 113 efficacy-evaluable patients, a 12% ORR in patients with advanced solid tumors; The highest anti-tumor activity in mUC, with a 34% ORR in all efficacy-evaluable patients enrolled in the dose escalation and expansion cohorts. Among patients receiving 6.5 mg/m2 every two weeks, a 31% ORR was observed in the dose escalation and expansion cohort and a 45% ORR was observed in the expansion cohort only...The company has begun assessing BT5528 at 6.5 mg/m2 every two weeks in combination with nivolumab. Results from this cohort are expected in 2025."

P1/2 data • Solid Tumor

Results From First-in-Human Phase I Dose-Escalation Study of a Novel Bicycle Toxin Conjugate Targeting EphA2 (BT5528) in Patients With Advanced Solid Tumors. (PubMed, J Clin Oncol) - "BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m2 once every 2 weeks."

Journal • Metastases • P1 data • Fatigue • Hematological Disorders • Neutropenia • Oncology • Solid Tumor

Results From First-in-Human Phase I Dose-Escalation Study of a Novel Bicycle Toxin Conjugate Targeting EphA2 (BT5528) in Patients With Advanced Solid Tumors (J Clin Oncol) - P1/2 | N=288 | NCT04180371 | Sponsor: BicycleTx Limited | "Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m2 once every week to 10.0 mg/m2 once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m2 once every 2 weeks was selected as a RP2D. At 6.5 mg/m2 once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional."

P1 data • Solid Tumor

Bicycle Therapeutics Reports Recent Business Progress and Second Quarter 2024 Financial Results (Businesswire) - "Four abstracts accepted for poster presentation at the European Society for Medical Oncology (ESMO) Congress 2024 being held September 13-17 in Barcelona. Bicycle Therapeutics will present four abstracts containing updated clinical data for zelenectide pevedotin (formerly BT8009) in metastatic urothelial cancer (mUC), BT5528 in advanced solid tumors such as mUC and ovarian, and BT7480 in advanced solid tumors."

Clinical data • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

Bicycle Therapeutics Announces Four Abstracts Accepted for Presentation at the ESMO Congress 2024 (Businesswire) - "Bicycle Therapeutics plc...announced the acceptance of four abstracts for poster presentation at the European Society for Medical Oncology (ESMO) Congress 2024, taking place September 13-17 in Barcelona."

P1/2 data • Gastrointestinal Cancer • Head and Neck Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer

Breaking from the paradigm of antibody-drug conjugates: Evaluation of clinical pharmacokinetics and safety of bicycle toxin conjugates (BTCs). (ASCO 2024) - P1/2 | "BT8009 and BT5528 are BTCs linked to monomethyl auristatin E (MMAE) targeting nectin-4 and EphA2, respectively, and have shown preliminary activity. Preliminary data show substantial differences between BTC and ADC PK, and a promising BTC safety profile, possibly resulting from the distinct PK and selectivity (and specificity) of Bicycle peptides. These data highlight the potential value of BTCs as a platform for developing therapies against advanced malignancies."

Clinical • PK/PD data • Biliary Tract Cancer

Bicycle Therapeutics to Present Pharmacokinetic and Safety Evaluation of Lead BTC Molecules in Phase 1/2 Trials at the 2024 ASCO Annual Meeting (Businesswire) - P1/2 | N=288 | NCT04180371 | P1/2 | N=329 | NCT04561362 | P1/2 | N=329 | NCT04561362 | Sponsor: BicycleTx Limited | "The company also announced zelenectide pevedotin as the International Nonproprietary Name (INN) for BT8009, and U.S. Food and Drug Administration (FDA) Fast Track Designation granted to BT5528 for the treatment of adult patients with previously treated, locally advanced or metastatic urothelial cancer (mUC)....BTC molecule half-life is substantially shorter than that of EV (<1 hour vs 3.6 days), resulting in extensive elimination of the BTC molecule within hours of dose administration rather than weeks. MMAE half-life is also shorter following BTC molecule administration relative to EV (1.9 days vs 2.6 days)​, potentially due to a slower rate of MMAE release from the ADC....Zelenectide pevedotin-related adverse events (AEs) occurred in 84% of patients, of which 31% were Grade ≥3."

Fast track • P1/2 data • PK/PD data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Bicycle Therapeutics Reports Recent Business Progress and First Quarter 2024 Financial Results (Businesswire) - "Continued progress across research and development (R&D) pipeline, with numerous clinical data readouts and program updates expected in 2H 2024. Importantly, Bicycle Therapeutics initiated the Phase 2/3 Duravelo-2 registrational trial for BT8009 in mUC, and patient enrollment is ongoing. The company continues to assess BT8009, BT5528 and BT7480 in Phase 1/2 clinical trials across a variety of tumor types, and plans to provide updates from its wholly owned Bicycle Radio Conjugate (BRC) pipeline."

Clinical data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Bicycle Therapeutics Reports Recent Business Progress and Fourth Quarter and Full Year 2023 Financial Results (Businesswire) - "Execute plan to become a leader in next-generation solid tumor therapeutics and combinations, which includes: Initiating the Phase 2/3 Duravelo-2 registrational trial for BT8009 in metastatic urothelial cancer (mUC) in 1Q 2024. The trial is now active and recruiting patients. Conducting further clinical studies to assess BT8009, BT7480 and BT5528 in emerging tumors of interest, with data from these studies expected in 2H 2024. Expand opportunities in oncology, which includes: Advancing the company’s next generation of Bicycle Toxin Conjugates (BTCs). The company plans to select a BTC clinical candidate using next-generation technology in 2H 2024. Validating the company’s Bicycle Radio Conjugates (BRC) pipeline and partner for success, with updates expected from its wholly owned BRC program by mid-2024."

Clinical data • New molecule • Trial status • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Bicycle Therapeutics Provides Data Updates for Three Clinical Programs and Strategy Overview at First R&D Day (Businesswire) - P1/2 | N=288 | NCT04180371 | Sponsor: BicycleTx Limited | "Encouraging early activity in mUC with a 39% ORR in 18 patients receiving 6.5 mg/m2, 8.5 mg/m2 or 10 mg/m2 every other week, and an mDOR of 4 months in 7 patients with one responder still on therapy. This includes 6 partial responses and 1 unconfirmed response. Encouraging emerging data in other cancers such as ovarian, gastric/upper gastrointestinal and head and neck that are informing the dose optimization strategy and further development. Given the promising tolerability profile of BT5528 at 6.5 mg/m2 every other week and in line with the FDA’s Project Optimus initiative, Bicycle Therapeutics has now commenced further cohorts in mUC and ovarian cancer to test 5 mg/m2 weekly, which will inform decisions about dose optimization, potential drug combinations and expansion into other tumor types. Data from these cohorts are expected to be available in the second half of 2024."

P1/2 data • Trial status • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Ovarian Cancer • Urothelial Cancer

Bioanalysis of the Bicycle toxin conjugate BT5528 and released monomethyl auristatin E via liquid chromatography-tandem mass spectrometry. (PubMed, Bioanalysis) - " BT5528 was quantified over the assay range of 5-2500 ng/ml and free MMAE was quantified over the assay range of 0.05-50 ng/ml. Bioanalytical methods were used in the bioanalysis of intact BT5528 and released MMAE, in a phase I/IIa clinical trial; to date, over 2000 human patient samples have been analyzed."

Journal

Trial in progress: First-in-human phase I dose-escalation study of a novel Bicycle toxin conjugate (BT5528) targeting EphA2 in patients with advanced solid tumors (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Late-breaking abstract • Metastases • P1 data • Oncology • Solid Tumor

[VIRTUAL] A first in class phase I/II study of the novel bicyclic peptide and MMAE conjugate, BT5528, in patients with advanced malignancies associated with EphA2 expression (AACR-NCI-EORTC 2021) - No abstract available

Clinical • P1/2 data • Oncology • EPHA2

[VIRTUAL] A survey of EphA2 expression by immunohistochemistry (IHC) in tumor tissue microarrays (TMAs) to support BT5528 indication selection (AACR-II 2020) - "Use of an IHC assay assessing expression of EphA2 across multiple TMAs and scoring TM and TC individually may help guide indication selection for the BT5528 clinical program."

Gynecologic Cancers • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer • Triple Negative Breast Cancer • EPHA2

[VIRTUAL] Rapid accumulation of cytotoxic payload in tumor tissue drives BT5528 activity in tumor models (AACR 2021) - P1/2 | "In contrast, BT5528 achieves prolonged toxin delivery to tumors, following transient exposure in plasma of less than one hour. A Phase I/II study of BT5528 in patients with solid tumors is ongoing, which will investigate if this PK novel, differentiated pharmacokinetic profile, unique to Bicycle toxin conjugates, gives rise to a favorable balance of efficacy and safety."

Preclinical • Breast Cancer • Gastric Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer • EPHA2

Bicycle Therapeutics Reports Third Quarter 2022 Financial Results and Provides Corporate Update (Businesswire) - "'In the third quarter, we announced top-line results from the completed dose escalation portion of the Phase I/II trial in BT5528 and expect to complete enrollment in the initial expansion cohorts this quarter. In addition, clinical development of BT8009 remains on-track and we look forward to providing an update this quarter following completion of the dose escalation portion of the Phase I/II clinical trial. Finally, the dose escalation portion of our Phase I/II trial of BT7480 continues at a healthy pace and we expect to share clinical information in 2023'."

Enrollment status • P1/2 data • Oncology • Solid Tumor

Bicycle Therapeutics Announces BT5528 Phase I Dose Escalation Results in Patients with Advanced Solid Tumors (Businesswire) - P1 /2 | N=312 | NCT04180371 | Sponsor: BicycleTx Limited | "Bicycle Therapeutics plc...announced Phase I dose escalation top-line results from its Phase I/II trial of BT5528, a BTC targeting EphA2, in patients with advanced solid tumors....Preliminary signs of anti-tumor activity observed....Among these nine late-line ovarian cancer patients, six patients (67%) were observed to have a reduction in target lesions, including one patient with a complete response (CR) and one with a partial response (PR) under Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, resulting in a disease control rate (DCR) of 67% and an overall response rate (ORR) of 22%; A total of eight urothelial patients were dosed. Of these, three response evaluable patients were determined to be EphA2-positive based on the IHC assay and of these three patients, two were observed to have tumor reductions constituting a PR under RECIST version 1.1 (ORR and DCR of 67%)."

P1/2 data • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer