zelenectide pevedotin (BT8009) / Bicycle Therap - LARVOL DELTA

From Cloudy to Clear: A Strategy to Resolve the Complex Structural Elucidation of Bicycle Drug Conjugate Zelenectide Pevedotin by NMR. (PubMed, Bioconjug Chem) - "Its structure is highly complex and comprises a Bicycle connected to microtubule inhibitor monomethyl aurostatin-E (MMAE) via a molecular spacer and a cleavable linker. This provides a unique challenge in structural elucidation, and this report shows a strategy to overcome this using an incremental, nuclear magnetic resonance spectroscopy-based approach, which may be applied to complex structures of a similar nature."

Journal • Bladder Cancer • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • NECTIN4

Phase 1/2 Duravelo-1 study: Preliminary results of nectin-4–targeting zelenectide pevedotin (BT8009) plus pembrolizumab in previously untreated, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. (ASCO 2025) - P1/2, P2/3 | "Zelenectide pevedotin (zele, previously BT8009) is a highly selective Bicycle Toxin Conjugate (BTC) targeting Nectin-4 and conjugated to MMAE, and has shown an objective response rate (ORR) of 45% and a generally tolerable safety profile as monotherapy in previously treated, enfortumab vedotin-naïve pts with mUC in the ongoing Phase 1/2 study (NCT04561362, Duravelo-1; Reig et al., 2024)... Zelenectide pevedotin + pembro shows promising anti-tumor activity as a first-line treatment in a cohort of cisplatin-ineligible pts with la/mUC including a large proportion of pts with PS = 2. The combination of zele + pembro was generally tolerable and broadly consistent with the existing safety profiles of each respective agent. No new safety signals were observed with the combination."

Clinical • Metastases • P1/2 data • Diabetes • Genito-urinary Cancer • Infectious Disease • Neutropenia • Oncology • Ophthalmology • Pain • Pneumonia • Respiratory Diseases • Solid Tumor • Urothelial Cancer • NECTIN4

Bicycle Therapeutics Highlights…Strategic Priorities for 2026 (Businesswire) - "...Anticipated Milestones:...(i) Report additional Phase 1 Duravelo-1 combination data with pembrolizumab in first-line cisplatin-ineligible mUC at a scientific conference in the first half of 2026; (ii) Report longer-term follow-up Phase 1 Duravelo-1 monotherapy data in late-line mUC at a scientific conference in the first half of 2026; (iii) Report Phase 1 BT7480 combination data with nivolumab at a scientific conference in the first half of 2026."

P1 data • Urothelial Cancer

2026 Strategic Priorities and Anticipated Milestones (Businesswire) - "(i) Provide an update on dose selection for Phase 2/3 Duravelo-2 pivotal trial and zelenectide pevedotin’s potential approval pathway in mUC following meetings with multiple regulatory agencies in the first quarter of 2026; (ii) Report dose selection data from Phase 2/3 Duravelo-2 pivotal trial evaluating zelenectide pevedotin in combination with pembrolizumab in patients with mUC at a scientific conference in the first half of 2026; (iii) Report initial data for Phase 1/2 Duravelo-3 trial for zelenectide pevedotin in NECTIN4-amplified breast cancer at a scientific conference in the second half of 2026."

Clinical data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer • Urothelial Cancer

BT8009-100 phase I/II study of novel bi-cyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies associated with nectin-4 expression (AACR 2022) - P1/2 | "Here, we describe the preliminary monotherapy dose escalation results of the ongoing multicenter Phase I/II clinical trial (NCT04561362) that assesses the safety and tolerability of BT8009 administration in patients with advanced solid tumors associated with Nectin-4 expression, not exposed to enfortumab vedotin. BT8009 exhibits a promising preliminary tolerability profile and preliminary antitumor activity. The molecule will continue to be explored in the current dose-escalation/dose-expansion study of BT8009 monotherapy and in combination with nivolumab."

Clinical • P1/2 data • Oncology • Solid Tumor • Urothelial Cancer • NECTIN4

Enhanced anti-tumor activity of zelenectide pevedotin in triple negative breast cancer (TNBC) patients (pts) with NECTIN4 gene amplification (amp) (SABCS 2024) - P1/2 | "Background: Zelenectide pevedotin (zele, formerly BT8009) is a highly selective Bicycle® Toxin Conjugate (BTC) comprised of a bicyclic peptide targeting Nectin-4 conjugated to monomethyl auristatin E. BTC® molecules have lower molecular weight and shorter plasma half-life than antibody-drug conjugates, with distinct pharmacokinetics/dynamics, i.e., potential for rapid tumor penetration and minimal healthy tissue exposure...All 3 NECTIN4 amp responders were previously treated with sacituzumab govitecan... NECTIN4 amplification appears to show predictive clinical utility in identifying pretreated TNBC pts with enhanced response to zelenectide pevedotin, with an ORR of 57.1% in NECTIN4 gene amp positive pts including polysomy versus an ORR of 13.3% in biomarker unselected TNBC. Despite the limited sample size, this post-hoc analysis underscores the promising anti-tumor activity of zelenectide pevedotin in pts with NECTIN4 amp TNBC, who continue to have..."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • NECTIN4

First-in-Human, Phase I/II Dose Escalation and Expansion Study of Zelenectide Pevedotin in Patients With Advanced Solid Tumors: Results From Monotherapy Dose Escalation. (PubMed, J Clin Oncol) - P1/2 | "Zelenectide pevedotin monotherapy demonstrated a generally well-tolerated safety profile and preliminary efficacy, particularly in UC, supporting investigation of UC and non-UC populations in the expansion phase."

First-in-human • Journal • Monotherapy • P1/2 data • Fatigue • Hematological Disorders • Neutropenia • Oncology • Pain • Solid Tumor • Urothelial Cancer • NECTIN4

A Phase 2 study of zelenectide pevedotin, a Bicycle Drug Conjugate, in patients with NECTIN4 amplified advanced breast cancer (Duravelo-3) (SABCS 2025) - P1/2, P2 | "Pharmacokinetics, correlation of efficacy and safety with biomarkers of NECTIN4 amp, and measurement of antidrug antibody are additional exploratory endpoints. This study is actively recruiting."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • NECTIN4

Duravelo-1: Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=329 | Active, not recruiting | Sponsor: BicycleTx Limited | Recruiting ➔ Active, not recruiting

Enrollment closed • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • ALK • ER • HER-2 • NECTIN4 • PGR • ROS1

A multi-integrin targeting peptide-drug conjugate induces durable tumor regression with a strong preclinical safety profile (SITC 2025) - "In head-to-head studies, PIP-MMAE outperformed clinical-stage benchmarks BT8009 (Nectin-4-targeting peptide-MMAE conjugate; Bicycle Therapeutics) and SGN-B6A (αvβ6 integrin-targeting ADC-MMAE; Pfizer).In a head and neck cancer model with high αvβ6 integrin expression, strong initial responses were observed with SGN-B6A treatment, but tumors eventually became resistant and continued to grow even when additional doses were administered. Finally, in repeated-dose toxicology studies, PIP-MMAE was well tolerated in both rats and NHPs with no indication of any PIP-related (target-dependent) toxicities.Conclusions PIP-MMAE demonstrates robust efficacy across various solid tumors, alongside a 'fast-in, fast-out' PK profile that confers remarkable safety. These preclinical data support the continued development of PIP-MMAE, with clinical trials planned to further evaluate its safety, PK, and anti-tumor activity in cancer patients.Ethics Approval All the procedures related..."

Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • NECTIN4

Zelenectide Pevedotin Shows Safety, Preliminary Efficacy in Advanced Solid Tumors (Targeted Oncology) - " Zelenectide pevedotin showed a favorable safety profile and promising antitumor activity in advanced solid tumors, especially urothelial carcinoma, in the Duravelo-1 trial. Among 49 patients, 94% experienced treatment-related adverse events, with neutropenia being the most common severe event. The drug demonstrated a 24% overall objective response rate and a 48% clinical benefit rate, with notable efficacy in urothelial carcinoma patients."

P1/2 data • Urothelial Cancer

NECTIN4-Amplified Breast Cancer Targeted by Zelenectide Pevedotin: Unveiling Linkage Lethality as a Novel Drug Mechanism and Therapeutic Class [WITHDRAWN] (ESMO 2025) - No abstract available

Breast Cancer • Oncology • Solid Tumor • NECTIN4

Phase 2/3 Duravelo-2 pivotal trial evaluating zelenectide pevedotin in combination with pembrolizumab in patients with metastatic urothelial cancer (mUC). (Businesswire) - "The company now expects to provide an update on dose selection for Duravelo-2 and zelenectide pevedotin’s potential approval pathway in mUC following meetings with multiple regulatory agencies in the first quarter of 2026."

Trial status • Urothelial Cancer

Trial in Progress data for Phase 1/2 Duravelo-3 trial for zelenectide pevedotin in NECTIN4-amplified breast cancer and tissue sample data in patients with NECTIN4-amplified non-small cell lung cancer (NSCLC) presented at the European Society for Medical Oncology (ESMO) Congress 2025. (Businesswire)

Trial status • Non Small Cell Lung Cancer

NECTIN4 amplification (amp) as an actionable alteration in non-small cell lung cancer (NSCLC) (ESMO 2025) - P1/2, P2 | "Combined with the enhanced efficacy of zelenectide pevedotin in NECTIN4 -amp NSCLC in Duravelo-1, these findings support NECTIN4 amp as a promising predictive biomarker for precision oncology in NSCLC. Legal entity responsible for the study The authors."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • CTLA4 • ERBB3 • HER-2 • KRAS • NECTIN4 • PD-1

A phase 2 study of zelenectide pevedotin, a bicycle drug conjugate, in patients with NECTIN4 amplified advanced breast cancer (Duravelo-3) (ESMO 2025) - P1/2, P2 | "Pharmacokinetics, correlation of efficacy and safety with biomarkers of NECTIN4 amp, and measurement of antidrug antibody are additional exploratory endpoints. This study is actively recruiting."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • NECTIN4

Antibody-drug conjugates targeting the cadherin, claudin and nectin families of adhesion molecules. (PubMed, Front Mol Med) - "Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs."

Journal • Review • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Genito-urinary Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer • CDH17 • CDH6 • CLDN18 • CLDN6

"Precision on Two Wheels"─Structural Refinement of 64Cu- and 68Ga-Labeled Bicyclic Peptides Targeting Nectin-4 for Improved Tumor Imaging: From Preclinical Development to First-in-Human Application. (PubMed, J Med Chem) - "For this purpose, we developed 64Cu- and 68Ga-labeled ligands derived from bicyclic peptide-drug conjugate BT8009...The suitability of the most promising ligand from the preclinical studies, NECT-224, for PET imaging purposes was also demonstrated in a first-in-human application using [68Ga]Ga-NECT-224. The results suggest its further clinical development, but also that of [64Cu]Cu-NECT-224."

First-in-human • Journal • P1 data • Preclinical • Oncology • Solid Tumor • Urothelial Cancer • NECTIN4

Duravelo-1: Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=329 | Recruiting | Sponsor: BicycleTx Limited | Trial primary completion date: Dec 2026 ➔ Mar 2026

Trial primary completion date • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • ALK • ER • HER-2 • NECTIN4 • PGR • ROS1

Bicycle Therapeutics Reports Recent Business Progress and Second Quarter 2025 Financial Results (Businesswire) - "Bicycle Therapeutics is on track to provide an update on dose selection from the Duravelo-2 trial and the accelerated approval pathway for zelenectide pevedotin in mUC following a meeting with the U.S. Food and Drug Administration planned for 4Q 2025....With several trials underway assessing the potential for zelenectide pevedotin to treat mUC, breast cancer and lung cancer, the company has decided to pause the previously announced Phase 1/2 Duravelo-5 trial in multiple tumors."

FDA event • Trial status • Breast Cancer • Non Small Cell Lung Cancer • Urothelial Cancer

Zelenectide Pevedotin in NECTIN4 Amplified Advanced or Metastatic Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=73 | Recruiting | Sponsor: BicycleTx Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Design, synthesis and antitumor evaluation of a novel nectin-4 targeting bicyclic toxin conjugate. (PubMed, Bioorg Med Chem Lett) - "In vivo antiproliferative activity assay results showed that BGC1614 (0.12 μM/kg) exhibited better antiproliferative activity than BT8009 (0.12 μM/kg, inhibition rate (IR) 87.6 %) in PC-3 (human prostate cancer cell) model with IR of 96.3 %, while BGC1614 (0.36 μM/kg) displayed similar inhibition with BT8009 (0.36 μM/kg, IR 72.7 %) in N87 (human gastric cancer cell) model with IR of 70.1 %, demonstrating that BGC1614 exhibited better antitumor effect in the same molar concentration in PC-3 model. In addition, BGC1614 was well-tolerated in efficacious doses in the nude model assays, while the pharmacokinetic (PK) parameters of BGC1614 were comparable to that of BT8009."

Journal • Gastric Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • NECTIN4

A phase 2/3 study of bicycle toxin conjugate zelenectide pevedotin (BT8009) targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC; Duravelo-2). (ASCO 2025) - P1/2, P2/3 | "Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy...Cohort 1 will be randomized 1:1:1 to receive: 1) zele 5 mg/m2 on days [D]1, 8, and 15 + pembro 200 mg on D1; 2) zele 6 mg/m2 on D1 and 8 + pembro 200 mg on D1; or 3) chemotherapy (gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance in appropriate patients)...Efficacy endpoints will be assessed per RECIST v1.1. This study is actively recruiting."

Clinical • Metastases • P2/3 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

ASCO 2025: Phase 1/2 Duravelo-1 Study: Preliminary Results of Nectin-4–targeting Zelenectide Pevedotin (BT8009) plus Pembrolizumab in Previously Untreated, Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer (UroToday) - P1/2 | N=329 | DURAVELO-1 (NCT04561362) |Sponsor: BicycleTx Limited | "As of January 3, 2025, a total of 22 patients were enrolled in Cohort B7 of the DURAVELO-1 study between November 2023 and July 2024. The median time on treatment was 22.9 weeks, with 12 patients remaining on study therapy at the time of data cutoff....Dr Giannatempo highlighted that among 20 efficacy-evaluable patients, the ORR was 65% (95% CI: 40.8–84.6), including five complete responses (25%) and eight partial responses (40%). Stable disease (SD) was observed in five patients (25%), resulting in a disease control rate of 90%. Median follow-up was 7.1 months (range: 1.0–13.2)."

P1/2 data • Urothelial Cancer

Bicycle Therapeutics Announces Poster Presentations at the 2025 ASCO Annual Meeting (Businesswire) - "Bicycle Therapeutics plc...announced the poster presentation of two abstracts at the 2025 American Society for Clinical Oncology (ASCO) Annual Meeting, taking place May 30-June 3 in Chicago."

P1/2 data • Trial status • Urothelial Cancer