Bicycle Therapeutics Shares Pipeline Update on Nuzefatide Pevedotin and EphA2 Programs at AACR 2026
Bicycle Therapeutics has unveiled a comprehensive set of updates from its EphA2-targeting oncology pipeline at the American Association for Cancer Research Annual Meeting, highlighting growing clinical and preclinical evidence supporting its proprietary bicyclic peptide platform. The company’s latest findings underscore the potential of its Bicycle® technology to successfully target EphA2, a receptor long considered difficult to drug, and to expand treatment possibilities across several hard-to-treat cancers.
EphA2 has emerged as an attractive yet historically challenging target in oncology. It is widely expressed across multiple tumor types, including pancreatic, bladder, and head and neck cancers. However, previous attempts to develop therapies against EphA2—particularly antibody-based approaches—have been hampered by issues related to toxicity and limited efficacy. Bicycle Therapeutics is attempting to overcome these barriers using its unique class of therapeutics known as bicyclic peptides, which are engineered to combine the targeting precision of antibodies with the pharmacokinetic advantages of small molecules.
At the center of these updates is nuzefatide pevedotin, formerly known as BT5528. This investigational agent represents a potentially first-in-class EphA2-targeting Bicycle Drug Conjugate (BDC®). It is designed to deliver a cytotoxic payload directly to EphA2-expressing tumor cells, thereby maximizing anti-tumor activity while minimizing off-target toxicity. According to company leadership, nuzefatide has already demonstrated a differentiated and generally well-tolerated safety profile in more than 150 patients across early-stage clinical studies.
One of the key datasets presented at AACR 2026 comes from an ongoing Phase 1/2 clinical trial evaluating nuzefatide in combination with nivolumab in patients with metastatic urothelial cancer (mUC). This combination approach aims to enhance anti-tumor immune responses by pairing targeted cytotoxic delivery with immune checkpoint inhibition. As of the February 2026 data cutoff, results from 14 patients treated with nuzefatide at 6.5 mg/m² every two weeks alongside nivolumab at 480 mg every four weeks demonstrated encouraging clinical activity.
Among patients with EphA2-positive tumors, the confirmed overall response rate reached 40%, with four out of ten patients experiencing a measurable response. Notably, in a subset of patients who had not previously been exposed to monomethyl auristatin E (MMAE), the cytotoxic payload used in many antibody-drug conjugates, the response rate reached 100% (three out of three patients). These findings suggest that prior exposure to similar cytotoxic agents may influence treatment outcomes and highlight the importance of patient selection in maximizing therapeutic benefit.
Durability of response also appeared promising. Patients who achieved either a partial response or at least 16 weeks of stable disease remained on treatment for a minimum of 56 weeks, with many continuing therapy at the time of data analysis. From a safety perspective, the combination therapy was generally well tolerated. There were no Grade 3 or higher treatment-related adverse events of significant clinical concern, and importantly, no hemorrhagic toxicities—an issue that has previously limited other EphA2-targeted therapies. Only one dose-limiting toxicity, consisting of Grade 3 fatigue lasting five days, was reported and subsequently resolved without requiring dose reduction.
Building on these results, Bicycle Therapeutics has identified 8 mg/m² administered every two weeks as the preferred dosing regimen for future studies of nuzefatide as a monotherapy. This dosing strategy is now being advanced into a Phase 2 clinical trial targeting pancreatic ductal adenocarcinoma (PDAC), a disease with limited treatment options and poor prognosis. The company announced that the first patient in this study has already been dosed, marking an important milestone in the clinical development of this agent.
Beyond clinical efficacy data, the company also presented compelling imaging results using a Bicycle® Imaging Agent (BIA) designed to target EphA2. These studies were conducted in collaboration with the German Cancer Consortium and the German Cancer Research Center. The imaging agent, labeled with gallium-68, was evaluated in patients with histologically confirmed pancreatic cancer using PET/CT scanning.
The imaging data revealed rapid and specific uptake of the agent in tumor tissues, with efficient clearance primarily through the kidneys. In six out of seven patients studied, the imaging successfully identified metastatic lesions across multiple sites, including the liver, bones, lymph nodes, and peritoneum. These findings are consistent with broader data from 15 out of 18 patients evaluated to date, reinforcing the reliability of EphA2 as a target for both therapeutic and diagnostic applications. Importantly, the imaging results demonstrate strong concordance with preclinical data, supporting the translational potential of Bicycle-based molecules.
Preclinical studies further strengthen the case for nuzefatide in pancreatic cancer. In patient-derived xenograft (PDX) models of PDAC, EphA2 expression was detected in all 16 models evaluated. Among the 14 models assessed for therapeutic response, 10 showed sensitivity to nuzefatide, with six exhibiting high levels of responsiveness. These results suggest that a significant proportion of pancreatic tumors may be amenable to treatment with this agent.
Additional preclinical work in cell-line-derived xenograft (CDX) models of head and neck squamous cell carcinoma (HNSCC) demonstrated potent anti-tumor activity in EphA2-expressing tumors. This expands the potential application of nuzefatide beyond pancreatic and bladder cancers, indicating that EphA2-targeted therapies could have broad utility across multiple malignancies.
Collectively, the data presented at AACR 2026 provide a compelling validation of EphA2 as a viable therapeutic target and highlight the versatility of Bicycle Therapeutics’ platform. By integrating clinical efficacy data, advanced imaging techniques, and robust preclinical evidence, the company is building a strong case for the continued development of nuzefatide and next-generation EphA2-targeted therapies, including radioligand approaches.
As the field of oncology continues to shift toward precision medicine, the ability to identify and effectively target specific molecular drivers of cancer will be critical. Bicycle Therapeutics’ approach—leveraging small, highly specific bicyclic peptides—offers a promising pathway to overcome longstanding challenges associated with difficult-to-drug targets. With ongoing clinical trials and expanding research efforts, the company is positioning itself at the forefront of innovation in targeted cancer therapeutics.
The full set of presentations and supporting data from these studies is available through the company’s official publications portal, providing researchers and clinicians with further insight into the evolving potential of Bicycle-based therapies.
About Bicycle Therapeutics
Bicycle Therapeutics is a clinical-stage pharmaceutical company developing a novel class of medicines, referred to as Bicycle® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development.
The company is evaluating nuzefatide pevedotin, formerly BT5528, a Bicycle® Drug Conjugate (BDC®) targeting EphA2, a historically undruggable target; a pipeline of other bicycle-based conjugate molecules, including Bicycle® Radioconjugates (BRC®) for radiopharmaceutical use; zelenectide pevedotin (formerly BT8009), a BDC® targeting Nectin-4, a well-validated tumor antigen; BT7480, a Bicycle Tumor-Targeted Immune Cell Agonist® (Bicycle TICA®) targeting Nectin-4 and agonizing CD137; and, through various partnerships, is exploring the use of Bicycle® technology to develop therapies for diseases in additional therapeutic areas.
Source Link:https://www.businesswire.com/
