FDA Grants Fast Track Status to BT8009 for Previously Treated Locally Advanced or Metastatic Urothelial Cancer

The FDA has granted a fast track designation to BT8009 for use as a monotherapy in adult patients with previously treated locally advanced or metastatic urothelial cancer.

The FDA has granted a fast track designation to BT8009 for use as a monotherapy in adult patients with previously treated locally advanced or metastatic urothelial cancer, according to an announcement from Bicycle Therapeutics, plc.1

The investigative agent is a bicycle peptide toxin conjugate that targets Nectin-4, which is highly expressed on the surface of cancer cells in a broad range of solid tumors.2,3 The agent was developed to have high affinity binding and to be highly selective for the cell adhesion molecule. Moreover, it has been shown to have a short plasma half-life and its hit-and-run delivery of toxin to cancer cells reduces systemic exposure.

In several patient-derived xenograft and cell line–derived xenograft models, BT8009 has resulted in rapid tumor regression, irrespective of tumor size. Specifically, the agent has been shown to have activity in non–small cell lung cancer, triple-negative breast cancer, esophageal cancer, and bladder cancer models. Earlier data indicated that the efficacy of the agent was dose related and correlated with Nectin-4 expression.3

More recent data showed that the investigative agent had superior or equivalent antitumor activity to that of an enfortumab vedotin-ejfv (Padcev) analog in several models.4 BT8009 quickly diffuses from the systemic circulation through tissues to enter the tumor and target cancer cells. The agent is then renally eliminated from the circulation. In rats and non-human primates, BT8009 was found to have a half-life of 1 to 2 hours.

Moreover, data from preclinical toxicity studies revealed that BT8009 had only a portion of the adverse effects that are usually observed with the MMAE cytotoxin payload. Notably, the agent was found to avoid liver, gastrointestinal, and renal toxicities.2

“Fast track designation represents another positive step in the development of BT8009 and reflects the pressing need for a clinically meaningful, differentiated therapy compared to what is available for patients,” Kevin Lee, PhD, chief executive officer of Bicycle Therapeutics, Inc., stated in a press release. “We believe this designation is a valuable component of our future clinical and regulatory strategy as we work to align with the FDA to address the pressing unmet needs of people living with urothelial cancer.”

BT8009 is under investigation as a monotherapy and in combination with pembrolizumab (Keytruda) in patients with advanced solid tumors linked with Nectin-4 expression and those who have advanced solid tumors and renal insufficiency as part of a first-in-human, open-label, multicenter, dose-escalation study.5 Patients are required to have a life expectancy of at least 12 weeks and have measurable disease by RECIST v1.1 criteria.

The key objectives of the trial will be to identify the recommended dose of the agent that can be administered safely either as a monotherapy or in combination with pembrolizumab and to better understand the safety and effectiveness of BT8009 alone and with the immunotherapy, among others.

Beyond BT8009, other Bicycle products are under exploration. These agents are “fully synthetic short peptides constrained with small molecule scaffolds to form 2 loops that stabilize their structural geometry,” according to the drug developer. “This constraint facilitates target binding with high affinity and selectivity…” Other agents under exploration include:

  • BT5528: second-generation Bicycle toxin conjugate that targets EphA2
  • BT7480: Bicycle TICA that targets Nectin-4 and agonizing CD137
  • BT1718: a Bicycle toxin conjugate that targets MT1-MMP


  1. Bicycle Therapeutics announces FDA fast track designation granted to BT8009 for the treatment of adult patients with previously treated locally advanced or metastatic urothelial cancer. News release. Bicycle Therapeutics plc. January 4, 2023. Accessed January 4, 2023. https://bit.ly/3Xbb26K
  2. Bicycle conjugates. Bicycle Therapeutics plc website; 2022. Accessed January 4, 2023. https://bit.ly/3VMZbub
  3. Rigby M, Beswick P, Mudd G, et al. Abstract 4479: BT8009: a bicycle peptide toxin conjugate targeting Nectin-4 (PVRL4) displays efficacy in preclinical tumour models. Cancer Res. 2019;79(suppl 13):4479. doi:10.1158/1538-7445.AM2019-4479
  4. Rigby M, Bennett G, Chen L, et al. BT8009; a Nectin-4 targeting Bicycle toxin conjugate for treatment of solid tumors. Mol Cancer Ther. 2022;21(12):1747-1756. doi:10.1158/1535-7163.MCT-21-0875
  5. Study BT8009-100 in subjects with Nectin-4 expressing advanced solid tumor malignancies. ClinicalTrials.gov. Updated November 28, 2022. Accessed January 4, 2023. https://clinicaltrials.gov/ct2/show/NCT04561362
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