Bicycle Therapeutics announced on Friday, August 8, 2025, that it would take measures to reduce costs as part of a realignment in order to reach several milestones in the 2nd half of 2025. In order to reduce costs by 30%, it had to reduce its workforce by 25%. In addition, with the fact that it had already initiated several trials using its lead drug zelenectide pevedotin [formerly BT8009] to treat a variety of solid tumors like breast cancer, lung cancer, and metastatic urothelial carcinoma (mUC), it also decided to cut off a phase 1/2 clinical trial targeting multiple tumor types with this drug known as Duravelo-5. The company noted that with an “evolving macroeconomic environment,” it was best for it to take these steps to conserve cash.
This was a bold move and likely one that was necessary in order to keep its company funded for an extended period of time. As a matter of fact, these strategic moves are set to allow it to extend its cash runway into 2028. This move had nothing to do with a faltering pipeline; on the contrary, the company is doing quite well, continuing to advance its drug candidates in the clinic. One milestone that is expected to happen in Q4 of 2025 is that it will meet with the FDA to discuss if it is possible for it to have an accelerated approval pathway using zelenectide for the treatment of patients with mUC with the phase 2/3 Duravelo-2 study. What the company is also expecting to do is to select a dose that is to be used in a possible next trial with a positive FDA meeting outcome.
The science of zelenectide is interesting in that it is designed to target Nectin-4, which is a molecule that has been shown to be overexpressed in tumor cells. The bottom line is that it results in the ability for tumor cells to achieve growth and proliferate throughout the body. This is an ideal way to treat cancer, and to accomplish the use of this drug to treat mUC and other tumors would be by using the Nectin-4 targeting Bicycle (the technology the company uses to develop its drugs) with a cleavable linker and an MMAE drug payload. MMAE stands for monomethyl auristatin E, and the goal of it to act as a toxic agent that is responsible for inhibiting cell growth and division.
Furthermore, there are actually two advantages to using a drug like zelenectide to target patients with solid tumors, like mUC and others. The first of which is that Nectin-4 is an ideal therapeutic target because it consists of high levels of embryonic and fetal tissue, and then in adults this subsides. That is, Nectin-4 is limited in tissue at this stage of a patient’s life. This is one way whereby the company adds a good competitive edge in terms of safety. Another way is with the MMAE payload I noted above, in that it is not deployed until it reaches the tumor cell, and the thought behind this is to limit system toxicity.
These competitive advantages are ideal, but the point is whether or not this drug works in helping these patients. The company did see a 45% objective response rate in the phase 1/2 Duravelo-1 study when patients were given zelenectide alone as a monotherapy. Furthermore, the company decided to make a push to test this drug in combination with Keytruda (pembrolizumab), and in doing so, it noted that there was a 65% ORR. The point here is that the mechanism of action (MOA) of using this bicycle Nectin-4 targeting drug to treat these specific solid tumor patients is shown by the high response rates.
The point here being that zelenectide is versatile and could possibly be applied towards effectively targeting other solid tumors. With that being said, besides the mUC and breast cancer indications it is focused on, it has even made a move to press forward with a trial using this drug to target patients with Nectin-4 amplified non-small cell lung cancer (NSCLC) in the Duravelo-4 study. The importance of this study’s scope goes beyond that of the company only testing out the use of the drug to target this patient population. By that, I mean it has put in place a way to look at a biomarker of Nectin4 gene amplification. The purpose of using this biomarker method is to see if a patient is more likely to respond to zelenectide. This is its second study to incorporate this biomarker for patient selection.
What’s not such good news for the company is that Roche’s subsidiary Genentech ended a collaboration agreement with Bicycle. This was a pact whereby both companies would collaborate to develop immunotherapies to treat patients with cancer on the basis of the Bicycle technology. Under this agreement the company earned a $30 million upfront payment and would then be eligible to obtain an additional $1.7 billion. However, as part of the release of earnings, there was an update provided on this partnership noting that Genentech gave notice in July 2025 that it would end this collaboration. The only bright spot here is that Bicycle is set to recognize about $6.5 million of deferred revenue in Q3 of 2025.