Bicycle finally falls

Bicycle Therapeutics' insistence that an accelerated approval path existed for its lead project zelenectide pevedotin in bladder cancer has long seemed unrealistic, and now the company has deprioritised the asset, apparently following meetings with regulators.

The company said on Tuesday in its fourth-quarter earnings release that based on regulatory feedback its phase 2/3 trial, Duravelo-2, was "no longer considered acceptable” to support registration. Bicycle is converting Duravelo-2 to a phase 2 study while it focuses on the remainder of its pipeline.

Bicycle is also discontinuing the phase 1/2 Duravelo-3 and Duravelo-4 studies in Nectin-4-amplified breast and non-small cell lung cancers respectively, and reducing its workforce by 30% in a bid to extend its cash runway into 2030.

The group’s stock opened up 2% on Tuesday, suggesting that investors had already written off zelenectide, an anti-Nectin-4 toxin conjugate.

Zelenectide questions

Bicycle might hope to find a partner for the asset, but there are doubts about its potential place in the evolving bladder cancer market, as well as the design of Duravelo-2. The study recruited both first and second-line patients; in the former, a Keytruda combo was being compared against chemo, while treatment-experienced patients received zelenectide with or without Keytruda.

Bicycle previously disclosed that it hoped to file for accelerated approval in 2027 based on overall response rate data, but didn’t specify whether this would be in the first or second line.

The elephant in the room, however, was Pfizer and Astellas’s Nectin-4-targeting ADC Padcev, which received full FDA approval in 2023 for first-line bladder cancer, alongside Keytruda, based on knockout results in the EV-302 study.

Zelenectide always looked unlikely to unseat Padcev: in the phase 1/2 Duravelo-1 trial, a Keytruda combo produced uncompetitive front-line data.

And in Duravelo-2’s first-line cohort the choice of chemo as control, rather than Padcev, raised questions about the viability of Bicycle’s accelerated approval plan.

Furthermore, patients who had previously received Padcev were excluded from Duravelo-2’s second-line cohort. This differs from the strategy of another Nectin-4 ADC contender, Innate Pharma, which last year took a more pragmatic approach by saying it would initially seek accelerated approval for its asset, IPH4502, in a post-Padcev population.  

Pipeline

Bicycle will now shift focus to its EphA2-targeting toxin conjugate nuzefatide (previously known as BT5528).

That project is in a phase 1/2 solid tumour trial, and a phase 2 study in pancreatic ductal adenocarcinoma. Bicycle promises an update from both this half. However, other anti-EphA2 assets have previously been scuppered by toxicity.

Meanwhile, it also looks like the end of the road for BT7480, which comprises a CD137 agonist attached to a Nectin-4-targeting moiety. Bicycle will report phase 1 Opdivo combo data this half, but will then seek a partner for that asset.

The group’s remaining pipeline is made up of radioconjugates. The most advanced, the MT1-MMP-targeting BT1702, is set to go into the clinic next year.

Bicycle Therapeutics’ pipeline highlights

Source: OncologyPipeline & company presentation.