Bicycle heralds the return of EphA2

Bicycle Therapeutics’ EphA2-targeting toxin conjugate BT5528 is “safer than any ADC”, the group’s chief executive, Kevin Lee, told yesterday’s Jefferies London healthcare conference. That’s quite a claim for a mechanism whose historic toxicity has deterred virtually all other competitors. About 10 years ago AstraZeneca dosed six patients in a first-in-human trial of MEDI-547, an anti-EphA2 ADC, five of whom discontinued because of bleeding and coagulation toxicity, prompting the programme’s discontinuation. Lee said Bicycle had some ideas about why this happened, and has been “thoughtfully careful about development”, seeing no similar toxicity with BT5528 in over 100 patients dosed. So far BT5528 has yielded two remissions in nine EphA2-positive ovarian cancer patients, and two in three EphA2-positive bladder cancer subjects; dose expansion is ongoing in these tumours as well as NSCLC, triple-negative breast, head and neck, and gastroesophageal cancers. More data on this “very underestimated molecule in our portfolio” will be presented at Bicycle’s 14 December R&D day, which will also feature updated results on BT7480. The latter is a CD137 agonist attached to a moiety targeting Nectin-4, the target of Bicycle’s lead, zelenectide pevedotin, which is currently on a controversial US accelerated approval path. Industry projects targeting EphA2ProjectCompanyMechanismStatusBT5528Bicycle TherapeuticsToxin conjugatePh1/2 in various EphA2-expressing tumoursSNL-EphA2 CAR-THebei Senlang BiotechnologyCar-T therapyPh1 in gliomaRAYZ-6114RayzeBioLu-177-linked radioconjugatePreclinicalABM-2526ABM TherapeuticsEphA2-RAF inhibitorPreclinicalBT7455Bicycle TherapeuticsCD137 agonist bispecificPreclinicalAPN-122597AtrecaT-cell engager (via CD3)PreclinicalATRC-301AtrecaADCDiscontinued after bleeding tox signal in preclinical trialMEDI-547AstraZenecaADCDiscontinued after bleeding & coagulation tox in ph1Source: OncologyPipeline.This story was amended to update the status of ATRC-301.