Innate shows Bicycle the path for Nectin-4

Innate Pharma, whose Nectin-4-targeting ADC IPH4502 has only just gone into the clinic, is already mooting the possibility of accelerated approval. But, in contrast to its rival Bicycle Therapeutics, Innate has accepted that the fast-track registration pathway for IPH4502 lies in bladder cancer patients previously treated with Pfizer’s approved anti-Nectin-4 ADC, Padcev.

Innate is also eyeing front-line bladder cancer, but going for Padcev-resistant patients first seems logical given the Pfizer drug’s standard-of-care status. For its part, Bicycle has long maintained that it can gain accelerated approval for its anti-Nectin-4 toxin conjugate zelenectide pevedotin in first-line bladder cancer, but this plan increasingly looks unsustainable.

Bicycle backpedalling?

That said, at the recent JP Morgan healthcare conference Bicycle seemed to be edging away from an all-in bet on the front line.

For the first time the company disclosed plans to file zelenectide for accelerated approval in 2027 – and, when asked by ApexOnco, it declined to say whether this would be in first or second-line disease. The group’s pivotal Duravelo-2 trial is enrolling both populations, with dose selection data due in the second half of this year.

Bicycle has insisted that it has "alignment" with the FDA on a pre-Padcev path, but a shift away from the front line wouldn’t be too surprising: Bicycle recently reported lacklustre results in treatment-naive bladder cancer from the uncontrolled phase 1/2 Duravelo-1 study.

Outside bladder cancer, Bicycle is now targeting a biomarker strategy after seeing a signal in breast and non-small cell lung cancer patients with Nectin-4 gene amplification.

Low expressers?

Innate, meanwhile, believes that IPH4502 might be active in Nectin-4-low tumours, helped in part by its topoisomerase 1 payload, which it says produces a higher bystander effect than Padcev’s MMAE payload.

Other topo1-based Nectin-4 ADCs are in development, notably Lilly’s two shots, LY4101174 and LY4052031, which use different linkers. Innate reckons its asset could have more efficient internalisation than Lilly’s, but now it has to prove that this makes a difference in the clinic.

The phase 1 trial of IPH4502 will enrol around 45 patients with various tumour types in its dose-escalation phase, Innate said during a conference call on Wednesday to discuss the asset. Patients won’t be prospectively selected for Nectin-4 expression, but Innate will collect Nectin-4 biomarker data to see if this has any impact on efficacy.

Preliminary data on safety and clinical activity are expected in late 2025 or early 2026; Innate will then select which use(s) to take into dose optimisation, with up to 30 patients planned per indication. A fast path forward in the Padcev-resistant setting will therefore depend on how many post-Padcev patients join the trial, conceded Innate’s chief medical officer, Sonia Quaratino.

Other plans include a basket trial in combination with standard of care, possibly PD-(L)1 inhibitors, and this could start in 2026 or 2027 – when monotherapy dose expansion data are also set to read out.

This timeline could set Innate on a collision course with Bicycle, if indeed the latter is turning towards the second line.