Asco-GU – Bicycle tries to put distance between itself and Seagen

However, results with BT8009, one of several datasets being presented this week at the Asco-GU conference, fail to convince many investors.

Since Bicycle’s BT8009 is one of only four nectin-4-targeting industry projects apart from Seagen’s Padcev, its maker is positioning it as a key pipeline asset. Yesterday brought more data suggesting that BT8009 might have a future in Padcev’s approved use of urothelial bladder cancer.

Bicycle’s job now is to put distance between BT8009 and Padcev, and it worked hard to play up its project’s safety, especially in terms of rash and neuropathy. But doubts about BT8009’s regulatory pathway are likely to continue to vex investors, as is the fact that the project appears to have negligible efficacy beyond bladder cancer.

This is not a new problem. Scant evidence of activity in other tumours combined with an unclear safety advantage contributed to Bicycle stock falling during last year’s AACR meeting.

Though BT8009 has been escalated up to 10mg/m2 every two weeks, Bicycle yesterday focused on 5mg/m2 once a week, which it has designated the recommended phase 2 dose, and on which it has the most data. An abstract to be presented at this week’s Asco-GU cited the same 50% remission rate among eight bladder cancer patients that had been disclosed at AACR.

Longer lasting?

What was new was duration of response, which Bicycle said hit a median of about 14 months for this cohort. This looks impressive against Padcev’s 7.6 months in cohort 1 of the EV-201 study, though with just four responses to go on the Bicycle data must be treated with extreme caution, and a 50% ORR looks comparable to Padcev’s 44% on a cross-trial basis.

As for other tumour types, the Asco-GU data include six lung cancer and seven breast cancer patients across all doses, but efficacy amounts to just one partial response in each. Bicycle stock slipped 4% yesterday.

So what does safety look like? Padcev’s label cites 45% rates of any-grade rash and peripheral neuropathy, and on this basis BT8009 might have an edge, with respective figures of 12% and 27%. However, the small patient numbers in Bicycle’s trial, and the fact severe adverse event rates look similar – 70% for Padcev and 67% for BT8009 – blunts the advantage.

Approvability is a further problem. Padcev already has full approval in third-line urothelial cancer after PD-(L)1 blockade and platinum chemo, and second line in cisplatin-ineligible patients, so without controlled – and perhaps head-to-head – data BT8009 would likely have to contend with an even later-line use initially.

First line is the big prize. Here a Padcev plus Keytruda combo has scored in an uncontrolled cohort, and Seagen’s phase 3 EV-302 trial reads out this year. As such, with the Seagen/Merck combo likely to be approved in 2024, and a front-line BT8009/Keytruda study not even under way, it is hard to see an accelerated pathway for Bicycle here.

The only other anti-nectin-4 assets are Mabwell Bioscience’s 9MW2821, Nectin Therapeutics’ NTX1105 and Shanghai Junshi’s JS114, according to Evaluate Pharma. In a damming note to clients B Riley wrote yesterday that it had “yet to witness a specific target or indication where [Bicycle’s] new modality would showcase a clear and meaningful therapeutic edge against conventional antibody-drug conjugates”.

Some datasets being presented at Asco-GU 2023
Project Company Mechanism Trial Data
BT8009 Bicycle Therapeutics Anti-nectin-4 bicycle conjugate NCT04561362 50% ORR in 8 bladder cancer pts at RP2D
LAVA-1207 Lava Therapeutics Anti-PSMA gamma-delta T-cell engager NCT05369000 Late-line mCRPC; no severe TRAEs, no responses (n=8) 
Talabostat Bioxcel DPP inhibitor NCT03910660 SCNC phenotype mCRPC; 25% ORR in 28 pts (Keytruda combo) 
Lorigerlimab Macrogenics Anti-PD-1xCTLA-4 MAb NCT03761017 mCRPC cohort; 26% ORR in 42 pts
Talzenna Pfizer Parp inhibitor Talapro-2 1L mCRPC; late-breaker embargoed until 16 Feb
Notes: mCRPC=metastatic castration-resistant prostate cancer; SNEC=small cell neuroendocrine carcinoma. Source: Asco-GU.

Other biotech assets being discussed at Asco-GU include Lava Therapeutics’ LAVA-1207 and Bioxcel’s talabostat (BXCL701), both in prostate cancer.

The former company is notable for having attracted Seagen as a deal partner, though LAVA-1207, which targets PSMA, sits outside this tie-up, and has yet to show any efficacy. Bioxcel is better known for CNS assets, and in cancer its talabostat/Keytruda combo now appears to be focusing on patients with the SCNC phenotype.

And also in prostate cancer, Macrogenics fell 17% yesterday after an Asco-GU abstract on its anti-PD-1xCTLA-4 bispecific lorigerlimab showed a 35% rate of severe treatment-related adverse events, leading to a 24% discontinuation rate. This was despite a 26% response rate in a prostate cancer cohort broadly similar to Bristol Myers Squibb’s Checkmate-650 trial, in which Opdivo plus Yervoy managed an ORR of just 10%.

Still, the big Asco-GU focus for many will be the Talapro-2 study of Pfizer’s Talzenna, under wraps until tomorrow. The trial, toplined positive but with no further detail disclosed so far, could help this fourth-to-market Parp inhibitor challenge Astrazeneca/Merck’s Lynparza and GSK’s Zejula in front-line prostate cancer.

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