Bridge mirrors Black Diamond and Blueprint’s search for something better

And now for something a little different. That’s what Black Diamond signalled when discontinuing BDTX-189 in favour of BDTX-1535, being rewarded with a 236% share price jump shortly afterwards, and today South Korea’s Bridge Biotherapeutics embarked on a similar strategy when deciding to turn to BBT-207.

Earlier Blueprint had done something analogous – moves that all mark a focus on so-called fourth-generation EGFR inhibitors in treating lung cancer, a space controlled by AstraZeneca’s blockbuster Tagrisso. The aim is to design molecules that can hit mutations not addressable by Tagrisso; in contrast to Black Diamond, however, Blueprint and Bridge already had such projects, whose discontinuation thus signals a drive to develop even better versions.

Last November Blueprint deprioritised BLU-701 in favour of BLU-525, and today Bridge sacrificed BBT-176 so it could focus on BBT-207.

Tagrisso resistance

BBT-176 was said to target mutations including C797S that appear after treatment with third-generation EGFR inhibitors like Tagrisso. Data at last year’s World Lung gave early backing to this claim, suggesting efficacy in patients treated with at least one EGFR-targeting drug; one patient who developed a partial response was found to have NSCLC with a C797S mutation.

However, this was clearly not enough, and Bridge swiftly unveiled another fourth-generation agent, BBT-207, which in April received US authorisation for phase 1. That first-in-human study started this month, testing BBT-207 against EGFR sensitising NSCLC mutations, normally addressable by Tagrisso and earlier-generation drugs, as well as against C797S-mutant NSCLC.

While Bridge acquired rights to BBT-176 from the South Korean government-owned Korea Research Institute of Chemical Technology, BBT-207 appears to have come from its own labs. The group says BBT-207 was designed to hit “a diverse spectrum of mutations”, and preclinically has shown activity in patients with brain metastases – an important consideration that others are also following.

Fast moving

The targeted treatment of mutation-driven NSCLC has developed quickly, and there are now at least five fourth-generation EGFR inhibitors in clinical trials.

Like Bridge, the US biotech Blueprint Medicines has taken several shots on goal. Blueprint had initially worked on the small molecules BLU-945 and BLU-701; both are technically fourth-generation EGFR inhibitors, with activity on C797S mutations, but BLU-945 had poor efficacy in exon 19 deletions while BLU-701 apparently didn’t work against T790m.

Subsequently Blueprint deprioritised BLU-701 in favour of a new fourth-generation molecule coded BLU-525, claimed to have a distinct chemical structure with improved kinome selectivity and differentiated metabolism, equivalent EGFR mutation coverage and CNS penetration. BLU-945 development has been narrowed to a first-line combo with Tagrisso.

4th-generation* projects targeting mutant EGFR

Note: *definition assumes that Iressa & Tarceva are 1st-generation, Gilotrif & Vizimpro are 2nd-generation, Tagrisso, nazartinib & others are 3rd-generation; 4th-generation implies activity in escape mutations developed in response to Tagrisso treatment, C797S and/or other "rare" EGFR mutations; **claimed to have CNS penetration and activity in “nearly all mutant forms of EGFR”, but ph1 trial excludes C797X mutations (these include C797S). Source: OncologyPipeline & company statements.

Meanwhile, Black Diamond’s BDTX-1535 has shown activity in subjects who had failed on Tagrisso, and while five had classical driver mutations (four of these also had acquired resistance mutations), a sixth was said to harbour an unusual “intrinsic driver” mutation, L747P. It’s unclear what activity BDTX-1535 has on T790m, an EGFR mutation acquired after Iressa treatment that was the basis for Tagrisso’s first approval.

In contrast to Bridge and Blueprint, Black Diamond has taken a first foray into fourth-generation EGFR blockade. The asset Black Diamond had discontinued in favour of BDTX-1535 was BDTX-189, a small molecule hitting an EGFR mutation called exon 20 insertion, which is the domain of a separate batch of projects, but which likely represents a tiny slice of the EGFR pie.

Fourth-generation EGFR competition includes Theseus’s THE-349, to which that company had pivoted after its shot at pan-KIT blockade disappointed. Dizal’s sunvozertinib remains something of an unknown quantity; that drug was designed as a “super-Tagrisso”, to hit a range of EGFR mutations, and is notable for having activity both in T790m-driven NSCLC and in exon 20 insertion.

However, sunvozertinib has apparently no activity against C797S, so technically can’t be called a fourth-generation agent. It was approved in China last month, in NSCLC with EGFR exon 20 insertion mutations.