Phase 1 entrants seek improved safety

As if there wasn’t already enough competition among KRAS G12C inhibitors, a new clinical project from BeBetter Med recently joined the fray. The private Chinese company’s BEBT-607 was flagged by OncologyPipeline in June and started phase 1 in September, but it’s only now that competitors can scrutinise this study’s design, courtesy of a new entry on clinicaltrials.gov.

Other first-time phase 1 entrants to this registry include a CDK4-specific inhibitor from BeiGene that could in time challenge Pfizer’s more advanced PF-07220060. Meanwhile, a very unusual strategy is being pursued by Shanghai Henlius Biotech, which has advanced into the clinic an antibody-drug conjugate that hits PD-L1.

That last asset is coded HLX43, and is scheduled to start phase 1 this week. According to OncologyPipeline only one other industry project features this modality: Seagen’s SGN-PDL1V is a vedotin-employing ADC said to employ direct cytotoxicity as well as bystander killing, and entered a phase 1 solid tumour study in January 2022.

The logic of this mechanism is that PD-L1 is often upregulated on tumour cells, and so the protein can act as a kind of marker for an ADC to deliver its payload, though presumably the risk of toxicity has deterred other players. HLX43 uses a humanised IgG1 MAb linked to a camptothecin-based toxin, and reportedly has a drug-to-antibody ratio of 8.

Improved safety

Seagen is of course being taken over by Pfizer in a $43bn deal, but in the meantime it’s still taking its own projects into the clinic, the latest of which is SGN-35T. This ADC uses the same anti-CD30 MAb (cAC10) and cytotoxic payload (monomethyl auristatin E) as Seagen’s blockbuster Adcetris, but employs a novel tripeptide linker – D-leucine-alanine-glutamate – to improve on Adcetris’s tolerability profile.

Meanwhile, the CDK4/6 inhibitors Ibrance, Verzenio and Kisqali are approved for HER2-negative breast cancer, but it’s been claimed that CDK6 inhibition results in neutropenia, and this is an obstacle to achieving complete CDK4 blockade.

Pfizer, for instance, argues that CDK4 is the key cell cycle driver in breast cancer, and to this end it took its CDK4-specific inhibitor PF-07220060 into phase 3 last month. Now BeiGene is trying the same trick with BGB-43395, which according to clinicaltrials.gov has just started its first human trial, comprising monotherapy and combos.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 30 Oct and 7 Nov 2023.

Other noteworthy new phase 1 entrants over the past week include Johnson & Johnson’s A2AR antagonist JNJ-86974680, which will start in the clinic in PD-(L)1 drug-relapsed NSCLC.

A2AR is the target of projects including iTeos’s inupadenant and Gilead/Arcus’s etrumadenant, the idea being that it might be synergistic with PD-(L)1 and TIGIT blockade, though data so far have failed to convince, most notably in the latter’s Arc-7 study. J&J’s idea is to combine JNJ-86974680 with its own anti-PD-1 MAb, cetrelimab.

And cytokines remain in focus, with Jazz progressing an IFN-α prodrug and Dragonfly taking an IL-2 into the clinic. The latter, private company was set back in February when Bristol Myers Squibb handed back DF6002, an IL-12 project.