KRAS crowding continues

It might be a new year, but KRAS inhibition continues to be in fashion. The latest new listings on the clinicaltrials.gov registry reveal a G12D inhibitor from Incyte, which obviously has not been deterred by the growing competition.

Meanwhile, Zai Lab hopes to succeed where Rova-T failed, AstraZeneca is not daunted by CD123’s track record, and China’s Cure Genetics tries a new cell therapy approach. 

Incyte joins the fray

With its KRAS G12D inhibitor INCB161734 going into humans, Incyte joins the likes of Mirati, Gilead and Revolution; Revolution is also testing its pan-KRAS inhibitor in patients with G12D mutations, among others. Still, the first clinical data with a G12D inhibitor, Jiangsu Hengrui’s HRS-4642, disappointed at last year’s ESMO meeting, so the remaining players here still have questions to answer.

In the even more crowded KRAS G12C arena, BridgeBio today said the FDA had cleared the IND for BBO-8520; the trial is not yet listed on clinicaltrials.gov. That small molecule is said to bind to KRAS G12C in both its on and off states, while currently approved drugs only hit the off state; BBO-8520 could therefore address resistance to first-generation KRAS inhibitors, BridgeBio believes. Revolution is also targeting the on state with its RAS inhibitors.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 21 Dec 2023 and 2 Jan 2024.

Another familiar target is DLL3, which has had a renaissance of late, several years after the discontinuation of AbbVie’s antibody-drug conjugate Rova-T over toxicity and unimpressive efficacy. The field has been helped by Amgen's success at ESMO with its bispecific T-cell engager tarlatamab in small-cell lung cancer; that project is due an FDA approval decision by 12 June.

Notably, Zai Lab’s newly clinical-stage ZL-1310 is an ADC, while the DLL3 pipeline mostly comprises bispecifics (and some trispecifics). The project, licensed from MediLink, is said to be a next-generation ADC, and Zai Lab must be confident of overcoming the problems seen with Rova-T which, it has been suggested, might have been down to a suboptimal payload or linker.

As easy as CD123

CD123 has also been linked with toxicity, with several projects on the scrapheap, including two Xencor-originated assets, the Johnson & Johnson-partnered MAb talacotuzumab, and the Novartis-partnered bispecific vibecotamab, following clinical holds. Deaths were also seen with Cellectis’s autologous Car-T contender UCART123, although this is still in play. 

Perhaps AstraZeneca is banking on a better risk/benefit profile with a more targeted approach: its CD123-targeting asset AZD9829 is an ADC. ImmunoGen looks to be the only other company with a similarly acting project; its pivekimab sunirine is in phase 2. 

Elsewhere, companies are increasingly looking to address resistance mutations seen with current EGFR inhibitors, illustrated by AstraZeneca’s preclinical deal with Allorion yesterday. South Korea’s Therapex has become the latest to hit the clinic here with TRX-221, which targets EGFR C797S. Therapex’s study, slated to start in April, will test the project in EGFR-mutant NSCLC patients who have progressed on an EGFR TKI like Astra’s Tagrisso; notably, the therapy is not being combined with an earlier-generation TKI.

Only one cell therapy features in this list of first-in-human projects, but it's an unusual one. Cure Genetics’ CGC-729 comprises natural killer (NK) T cells, a relatively rare subtype that is distinct from NK cells. Still, this approach has not had much success in the past, with little progress from the likes of Cell Medica, which began work on NKT cells in 2016. CGC-729 actually went into the clinic in July, but it was only recently listed on clinicaltrials.gov.