Pan-KRAS inhibition, already a popular space, is becoming busier still with the imminent clinical entry of assets from China’s Chia Tai and the private US group Kestrel Therapeutics. Kestrel is claiming potential best-in-class efficacy with its project, KST-6051, but it’s behind other players in this space, which include the likes of AstraZeneca.
Meanwhile, the latest listings on clinicaltrials.gov also highlight a joint venture between BioLineRx and Hemispherian, which is taking aim at a novel target, TET2, and show Kelun progressing with a bispecific ADC against tumour-associated antigen (TAA) and PD-L1.
Pan-KRAS
Various companies are developing both pan-RAS and pan-KRAS inhibitors, though it's unclear whether either approach has the edge. The leader across the two fields is Revolution Medicines, whose pan-RAS blocker daraxonrasib is soon to report its first randomised phase 3 data.
The jury might still be out on the merits of the two approaches, but it's clear that pan-RAS is less crowded that pan-KRAS; AstraZeneca put its bet on pan-KRAS inhibition when it gained ex-China rights to Jacobio’s JAB-23E73 late last year. Others, like Astellas, are developing pan-KRAS degraders, while Erasca has a pan-RAS “molecular glue” in the Joyo-originated ERAS-0015.
Chia Tai and Kestrel will have their work cut out to set their projects apart.
Elsewhere, BioLineRx and Hemispherian established a joint venture last September primarily to develop GLX1, a TET2 agonist. By restoring TET2 activity, GLX1 is designed to spur the formation of double-stranded DNA breaks and apoptosis specifically in cancer cells.
GLIX1 is being tested in glioblastoma; there are no other TET2-targeting projects in development, according to OncologyPipeline.
Mystery asset
Kelun’s big claim to fame is attracting Merck & Co as a partner, first for the anti-TROP2 sacituzumab tirumotecan, then for various other assets, including undisclosed preclinical compounds.
It’s therefore possible that the latest project, SKB103, could be covered by the Merck deal, although this is still unknown. The upcoming Chinese phase 1/2 solid tumour trial is due to start at the end of April. A look at OncologyPipeline shows that there are no other bispecific ADCs against TAA and PD-L1, although several PD-L1 ADCs are in development, including Pfizer's fetrastobart vedotin and Henlius's HLX43, both in, or about to enter pivotal studies.
Earlier this year it emerged that another Kelun-Merck ADC, SKB571, likely targets EGFR and cMet – the same targets as Johnson & Johnson’s approved bispecific MAb Rybrevant. The field seems to be moving increasingly towards ADC, a shift that includes J&J, which is challenging itself with JNJ-95437446.
Coincidentally, another newly listed clinical-stage asset, Shanghai Henlius’s ADC HLX48, could also go up against Rybrevant.
And EpiBiologics’ EPI-326 is a “tissue-selective” bispecific MAb designed to degrade oncogenic forms of EGFR while sparing healthy tissue. The private California-based company raised $107m in a series B round in January co-led by Google Ventures and J&J Innovation.
Another first-in-human project with an undisclosed mechanism is BioNTech’s bispecific MAb BNT3214 (PM8102), gained via its $800m acquisition of Biotheus in 2024. While that deal was primarily driven by the PD-L1 x VEGF project pumitamig, later flipped to Bristol Myers Squibb, Biotheus also had an extensive clinical and preclinical pipeline, and it seems that BioNTech remains interested in at least some of these assets.
Recently disclosed first-in-human studies*
This story has been updated to include the targets of Kelun's SKB103.
