Gilead is next into target degradation

Gilead has quickly become the biggest oncology dealmaker of the year so far, following the $7.8bn takeover of Arcellx and $3.2bn acquisition of Tubulis with a full licence to Kymera Therapeutics’ CDK2 degrader KT-200, announced on Thursday.

The latest deal is tiny by comparison, involving a $45m payment, structured as an exercise fee that comes 10 months after Gilead took out an option over this asset for $85m. But it marks Gilead’s first move into target degradation, an increasingly popular approach, and features CDK2, which despite some setbacks has benefited from buy-in from several big pharma groups.

In CDK2 inhibition Incyte last year took INCB123667 into the phase 3 Maestra-2 study in platinum-resistant ovarian cancer, making this molecule the industry’s most advanced with this mechanism. Other notable CDK2 inhibitors include Pfizer’s tegtociclib, AstraZeneca’s AZD8421 and Novartis’s ECI830, while in 2024 Roche paid Regor $850m for RGT-419B, a CDK4 inhibitor that has some activity at CDK2.

But degradation is seen as a more potent modality than mere inhibition, and indeed Gilead and Kymera have played up this possible advantage, claiming that “traditional CDK2 inhibitors” can lack specificity and interfere with closely related proteins, causing toxicity, but that degraders might prove more precise, and as a result be safer.

Very early

While the total outlay on KT-200 of $130m so far might not seem like much, it represents a significant bet on a molecule still in very early development, with Gilead not expecting even to submit an IND filing for it until 2027.

That puts Gilead behind NiKang’s NKT3964 and BeOne’s BG-75098, which are both in phase 1 already. On the plus side, however, this is still a relatively new area, and those are the only two companies with clinical-stage CDK2 degraders at present; NiKang is additionally developing a dual CDK2/4 degrader, NKT5097, also in phase 1.

BeOne is also notable for developing a CDK2 inhibitor (BG-68501) in addition to trying the degrader approach. As for the CDK2 degrader competition, the next molecule into human trials might be Monte Rosa’s MRT-51443, which that company recently said it was moving towards clinical development.

Another preclinical player, Cullgen, was last month bought out by the fibrosis specialist Gyre Therapeutics in a $300m all-stock deal, though the focus for that was probably two other, clinical-stage, degraders. Cullgen’s pipeline also includes undisclosed preclinical degrader-antibody conjugates – a novel approach that on Thursday saw Roche tie up with C4 Therapeutics in a discovery deal worth $20m up front.

The CDK2 degrader pipeline

Note: *dual CDK2/4 degrader. Source: OncologyPipeline.