Cell cycle niche seeks clinical validation
Several companies have followed Pfizer into CDK2 inhibitor development, but the jury is out on this field’s promise.
Several companies have followed Pfizer into CDK2 inhibitor development, but the jury is out on this field’s promise.
Blueprint’s abandonment of EGFR inhibitor development for lung cancer this week, a move driven by growing industry competition, was just as notable as one of the areas on which the company now plans to double down: CDK2 blockade.
This second field has quietly been growing, with Pfizer leading an effort to develop a therapy for HER2-negative breast cancer patients who relapse after treatment with a CDK4/6 inhibitor. Though there are many unknowns – for instance whether CDK2 inhibition will work as monotherapy – this space has seen deal activity in addition to an uptick in clinical work.
Just last week Allorion Therapeutics licensed ex-China rights to its CDK2 inhibitor ARTS-021 to the private US biotech Avenzo for $40m up front. The project, now coded AVZO-021, is in a phase 1/2 US study aiming to enrol patients with CCNE1-amplified solid tumours, HER2-negative breast cancer progressed after CDK4/6 inhibitor, or cyclin E1-amplified ovarian cancer progressed after chemo.
Meanwhile, two months ago BeiGene paid an undisclosed up-front fee for rights to Ensem Therapeutics’ ETX-197. And last June Bayer licensed unnamed CCNE1/CDK2 inhibitors that had been in preclinical development at a private US company called Cedilla Therapeutics, which had ceased operations. Deal terms weren’t disclosed, but given Cedilla’s winding up they can’t have been too demanding.
Resistance
What’s so exciting about CDK2 blockade? Put simply, CDK2 is thought to represent a resistance mechanism acquired after treatment with CDK4/6 inhibitors like Kisqali, Verzenio and Ibrance, a phenomenon driven by upregulation of CCNE1 (cyclin E1). And, independent of CDK4/6 inhibitor exposure, some tumours overexpress CCNE1 or harbour CCNE1 gene amplifications.
Still, despite the preclinical promise offered by these pathways, there’s very little clinical data to go on. The most advanced result concerns Pfizer’s PF-07104091, from a monotherapy dose-escalation phase in which three partial responses were seen among 16 post-CDK4/6 inhibitor breast cancer patients.
The data, presented at last year’s ASCO, showed no activity in a further 16 subjects with other tumour types. Interestingly, Pfizer’s first-in-human study had included a combination with Ibrance that has now been discontinued; in a separate trial the company is combining PF-07104091 with its own CDK4-specific inhibitor PF-07220060.
If Pfizer has now seen a promising sign of monotherapy activity the same can’t be said of an ASCO poster featuring the Vela trial of Blueprint’s BLU-222. This yielded just one partial response, in a sixth-line breast cancer patient, among 27 treated, and Blueprint is now focusing on BLU-222 combinations.
It’s notable that, while the company claims that BLU-222 has best-in-class potential, it’s hedging its bets with a “next-generation” CDK2 inhibitor, BLU-956, as well as an unnamed CDK2 degrader. Also working preclinically on CDK2 degraders are Monte Rosa, which hopes to nominate a lead this year, and the private company Plexium.
CDK2 inhibitors in development
Note: excludes preclinical CDK2 degrader projects from Monte Rosa, Plexium & Blueprint; Rhizen has patented CDK2 inhibitors, but none appears in its pipeline. Source: OncologyPipeline.
Among the handful of other clinical players, Incyte this week promised first formal data on INCB123667 in 2024, claiming to have seen partial responses in multiple tumour types including CCNE1-positive ovarian cancer. Still, Incyte is being cautious, saying already that this field is getting crowded.
Certainly, the presence of big pharma players might be daunting. Pfizer was recently joined in the clinic by AstraZeneca, which took its CDK2 inhibitor AZD8421 into a complex first-in-human study that includes not only monotherapy and CDK4/6 combos, but also combination with the company’s SERD camizestrant.
One other private group, Incyclix Bio, has a CDK2 inhibitor in phase 1/2. However, though it had preclinical data at last year's AACR, its last raise appears to have been a $30m series B led by Boxer Capital in March 2022, so the precise status of this project, INX-315, is unclear.
On the plus side the CDK2 space is nowhere near as crowded as EGFR. How long it remains that way will likely depend on the strength of clinical data from Pfizer, Blueprint and Incyte.
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