A pivotal push from BeiGene

BeiGene's full-year update last week revealed the fast progression of two of the group's highest-profile oncology assets, the BTK degrader BGB-16673 and the CDK4 inhibitor BGB-43395, into phase 3 trials.

The latter lags Pfizer's rival atirmociclib, which entered its first pivotal study in mid-2023, a fact that might explain BeiGene's haste; at the time atirmociclib went pivotal BGB-43395 hadn't even been tested in a human subject. Meanwhile, the race in BTK degradation is against Nurix's NX-5948, and BeiGene has revealed plans to pit BGB-16673 head to head against Lilly's Jaypirca.

Nurix isn't sitting still either. In January the biotech said NX-5948 would enter pivotal development in 2025, in trials involving monotherapy and combinations across different therapy lines, and including a likely first-line combo with Venclexta. BTK is one of the few targets where degradation has shown promise, and early data have shown BGB-16673 and NX-5948 to be running neck and neck in terms of efficacy.

Start this month

A new entry on the clinicaltrials.gov registry in fact revealed that the first pivotal study of BGB-16673 would begin within a week, involving a late-line setting where CLL patients have progressed on a (presumably first-generation) BTK inhibitor as well as an anti-BCL2 drug like Venclexta. This is broadly analogous to the settings in which BGB-16673 and NX-5948 have yielded ORR data.

But for any BTK degrader it will be key to challenge non-covalent BTK inhibitors like Jaypirca, given the latter's potential to remain active in CLL patients who relapse on first-generation covalent BTK drugs like Imbruvica, Brukinsa and Calquence. This is why BeiGene's revelation of the head-to-head trial against Jaypirca is so important.

Nothing is known yet about the precise design of this study beyond its planned initiation in 2025. BeiGene's argument is that only some BTK relapse mechanisms are overcome by non-covalent inhibition, and target degradation could be longer-lasting.

The company claims that median PFS in its Cadance-101 phase 1 study hasn't been reached at median 10.2 months' follow-up, while Japyirca's Bruin-321 trial has shown a median of 14.0 months, in a less BTK and BCL2 inhibitor exposed population.

BeiGene's new pivotal efforts

Source: OncologyPipeline.

Meanwhile, in CDK4 inhibition Pfizer has already made a concerted push with atirmociclib, positioning it as an improved follow-up to its established CDK4/6-targeting breast cancer drug Ibrance.

A pivotal second-line trial is well under way, and could deliver results this year, while a front-line study, Fourlight-3, pitting atirmo head to head versus investigator's choice of CDK4/6 inhibition, began in January. Meanwhile, BeiGene's shot at CDK4-specific inhibition, BGB-43395, only started phase 1 in December 2023, and this study has so far yielded only safety and early pharmacology data, at last year's San Antonio Breast Cancer Symposium.

But BeiGene has big plans, citing internal estimates of peak BGB-43395 sales of $5bn a year. It had already talked up taking the molecule into phase 3 studies in the second and first-line settings, and now says the latter trial could start "as early as the fourth quarter of 2025". Presumably, however, moving at such speed will depend on phase 1 generating some promising data.