Lilly’s big Jaypirca test approaches

Lilly’s non-covalent BTK inhibitor Jaypirca is supposed to be better than covalent BTK drugs like Imbruvica or Brukinsa, and a key test for this thesis is approaching. Phase 3 data are expected soon from two phase 3 trials in first-line chronic lymphocytic leukaemia – one of which is testing Lilly’s drug head-to-head against Imbruvica.

The pressure is on Lilly after Jaypirca showed a benefit on progression-free survival – but not on overall survival – in its confirmatory second-line CLL trial, Bruin CLL-321. That study was confounded by crossover, but the result still raised questions about whether Jaypirca’s third-line approval, on an accelerated basis, might be rescinded.

A first-line win could also help Lilly justify the $8bn purchase of Loxo, for which Jaypirca was a key driver. The drug, which also has accelerated approval for third-line mantle cell lymphoma, sold $337m in 2024.

Covalent vs non-covalent

As a non-covalent BTK inhibitor Jaypirca is said to remain active where traditional, covalent BTK drugs can trigger escape mutations in the BTK protein that cause patients to relapse.

In the next few months it should become apparent whether this gives Jaypirca an edge when it comes to efficacy. The Bruin CLL-314 trial is testing Lilly’s drug against AbbVie and Johnson & Johnson’s Imbruvica, in both treatment-naive and experienced subjects, but all patients must be naive to previous BTK inhibition.

Given that Jaypirca's possible advantage centres on preventing relapse, it's curious that CLL-314's primary endpoint is overall response rate. Perhaps Lilly's first aim is to show non-inferiority to covalent BTK inhibition on ORR, with the potential of a survival advantage coming later as the cherry on the cake.

Either way, the Resonate and Resonate-2 trials of Imbruvica in previously treated and treatment-naive CLL respectively, give an idea what Jaypirca will need to do. In Resonate Imbruvica produced an ORR of 43%, and the corresponding number in Resonate-2 was 82%.

Primary completion of Bruin CLL-314 is set for June, a delay to the previous estimate of February 2025, but an advance on the original date in 2028. And Bruin CLL-314 is now just a month behind another first-line study, Bruin CLL-313, which was originally expected to complete much faster.

Bruin CLL-313 tests Jaypirca against bendamustine plus Rituxan, with a primary endpoint of PFS. Chemo is still used in first-line CLL, but in recent years it’s been joined by targeted therapies like BTK and BCL-2 inhibitors.

While Lilly hopes to gain market share from the covalent BTK inhibitors, a challenge could be coming from BTK degraders; BeiGene recently revealed plans to start a study testing its contender, BGB-16673, head-to-head against Jaypirca in second-line CLL.

Phase 3 trials of Jaypirca in CLL

Source: OncologyPipeline & clinicaltrials.gov.