Lilly makes steady progress in non-covalent BTK inhibition

It took just over two years from Jaypirca’s groundbreaking ASH 2020 data for this Lilly non-covalent BTK inhibitor to secure its first US approval, in mantle cell lymphoma, and now the same trial has backed a second use in the more important setting of chronic lymphoblastic leukaemia.

The FDA has greenlit both late-line uses on an accelerated basis, and Lilly on Friday revealed that the phase 3 confirmatory CLL trial had already yielded a positive result; these data haven’t been disclosed, but they are under review by the regulator. The key to unlocking Jaypirca’s full potential lies in front-line settings, however, and here the market is changing fast.

At the time Jaypirca was conceived – at the UK company Redx, before its purchase by Loxo, which itself was sold to Lilly – the dominant BTK inhibitor was AbbVie/Johnson & Johnson’s Imbruvica. Patients treated with this covalently acting drug are liable to relapse via C481S and other mutations, against which Jaypirca is said to remain active.

Jaypirca’s MCL and CLL approvals support this mechanism – both concern patients who have failed at least two therapies, including a covalent BTK inhibitor. The uncontrolled Bruin study that backs both settings showed a 71% ORR in CLL patients who had failed BTK inhibition specifically via C481S (in MCL the C481S mutation is rare, so relapse here generally had a different mechanism).

The phase 3 trial Lilly said had read out positively for PFS is Bruin CLL-321; not only is this designed to confirm the third-line setting of Jaypirca’s current CLL label, it could support expansion into second-line CLL.

And the big prize is front-line CLL, where the Bruin CLL-313 trial ends late next year, testing Jaypirca versus Rituxan. A study head-to-head against Imbruvica (Bruin CLL-314) won’t read out for a number of years, and includes settings other than the front line.

Key trials of Jaypirca

Source: OncologyPipeline.

When these trials were designed Imbruvica was still seen as the BTK inhibitor to beat, but today BeiGene’s Brukinsa is fast emerging as the best covalent BTK drug.

At last year’s ASH, in BeiGene’s Alpine trial Brukinsa beat Imbruvica head to head, with a PFS benefit that looked better than Calquence's on a cross-trial basis; Calquence’s own study against Imbruvica, Elevate-RR, showed only non-inferiority versus the AbbVie/J&J drug.

Other changes

Such considerations will be sobering for Lilly, which could have its work cut out to convince doctors of Jaypirca’s preference above all BTK drugs, not just Imbruvica.

And there are other changes in this market too. BeiGene told the recent Jefferies London healthcare conference that it saw Brukinsa plus its Bcl-2 inhibitor sonrotoclax as a future first-line CLL standard of care; at ASH it will present a poster on an in-house BTK degrader, BGB-16673, given after non-covalent as well as covalent BTK inhibition. 

There is movement on the non-covalent scene too. Merck & Co, which in 2019 paid $2.7bn to acquire ArQule, last month put the latter’s non-covalent asset nemtabrutinib into phase 3 at last. This trial is going head-to-head against Imbruciva or Calquence first line, so this project could represent a future threat to Lilly.

With such bold plans across the BTK scene it’s worth remembering how Lilly ended up with Jaypirca. The story began with Redx, the inventor of Jaypirca’s active ingredient, pirtobrutinib, being put into administration when a local UK authority, Liverpool City Council, called in an infrastructure loan of just £2m ($2.6m) after the company moved its headquarters out of the region.

With the administrator keen to make a quick sale to keep the business afloat, rights to the molecule were sold to Loxo in 2017 for just $40m with no future earnouts. Two years later Lilly bought Loxo for $8bn.