A new order in BTK inhibition

If Imbruvica set a new standard in treating chronic lymphoblastic leukaemia then it hasn’t enjoyed its monopoly for long. Several newcomers have emerged, with BeiGene’s Brukinsa challenging it on its own turf while even more novel BTK inhibitors have sought to cut off future avenues.

The recent ASH conference featured several novel drugs – not only Lilly’s non-covalent Jaypirca, but also projects from Nurix, Dizal and BeiGene designed to overcome resistance to the latest BTK inhibitors. As for the traditional space of covalent BTK blockade, perhaps the biggest head-turner was Brukinsa’s failure to beat Imbruvica on overall survival in the Alpine study.

Still, it’s early days here, and neither cohort has reached a median. A landmark analysis showed 82.5% of the relapsed/refractory CLL patients given Brukinsa still alive at 36 months, versus 79.6% of those on Imbruvica, so there is at least hope that an OS benefit will emerge with even longer follow-up.

Alpine was the first large trial comparing two BTK inhibitors head to head to show a statistical PFS benefit, and this showed Brukinsa to be superior to Imbruvica; these data have just been added to Brukinsa’s US label. On a cross-trial basis Brukinsa also seemed better than AstraZeneca’s Calquence, which itself had only been shown to be non-inferior to the AbbVie/J&J drug.

Non-covalent

This trio are all covalent BTK inhibitors, and the subsequent development of non-covalent BTK blockers, of which Jaypirca was the first approved, was aimed at overcoming primary resistance.

A focus for Lilly is moving Jaypirca forward in treatment, with a first-line CLL trial reading out next year, and a head-to-head study versus Imbruvica still years from completion. The next furthest advanced non-covalent BTK inhibitor is the Arqule-originated nemtabrutinib, which Merck & Co has taken into phase 3.

A curious approach is Newave’s LP-168, said to bind covalently under normal circumstances, but non-covalently if BTK carries the C481 resistance mutation. An ASH oral session did back this up, but there was no activity in patients who had already received a covalent as well as a non-covalent BTK inhibitor.

This suggests that non-covalent drugs like Jaypirca aren’t the end of the story, as patients can develop resistance to them too. For this reason some companies are working on projects that, rather than just inhibiting, degrade the BTK receptor.

Degradation

Nurix has two of these, NX-5948 and NX-2127, and first-in-human trials of both featured in ASH posters. For the former the focus was a seven-strong cohort of CLL patients, three of whom went into partial remission after getting NX-5948. All had progression after BTK blockade, but only one had received Jaypirca; it wasn’t stated whether the post-Jaypirca subject responded.

Though this study also included lymphoma, Nurix will pursue this indication not with NX-5948 but with NX-2127; the latter degrades BTK as well as the cereblon substrates Ikaros and Aiolos.

In the NX-2127 study (on partial hold since November) Nurix cited two partial and two complete remissions among 17 lymphoma subjects. One remission was in diffuse large B-cell lymphoma, while the other three were in the less aggressive, follicular subtype; again, activity specifically in post-Jaypirca patients, of whom there were five, wasn't disclosed.

The CLL cohort of the NX-2127 study did show partial responses in post-Jaypirca patients, but CLL isn’t a focus for NX-2127. At an investor event Nurix argued that doctors don’t differentiate between covalent and non-covalent BTK inhibitors; this might be so, but unless Nurix consistently shows activity in Jaypirca-relapsed patients it could find it tough to find a way in.

BeiGene and Dizal

One company that, going into ASH, had specifically promised activity in patients in whom non-covalents have failed was BeiGene, with its own BTK degrader BGB-16673. Its 28-strong efficacy-evaluable dataset included four patients who had progressed on non-covalent BTK blockade; three of these responded to BGB-16673.

And a separate tack entirely is being pursued by China’s Dizal, which is developing DZD8586, a blocker of BTK as well as of Lyn. This molecule was designed because of the finding that only 50% of patients who develop resistance to a first-generation BTK inhibitor do so via the C481 mutation.

The rest “have mutations where BTK is ‘dead’, or has substantially decreased enzymatic activity”, Dizal’s chief executive, Xiaolin Zhang, told ApexOnco during ASH. “Clearly this suggests that one BTK resistance mechanism isn’t BTK dependent.” 

Lyn, a member of the Src tyrosine kinase family, was found to be one such non-BTK resistance mechanism, which is why DZD8586 aims to hit it as well as C481. Dizal’s ASH poster, however, backed only the latter claim, so the question of overcoming resistance to Japyirca remains open.

Selected next-generation BTK data

Source: ASH 2023.