EHA 2024 – Nurix and BeiGene’s degraders shine

Efficacy data presented at the European Hematology Association meeting suggest that BTK degradation, specifically involving projects in development by Nurix and BeiGene, could one day represent a new approach to treating chronic lymphoblastic leukaemia, where BTK inhibitors are currently used.

The data, unveiled over the weekend, are a significant advance on the handful of patients detailed at the ASH conference in December. Especially intriguing findings are those of activity in BTK C481S mutants – the target of the new generation of non-covalent BTK inhibitors like Lilly’s Jaypirca – as well as in patients in whom such novel BTK inhibitors had already failed.

Nevertheless, the markets seem hard to please. Nurix, whose $930m market cap is most exposed to BTK degradation (the company has two assets here, NX-5948, the subject of the EHA dataset, and NX-2127), saw its stock fall 9% on Friday ahead of Sunday’s presentation at EHA, before closing up just under 1% yesterday.

So far investors have an NX-5948 dataset comprising 27 CLL patients at a 17 April data cutoff, up from seven presented at ASH. The headline number is a 67% partial response rate.

It’s possible that investors are still waiting for more on response durability – all but six patients are at under six months’ follow-up, though Nurix stressed that all responses were ongoing. Possibly the stock performance reflects the likelihood of an imminent fund raising, or disappointment at the lack of any complete responses seen so far.

On an investor call Nurix said complete responses weren’t common in CLL, but that some would be seen once more patients were treated with NX-5948. 

For its part, BeiGene presented an EHA update on its BTK degrader, BGB-16673, comprising 43 evaluable patients and showing an ORR of 72%, which included two complete remissions.

If on a cross-trial basis BGB-16673 looks slightly better than NX-5948, there could be a toxicity price. 12% of patients treated with the BeiGene degrader discontinued owing to an adverse event, versus 3% among all-comers in the Nurix study.

Activity in BTK mutations

Follow-on BTK approaches are in focus because of resistance build-up to the first generation of covalent inhibitors, Imbruvica, Calquence and Brukinsa. For this reason several non-covalent BTK inhibitors are in development, most notably Lilly’s Jaypirca, which are said to overcome resistance mechanisms, in particular the C481S mutation.

It’s especially important for a BTK degrader to show activity in resistance mutations too, while activity in patients in whom a non-covalent BTK inhibitor has failed is the icing on the cake. So far only hints of activity are available in the EHA presentations, but nevertheless the signs seem highly positive for both Nurix and BeiGene.

Both projects look active in patients with the C481S mutation, with ORRs of 55-83%. And, in those already treated with a non-covalent drug like Jaypirca, the ORRs were 43% for NX-5948 and 55% for BGB-16673; caveats include the still small numbers of patients and relatively short follow-up.

It’s now up to both companies to show consistent longer-term data in additional subjects. Nurix next plans to go into dose expansion in CLL, and promises data from non-Hodgkin’s lymphoma and Waldenström's macroglobulinaemia patients in the second half.

Battle of the BTK degraders

Notes: ORR data include partial responses with rebound lymphocytosis; *includes 2 complete remissions; **includes 1 complete remission. Source: EHA.