A class of targeted protein degraders offers a possible strategy to overcome BTK inhibitor resistance in chronic lymphocytic leukemia

[CLLerinOz]

A research article published in the journal Blood this week reports on a possible way forward for those with CLL who develop BTK inhibitor resistance that is associated with C481 mutations.

The article is about NRX-0492, a targeted protein degrader.

"NRX-0492 induced rapid and sustained degradation of wild type and C481 mutant BTK at sub-nanomolar concentrations in primary CLL samples.

Orally administered NRX-0492 abrogated BTK dependent signaling and demonstrated anti-CLL activity in patient derived xenografts in vivo."

"Oral bioavailability, >90% degradation of BTK at sub-nanomolar concentrations and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022)." (my emphasis)

NRX-0492 Degrades Wildtype and C481 Mutant BTK and Demonstrates in vivo Activity in CLL Patient Derived Xenografts. Blood 2022; blood.2022016934. doi.org/10.1182/blood.20220...

Trial NCT04830137 is "A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies"

clinicaltrials.gov/ct2/show...

Trial NCT05131022 is "A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies"

clinicaltrials.gov/ct2/show...

NRX-0492 "links a non-covalent BTK binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK."

Here is an earlier 2019 report about NRX-0492:

ashpublications.org/blood/a...

While resistance remains an ongoing challenge in CLL, it's worth remembering that BTK inhibitors provide an excellent outcome for so many. An abstract being presented at ASH 2022, reports on a study that found that patients "who initiate Ibr [ibrutinib] over an 8- y follow-up have similar survival estimates as age-matched pts in the general population."

healthunlocked.com/cllsuppo...

Note: This is an open (unlocked) post.

[jonathan7176]

Brilliant - fingers crossed for the trial ......

[Justasheet1]

Ozzie,

This sounds very promising. I hope more data is posted soon on the progress of the Phase 1 clinical trial.

For now we have Pirtobrutinib almost ready for approval for the resistant clones.

Jeff