AACR: BTK degrader could treat CNS B-cell malignancies

First evidence of clinical activity in the brain for a targeted protein degrader has been demonstrated with NX-5948, an orally available, selective degrader of Bruton’s tyrosine kinase (BTK).

The small molecule anti-cancer treatment from Nurix Therapeutics is currently being investigated in a Phase I clinical trial in patients with relapsed or refractory B cell malignancies.

NX-5948: a novel small molecule treatment

One case study demonstrated partial response with the BTK degrader in chronic lymphocytic leukaemia with secondary central nervous system (CNS) involvement and disease progression following three prior lines of treatment.

The patient was given NX-5948 100mg once per day. By week 16, the patient had experienced continued reduction in lymph nodes and spleen size and improvements in haematologic measures consistent with a partial response, which was confirmed by week 24, the data showed.

“[Clinical responses] seen to date with NX-5948 in patients with significant brain disease support future exploration of NX-5948 both as a single agent and in combination with other therapies that are used for primary and secondary CNS lymphoma and leukaemia,” shared Dr Arthur Sands, PhD, President and Chief Executive Officer of Nurix.

“The [chronic lymphocytic leukaemia] patient with CNS involvement showed an impressive durable response with NX-5948 as single agent therapy in this setting. [Based on a second case study], the patient with [primary central nervous system lymphoma], and an aggressive NHL histology, showed a rapid, complete response, providing clear evidence of therapeutic effect in the brain that has the potential to be augmented through combination therapies to improve durability of response,” Dr Sands added.

Significance of the BTK degrader Phase I results 

“These data are the first demonstration of clinical activity in the brain of a targeted protein degrader, opening the door for new therapeutic strategies to treat leukaemia’s and lymphomas with CNS involvement,” commented Dr Gwenn Hansen, PhD, Chief Scientific Officer of Nurix.

“The brain penetration of NX-5948 coupled with the clinical activity and safety profile presented to date, suggests a potential role in the treatment of B-cell lymphomas and chronic lymphocytic leukaemia involving the [central nervous system] which are notoriously difficult to treat. It also suggests the potential to use NX-5948 as a therapeutic option for immune indications with CNS involvement such as multiple sclerosis.”

These data were presented at the 2024 American Association for Cancer Research (AACR) 2024 Annual Meeting.