Novel Bruton’s Tyrosine Kinase-Targeted Protein Degrader NX-2127 Shows Promise in Double-, Triple-Refractory CLL

The treatment prospects for patients with double- and emerging triple-refractory chronic lymphocytic leukemia (CLL) are currently minimal with no approved therapeutic options available, explained Anthony R. Mato, MD, MSCE, director of the CLL Program at the Memorial Sloan Kettering Cancer Center, during a presentation at the 64th American Society of Hematology (ASH) Annual Meeting and Exhibition in New Orleans, Louisiana. This includes patients who progressed on covalent Bruton’s tyrosine kinase (BTK) inhibitors (cBTKi), non-covalent inhibitors (ncBTKi), and B-cell lymphoma 2 (BCL2) inhibitors. Additionally, Mato noted that survival outcomes for these patients are low.^1,2

“Patients with relapsed/refractory CLL continue to have an unmet medical need, despite the availability of multiple active therapies. BTK mutations underlie that unmet medical need in a growing part of the relapsed/refractory CLL population,” Mato said.¹

Because of the high unmet medical need for this disease state, Mato explained that patients with double- and emerging triple-refractory CLL could benefit from the interruption of BTK kinase-independent scaffolding signaling.¹

“I think we all would agree that there's a major unmet need for new treatment modalities that can target both emerging resistant mutations and BTK scaffolding activity in patients who have otherwise exhausted all approved and emerging treatment options,” Mato said. “NX-2127 [Nurix Therapeutics] is a BTK degrader with immunomodulatory activity, which offers a novel approach to the treatment of relapsed/refractory CLL.”¹

Mato explained that during the clinical trial (NCT04830137) assessing NX-2127 in adults with relapsed/refractory B-cell malignancies, clinical responses and benefit were observed in patients with CLL who were heavily pretreated (with a median of 6 prior therapies) and who had poor prognostic factors (such as BTK mutations resistant to cBTKi and ncBTKi), BCL2 mutations, and were previously treated with BTKi and BCL2 inhibitors.^1,2

Mato noted that the results of this first-in-human phase 1a/1b multicenter, open-label study support further clinical development of NX-2127 for the treatment of CLL, including expansion at the 100 mg dose level, and continued dose exploration for other B-cell malignancies.¹

“Phase 1 clinical and correlative data show the drug to be active with evidence of clinically meaningful responses, a manageable safety profile, and correlative studies confirming on-target activity in patients with relapsed/refractory CLL, independent of their prior treatments or BTK mutational status,” Mato said.¹

Targeted therapies focusing on 2 key pathways, BTK and BCL2, are now the standard of care in CLL and have changed the treatment landscape both in the frontline and in the relapsed/refractory settings, Mato explained. However, emerging patterns of resistance and intolerance can limit the utility of currently available therapies, as well as emerging therapies.^1,2

For example, novel BTK mutations confer broad resistance both to cBTKi and to ncBTKi. Yet, Mato noted that some of these mutations can lead to kinase-dead BTK mutants with intact downstream NF-κB signaling, pointing to a potential scaffolding function of BTK. Additionally, Mato explained that dual resistance to both the BTK inhibitor and venetoclax (Venclexta; Genentech) is a growing problem in the clinic, contributing to a significant treatment challenge in the relapsed/refractory setting.^1,2

Mato noted that NX-2127 works by taking advantage of the ubiquitin proteasome pathway to insert its effects on malignant B-cells. NX-2127 then brings BTK proteins and the cereblon E3 ligase complex together, targeting that BTK protein for ubiquitination and subsequent destruction by the proteasome. Importantly, NX-2127 is recycled during this process, which allows it to be repeated as BTK proteins or are regenerated.^1,2

Further, NX-2127 can degrade BTK and decrease the amount of BTK produced by both wild type and BTK mutated cell lines, resulting in decreased cell viability.¹

“These data suggest that NX-2127 has the potential to address the emerging unmet need arising in the setting of all of these BTK treatment journey mutations,” Mato said.¹

In terms of patient eligibility in the trial, Mato explained that patients with CLL who were enrolled had to have failed at least 2 prior treatments, including the BTK inhibitor. In total, 36 subjects were enrolled, of whom 23 patients had relapsed/refractory CLL and 18 patients were ineligible.¹

“In terms of baseline characteristics, this was an elderly, heavily pre-treated CLL patient population. The median age at enrollment was age 75, and the median number of prior therapies was 5, meaning NX-2127 was, on average, the sixth therapy for these patients,” Mato said. “In addition, 100% of patients were previously treated with a cBTKi, 78% were exposed to both the BTK inhibitor and venetoclax, 35% were previously exposed to pirtobrutinib [L0X0-305], and 30% were triple exposed—a new definition—patients who were previously treated with a cBTKi, ncBTKi, and venetoclax.”¹

In terms of resistance profiles, Mato explained that 48% of patients had at least 1 BTK resistance mutation, with 24% having a newly described BTK mutation that may confer resistance to a ncBTKi. Additionally, 19% of patients had BCL2 mutations.¹

“Given the advanced age, the heavily pretreated character of the patient population, and the resistance profile of the population, this to me represents a very modern population resistant to both current and future therapies with the greatest unmet need,” Mato said. “Overall, the molecule was well tolerated.”¹

References

1. Mato AR. NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton’s Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies. Presented at: 64th ASH Annual Meeting and Exhibition in New Orleans, LA; December 12, 2022.
2. Mato AR, Wierda WG, Weiyun AZ, et al. 965 NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton’s Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies. Accessed December 12, 2022. https://ash.confex.com/ash/2022/webprogram/Paper164772.html