zelebrudomide (NX-2127)

While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance-both intrinsic and acquired-poses a significant challenge, often associated with BTK mutations like C481S...Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials...These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy.

We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL.

P1, N=266, Recruiting, Nurix Therapeutics, Inc. | Active, not recruiting --> Recruiting | N=160 --> 266 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

P1, N=160, Active, not recruiting, Nurix Therapeutics, Inc. | Recruiting --> Active, not recruiting

This first-in-human study of NX-2127 is actively enrolling and dose-expansion cohorts in DLBCL and MCL have been initiated at the 300 mg daily dose. Findings include dose-dependent PK accompanied by degradation of BTK and Ikaros. Encouraging and persistent responses were observed in heavily pretreated patients with relapsed/refractory CLL and NHL with a manageable safety profile.

P1, N=160, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: Nov 2023 --> Dec 2025 | Trial primary completion date: Oct 2023 --> Dec 2024

The C481S and C481R mutations eliminated the anti-proliferative effects of covalent inhibitors ibrutinib, acalabrutinib, and zanubrutinib, whereas the V416L, T474I, and L528W mutations had variable effects on the covalent inhibitors. By contrast, the non-covalent inhibitors pirtobrutinib, vecabrutinib, and fenebruitnib maintained activity against C481S but displayed partially reduced potency against the C481R mutation and dramatically reduced potency against the V416L, T474I, and L528W mutations...These degrader molecules may also have utility in earlier lines of therapy due to their ability to suppress scaffold-mediated BTK signaling. Phase 1a/b trials of NX-5948 and NX-2127 in patients with relapsed or refractory B-cell malignancies are ongoing (NX-5948: NCT05131022; NX-2127: NCT04830137).

In addition to direct anti-neoplastic effects, BTK inhibitors ibrutinib and acalabrutinib were found to favorably modulate T-cell function in pre-clinical and clinical studies of CLL...In vitro polarization assays indicated that treatment with 1 μM NX-2127, but not NX-5948, resulted in a dramatic and significant upregulation of both IFN-γ and IL-2 under TH1-polarizing conditions, to a degree which significantly exceeded the effect of either ibrutinib or lenalidomide... CRBN-recruiting BTK degraders NX-2127 andNX-5948 induce degradation of BTK in primary CLL cells and do not interfere with T-cell activation and survival in vitro. More importantly, CRBN-immunomodulatory activity was required to upregulate CD38 (an IFN response gene), promote T-cell differentiation towards a TH1 phenotype, downregulate Treg differentiation, and facilitate immunological synapse formation, suggesting NX-2127 has the potential to reverse the immunosuppressive environment of CLL. Overall, our findings provide a strong rationale for continued investigation of these BTK degraders in CLL and lymphoid malignancies.

1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9 “BTK degraders”, such as NRX- 2127 (Nurix Therapeutics) and BGB-16673 (Beigene), have entered clinical trials in patients with lymphoid malignancies...Additionally, NX-2127 has shown preclinical activity similar to immunomodulatory drugs (IMiDs) by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in increased T-cell activation.10 Early results of an ongoing clinical trial of NX-2127 demonstrate an ORR of 33% in heavily pre-treated patients with CLL, and overall good tolerability 11...The preclinical activity of AZD5991 has shown that selective targeting of MCL1 induced metabolic dysfunction and abrogated survival of diffuse large B cell lymphoma and ibrutinib-resistant mantle cell lymphoma cell lines in vivo and in vitro.13 Other BH3-mimetics targeting MCL1 include AMG176 and S63845.14-16 In an experimental design testing the effects of AMG-176 on CLL and normal hematopoietic cell death it was demonstrated that AMG-176 is an active agent in inducing CLL cell death while sparing normal blood cells...Anti-CD20 monoclonal antibodies – rituximab, obinutuzumab and ofatumumab – have significantly improved the survival outcomes. The B cell activating factor receptor (BAFF-R) is one of the main pro-survival receptors in B cells.18 In a preclinical study, ianalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells and showed promising activity both as a single agent and in combination with ibrutinib.19 A phase 1 study of dose escalation and dose expansion investigated the combination of ianalumab with ibrutinib in 32 patients with CLL with median one prior line of therapy (range, 0-4)...This study showed promising results not expected with ibrutinib alone.20 Tafasitamab – a Fc-enhanced, humanized, monoclonal antibody to CD19 – in combination with idelalisib or venetoclax in 24 patients has been associated with an ORR of 77% and 91%, respectively...In a phase 1 study involving 26 patients with R/R CLL, cirmtuzumab administered at four biweekly infusions was shown to have a long plasma half-life and did not have dose-limiting toxicity, potentially providing another treatment opportunity for patients with CLL.22 Immune Cell Enabling Therapies...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confirmed efficacy in patients with R/R CLL.23 In this study, 23 patients with median 4 prior lines of therapy (range 2-11) were enrolled, 10 of whom were considered double exposed/refractory...In total, 65% of patients required administration of tocilizumab and/or corticosteroids.23 In addition to the ongoing phase 2 portion of this study, efforts now focus on innovative CAR T-cell designs as well as combination strategies...A phase 1b/2 ongoing trial is currently examining the safety and tolerability of the product in patients with R/R CLL. The early results suggest that epcoritamab administered subcutaneously is well tolerated in a heavily pretreated patient population with multiple high-risk features and shows clinical activity.25 Furthermore, an ongoing study is demonstrating preliminary efficacy of epcoritamab in patients with Richters transformation, a notoriously difficult-to-treat complication of CLL.26