P1/2, N=158, Recruiting, C4 Therapeutics, Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Sep 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=80, Suspended, Kymera Therapeutics, Inc.

P1, N=72, Not yet recruiting, Salarius Pharmaceuticals, LLC | Trial completion date: Aug 2026 --> Aug 2027 | Initiation date: Aug 2023 --> Mar 2024 | Trial primary completion date: Aug 2024 --> Aug 2025

P1, N=80, Suspended, Kymera Therapeutics, Inc. | Recruiting --> Suspended

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.

To date, the majority of CRBN-binding molecular glues, including lenalidomide, pomalidomide, and avadomide, are glutarimides with an unstable chiral center that results in interconversion between the desired, active ( S )-enantiomer and the inactive ( R )-enantiomer...Additionally, we showed SP-3164's potent activity in an in vivo DLBCL model as a single agent and in combination with rituximab...In addition, the combination of SP-3164 with venetoclax (50 mg/kg QD PO, 5 on/2 off) resulted in more significant TGI than either SP-3164 or venetoclax alone (Figure)... SP-3164 is a novel, orally available, CRBN-binding molecular glue with potent immunomodulatory activity andattractive therapeutic properties in NHL models, including FL. Further assessment of SP-3164's potential as a treatment for NHLs is warranted and a clinical trial is planned to start in 2023. Non-Hodgkin's lymphoma, Immunomodulation, B cell lymphoma

Initial clinical data with KT-413 demonstrate degradation of IRAK4 and Ikaros/Aiolos in PBMC and tumor. It is anticipated that higher doses will achieve the predicted degradation profile in tumors that may confer clinical benefit in MYD88-mutant patients. Dose escalation is ongoing, and analyses from additional patients will be presented at the meeting.

Combination therapy with ibrutinib, lenalidomide and rituximab demonstrated clinical activity in recurrent DLBCL [Goy et al. In this first-in-human, first-in-class study of a BTK degrader, NX-2127 was well tolerated and showed promising activity in a patient with non-GCB DLBCL. These data support further clinical development of NX-2127 in B cell lymphoid malignancies including DLBCL.

Cereblon (CRBN)-binding Ikaros and Aiolos (I/A) protein degraders (i.e., lenalidomide (LEN) and pomalidomide (POM)) have had great success in treating MM. In vivo, SP-3164 has superior single agent and combination activity compared to approved molecular glues. These data support the continued development as a novel therapy in MM.

In pre-clinical safety studies, NX-2127 demonstrates an acceptable safety profile. NX-2127 is currently in phase 1 clinical trials (NCT04830137) for hematological malignancies.

Lenalidomide (LEN), a molecular glue degrader, is approved for treatment of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other NHLs. SP-3164 is a novel, orally available, CRBN-binding molecular glue with desirable therapeutic properties and significant anticancer activity in NHL models. Further assessment of SP-3164’s potential as a treatment for NHLs is warranted and a clinical trial is planned to start in 2023.

Preclinical data support the activity of NX-2127 in tumor models harboring either wild-type BTK or BTK-mutants conferring clinical resistance to approved and investigational inhibitors. NX-2127 is currently being evaluated in an ongoing Phase 1 trial for patients with relapsed or refractory B-cell malignancies (ClinicalTrials.gov NCT04830137).

Furthermore, based on new genetic classifications, co-mutations in MYD88 and CD79 (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. Enrollment in the Phase 1a portion of the KT413-DL-101 study is ongoing. NCT05233033.

Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes of non-Hodgkin's lymphoma (NHL)...Clinically, immunomodulatory drugs have shown activity as single agents and when used in combination with several classes of targeted therapies, such as rituximab, in both first line and relapsed/refractory NHL subtypes.We previously described the preclinical characterization of CFT7455 as a novel IKZF1/3 degrader with 800-1600-fold increased potency over pomalidomide in CRBN binding and cellular IKZF1 degradation assays...Combination studies were conducted, dosing CFT7455 in combination with rituximab, ibrutinib, or the HDAC inhibitor romidepsin in several models of NHL...Synergistic activity was also observed with the combination of CFT7455 and romidepsin in two models of anaplastic large cell lymphoma (ALCL). In conclusion, CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent and combination antitumor activity in DLBCL, ALCL, and MCL models, supporting clinical investigation of CFT7455 for NHL.

Background: Based on new genetic classifications, co-mutations in MYD88 and CD79B (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. Preclinical studies highlight the potential of IRAKIMiDs as a therapeutic approach for the treatment of MYD88MT DLBCL. KTX-582 demonstrates preferential activity in MYD88MT ABC-DLBCL. Single agent venetoclax demonstrated varying potency in ABC-DLBCL cell lines, irrespective of MYD88 mutational status.

Background: Targeted protein degradation (TPD) is attracting significant interest given the success of early protein degraders, e.g., lenalidomide and pomalidomide, and TPD's potential advantages over other therapeutic approaches. SP-3164 is a novel, CRBN-binding molecular glue with potential attractive therapeutic properties compared to the racemate, avadomide, and to lenalidomide. SP-3164 showed increased IKZF1 degradation efficiency compared to other molecular glues and significant anti-cancer activity as a monotherapy in an in vivo lymphoma mouse xenograft model. Future studies will evaluate SP-3164 efficacy and direct potential combinations to support clinical development of SP-3164 in DLBCL and other non-Hodgkin's lymphomas.

Lenalidomide redirects the CRL4 ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8 T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28 T cells.

Early observations from the FIH clinical trial (NCT04756726) along with supporting translational studies are presented here. Pre-clinical studies comparing CFT7455 and CC-92480 in both in vitro and xenograft models were performed. While CFT7455 showed clinical benefit at 50 ug with deep target degradation, neutropenia was dose limiting. PK/PD modeling suggests alternative dosing regimens may result in increased tolerability with preserved efficacy, and evaluation of them is underway. Updated results will be presented at the meeting.

Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2 (CK2) mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.

Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned...Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody...Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726 , enrollment is ongoing.