deuterated S-avadomide (SP-3164)

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

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

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.

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.

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.