P1, N=22, Active, not recruiting, Celgene | Phase classification: P1/2 --> P1

P1/2, N=22, Active, not recruiting, Celgene | Phase classification: P1b --> P1/2 | N=76 --> 22

P1/2, N=135, Recruiting, Monte Rosa Therapeutics, Inc

Induction of full-length Rb protein was potentiated by the cereblon E3 ligase modulator CC-90009. These results suggest that pharmacological induction of translational readthrough could be a feasible strategy for therapeutic targeting of tumors with nonsense mutant RB1.

GT19715 but did not reduce total mouse BM CD45+ cells, suggesting favorable toxicity profiles of GT19715. In conclusion, TP53mut AML comprised highly enriched LSC populations compared to TP53wt AML and targeting of c-MYC protein is highly effective in TP53mut AML in vitro and in vivo with a therapeutic window between AML LSC and normal hematopoietic cells.

GT19715 also enhanced cell death induced by dexamethasone. Targeted protein degradation of c-MYC induces promising anti-leukemia efficacy in T-ALL cells in vitro and in vivo. Further mechanistic and in vivo studies are ongoing.

In Phase-1 findings with a selective IRAK4 inhibitor (CA-4948; Curis Therapeutics), it was found that MDS and AML patients with splicing factor mutations responded best to monotherapy IRAK4 inhibition, although the overall response rate with monotherapy was modest...CC-90009 did not result in complete cell death up to concentrations of 10mM in both WT and IRAK4KO, suggesting that the selective sensitivity of IRAK4KO AML cells to CC-885 is not due to inhibition of GSPT1...These findings suggest that IRAK4 inhibition alters the pool of neosubstrates in AML cells for certain CELMoDs. Overall, our study demonstrates that IRAK4 is a therapeutic target in AML, but that combination therapies, such as with certain CELMoDs, will be necessary to achieve better clinical responses.

P1b, N=76, Active, not recruiting, Celgene | Trial completion date: Jan 2025 --> Oct 2025 | Trial primary completion date: Jan 2024 --> Oct 2023

P1b, N=76, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P1b, N=76, Recruiting, Celgene | N=43 --> 76

P1, N=101, Active, not recruiting, Celgene | N=162 --> 101

SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression...Genome wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed components of the CRL4CRBN complex, associated adaptors, regulators and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

ORM-5029 is a first-in-class human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) comprised of SMol006, a highly potent GSPT1 degrader, conjugated to pertuzumab, a clinically validated antibody...ORM-5029 showed robust in vitro and in vivo efficacy in multiple HER2-expressing models with comparable activity to trastuzumab deruxtecan and strong activity in trastuzumab emtansine-refractory models...Escalation cohort 1 was completed without DLT; enrollment in cohort 2 began as of December 2022. Clinical trial information: NCT05511844.

Finally, our current lead compounds showed safer profiles in various normal cells compared to other known GSPT1 degraders. Collectively, we have identified novel GSPT1 MGDs as promising development candidates for the treatment of AML and solid tumors.

It delivers a highly potent and precise catalytic GSPT1 protein degrader molecule (SMol006) selectively to HER2-expressing tumor cells via conjugation to pertuzumab. The optimized protocol is currently being developed into RNAscope multiplex workflow using BT474 FFPE sections and tissue microarrays. In summary, RNAscope multiplex assay could be used as a method to determine pharmacodynamic response in HER2+ breast cancer patients treated with ORM-5029.

P1b, N=43, Recruiting, Celgene | Trial completion date: Jun 2026 --> Jan 2025 | Trial primary completion date: Jun 2025 --> Jan 2024

P1b, N=43, Recruiting, Celgene | Trial completion date: Jan 2025 --> Jun 2026 | Trial primary completion date: Jan 2024 --> Jun 2025

P1/2, N=133, Recruiting, Monte Rosa Therapeutics, Inc | Not yet recruiting --> Recruiting

P1b, N=43, Recruiting, Celgene | Trial primary completion date: Jan 2025 --> Jan 2024

P1, N=87, Recruiting, Orum Therapeutics USA, Inc. | Not yet recruiting --> Recruiting

First results with the novel dual c-Myc/GSPT1 degrader GT19715 demonstrate promising preclinical anti-lymphoma and -leukemia efficacy, providing rationale for its clinical development.

MYC is highly expressed in TP53 mutant or venetoclax (ven) resistant AML (Sallman, Blood 2021, Nishida, ASH 2021)...C-Myc was effectively pulled down by biotinylated GT19630 in a cell-free, in vitro affi nity purifi cation assay; and a proteasome inhibitor ixazomib completely blocked c-Myc degradation... First results with the novel dual c-Myc/ GSPT1 degrader GT19715 demonstrate promising preclinical antilymphoma and -leukemia effi cacy, providing rationale for its clinical development.

P1/2, N=133, Not yet recruiting, Monte Rosa Therapeutics, Inc

P1, N=87, Not yet recruiting, Orum Therapeutics USA, Inc.

We defined two Crbn amino acids that prevent Gspt1 degradation in mice, generated a knock-in mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant AML.

P1b, N=43, Recruiting, Celgene | Phase classification: P1/2 --> P1b | N=66 --> 43

Based on these results, the combination activity of CC-90009 with venetoclax (VEN)/azacitidine (AZA) is being evaluated in a phase 1/2 trial in patients with AML (NCT04336982)...Synergy between the isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib and CC-90009 was evaluated in a TF‑1 erythroleukemia cell line overexpressing IDH2 R140Q mutant, and an IDH2 R140Q PDX model, AM7577...FLT3 inhibitors, including sunitinib, pexidartinib, midostaurin, lestaurtinib, crenolanib, and gilteritinib, synergized with CC-90009 to reduce viability in FLT3-ITD AML cell lines MV4-11 and MOLM-13...The FLT3 inhibitor quizartinib significantly prolonged survival when combined with CC‑90009 compared with either agent alone ( P < 0.001)... Using a high-throughput combination screen, we identified rational combination partners that synergize with CC-90009 in in vitro and in vivo AML models. Collectively, these results support the clinical evaluation of CC-90009 in combination with FLT3, BCL2, and IDH2 inhibitors to further improve treatment outcomes for patients with AML.

Further addition of CC-90009, a cereblon E3 ligase modulator that targets protein translation termination and is under clinical study for treatment of acute myeloid leukemia, rescued 19% and 12% of wild-type CFTR function in the nasal cell line and primary cells, respectively. These studies demonstrate that hTERT and Bmi-1 growth enhanced HNEC lines mirror the primary cell response to CFTR modulators. In cells from 2 donors harboring the F508del CFTR allele, electrophysio logical CFTR rescue also correlated with clinical response to elexacaftor/ tezacaftor/ivacaftor. Results with the novel W1282X CFTR homozygous cell line and unique compound combinations may illuminate a strategy to develop CFTR modulators and other therapies for CF individuals with PTC CFTR variants.