eragidomide (CC-90009)

P1, N=22, Terminated, Celgene | Trial completion date: Oct 2025 --> Apr 2024 | Active, not recruiting --> Terminated; Business objectives have changed.

P1, N=101, Terminated, Celgene | Trial completion date: Jul 2025 --> Apr 2024 | Active, not recruiting --> Terminated; Trial terminated because of lack of efficacy in the short term acute phase.

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

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.

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.

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

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

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.

Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM), myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) and other hematological malignancies...In this review, we describe the mechanism of IMiDs in cancer treatment and summarize the key regulators of IMiD sensitivity. Furthermore, we introduce genome-wide CRISPR-Cas9 screenings, through which the regulatory networks of IMiD sensitivity could be identified.

CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSC, whose elucidation gives insight into further assessment of CC-90009's clinical utility.

The ongoing trial was amended to allow the use of prophylactic DEX; dose escalation is still ongoing, including dose levels higher than the non-tolerated dose defined prior to mandating the use of prophylactic DEX. The insights derived from this study have facilitated GSPT1 targeting in AML therapy by enabling the testing of higher drug exposures.

Deeper and more rapid GSPT1 degradation as well as delayed rebound were associated with more rapid, deeper, and more persistent blast reductions. Characterization of these PD responses in the ongoing phase 1 trial will help to identify the optimal scheme for the expansion phase and provide further insight into the mechanism of clinical response.

CC-90009 is a novel CELMoD and a first-in-class GSPT1 degrader. A suite of novel pharmacodynamic assays performed on patient-derived peripheral blood cells and BM demonstrated a dose-dependent modulation of GSPT1, and showed that the preclinical mechanisms of ISR induction, NMD inhibition, and apoptosis can be confirmed in AML cells in patients. Deeper and more rapid GSPT1 degradation as well as delayed rebound were associated with more rapid, deeper, and more persistent blast reductions.