cerdulatinib (ALXN2075)

The dual SYK and JAK/STAT6 inhibitor cerdulatinib most effectively compromised the proliferative advantage conferred by UGT2B17 compared to the selective BTK inhibitor ibrutinib. Findings point to an oncogenic role for UGT2B17 as a novel constituent of BCR signalosome also connected with microenvironmental signaling.

Despite recent advances in chronic lymphocytic leukemia (CLL) therapy, such as the use of targeted agents including, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the potent BCL-2 antagonist venetoclax, this disease remains incurable for most patients, who are refractory or become resistant to the novel agents...Other drugs that demonstrated high priming included navitoclax (BCL-XL/BCL-2), nutlin-3 (MDM2), abexinostat (HDAC), gandotinib (JAK2), duvelisib (PI3K δ/γ), idelalisib (PI3Kδ) and cerdulatinib (SYK/JAK)...First, we found that IGHV-mutated CLLs (M-CLLs) became more primed to apoptosis than IGHV-unmutated CLLs (U-CLLs) across the panel of drugs (p<0.001, paired t-test) and significantly in response to fludarabine and umbralisib (FDR<0.1, t-test)...EC-i, associated with the intermediate methylation subtype of CLL, was the most resistant EC to ibrutinib but was very sensitive to navitoclax, more than to any other drug. Altogether, we present a framework that links ex-vivo drug response with molecular features including expression subtypes to highlight new therapeutic opportunities in CLL.

P1/2, N=220, Completed, Portola Pharmaceuticals | Active, not recruiting --> Completed

The cerdulatinib + rituximab combination appeared to be well tolerated, with tumor reductions in all evaluable pts. These data provide proof of concept and a promising efficacy/safety profile for a first-in-class, dual SYK/JAK inhibitor in relapsed/refractory FL.

Methods Eligible patients in the PTCL cohort were aged ≥18 years and had histologically confirmed PTCL with relapsed/refractory disease after ≥1 prior systemic therapy (prior brentuximab was required for CD30+ patients) and an Eastern Cooperative Oncology Group performance status ≤1. Overall the benefit/risk profile of cerdulatinib treatment appears favorable in this population, with the exception of the PTCL NOS subgroup, in whom no responses were seen. This subtype-specific activity raises the potential for biomarker identification to optimize patient selection.

P1/2, N=220, Active, not recruiting, Portola Pharmaceuticals | Trial completion date: Jul 2020 --> Dec 2020 | Trial primary completion date: Jul 2020 --> Dec 2020

In addition, cerdulatinib was identified as a novel drug against MYB-TYK2 altered disease in vitro and in vivo to aid development of targeted therapeutic approaches against this aggressive ALL subtype. This inhibitor may also be effective against other genomic alterations that result in aberrant JAK-STAT signalling.

Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).

Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed... The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL.