PRT543

In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.

Combining C220 or PRT543 with olaparib or chemotherapeutic agents such as cisplatin demonstrates a potent synergistic interaction in breast and ovarian cancer cells in vitro. Furthermore, PRT543 treatment significantly inhibits growth of Olaparib resistant tumors in vivo. These studies reveal a novel mechanism of PRMT5 inhibition and suggest beneficial combinatorial effects with other therapies, particularly in patients with tumors that are resistant to therapies dependent on DNA damage as their mechanism of action.

Selectively inhibiting PRMT5 has shown significant anti-tumor activity in preclinical MCL models, and a Phase 1 clinical trial with PRT543 (Prelude), a novel PRMT5 inhibitor, is underway...Combinatorial treatment was tested in vivo using the PDX.AA.MCL model of ibrutinib resistant MCL...Navitoclax and PRT808 single agent as well as PRT808+PRT1419 regimens significantly slowed disease progression...Of note, navitoclax dosing alone or in combination did not induce additional platelet loss. Our results provide rationale for combining BH3 mimetics and PRMT5 inhibition in clinical trials as a novel treatment strategy for MCL.

Partial response has been seen in adenoid cystic carcinoma from both GSK3326595 and JNJ-64619178, with four cases of stable disease seen with PRT543. Highly significant is a durable complete response in isocitrate dehydrogenase 1-mutated glioblastoma multiforme with PRT811...Further studies are warranted, and there are clinical trials to come whose data will be telling of the efficacy of PRMT5 inhibitors in both hematologic and solid malignancies. The aim of this study is to compile available results of PRMT5 inhibitors in oncology clinical trials.

Selectively inhibiting PRMT5 has shown significant anti-tumor activity in preclinical MCL models, and a Phase 1 clinical trial with PRT543 (Prelude), a novel PRMT5 inhibitor, is underway...BH3 mimetics navitoclax (BCL2, BCLXL, and BCLw inhibitor), A852 (BCLXL inhibitor), and AMG176 (MCL1 inhibitor) were found to have IC50s below 1uM in five, two, and four of the nine cell lines respectively...iBH3 flow-based analysis revealed increased sensitivity of ex vivo PDX cells to pan BCL2, BCLXL, and MCL1 inhibition. These results provide rationale for combining BH3 mimetics and PRMT5 inhibition in clinical trials as a novel treatment strategy for MCL.

Efficacy studies in patient-derived xenograft (PDX) models, as well as genomic profiling of spliceosome-mutant cellular models in response to PRT543 are ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831).

PRT543 was well tolerated with a favorable safety profile. Dose-dependent inhibition of target engagement and functional activity of PRMT5 were observed. PRT543 treatment demonstrated reduction in inflammatory markers and improvement in symptoms and anemia in select patients.

In summary, PRMT5 inhibition with PRT543 can release a differentiation block in MDS/AML, specifically in splicing mutant samples. PRMT5 inhibition decreases IRAK4-long isoform expression providing a potential mechanism for its activity in splicing factor mutant cases.

Western blot analysis confirmed E2F target gene repression (TK1, CCNA2, CHK1, CDK1) and accumulation of DNA damage response proteins (cleaved PARP, cleaved CASP3, p-H2AX) that are further enhanced with combination of doxorubicin. Pharmacologic inhibition of PRMT5 with the clinical-grade, novel small molecule inhibitor (PRT543, Prelude Therapeutics) merits further investigation in ongoing clinical trials (NCT03886831, clinicaltrials.gov), specifically for the treatment of IR-MCL with deletion of MTAP and prior to the genomic mutation of TP53 . We are currently exploring novel combinations to maximize the therapeutic potential of PRMT5 inhibition in this disease.

No abstract available

These studies not only reveal a novel mechanism of PRMT5 inhibition, but also suggest beneficial combination effects with other therapies, particularly in patients with tumors that are resistant to therapies that are dependent on DNA damage as their mechanism of action. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831).

In summary, our results suggest that PRMT5 inhibition regulates cancer-associated RNA splicing machinery and the DNA damage response, resulting in synergistic antitumor activity when combined with chemotherapy and/or PARP inhibitors, particularly in cancers with spliceosomal mutations. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831).