Phase Ib Study of PRT543, an Oral Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, in Patients with Relapsed or Refractory, Splicing Factor-Mutant Myeloid Malignancies
Authors: Bewersdorf Jan Philipp , Mi Xiaoli , Lu Bin , Kuykendall Andrew T. , Sallman David , Patel Manish , Stevens Don A. , Philipovskiy Alexander , Sutamtewagul Grerk , Masarova Lucia , Keiffer Gina , Verma Amit , Bhagwat Neha , Heiser Diane , Ro Sunhee , Hong Wan-Jen , Abdel-Wahab Omar , Stein Eytan M. 
Published: December 2024

Mutations in RNA splicing factors are common in MDS and secondary AML. There are currently no targeted therapies for patients (pts) with splicing factor mutations. PRMT5 catalyzes symmetrical dimethylation of arginine, a post-translational modification required for normal RNA splicing. Pre-clinical studies identified synthetic lethality between PRMT5 inhibition and splicing factor mutant myeloid malignancies. PRT543 is a SAM-competitive, potent and selective oral inhibitor of PRMT5 that demonstrates anti-proliferative activity along with dose-dependent inhibition of symmetric dimethyl arginine (SDMA) in vitro and in in vivo models of myeloid malignancies. In a phase 1 study, PRT543 was safe and well tolerated and 35 mg 5x/week was identified as the recommended phase 2 dose (Patel et al. ASH 2021). As responses were seen primarily in pts with splicing factor mutations, we performed a multicenter, open-label phase Ib study of PRT543 in pts with relapsed or refractory (R/R) MDS, AML and MDS/MPN overlap (NCT03886831).

The study population consisted of patients with low and high risk MDS, AML and MDS/MPN overlap syndromes. To participate, pts with lower-risk MDS had to be red blood cell transfusion-dependent (≥2 units/8 week) during the 16 weeks prior to study entry with an inadequate response to ESAs or a baseline serum EPO level &gt;200 U/L. Pts with higher-risk MDS, AML, or MDS/MPN overlap had a splicing factor mutation and R/R disease after prior HMA +/- venetoclax, ≥2 cycles of intensive induction chemotherapy, or any other therapies. All pts had to have an ECOG Performance Score of ≤1 and adequate end-organ function. The primary endpoint was best overall response rate (composite of CR, PR, mCR, and HI per IWG 2006 criteria for MDS and MDS/MPN pts or composite of CR, CRi, PR, and MLFS per ELN 2017 criteria for AML pts). Correlative studies analyzing SDMA abundance and differential gene expression and splicing from RNA-seq were performed in peripheral blood at baseline and C1D25.

40 pts (19 lower-risk MDS, 10 higher-risk MDS, 7 AML, and 4 MDS/MPN) were enrolled. The most common splicing mutations were SF3B1 (n=13; 31.0%), U2AF1 (12; 30.0%), and SRSF2 (8; 20.0%). Median age at enrollment was 73.5 years (Range [R]: 46 - 84 years) and pts had received a median of 2 prior lines of therapy (R: 0 - 8 lines). Median duration of treatment with PRT543 was 3.6 months (R: 0.4 - 17.6 months). Best response by central assessment among MDS and MDS/MPN pts were mCR in 1 pt (3.0%) and HI in 3 pts (9.1%; 2 HI-erythroid and 1 trilineage HI). One AML pt (14.3%) achieved CRi and 1 additional pt with SD achieved platelet transfusion independence from a baseline of requiring 9 units of platelets over the 8 weeks preceding the trial. All pts with HI and the AML pts with CRi and platelet transfusion independence had mutations in SRSF2 or U2AF1. At a median follow-up of 4.6 months, the median PFS was 5.6 months (95% CI: 2.6 months - not estimable) for MDS patients. The median PFS for AML pts was 2.8 months (95% CI: 1.1 months - not estimable) at a median follow-up of 3.8 months (range: 1.4 - 7.3). 6-month survival rates were 89% (95% CI: 69-97%) for MDS pts and 69% (95% CI: 21-91%) for AML pts. Median OS was not reached in either cohort. Anemia (n = 20; 50.0%) and thrombocytopenia (n = 12; 30.0%) as well as nausea (n = 11; 27.5%) and diarrhea (n = 11; 27.5%) were the most common hematologic and non-hematologic treatment-emergent adverse events (TEAE) of any grade. The most common ≥grade 3 TEAEs were anemia (n = 20; 50.0%), thrombocytopenia (n = 11; 27.5%) and neutropenia (n = 6; 15.0%). There was 1 grade 5 event (respiratory failure) in an AML pt, which was unrelated to PRT543. In correlative studies, we found a mean reduction in peripheral blood serum SDMA by 41.9% in 8 paired pre- and post-treatment samples confirming target engagement in vivo. We observed global disruption in RNA splicing in peripheral blood mononuclear cells at C1D25, but the number of significant splicing changes in patient samples was substantially less than in cell lines treated with PRT543 in vitro.

In summary, monotherapy with PRT543 is safe in pts with R/R splicing mutant myeloid malignancies and demonstrated clear target engagement and splicing changes with objective responses in 5 out of 40 pts including 1 AML pt with a CRi and a HR-MDS pt with trilineage HI. Additional preclinical data including the PRT543 structure will be presented.