Abstract
Background: PRMT5 is overexpressed in certain myeloid malignancies and catalyzes symmetric arginine dimethylation of protein substrates that regulate expression of genes associated with disease pathogenesis (Pastore et al. Cancer Discov. 2020). PRT543 is a potent, selective, oral PRMT5 inhibitor with preclinical antitumor activity in acute myeloid leukemia and myeloproliferative neoplasm models (Bhagwat AACR 2020). An open-label phase 1 study of PRT543 in unselected patients (pts) with advanced solid tumors and hematologic malignancies (NCT03886831) is ongoing. Dose escalation results from pts with myeloid malignancies are presented herein.
Materials and Methods: This study assesses the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy per International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) and myeloproliferative neoplasm of PRT543 administered at varying schedules beginning with twice weekly (BIW) and increasing to once daily (QD) with doses ranging from 5 to 40 mg in 28-day cycles. Dose escalation followed a modified 3+3 design, allowing for accelerated titration at lower doses. Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively.
Results: As of 16 July 2021, 23 unselected pts (12 with myelofibrosis [MF] and 11 with MDS) with disease refractory to established therapies had enrolled (5 pts were dosed BIW, 6 pts 3 times per week [TIW], 5 pts 5 times per week, and 7 pts QD). The median number of prior lines of systemic therapies was 2 (range, 0 to 6). Ten of 12 MF pts had prior exposure to ruxolitinib. Median platelet counts at baseline were 176,500/µL for MF pts and 52,000/µL for MDS pts. Three of 23 pts (13%) experienced dose limiting toxicity (DLT) of thrombocytopenia, with a single occurrence at each of 3 different doses/schedules (40 mg TIW, 35 mg 5 times per week, and 20 mg QD). No other DLTs were reported. The most frequent treatment-related adverse events (TRAEs), any grade, in all regimens were nausea (n=5, 22%), thrombocytopenia (n=5, 22%), anemia (n=4, 17%), diarrhea (n=4, 17%), and fatigue (n=3, 13%). Grade ≥3 TRAEs in all regimens were limited to anemia (n=4, 17%) and thrombocytopenia (n=4, 17%). Cytopenias were reversible and managed with dose modifications. Eighteen pts discontinued treatment, primarily due to disease progression or investigator decision. One pt was discontinued due to an AE (performance status decreased/weakness). PRT543 demonstrated dose-dependent increases of C max (nM) and AUC (nM.hr). At the expansion dose (35 mg 5 times per week), half-life (T ½) was 14 hrs, and plasma drug exposures (C max, 1988 nM; AUC, 19813 nM.hr) exceeded those required for preclinical efficacy. Serum sDMA decreased in a dose-dependent manner reaching 58% reduction with the expansion dose. Increased intron retention in select transcripts was observed in peripheral blood mononuclear cells at the expansion dose. Reductions in inflammatory serum markers, including C-reactive protein and serum amyloid A and cytokines interleukin (IL)-6 and IL-8 were observed. Improvement in individual symptoms such as night sweats, fever and pruritis were noted. Of the 5 MF patients with spliceosome mutations, 1 MF pt (SF3B1) with anemia and transfusion history (8 units over the 121 days prior to baseline) experienced a substantial improvement in anemia (hemoglobin increase from 6.0 to ≥11.1 g/dL). This pt has been transfusion-free for over 300 days and remains on study. Three pts with MF exhibited stable disease per IWG for at least 1 year, with 1 MF pt demonstrating improvement in bone marrow reticulin fibrosis (+2-3 to +1-2).
Conclusions: 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. Prolonged stable disease per IWG was observed in several pts with refractory MF. PRT543 is currently being evaluated as monotherapy in pts with at least one spliceosome mutation (MF and MDS pts with anemia and pts with high-risk myeloid malignancies) and in combination with ruxolitinib in MF patients demonstrating a suboptimal response to ruxolitinib.
Patel: Vigeo: Research Funding; Portola Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; AstraZeneca: Research Funding; TopAlliance: Research Funding; Tesaro: Research Funding; Vedanta: Research Funding; Curis: Research Funding; Ciclomed: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Lycera: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bicycle Therapeutics: Research Funding; Hutchinson MediPharma: Research Funding; Ignyta: Research Funding; Taiho: Research Funding; Loxo Oncology: Research Funding; Millennium Pharmaceuticals: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Prelude Therapeutics: Research Funding; H3 Biomedicine: Research Funding; Revolution Medicines: Research Funding; Hengrui: Research Funding; Cyteir Therapeutics: Research Funding; Ribon Therapeutics: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Takeda: Research Funding; Forma Therapeutics: Research Funding; Artios Pharma: Research Funding; Aileron Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Verastem: Research Funding; Phoenix Molecular Designs: Research Funding; Macrogenics: Research Funding; Mabspace: Research Funding; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; GlaxoSmithKline: Research Funding; Gilead: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus: Research Funding; Checkpoint Therapeutics: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Daiichi Sankyo: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; ORIC Pharmaceuticals: Research Funding; Stemline Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioNTech: Research Funding; ModernaTX: Research Funding; Mirati Therapeutics: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; LSK Biopartners: Research Funding; Placon Therapeutics: Research Funding; Calithera: Research Funding; Effector Therapeutics: Research Funding; Clovis: Research Funding. Monga: Gunderson Foundation: Other; Rising Tide Foundation: Other; Amgen: Research Funding; Orbus Therapeutics: Research Funding; Prelude Therapeutics: Research Funding; Deciphera: Research Funding; Forma Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. McKean: Ascentage Pharma Group: Research Funding; Bicycle Therapeutics: Research Funding; Dragonfly Therapeutics: Research Funding; Epizyme: Research Funding; Exelixis: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; IDEAYA Biosciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ikena Oncology: Research Funding; Infinity Pharmaceuticals: Research Funding; Jacobio Pharmaceuticals: Research Funding; Moderna: Research Funding; NBE Therapeutics: Research Funding; Novartis: Research Funding; Oncorus: Research Funding; Plexxikon: Research Funding; Prelude Therapeutics: Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sapience Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tizona Therapeutics: Research Funding; TMUNITY Therapeutics: Research Funding; TopAlliance Biosciences: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BicycleTX Limited: Membership on an entity's Board of Directors or advisory committees; Castle Biosciences: Membership on an entity's Board of Directors or advisory committees; MedPage Today: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mauro: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Viscusi: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Scherle: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhagwat: Prelude Therapeutics: Current Employment. Moore: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sun: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chiaverelli: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mintah: Prelude Therapeutics: Current Employment. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Stein: PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy; Syndax Pharmaceuticals: Consultancy; Astellas: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy. Palmisiano: Genentech: Research Funding; Takeda: Consultancy; AbbVie: Consultancy, Research Funding; Foundation One: Consultancy. Verstovsek: Ital Pharma: Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI BioPharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.
