Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

Abstract

Background Myelodysplastic syndromes (MDS) are characterized by frequent mutations in RNA splicing factor genes. Protein arginine methyltransferase 5 (PRMT5) regulates the activity of the splicing machinery through methylation of key spliceosome proteins. PRMT5 inhibitors have demonstrated preferential killing of acute myeloid leukemia cells with splicing factor mutations. JNJ-64619178 is a potent, selective, oral PRMT5 inhibitor that causes accumulation of splicing abnormalities in preclinical models. It is hypothesized that inhibition of PRMT5 by JNJ-64619178 may target splicing factor gene mutant MDS clones, leading to recovery of normal hematopoiesis. Here we present Part 2 of a phase 1 study of JNJ-64619178 evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of JNJ-64619178 in adult patients (pts) with lower risk MDS (International Prognostic Scoring System [IPSS] score Low or Intermediate-1) who are red blood cell (RBC) transfusion-dependent and relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. Methods Dosing was initiated at 2 mg, 14 days on/7 days off (intermittent) on a 21-day cycle, a tolerable dose from the ongoing dose escalation in solid tumors and lymphomas in Part 1. Confirmation of tolerability followed a modified 3+3 design with de-escalation allowed based on the totality of the data. Enrollment was expanded at the selected, tolerable dose level to further evaluate safety, PK, PD, and preliminary clinical activity. Results As of 29 May 2021, 21 pts were enrolled. Median age was 71 (range 52-85). Revised IPSS score was Very Low (10%), Low (71%) or Intermediate (19%). Pts had a median of 1 prior line of therapy post-ESA (range 0-4), including lenalidomide (33%), hypomethylating agents (29%), and luspatercept (19%). SF3B1 mutations were identified in 71% of pts. Median treatment duration was 3.1 months (range 0.03-6.37). No dose-limiting toxicities were observed. While the 2 mg intermittent starting dose was tolerable, lower dose schedules of 1 mg intermittent and 0.5 mg continuous (once daily [QD]) dosing were evaluated to reduce myelosuppression, and enrollment was expanded at 0.5 mg QD (n=13 pts). Fifteen pts (71%) experienced ≥1 treatment emergent adverse event (TEAE) that was considered related to the study agent (TRAE). TRAE in >10% of pts were thrombocytopenia (52%), neutropenia (48%), anemia (19%), and dysgeusia (14%). Grade 3 or higher TRAE were reported for 57% of pts. Grade 3 or higher TRAE worsening from baseline in >1 pt were neutropenia (29%); anemia and thrombocytopenia (19.0% each); and diarrhea (9%). TEAEs contributed to treatment interruption, dose reduction, and treatment discontinuation in 57%, 14%, and 19% of pts, respectively. Anemia, thrombocytopenia, and neutropenia were the only TRAE leading to treatment modification in >1 pt. Hematologic toxicities were dose-dependent and reversible. Grade ≥3 thrombocytopenia and neutropenia were observed, respectively, in 67% and 50% of pts at 2 mg intermittent versus 0% and 31% at 0.5 mg QD. Serious AE considered possibly related to JNJ-64619178 by the investigator included 1 pt with Grade 3 anemia and 1 pt with Grade 1 atrial fibrillation, Grade 3 cardiac troponin I increase, and Grade 5 cardiac failure (>30 days from last dose). One other death of unknown cause was not considered related to treatment. Comparison of the multiple dose C trough across all dose levels suggests a dose-dependent increase in JNJ-64619178 plasma concentration. Robust target engagement, as measured by plasma symmetric dimethylarginine, was achieved at all dose levels. Serial analysis of variant allele frequency of clonal mutations in a subset of pts did not show significant reductions from baseline in peripheral blood or bone marrow. No pts experienced objective response or hematologic improvement according to International Working Group criteria, RBC transfusion independence, or meaningful reduction in transfusion requirements. Conclusion JNJ-64619178 demonstrated primarily hematologic toxicity in pts with transfusion-dependent lower-risk MDS, which was manageable at the selected expansion dose. Despite robust target engagement, clinical activity was not observed, and enrollment was stopped. The role of PRMT5 in MDS and the differential impact of PRMT5 inhibition on normal and malignant hematopoiesis require further study. Disclosures Platzbecker: Novartis: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria. Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Brunner: Agios: Consultancy; Keros Therapeutics: Consultancy; Aprea: Research Funding; AstraZeneca: Research Funding; GSK: Research Funding; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Morillo: Janssen: Honoraria; Abbvie: Honoraria; Takeda: Honoraria. Patel: Acerta Pharma: Research Funding; Curis: Research Funding; Clovis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aileron Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Effector Therapeutics: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Mirati Therapeutics: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Ciclomed: Research Funding; Checkpoint Therapeutics: Research Funding; Calithera: Research Funding; Boehringer Ingelheim: Research Funding; Bicycle Therapeutics: Research Funding; AstraZeneca: Research Funding; Artios Pharma: Research Funding; Agenus: Research Funding; Florida Cancer Specialists: Research Funding; BioNTech: Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Ignyta: Research Funding; Hutchinson MediPharma: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Hengrui: Research Funding; H3 Biomedicine: Research Funding; GlaxoSmithKline: Research Funding. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Lauring: Janssen Research and Development: Current Employment; Johnson and Johnson: Current holder of stock options in a privately-held company. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company.

Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma

“…The pharmaceutical industry and academic institutions have devoted considerable research efforts to identifying effective and selective CARM1 inhibitors, given the significant potential of CARM1 in both physiological and pathological contexts. Numerous reports document the success of selective substrate inhibitors or SAM inhibitors in this regard. ,, However, it is essential to note that these inhibitors primarily target hematopoietic cell malignancies and exhibit limitations in cytotoxicity. Therefore, it is valuable to explore the development of more effective selective inhibitors through the design of novel skeletal structures.…”

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Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies

“…Second, first-generation PRMT5 inhibitors suffer from hematological toxicity, which limits theirdose escalation. As PRMT5 also plays an essential role in maintaining adult hematopoietic cells, indiscriminate PRMT5 inhibition by the first-generation inhibitors has resulted in adverse effects, such as thrombocytopenia, anemia, and neutropenia in clinical studies. ,,, Accordingly, novel chemotypes with favorable PK and PD properties deserve further exploration to afford more potent PRMT5 enzymatic inhibitors that can be administered at low doses and enable the redefinition of dose-limiting toxicity.…”

Myelodysplastic syndromes del(5q): Pathogenesis and its therapeutic implications

“…JNJ‐64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, showed a favorable safety profile in lower‐risk MDS during a phase I study. Unfortunately, no discernible evidence of clinical benefit was observed 77 …”

“…JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, showed a favorable safety profile in lower-risk MDS during a phase I study. Unfortunately, no discernible evidence of clinical benefit was observed 77. T A B L E 3Abbreviations: AML, acute myeloid leukemia; CyCR, complete cytogenetic response; CyR, cytogenetic response; IPSS, international prognostic scoring system; MDS; myelodysplastic syndromes; RBC-IT, red blood cells transfusion independence; TD, transfusion dependent; TI, transfusion independent.…”