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Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

01-nov-2023 | Revista: Leukemia Research

Tamanna Haque  1 , Felix López Cadenas  2 , Blanca Xicoy  3 , Ana Alfonso-Pierola  4 , Uwe Platzbecker  5 , Irit Avivi  6 , Andrew M Brunner  7 , Jöerg Chromik  8 , Daniel Morillo  9 , Manish R Patel  10 , Jose Falantes  11 , Heather A Leitch  12 , Ulrich Germing  13 , Meir Preis  14 , Laurie Lenox  15 , Josh Lauring  15 , Regina J Brown  15 , Anna Kalota  15 , Jaydeep Mehta  15 , Friederike Pastore  15 , Junchen Gu  15 , Pankaj Mistry  16 , David Valcárcel  17


Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study.

The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent.

Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent.

Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

CITA DEL ARTÍCULO  Leuk Res. 2023 Nov:134:107390.  doi: 10.1016/j.leukres.2023.107390

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