Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms

David P Steensma,Justin Taylor,Catherine Scholz,Guillermo Garcia‐Manero ,Felicitas Thol,Jaime Pérez De Oteyza ,Antonio Gualberto,James M Foran,Ana Alfonso Piérola ,Jie Xiao ,Lionel Adès ,Andrew M Brunner,Xiaobin Yuan,Richard Stone,Benoit Destenaves,Malgorzata Mcmasters,Eunice S Wang,Sara Dar,Martin Wermke,Keisuke Kuida,Jean Baptiste Micol ,Justin M Watts,Virginia M Klimek,H Joachim Deeg,Huilan Yao,Catherine C Coombs,Alyssa J Marino,Lernik Ohanjanian,Patricia Font,Peter L Greenberg,Jay Yang,Hetty E Carraway,Ian W Flinn ,Kun Yu,Vikram Gourineni,Juan-Manuel Alonso-Domínguez ,Aref Al‐Kali ,Rami Komrokji ,Michael B Maris,Uwe Platzbecker

doi:10.1038/s41375-021-01328-9

Abstract

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Highlights

Somatic mutations in components of the RNA spliceosome are highly recurrent in myeloid neoplasia, representing the most common class of acquired mutations in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and secondary acute myeloid leukemia (AML) arising from MDS [1,2,3]
The observation of red blood cell (RBC) transfusion independence (TI) and the identification of a subset of MDS patients who could benefit from H3B-8800 treatment in terms of RBC transfusion requirements was a key finding of this study
Mutated Splicing Factor 3B1 (SF3B1) has been associated with the ring sideroblast phenotype, which is characterized by defects in heme biosynthesis and iron accumulation in mitochondria

Summary

Introduction

Somatic mutations in components of the RNA spliceosome are highly recurrent in myeloid neoplasia, representing the most common class of acquired mutations in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and secondary acute myeloid leukemia (AML) arising from MDS [1,2,3]. The most frequently mutated spliceosomeassociated genes in hematological neoplasms include SF3B1, SRSF2, U2AF1, and ZRSR2 [4,5,6,7,8]. Novel therapies for MDS, AML, and CMML are needed, as many patients diagnosed with these malignancies die of complications of their disease and experience cytopenias, including transfusiondependent anemia, that impair the patients’ quality of life [13,14,15,16]. Altered splicing is an attractive target for novel therapies, given the high frequency with which spliceosome-associated mutations are seen in myeloid neoplasms [17,18,19]. Aberrant splicing of genes involved in heme metabolism, such as TMEM14C, PPOX, and ABCB7, has been observed in MDS patients,

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Results

Conclusion