Bomedemstat (IMG-7289), an LSD1 Inhibitor, Manages the Signs and Symptoms of Essential Thrombocythemia (ET) While Reducing the Burden of Cells Homozygous for Driver Mutations

Abstract

<p>The ultimate goal in the treatment of ET is to eliminate mutant cells with the capacity to both proliferate and self-renew. Lysine-specific demethylase-1, LSD1, is an enzyme critical for regulating the proliferation of hematopoietic stem cells and the maturation of progenitors (Sprussel <em>et al.</em> 2012). Bomedemstat is an orally active LSD1 inhibitor that reduces platelets, inflammatory cytokines, and the mutant cell burden in mouse models of myeloproliferative neoplasms (Jutzi <em>et. al.</em>, 2019). All current treatments - hydroxyurea, interferon, or anagrelide - have their limitations and do not substantially affect the natural history of ET.</p><p>IMG-7289-CTP-201 was a global, open-label, Phase 2b study of bomedemstat (IMG-7289, MK-3543) taken once daily for 24+ weeks in patients with ET resistant to or intolerant of at least one standard treatment (NCT04254978). The primary endpoint was reduction of platelets to <400 x 10 ⁹/L in the absence of new thromboembolic events. Exploratory endpoints included changes in frequencies of mutant alleles (VAF) assessed by deep sequencing (median exonic depth =1784 reads) of 261 genes of germline and somatic DNA. Homozygosity of mutant alleles was imputed when VAF >50% and/or loss-of-heterozygosity (LOH) was evident based on the difference between the minor allele frequency of flanking single nucleotide polymorphisms (“MAF method”) in germline <em>versus</em> granulocyteDNA. Single cell genotypes (scDNA) (Tapestri ®) were determined in stem/progenitor (CD34+) and monocytes (CD14+) cells in patients with LOH (using the MAF method) showing a decrease in LOH in whom follow-up samples were available.</p><p>For patients treated ≥24 wks, 95% (61/64) had reduced platelet counts to ≤400 x 10 ⁹/L without new thromboembolic events, in a median time of 10 wks. In the first 48 weeks, four patients experienced a thromboembolic event ( <em>per</em> PI) (1 PE, 2 TIAs, and 1 transient global amnesia). Of the 14/73 (19%) patients with Day 1 WBC count >10 x 10 ⁹/L, 100% treated for ≥24 wks had reduced the WBC count to ≤10 x 10 ⁹/L; mean Hb remained stable. In patients with baseline MPN-SAF TSS >20 (28/73), at Wk 24, 78% (18/23) experienced an improvement with 52% (12/23) improving ≥10 points. The median baseline score for worst fatigue was 4.0 (N=73); by Wk 24, the score had improved to 3.0 (N=62).</p><p>Among all patients (N=73), the most common AEs regardless of causality were dysgeusia (55%), constipation (38%), thrombocytopenia (34%), and arthralgia (27%). Twenty-four patients reported serious AEs (SAE), with related events ( <em>per</em> PI) in 4 patients. Twenty-one patients discontinued treatment, 11 due to AEs (3 for dysgeusia), 7 subject's decisions, 1 PI decision, 1 disease progression, and 1 unrelated death due to aspiration pneumonia. There have been no safety signals or deaths related to drug in patients treated for up to 979 days. At Wk 24, 86% patients remained on study and 75% at Wk 48.</p><p>At ~Wk 24, 39 of 46 (85%) of evaluable patients had a decrease in driver VAF (Fig. 1). The greatest changes in VAF occurred in patients with cells homozygous for a driver mutation (Fig. 1). Nine of ten patients with homozygous driver clones had follow-up data: by bulk sequencing of germline+granulocyte DNA, 7 showed a reduction in the proportion of homozygous cells. In all cases tested, scDNA of CD14+ (monocytes) and CD34+ (stem/progenitor) cells were qualitatively similar to results obtained with bulk granulocyte sequencing (Fig.2). By bulk sequencing, the proportion of homozygous cells dropped by a mean of 66% (-4% to -100% (-100% = homozygosity not detectable)). Decreases in LOH by bulk and sc sequencing during treatment with bomedemstat were identified in patients with homozygosity at <em>JAK2, CALR</em>, and <em>MPL.</em></p><p>This study demonstrates that treatment with bomedemstat results in a consistent hematologic response in the majority of patients with ET. Further, deep bulk sequencing of germline+granulocyte DNA reveals LOH ( <em>i.e</em>., homozygosity) events with high accuracy that enables determination of the distribution of homozygote, heterozygote and wild-type genotypes. Furthermore, this study shows that sequencing germline+granulocyte DNA provides a reliable qualitative view of the impact of treatment on the genotypic distribution among CD34+ cells as revealed by scDNA genotyping. Finally, bomedemstat showed activity reducing stem/progenitor cells homozygous for mutations in <em>JAK2, CALR</em>, and <em>MPL</em>.</p>