JP-7855512-B2 - Lysine-specific histone demethylase inhibitors for the treatment of myeloproliferative neoplasms

Inventors

• リエンホフ，ヒュー

Assignees

• イマーゴ バイオサイエンシーズ インコーポレイテッド

Dates

Publication Date

20260508

Application Date

20201208

Priority Date

20191209

Claims (1)

1. N-[ (2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazole-1-yl)benzamide, bis-tosylate salt , in the manufacture of a pharmaceutical product for the treatment of primary myelofibrosis (PMF), post-PV myelofibrosis (PPV-MF), or post-ET myelofibrosis (PET-MF) in subjects requiring it. The use of ("Compound 1"), wherein Compound 1 is administered in an amount sufficient to maintain a platelet count of 50 × 10⁹ to 75 × 10⁹ platelets/L. The subjects were administered compound 1 at an initial dose of 0.5 mg/kg/d, and then one week later, If the platelet count is ≥90 × 10⁹ platelets /L and the % platelet reduction is <50% from the previous examination, the dose for the subject is adjusted to add 0.2 mg/kg/d of compound 1 to the daily dose. If the platelet count is ≥90 × 10⁹ platelets /L and the % platelet reduction is ≥50% from the previous examination, the dose for the subject is adjusted to add 0.1 mg/kg/d of compound 1 to the daily dose. When the platelet count is between 40 × 10⁹ platelets /L and 89 × 10⁹ platelets/L, the daily dose of compound 1 is maintained. When the platelet count is between 25 × 10⁹ platelets /L and 39 × 10⁹ platelets/L, the dose of the subject is adjusted to reduce the current mg/kg daily dose of compound 1 by 25%. If the platelet count is <25 × 10⁹ platelets /L, administration is withheld until the platelet count returns to >50 × 10⁹ platelets /L, and then the dose of compound 1 is adjusted to 50% of the dose administered when the platelet count fell below 25 × 10⁹ platelets/L, and Throughout the course of therapy, the platelet count evaluation and dose adjustment process is repeated once a week until the target platelet count reaches 50 × 10⁹ to 75 × 10⁹ platelets/L.

Description

This application claims the benefits of U.S. Provisional Application No. 62/945,609 filed on 9 December 2019 and U.S. Provisional Application No. 63/121,461 filed on 4 December 2020 (both in their entirety are incorporated herein by reference as if they were described herein in their entirety). Myeloproliferative neoplasms (MPNs), a disease category encompassing polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF), are a distinguishable family of hematopoietic disorders resulting from somatic mutations in pluripotent hematopoietic stem cells/progenitor cells, leading to hematological abnormalities in red blood cell, white blood cell, and platelet production, as well as splenomegaly and systemic symptoms. MPNs share common mutations that constitutively alter normal physiological signals responsible for hematopoiesis. While MPNs can manifest clinically as benign clonal myeloproliferation, the initiating abnormal stem cells/progenitor cells are susceptible to novel mutations and epigenetic modifications that enable rapid evolution to myelofibrosis-associated myelofibrosis or transformation into acute myeloid leukemia (AML). Many MPN patients are asymptomatic at the time of diagnosis. Due to confounding between definitive diagnosis and prognosis, ET, PV, and PMF can be masked by each other. Common symptoms include fatigue, weight loss, night sweats, fever, dyspnea, and sometimes abdominal discomfort due to massive splenomegaly. The three MPN disorders overlap phenotypically and also share similarities with other myeloid neoplasms. Specific point mutations in JAK2 (JAK2V617F) and mutations in calreticulin (CALR) and thrombopoietin receptor (MPL) are found in 90% of MPN patients. The distribution of these mutations is not equal among PV, ET, and primary MF, i.e., PMF, but they do not diagnostically determine specific MPN or prognosis, nor are they mutually exclusive. Healthy individuals may carry one of these mutations without developing MPN, and in fact, some of these mutations may be carried as germline mutations that cause the genetic form of MPN. Nevertheless, PV, ET, and PMF are considered distinct clinical entities based on their identifiable epidemiological, natural history, and molecular profiles. PV is the most common MPN, and phenotypic mutations in JAK2 will be present. PV is the only MPN characterized by polycythemia, defined as hematocrit ≥ 60% and hemoglobin ≥ 20 gm/dL. ET is characterized by a persistent platelet count > 450,000/μL and occurs primarily in women. MF is primary or secondary myelofibrosis, sometimes called myeloid metaplasia, myeloid metaplasia of unknown cause, or myelofibrosis with primary myelosclerosis, and is a chronic inflammatory process in which excess collagen accumulates in the bone marrow, impairing hematopoiesis in association with myelofibrosis and extramedullary hematopoiesis. Major complications arise from cytopenia secondary to bone marrow failure, extramedullary hematopoiesis (primarily in the spleen and liver), and progression to acute myeloid leukemia. For patients, splenomegaly is the most distressing complication of primary myelofibrosis, leading to mechanical discomfort, starvation and debilitation, splenic infarction, portal and pulmonary hypertension, and blood cell capture. Both ET and PV are associated with thrombosis. ET and PV can progress to MF and AML. Many other somatic mutations found in MPN are also present in myelodysplastic syndromes (MDS) and de novo AML, including mutations in DNMT3A, IDH1/2, TET2, ASXLI, EZH2, TP53, NF1, NRAS, KRAS, SF3B1, U2AF1, SRSF2, and RUNX1. This shared mutation spectrum contributes to the phenotypic overlap of these disorders and further influences their natural history, including evolution to bone marrow failure or AML. There are no specific treatments for primary myelofibrosis, essential thrombocythemia, or polycythemia vera. Current treatments do not significantly alter the natural history of the disease and therefore primarily aim to improve symptoms. Anemia with erythropoietin (EPO) levels <100 mU/ml may respond to recombinant EPO therapy, but is accompanied by increased hepatosplenomegaly. Prednisone may be effective in patients with evidence of active inflammation or autoimmune disease. Hyperuricemia is managed with allopurinol. The non-selective JAK1/2 inhibitor ruxolitinib is approved for intermediate 1 and 2 as well as high-risk MF patients, and also for high-risk PV patients. Ruxolitinib alleviates systemic symptoms and is effective in reducing spleen size or volume by 35% in approximately 50% of patients. Ruxolitinib has extended survival and reduced JAK V617F allele burden in high-risk patients with primary MF (PMF). Anemia is worsened by ruxolitinib in some patients, but thrombocytopenia, even severe, may improve. Ruxolitinib is effective only during the duration of drug administration, and symptoms will likely recur once the drug is discontinued. Marrow fibrosis is unaffected, and rux