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Lysine-specific demethylase-1 (LSD1) is a histone H3K4 demethylase that is required for the regulation of the proliferation of blood stem cells, and the differentiation of progenitor cells into mature megakaryocytes. It is overexpressed in myeloproliferative neoplasms (MPN) and LSD1 inhibition has been associated with the loss of self-renewal of malignant myeloid cells.
IMG-7289 (bomedemstat) is an orally active LSD1 inhibitor which is known to have favorable impact on myelofibrosis (MF) symptoms. Recently, Gill et al.1 and Ross et al.2 presented updated results at the 26th Congress of the European Hematology Association (EHA2021), for two ongoing phase II studies in patients with MF (IMG-7289-CTP-102; NCT03136185) and essential thrombocythemia (ET) (IMG-7289-CTP-201; NCT04254978), respectively.
This is a multinational, open-label, 24-week phase II study in patients with MF. Further information—the study design including primary endpoints, eligibility criteria, and previous results from a 12-week analysis—can be found here.
The starting dose was 0.6 mg/kg once daily given orally. Dose adjustments were made individually to achieve a platelet count of 50−75 × 109/L.
A total of 86 patients were enrolled; 62% completed at least 12 weeks of study, and 49% are still on study (Figure 1).
Figure 1. Patient enrollment according to the most recent updates of the study*
*Adapted from Gill et al.1
The reasons for early termination before Week 24 included adverse events (AEs) (related or unrelated to treatment), investigator decision, disease progression, limited clinical benefit, and other reasons.
Baseline characteristics are similar to those included in the 12-week analysis as published previously.
Patients with MF had an improvement in symptom scores, spleen volume, and anemia. A decrease in MAFs was seen in 44% of evaluable patients including driver and HMR mutations, such as ASXL1. No new mutations or transformation to AML were observed in patients at high-risk of progression. The reduction in MAFs and suppression of new mutations observed suggest that bomedemstat may be a disease-modifying therapy with respect to AML.
This is an ongoing, multinational, open-label, 24-week phase IIb study in patients who had the following characteristics:
Key objectives of the CTP-201 study in patients with ET2
A flow diagram showing patient enrollment is depicted in Figure 2.
Figure 2. Flow diagram of patient enrollment in the beginning of the study and active participants according to the most recent updates of the study*
ET, essential thrombocythemia.
*Adapted from Ross et al.2
The results summarized below were obtained at Week 12. Baseline characteristics are summarized in Table 1.
Table 1. Baseline characteristics for patients with ET*
Characteristic |
N = 28 |
---|---|
Median age, years (range) |
67 (42−84) |
Male, % |
36 |
Mean blood counts |
|
WBC |
9.9 × 109/L |
Hb |
13 g/dL |
Platelets |
892 × 109/L |
Mutation (n = 20), % |
|
JAK2 |
50 |
CALR |
40 |
Triple-negative |
10 |
≥1 myeloid disease-associated mutation |
30 |
Median symptom score |
30 (range, 11−74) |
Patients with TSS >10, n |
18 |
Most recent therapy prior to bomedemstat, % |
|
Hydroxyurea |
78 |
Anagrelide |
7 |
Interferon |
7 |
Ruxolitinib |
4 |
Other |
4 |
CALR, calreticulin gene; ET, essential thrombocythemia; Hb, Hemoglobin; JAK2, Janus kinase 2 gene; TSS, total symptom score; WBC, white blood cells. |
Seventy-eight of the 160 AEs reported by 19 patients were considered treatment related.
Overall, for ET patients, IMG-7289 was considered as safe. Improvement on platelet and WBC counts was observed with a stable Hb. There was also a symptomatic improvement for patients with significant MPN symptoms. There was no obvious relationship among driver mutations, starting platelet counts, final optimal dose, or response rates. Data about changes in MAFs are expected to be known soon as patients reach 24 weeks.
IMG-7289 (bomedemstat) is a generally safe and well tolerated therapeutic option in patients with MF and ET and has shown clinical activity as a monotherapy. Another clinical trial investigating IMG-7289 in patients with polycythemia vera (PV) is currently enrolling patients (NCT04262141).
Cumulative safety experience from 159 patients with AML, myelodysplastic syndromes (MDS), MF, and ET have demonstrated that there are no dose-limiting toxicities to a maximum of 6 mg/kg daily dose. There were no safety signals in 4 years with IMG-7289. Furthermore, no genotoxicity or mutagenicity have been observed.
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