Bomedemstat Demonstrates Early Promise in Advanced Myelofibrosis

Article
Pipeline Report: July 2022

Single-agent bomedemstat was found to improve symptom scores, bone marrow fibrosis, spleen volumes, and anemia in patients with advanced myelofibrosis, according to findings from the phase 1/2 IMG-7289-CTP-102 trial (NCT03136185) presented during the 2022 EHA Congress.

Single-agent bomedemstat (IMG-7289) was found to improve symptom scores, bone marrow fibrosis, spleen volumes, and anemia in patients with advanced myelofibrosis, according to findings from the phase 1/2 IMG-7289-CTP-102 trial (NCT03136185) presented during the 2022 EHA Congress.

Results indicated that 64% of all evaluable patients who received the LSD1 inhibitor (n = 50) experienced a decrease in spleen volume reduction (SVR) at 24 weeks, with 28% of patients experiencing a decrease of at least 20% and 6% achieving a decrease of at least 35%.

Moreover, 55% of all patients (n = 51) were found to have a decrease in total symptom score (TSS) at the same time point; 22% of these patients experienced a decrease of 50% or higher. Moreover, of 26 evaluable patients with high symptom burden, 65% experienced a decrease in TSS at 24 weeks; notably, 19% of these patients experienced a decrease of at least 50%.

Ninety percent of patients who were transfusion independent at baseline (n = 41) were reported to have stable or improved hemoglobin levels; specifically, 44% experienced an increase in levels of at least 1.0 g/dL, and 46% had stable hemoglobin (△± 1.0 g/dL). Additionally, 52% of 21 patients who were transfusion dependent at baseline were found to have either stable or reduced transfusion burden.

Most patients, or 85%, were reported to have improved or stable bone marrow fibrosis scoring post baseline.

“Bomedemstat as monotherapy for patients with advanced myelofibrosis offers a distinct clinical profile,” lead study author Harinder Gill, MD, MBBS, FRCP, FRCPath, of the Department of Medicine at The University of Hong Kong, and colleagues, wrote in a poster on the data. “[The agent was] generally safe and well tolerated to date.”

It is known that LSD1 is a key regulator of hematopoietic differentiation. LSD1 regulates the proliferation of blood stem cells and is needed for differentiation into mature megakaryocytes and granulocytes. In myeloproliferative neoplasm mouse models, inhibition of LSD1 has been found to decrease the hallmark symptoms; this also resulted in a lower number of cells with the mutations that drive these diseases.

Pharmacokinetic and dose-response data with bomedemstat has allowed for once-daily dosing of the agent, which has not been found to penetrate across the blood-brain barrier. To date, the drug has been examined in over 200 patients with myeloid malignancies.

The global trial, which is now fully recruited, enrolled patients with primary myelofibrosis, post–essential thrombocytosis (ET) myelofibrosis, and post–polycythemia vera (PV) myelofibrosis. To be eligible for enrollment, patients needed to be refractory or resistant to, intolerant of, unacceptable control by, or ineligible for, available approved therapies. Patients also needed to have International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk disease. Other inclusion criteria included having platelet counts of at least 100 x 109/L, peripheral blasts of 10% or less, spleen of any size, and an ECOG performance status of 0 to 2.

Bomedemstat was given once daily, with each patient dose-titrated to a target platelet count ranging from 50 x 109/L to 75 x 109/L. The starting dose of the phase 1/2a portion of the trial was 0.25 mg/kg, which was given to 18 patients. The starting dose for the phase 2b portion was 0.5 mg/g in 25 patients; later, the examined dose was 0.6 mg/kg (n = 46).

A total of 90 patients were dosed with the agent. In the phase 1/2 portion of the research, 3 of the 18 patients discontinued treatment before week 12 because of toxicity (n = 2) or limited clinical benefit (n = 1). In the phase 2b portion, 27 of the 71 patients discontinued treatment. The most common reason for discontinuation was treatment-related adverse effects (AEs; n = 9), followed by unrelated AEs (n = 7), other unspecified reasons (n = 5), progressive disease (n = 2), principal investigator decision (n = 2), and lack of efficacy (n = 2).

Among the 89 patients enrolled to the trial, the median age was 68 years (range, 35-88), and 52% were male. Regarding disease subtype, 46% had primary disease, 33% had post-ET disease, and 21% had post-PV disease. Most patients (53%) had high-risk disease, 40% had intermediate-2 risk disease, and 7% had intermediate-1 risk disease. The median spleen length was 12 cm BLCM, and the median spleen volume was 1354 cm3. The median symptom score was 25 (range, 0-82).

Regarding mutational status, 65% had JAK2, 39% had high-molecular risk, 22% had CALR, 7% had MPL, and 6% had triple-negative status. The median number of prior therapies received was 2 (range, 0-6). Prior treatments received included ruxolitinib (Jakafi), anagrelide (Agrylin), fedratinib (Inrebic), and hydroxyurea (Hydrea).

Additional findings showed that 83% of evaluable patients (n = 52) experienced a reduction in cytokine levels at 12 weeks. Reduction normalized levels of CCL5 was observed in 42 of 43 patients. Sixty-two percent of 52 patients experienced a decrease of more than 50%. Moreover, 52% of 69 evaluable patients experienced a decrease in allele frequencies, with the greatest decrease observed in ASXL1.

Ninety patients comprised the safety population. The most common non-hematologic toxicity associated with study treatment was dysgeusia (33%); this effect resulted in 1 discontinuation.

The most common toxicities reported with the agent included thrombocytopenia (any grade, 48%; grade 3/4, 41%), dysgeusia (any grade, 36%), diarrhea (any grade, 33%), anemia (any grade, 34%; grade 3/4, 22%), nausea (any grade, 30%; grade 3/4, 2%), fatigue (any grade, 26%; grade 3/4, 4%), constipation (any grade, 23%; grade 3/4, 1%), peripheral edema (any grade, 23%; grade 3/4, 1%), arthralgia (any grade, 24%; grade 3/4, 1%), abdominal pain (any grade, 18%; grade 3/4, 2%), contusion (any grade, 18%), decreased appetite (any grade, 17%; grade 3/4, 2%), pyrexia (any grade, 16%; grade 3/4, 2%), and pruritus (any grade, 16%; grade 3/4, 2%).

Forty-nine percent of patients experienced serious AEs (SAEs), the most common of which were cellulitis, diverticulitis, and pneumonia. Sixteen percent of SAEs were associated with bomedemstat per investigator assessment. Notably, no deaths were linked with study treatment.

A phase 2 trial (NCT04254978) is evaluating bomedemstat in patients with ET, and another phase 2 trial (NCT04262141) is examining the drug in patients with either ET or PV.

Reference

Gill H, Yacoub A, Pettit K, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) in patients with advanced myelofibrosis. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P1051.

Related Videos