SAN FRANCISCO—Imago BioSciences Inc. announced in June that positive safety and early efficacy clinical data regarding its lysine-specific demethylase (LSD1) inhibitor, IMG-7289, were presented at the 24th Congress of the European Hematology Association.
According to Dr. Hugh Young Rienhoff, Jr., CEO of Imago BioSciences, “IMG-7289 is an inhibitor of the epigenetic enzyme lysine-specific demethylase 1, which regulates differentiation in maturing blood cells. LSD1 is a remarkable enzyme that regulates many of the key features of hematopoiesis, such as stem cell self-renewal, differentiation and growth. Inhibition of the enzyme appears to be very safe if one monitors blood counts. In malignant myeloid cells, LSD1 is required for high expression of inflammatory cytokines such as interleukin 8.
“In addition, IMG-7289 may have uses outside of hematologic disease, given that it causes tumor cells to become more immunogenic. This was an unanticipated finding and suggests that there is much more to learn about LSD1 and its inhibition outside of oncology.”
The data from the ongoing IMG-7289-CTP-102 Phase 1/2a clinical trial showed that IMG-7289 was well tolerated in patients with high or intermediate-2 risk myelofibrosis that was resistant to or intolerant of approved therapy. The therapy was also effective in reducing spleen volumes and substantially improved symptom scores in a majority of evaluable patients.
“IMG-7289 has shown tremendous promise to be a meaningful treatment option for myelofibrosis patients, and these data support our clinical program,” says Rienhoff. “These data, particularly the strong safety and efficacy signals, have informed our Phase 2b dosing strategy and encourage us to explore additional indications in myeloproliferative diseases.”
The data presented were from a cohort of 16 enrolled patients, 15 of whom had received one or more prior treatments, including ruxolitinib. All patients began treatment with a sub-therapeutic dose of 0.25 mg per kg, with doses increasing until platelet count rested between 50 and 100K/μL.
Twelve patients (75 percent) sustained a platelet count within this target zone at a dose of 0.81 mg/kg, with 14 patients (88 percent) completing the 85-day study. Nine patients were evaluable for efficacy, with six (66 percent) showing a reduction of spleen volume via imaging and five (56 percent) recording a greater than 50 percent reduction in total symptom score and two (22 percent) recording an improved bone marrow fibrosis score at 12 weeks.
“The only approved treatment for myelofibrosis [MF] is ruxolitinib, an inhibitor of the JAK1 and JAK2 kinases which are at the proximal end of a pathway signaling growth of blood cells. The basic therapeutic thesis for treating MF with IMG-7289 is to tame the mutant megakaryocytes which make many of the protein factors that drive the clinical aspects of the disease,” Rienhoff notes.
The study has not shown safety signals, dose-limiting toxicities or patient deaths with a median duration of treatment at 156 days. Fourteen patients in the study reported a total of 239 adverse events. There were 15 serious adverse events, only one of which was deemed related—painful splenomegaly.
“Even with a conservative dosing approach to evaluate safety, we saw encouraging improvements in patients’ symptoms and spleen sizes,” mentioned Dr. Kristen Pettit, assistant professor of medicine at the Rogel Cancer Center at The University of Michigan and a principle investigator of the study. “Continued evaluation of this therapeutic candidate under the modified clinical trial design with a more aggressive dosing approach will be a critical next step. We look forward to continuing evaluation of this therapeutic candidate under the modified clinical trial design with a more aggressive dosing approach.”
Based on the findings, Imago has expanded the study into a Phase 2b trial and is evaluating clinical investigations in additional myeloid diseases. The expanded study, which is expected to enroll 35 additional patients, will utilize a modified dosing schedule of IMG-7289 that safely optimizes efficacy. Additional trial sites have been added in the U.S., EU and U.K.
“With the safety, PK and dose-response data in hand, the principle features of the Phase 2b protocol focus on documenting efficacy and clinical benefit, which include reduction in spleen volume, improvement in symptom scores and quality of life, and a reduction of bone marrow fibrosis and tumor load,” notes Rienhoff. “Among other changes, the amended protocol allows for longer uninterrupted treatment (24 weeks) and a higher starting dose. The patient populatio
and the clinical assessments remain the same.”
When asked about the next steps for IMG-7289, Rienhoff tells DDNews that, “IMG-7289 will be studied for the treatment of polycythemia vera, essential thrombocythemia. It may also be effective in sickle cell anemia and thalassemia intermedia. In combination with other agents, IMG-7289 will be studied in patients with acute myeloid leukemia and solid tumors.” He adds that Imago will “finish enrollment of the 2b study, begin the studies in polycythemia vera and essential thrombocythemia in 2019 and consider the merits of initiating other clinical studies in 2020.”