お知らせ • Mar 07
Imara Inc. Expects to Conduct Phase I/Ii Clinical Trial in Adolescents
IMARA Inc. announced Overall, the Phase IIa demonstrated that IMR-687 was well tolerated as a monotherapy and in combination with HU at all dose levels. A 30% lower rate of vaso-occlusive crises or sickle cell pain crises as part of the safety analysis was observed in the population A group when compared to placebo. Furthermore, the rate of VOC related hospitalizations was lower in the population A1 group when compared to placebo. There were no meaningful differences in VOCs or VOC-related hospitalizations between the population B1 group and placebo. Biomarker results for population A1 showed minimal changes in F-cells, HbF levels and total Hb from baseline through week-24. Biomarker results in population B1 treated patients showed an overall increase in F-cells and HbF levels from baseline of week-24, while Hb levels do not meaningfully change. As a reminder, the 4-year OLE trial allows patients from the Phase IIa program to enroll in a long-term safety and tolerability study of IMR-687, following completion of the Phase IIa. The OLE trial was initially designed for patients who were administered a daily dose of 100-milligram of 687. And in the second quarter of 2020, a protocol amendment increased the daily dose to 200-milligram. Patients from the combination sub-study continue to receive the same dose of HU that they received while they're on the Phase IIa and throughout the duration of the OLE trial. Based on the tolerability profile of IMR-687 observed thus far, the Safety Review Committee has approved a dose escalation in the OLE trial to a minimum daily dose of 300 milligram, up from 200 milligram, with certain patients being eligible for a daily dose of 400 milligrams based on their weight. This weight-based approach is similar to ongoing Ardent Phase IIb clinical trial for sickle cell disease. The Safety Review Committee approved these dose adjustments, contingent upon the independent Data Monitoring Committee opening up the higher dose arm in the Ardent Phase IIb trial in sickle cell. It expects the Ardent Phase IIb DMC to make a decision on opening this higher dose in March 2021, paving the way for the OLE dose adjustment via protocol amendment. In the OLE, the company conducted a preliminary review of 24 patients as of December 31, 2020. Overall, data from the 24 patients enrolled in the OLE trial demonstrate that IMR-687 was well tolerated and had a safety profile similar to that observed in the Phase IIa clinical trial. As of December 31, 2020, approximately 12 of these patients had evaluable PD biomarker data for at least 4 months of treatment on the OLE trial. Biomarker results demonstrated absolute increases in both HbF and F-cells after 4 months of treatment in both the treatment-interrupted subgroup and the direct rollover subgroup. Specifically, there was a mean absolute increase of the HbF of 1.7% in the treatment-interrupted subgroup and a mean absolute increase of F-cells of 5.9%. In the direct rollover subgroup, there is a mean absolute increase of HbF of 2.3% and a mean absolute increase in F-cells of 10.2%. There were minimal changes in total Hb in both subgroups. Patients in the treatment-interrupted subgroup also demonstrated improvements in markers of hemolysis after 4 months of treatment, whereas the direct rollover subgroup showed variable changes in these measures. Both patients in these case narratives have continued to see absolute increases in HbF from baseline of greater or equal to 4.5% as well as absolute increases in F-cell measurements. Patient 1 is part of the Pop A monotherapy substudy of the Phase IIa trial and enrolled in the OLE as a direct rollover patient. As of December 31, 2020, patient 1 had been on the OLE trial for approximately 18 months and on IMR-687 for approximately 24 months and has shown in continued increase in levels of HbF with an absolute increase over baseline of 4.8% after 18 months of the OLE trial. Furthermore, this patient has seen increased F-cells compared to baseline as well as improvements in several SCD disease biomarkers. In addition, a comparison of VOC data for the 24-month period that the patient has been on IMR-687, that 6 months on the Phase IIa and 18 months on the OLE versus data from a retrospective review of the patient's medical records for the 24 months prior to initiation of IMR-687 indicate additional VOC episodes. In the 24-month period on IMR-687, the patient-reported 20 VOCs as compared to 50 reported -- 55 reported VOCs in the 24-month period prior to IMR-687 administration, a 64% reduction in the rate of VOCs. Patient 2 was part of the HU combination sub-study in the Phase IIa trial, was randomized to the placebo dose group and, therefore, never received IMR-687 during the Phase IIa. The patient started the OLE trial 14 months after completing the Phase IIa trial and is a treatment-interrupted patient. The patient has remained on stable dose of HU during this interim period and while on the OLE trial. As of December 31, 2020, had data on this patient through 8 months of treatment, reflecting the most recent OLE visit. Patient #2 has shown a sustained increase in levels of HbF, with an absolute increase over baseline of 4.5% after 8 months on the OLE trial and an increase over baseline in F-cells; however, this patient has also showed increasing variability of their SCD biomarkers versus the original case narrative. In addition, a comparison of VOC data for patient #2 for the 8-month OLE trial period versus data from a retrospective review of the patient's medical records for the 8-month period prior to the initiation of the OLE trial, indicates potential benefits of IMR-687 being administered in combination with HU. In the 8-month period on IMR-687, a patient had a 69% reduction in the rate of reported VOCs, 16 to 5 events as compared to the 8-month period prior to IMR-687, and while on HU alone. The 2 Phase IIb clinical trials of IMR-687, including Ardent trial in adult patients with sickle cell disease and Forte trial in adult patients with beta thalassemia. It expended significant effort last year in initiating these trials, and continue to expect to report interim data in the second half of 2021. continue to expand the global footprint for both studies with 22 and 36 active clinical centers for Ardent and Forte, respectively, across multiple countries and with continued near-term activation of the digital centers. The Ardent Phase IIb trial will enroll approximately 99 patients with sickle cell disease, that is a double-blind, randomized trial, where patients will be stratified by use of hydroxyurea as well as by region. The company currently anticipate initiating pediatric clinical program of IMR-687 on sickle cell disease in the first half of 2021. The company expects to conduct a Phase I/II clinical trial in adolescents between 12 to 17 years old comprised of the single ascending dose phase followed by a 36-week multiple dose expansion phase.