High-/Low-Dose Sabatolimab Exhibit Comparable Pharmacokinetics in MDS and AML

Andrew H. Wei, MBBS, PhD

In patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), treatment with sabatolimab administered at 200 mg every 2 weeks and 800 mg every 4 weeks demonstrated similar pharmacokinetic activity, according to findings from a dose-selection and dose-response analysis presented during the 2020 American Society of Hematology (ASH) Annual Meeting.

In evaluating sabatolimab Ctrough concentration in patients with myeloid malignancies (n = 92), no relationship was found between increased exposure and increased efficacy as measured by a bone marrow reduction in blasts or in clinical responses as measured by complete remission (CR), marrow CR, CR with incomplete hematologic recovery, or partial remission.

“There was no evidence that sabatolimab exposure was related to efficacy,” said Andrew H. Wei, MBBS, PhD, lead study author and hematologist at The Alfred Hospital and Monash University, in a virtual presentation of the data. “These results validate the selection of the sabatolimab 400-mg dose given every 2 weeks or 800 mg given every 4 weeks as a go-forward dose for registration enabling–studies, such as the STIMULUS clinical trial program.

Sabatolimab is an IgG4 monoclonal antibody, which binds with high affinity to TIM-3. TIM-3 is expressed on immune effector cells and leukemic cells, but not normal hematopoietic progenitor cells, making it an attractive target in AML.

Although TIM-3 is expressed on the cell surface, it can also shed to become soluble. When sabatolimab binds to soluble TIM-3, it leads to its stabilization. Therefore, increased concentrations of sabatolimab cause increased levels of soluble TIM-3 until a plateau of saturated, soluble TIM-3 and receptor- and membrane-bound TIM-3 is attained.

Sabatolimab had been evaluated in solid tumors (NCT02608268) and myeloid malignancies (NCT03066648) as a single agent and in combination with HMAs. These data served as the basis upon which the pharmacokinetic evaluations of efficacy, receptor occupancy, and adverse effects (AEs) were made.

In solid tumor studies, sabatolimab doses of at least 240 mg every 2 weeks and at least 800 mg every 4 weeks reached the same plateau level in the accumulated total of soluble TIM-3, reflecting a proportional dose-exposure relationship. Similar results for saturated receptor occupancy were reported in the studies of patients with MDS/AML and chronic myelomonocytic leukemia.

Population pharmacokinetic modeling also demonstrated that the 400- and 800-mg doses of sabatolimab led to a more than 95% membrane bound–TIM-3 receptor steady-state occupancy rate in the bone marrow in at least 95% of patients. Although the 400-mg dose of sabatolimab had the highest Ctrough at steady state, both doses had similar steady-state Cavg.

Pharmacokinetic exposure-response analyses with sabatolimab also demonstrated comparable frequency of AEs across exposure levels when patients with myeloid malignancies (n = 102) were categorized into 4 exposure quartiles––55.4-119 µg/mL; 119-171 µg/mL; 171-225 µg/mL; and 225-471 µg/mL––based on steady-stage Cmax and Cavg.

“[From this, we found that] increasing exposures of sabatolimab were [not] associated with a high frequency of high-grade AEs,” said Wei.

Regarding the safety of 118 patients with myeloid malignancies who received 240 or 400 mg of sabatolimab every 2 weeks or 800 mg every 4 weeks, the rates of grade 3 or greater treatment-emergent AEs, which included neutropenia, thrombocytopenia, febrile neutropenia, anemia, and pneumonia, and potential immune-mediated AEs related to treatment were not found to be dose dependent.

Andrew H. Wei, MBBS, PhD

Sabatolimab demonstrated comparable pharmacokinetic activity at doses of 200 mg every 2 weeks and 800 mg every 4 weeks in combination with hypomethylating agents (HMAs) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), according to findings from a dose-selection and dose-response analysis that were presented during the 2020 ASH Annual Meeting & Exposition.

In evaluating sabatolimab Ctrough concentration in patients with myeloid malignancies (n = 92), no relationship was found between increased exposure and increased efficacy as measured by a bone marrow reduction in blasts or in clinical responses as measured by complete remission (CR), marrow CR, CR with incomplete hematologic recovery, or partial remission.

“There was no evidence that sabatolimab exposure was related to efficacy,” said Andrew H. Wei, MBBS, PhD, lead study author and hematologist at The Alfred Hospital and Monash University, in a virtual presentation of the data. “These results validate the selection of the sabatolimab 400-mg dose given every 2 weeks or 800 mg given every 4 weeks as a go-forward dose for registration enabling–studies, such as the STIMULUS clinical trial program.

Sabatolimab is an IgG4 monoclonal antibody, which binds with high affinity to TIM-3. TIM-3 is expressed on immune effector cells and leukemic cells, but not normal hematopoietic progenitor cells, making it an attractive target in AML.

Although TIM-3 is expressed on the cell surface, it can also shed to become soluble. When sabatolimab binds to soluble TIM-3, it leads to its stabilization. Therefore, increased concentrations of sabatolimab cause increased levels of soluble TIM-3 until a plateau of saturated, soluble TIM-3 and receptor- and membrane-bound TIM-3 is attained.

Sabatolimab had been evaluated in solid tumors (NCT02608268) and myeloid malignancies (NCT03066648) as a single agent and in combination with HMAs. These data served as the basis upon which the pharmacokinetic evaluations of efficacy, receptor occupancy, and adverse effects (AEs) were made.

In solid tumor studies, sabatolimab doses of at least 240 mg every 2 weeks and at least 800 mg every 4 weeks reached the same plateau level in the accumulated total of soluble TIM-3, reflecting a proportional dose-exposure relationship. Similar results for saturated receptor occupancy were reported in the studies of patients with MDS/AML and chronic myelomonocytic leukemia.

Population pharmacokinetic modeling also demonstrated that the 400- and 800-mg doses of sabatolimab led to a more than 95% membrane bound–TIM-3 receptor steady-state occupancy rate in the bone marrow in at least 95% of patients. Although the 400-mg dose of sabatolimab had the highest Ctrough at steady state, both doses had similar steady-state Cavg.

Pharmacokinetic exposure-response analyses with sabatolimab also demonstrated comparable frequency of AEs across exposure levels when patients with myeloid malignancies (n = 102) were categorized into 4 exposure quartiles––55.4-119 µg/mL; 119-171 µg/mL; 171-225 µg/mL; and 225-471 µg/mL––based on steady-stage Cmax and Cavg.

“[From this, we found that] increasing exposures of sabatolimab were [not] associated with a high frequency of high-grade AEs,” said Wei.

Regarding the safety of 118 patients with myeloid malignancies who received 240 or 400 mg of sabatolimab every 2 weeks or 800 mg every 4 weeks, the rates of grade 3 or greater treatment-emergent AEs, which included neutropenia, thrombocytopenia, febrile neutropenia, anemia, and pneumonia, and potential immune-mediated AEs related to treatment were not found to be dose dependent.

Of note, immune-mediated AEs were identified in less than 10% of patients across the study population.

To date, no significant differences in efficacy or association with duration of response have been reported among the 3 dose levels (n = 104). In patients with high-risk MDS, the response rates were 50.0% (n = 12), 46.2% (n = 13), and 57.2% (n = 14) among the 240-, 400-, and 800-mg dose levels, respectively. In patients with AML, the response rates were 35.3% (n = 17), 34.5% (n = 29), and 31.6% (n = 19), respectively.

“There was no evidence of dose-response relationships with the response rate in evaluable patients with AML or MDS. Sabatolimab at these dose schedules was associated with good efficacy and no unexpected toxicities. There was no evidence that alternative schedules were able to produce better safety or clinical efficacy profiles,” concluded Wei.

_Reference:

_{Wei A, Esteve J, Porkka K, et al. Sabatolimab (MBG453) dose selection and dose-response analysis in myelodysplastic syndrome/acute myeloid leukemia: population pharmacokinetics modeling and evaluation of clinical efficacy/safety by dose. Presented at: 2020 American Society of Hematology Meeting & Exposition; December 5-8, 2020; virtual. Abstract 2192.}