IO-202 Receives FDA Orphan Drug Designation for CMML


The FDA has granted IO-202 an orphan drug designation for patients with chronic myelomonocytic leukemia.



The FDA has granted an orphan drug designation to IO-202 for the treatment of patients with chronic myelomonocytic leukemia (CMML). IO-202 is a first-in-class, humanized IgG1 antibody designed to have high-affinity binding to leukocyte Immunoglobulin-like receptor subfamily B4 (LILRB4).1

“Although current therapeutic options for CMML can improve a patient’s quality of life, there is a high unmet need for effective disease-modifying approaches that are potentially curative,” Charlene Liao PhD, chief executive officer and board chair of Immune-Onc, the manufacturer of IO-202, said in a press release. “We are very proud that the FDA has granted IO-202 orphan drug designation for the treatment of [patients with] CMML. We look forward to continued collaborations with our investigators and the FDA as we work to bring this potentially important therapy to patients with hard-to-treat blood cancers.”

IO-202 is being evaluated as monotherapy and with azacitidine (Vidaza) with or without venetoclax (Venclexta) in a phase 1 trial (NCT04372433) in patients with relapsed/refractory acute myeloid leukemia (AML) with monocytic differentiation or CMML. To be eligible for the multicenter, open-label phase 1 study, patients need be at least 18 years of age, have an ECOG performance status of 2 or lower, have adequate hepatic and renal function, and have not received systemic calcineurin inhibitors for at least 4 weeks prior to study treatment.2 Those who have received previous treatment with a LILRB4-targeted monoclonal antibody, have undergone hematopoietic stem cell transplantation within 60 days of the first dose of IO-202, or for whom a potentially curative anticancer therapy is available are excluded.2

During the dose-escalation portion of the trial, patients received intravenous IO-202 in dose levels ranging from 0.03 mg/kg to 60 mg/kg on days 1 and 15 of each 28-day cycle.3 Azacitidine at 75 mg/m2 was given on days 1 through 7 of each cycle.3

The primary end points of the phase 1 trial were the safety and tolerability of IO-202 as monotherapy and in combination with azacitidine with or without venetoclax.2 Secondary end points included pharmacokinetics, response rates, and incidence of antidrug antibodies against IO-202.2

Findings from the dose-escalation portion of the study were presented during the 2023 EHA Congress and included patients with AML who received IO-202 monotherapy (n = 26) and IO-202 plus azacitidine (n = 10). Additionally, a cohort of patients with CMML received IO-202 monotherapy (n = 5) and IO-202 plus azacitidine (n = 5).3

In the AML cohort, 1 patient treated with IO-202 monotherapy at 9 mg/kg achieved a partial remission (PR), and 1 patient with high LILRB4 expression who received IO-202 at 30 mg/kg plus azacitidine achieved a complete remission (CR) lasting longer than 10 months. In the CMML cohort, 1 patient who received IO-202 monotherapy at a dose increasing from 0.1 mg/kg to 0.3 mg/kg achieved a clinical benefit lasting for longer than 1 year. In the CMML combination arm, 1 patient achieved a PR at the 4.5 mg/kg dose, 1 patient experienced clinical benefit at the 9 mg/kg dose, and 1 patient who was treated at the 60 mg/kg dose experienced an optimal marrow response with a duration of over 3 months.

In terms of safety, patients in the overall monotherapy (n = 31) and combination (n = 15) safety populations experienced any-grade treatment-emergent adverse effects (TEAEs) at rates of 100% and 100%, respectively. Patients in both groups experienced TEAEs of grades 3 to 5 in severity (90.3% vs 86.7%), TEAEs leading to discontinuation (16.1% vs 6.7%), serious TEAEs (77.4% vs 66.7%), TEAEs that were serious and led to discontinuation (16.1% vs 6.7%), and TEAEs leading to death (25.8% vs 13.3%). Notably, no deaths were attributed to IO-202 administration, no dose-limiting toxicities were reported, and the maximum tolerated dose was not reached.

Study authors concluded that IO-202 was safe and well tolerated at a maximum dose of 60 mg/kg twice weekly as monotherapy and in combination with azacitidine and generated encouraging responses. They noted that the CR in the patient with AML and the optimal marrow response in the patient with CMML warranted moving IO-202 to the dose-expansion phase with a strategy to select patients with AML who displayed high LILRB4 expression levels.

In 2023, IO-202 received fast track designation from the FDA for the treatment of patients with relapsed/refractory CMML.1 Additionally, the agent received fast track designation from the FDA in February 2022 for the treatment of patients with relapsed/refractory AML, after receiving orphan drug designation for the same indication in 2020.1


  1. Immune-Onc Therapeutics announces orphan drug designation granted by US FDA for IO-202 (anti-LILRB4) for the treatment of chronic myelomonocytic leukemia (CMML). News release. Immune-Onc Therapeutics, Inc. February 21, 2024. Accessed February 22, 2024.
  2. IO-202 as monotherapy and IO-202 plus azacitidine ± venetoclax in patients in AML and CMML. Updated January 8, 2024. Accessed February 21, 2024.
  3. DiNardo C, Pollyea D, Aribi A, et al. A first-in-human phase 1 study of IO-202 (anti-LILRB4 mAb) in acute myeloid leukemia with monocytic differentiation and chronic myelomonocytic leukemia. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P536.
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