Trial in Progress: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 2 Study of AK117/Placebo in Combination with Azacitidine in Patients with Newly Diagnosed Higher-Risk Myelodysplastic Syndromes (AK117-205)

Background and Significance

Patients with higher-risk myelodysplastic syndromes/neoplasms (MDS) are treated with hypomethylating agents including azacitidine as the standard of care for patients who are ineligible for curative intent allogeneic hematopoietic stem cell transplantation. However, complete response (CR) is observed in less than 20% of patients with limited duration of CR and overall survival is < 2 years. Therefore, safe and effective novel therapy that translates into higher CR rate and ultimately improved survival is much needed.

AK117 (ligufalimab) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody directed against CD47, a “don't eat me” signal on cancer cells. In preclinical studies, AK117 effectively triggers macrophage-mediated phagocytosis of hematological malignancy cells. When combined with azacitidine, it synergistically enhances the activation of “eat me” signals. Additionally, unlike the first generation anti-CD47 agents such as magrolimab, AK117 does not cause red blood cell agglutination and on-target anemia. Notably, AK117 does not require a priming dose, higher hemoglobin transfusion thresholds or increased blood count monitoring. Data from a Phase 1 expansion study AK117-103 (Miao M, et al. ASH.2023) showed that combining AK117 with azacitidine in newly diagnosed HR-MDS patients offers a promising therapeutic approach (CR rate of 48.1% and duration of CR not reached) and a manageable safety profile with an anemia rate of 29.1% and grade 3 or above anemia rate of 24.4%. Red blood cells transfusion independence rate is 61.5%.

Study Design and Methods

Given the high CR rate and limited toxicity of the combination, we are conducting this Phase 2, randomized, double-blind, placebo-controlled, multicenter study (NCT06196203) evaluating the efficacy and safety of AK117 in combination with azacitidine in patients with newly diagnosed HR-MDS.

Approximately 90 patients will be enrolled with 45 patients from USA and 45 patients from China. Eligible patients must be aged ≥18 years, newly diagnosed with HR-MDS per the 2016 WHO classification, with <20% blasts in bone marrow and peripheral blood, and an overall IPSS-R score ≥3.5. Patients must be treatment-naive, have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate organ function. Exclusion criteria include MDS evolving from pre-existing myeloproliferative neoplasms (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), prior treatment with CD47 or Signal-regulatory protein alpha (SIRPα)-targeting agents, prior allogeneic hematopoietic stem cell transplantation (allo-HSCT), organ transplantation or Chimeric Antigen Receptor T-Cell (CAR-T) therapy, residual disease from another malignancy, autoimmune disease, and uncontrolled infections.

Patients will be randomized in a 1:1:1 ratio to receive either AK117 30 mg/kg every two weeks (Q2W), AK117 20 mg/kg Q2W, or placebo, all in combination with azacitidine administered every four weeks (Q4W). Treatment will continue until unacceptable toxicity, initiation of subsequent anticancer therapy, or disease progression after at least six cycles. Stratification factors will be based on IPSS-R scores: ≤4.5, >4.5-6, and >6.

The primary endpoint is complete remission rate (CRR) assessed by investigators based on 2023 International Working Group (IWG 2023) response criteria (Zeidan A et al, Blood, 2023), and to determine the optimal dose of AK117 for future confirmatory trials (can expand this Phase 2 trial to a Phase 3 trial). Key secondary endpoints include overall response rate (ORR), duration of response (DoR), event-free survival (EFS), overall survival (OS), rate and duration of transfusion independence (TI), time to transformation to acute myeloid leukemia (AML), safety assessed by incidence and severity of adverse events (AEs), pharmacokinetics (PK) and immunogenicity.

Baratam:GlaxoSmithkline: Speakers Bureau; Kite: Honoraria; Incyte: Honoraria; Ono Pharma: Honoraria; Novartis: Honoraria; Rigel: Speakers Bureau. Borate:Ryvue: Other: IDMC; Beigene: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: IDMC; Astellas: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Rigel: Consultancy; Daiichi Sankyo: Consultancy; Sumitomo: Consultancy; BMS: Consultancy; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Abbvie: Consultancy. Sallman:Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding.