Moleculin Biotech is making strides in the development of Annamycin, a next-generation anthracycline, as a potential treatment for acute myeloid leukemia (AML), particularly in cases where resistance to existing therapies like Venetoclax has developed. Recent data from preclinical studies and preliminary clinical trials suggest that Annamycin can effectively target AML cells resistant to both Cytarabine (Ara-C) and Venetoclax, offering a new treatment avenue for patients with limited options. The company's Phase 3 MIRACLE trial is set to evaluate Annamycin in combination with Cytarabine for patients with relapsed or refractory AML (R/R AML).
Annamycin's Activity Against Venetoclax-Resistant AML
Preclinical data presented at the American Society of Hematology (ASH) Annual Meeting demonstrated Annamycin's ability to overcome resistance to Venetoclax in AML models. These in vitro studies showed that Annamycin displayed synergy with both Ara-C and Venetoclax in reducing the viability of AML cell lines, including those resistant to these drugs.
These findings correlate with preliminary clinical data from the MB-106 trial, where relapsed or refractory AML subjects previously treated with Venetoclax regimens achieved a 60% complete remission (CR/CRi) rate when treated with Annamycin in combination with Ara-C (AnnAraC). This is more than four times the rate expected based on historical data for salvage therapy in this patient population.
MIRACLE Trial: A Phase 3 Evaluation of Annamycin
Moleculin Biotech is advancing Annamycin through the MIRACLE trial (MB-108), a Phase 3 pivotal study evaluating AnnAraC for the treatment of AML patients who are refractory to or relapsed after induction therapy (R/R AML). The MIRACLE trial is a global study with sites in the US, Europe, and the Middle East.
The trial employs an adaptive design. The first 75 to 90 subjects will be randomized (1:1:1) in Part A of the trial to receive high-dose cytarabine (HiDAC) combined with either placebo, 190 mg/m2 of Annamycin, or 230 mg/m2 of Annamycin. The doses of Annamycin were specifically recommended by the FDA in the Company's end of Phase 1B/2 meeting. The amended protocol allows for the unblinding of preliminary primary efficacy data (Complete Remission or CR) and safety/tolerability of the three arms at 45 subjects, in addition to the conclusion of Part A (at 75 to 90 subjects). This early unblinding will yield 30 subjects with Annamycin (190mg/m2 and 230/m2) and HiDAC and 15 subjects with just HiDAC. The Company expects to reach the first unblinding (45 subjects) in the second half of 2025, in addition to the second unblinding, which is expected in the first half of 2026.
Part B of the trial will randomize approximately 244 additional subjects to receive either HiDAC plus placebo or HiDAC plus the optimum dose of Annamycin (randomized 1:1). The selection of the optimum dose will be based on the overall balance of safety, pharmacokinetics, and efficacy, consistent with the FDA's new Project Optimus initiative.
Regulatory Progress and Milestones
Moleculin Biotech has received several key regulatory designations for Annamycin, including Fast Track Status and Orphan Drug Designation from the FDA for the treatment of relapsed or refractory acute myeloid leukemia, in addition to Orphan Drug Designation for the treatment of soft tissue sarcoma. Annamycin also has Orphan Drug Designation for the treatment of relapsed or refractory acute myeloid leukemia from the European Medicines Agency (EMA).
The company has received regulatory approval in Ukraine to begin recruiting for the Phase 3 MIRACLE trial. The FDA has also provided positive guidance on Moleculin's IND amendment, potentially accelerating the approval timeline for Annamycin in AML treatment. The FDA recommended an alteration to the statistical plan that will allow Moleculin to reduce the size of Part B of their trial by approximately 10%.
"From investigating clinicians to regulatory authorities around the world, people are starting to realize the potential significance of approving the first-ever non-cardiotoxic anthracycline," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin.
Moleculin expects to reach an initial unblinded data readout in late 2025, with full recruitment and additional interim data expected in 2026. The company anticipates beginning submission of a Rolling New Drug Application (NDA) for the treatment of R/R AML for accelerated approval on primary endpoint of CR from MIRACLE in 2028.
