Moleculin Biotech has concluded an end-of-phase 2 meeting with the FDA regarding the investigation of annamycin (MB-106) in combination with cytarabine for treating patients with acute myeloid leukemia (AML). This development marks a significant step forward in exploring new treatment options for this challenging hematologic malignancy.
The discussions centered on data from a phase 1b/2 trial (NCT05319587) evaluating the combination therapy in both newly diagnosed and relapsed/refractory AML patients. The trial's findings, presented at the 2024 EHA Congress, revealed promising efficacy and tolerability, paving the way for potential future regulatory submissions.
Clinical Trial Results
The phase 1b/2 trial included an intention-to-treat (ITT) population of efficacy-evaluable patients (n = 20). Results showed a composite complete remission (CRc) rate of 45%, comprising a complete remission (CR) rate of 40% and a CR with incomplete count recovery (CRi) rate of 5%. Notably, patients in the ITT population received annamycin plus cytarabine across various lines of therapy, ranging from first-line to seventh-line treatment.
Among the 9 patients who achieved a CRc, the median duration of response was approximately 7 months and continues to increase with further follow-up. Two additional patients were enrolled and treated, with their efficacy outcomes pending.
Efficacy in Specific Treatment Settings
Patients treated with annamycin plus cytarabine in the second-line setting (n = 10) demonstrated a CRc rate of 60%, including a CR rate of 50%. When considering patients treated in either the first- or second-line settings (n = 13), the CRc and CR rates were 62% and 54%, respectively. These results suggest a potential benefit in earlier lines of therapy.
Trial Design and Patient Population
The ongoing, multicenter, open-label phase 1b/2 study enrolls patients aged 18 years and older with pathologically confirmed AML, according to World Health Organization classification. Patients may be treatment-naive or have relapsed/refractory disease following induction therapy. During the dose-expansion phase, patients are limited to a maximum of two prior therapies.
Key inclusion criteria include adequate laboratory results and an ECOG performance status of 0 to 2. Patients were excluded if they had acute promyelocytic leukemia, prior mediastinal radiotherapy, central nervous system involvement, a left ventricular ejection fraction below 50%, valvular heart disease, severe hypertension, or any evidence of mucositis/stomatitis at enrollment, or a history of grade 3 or higher mucositis from prior therapy.
All patients received intravenous annamycin for 3 consecutive days, followed by 18 days off treatment, during each 21-day cycle. Cytarabine was administered during cycle 1 at 2.0 g/m2 per day for 5 consecutive days.
Endpoints and Safety
The primary endpoints of the study were the incidence of dose-limiting toxicities and the establishment of the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included pharmacokinetics and anti-leukemic activity.
The median age of patients in the ITT population was 69 years. Significantly, 89% of patients achieving a CRc had cytogenetics and/or mutations associated with poor prognosis, including FLT3, IDH2, ASXL1, KMT2A, and other alterations.
Safety data indicated that two patients discontinued treatment early due to allergic reactions. No clinically significant signs of cardiotoxicity were observed during or after treatment in any patients. The combination was generally well-tolerated, with the most common adverse effects being myelosuppression and infections.
Regulatory Designations
The FDA has previously granted fast track and orphan drug designations to annamycin for relapsed/refractory AML, and the European Medicines Agency has also awarded orphan drug designation for this indication. The FDA also granted orphan drug designation to annamycin for soft tissue sarcoma.
"The Moleculin team, along with our regulatory advisors and key opinion leaders, discussed with FDA the [annamycin] safety and efficacy clinical findings and proposed next steps for our AML clinical development program," said Walter Klemp, chairman and chief executive officer of Moleculin Biotech.
