On January 8, 2025 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a late-stage pharmaceutical company with a broad portfolio of drug candidates targeting hard-to-treat tumors and viruses, reported a business outlook and outlined expected upcoming milestones (Press release, Moleculin, JAN 8, 2025, View Source [SID1234649507]).

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"We have positioned Moleculin to achieve value-driving milestones through the next several years, starting with the imminent beginning of enrollment for MIRACLE and the first interim read-out from that study later this year. Having a readout in the first year of a Phase 3 approval trial is, we believe, exceptional. Prior data support our belief that Annamycin is a potential game-changing asset for the treatment of AML, and we believe it can lead to significant value creation for Moleculin as we aggressively move forward with our clinical development plan. Not only has Annamycin appeared to be safer and more effective than currently prescribed anthracyclines, but we believe the recently announced preclinical data demonstrating significant activity of Annamycin in a Venetoclax-resistant AML model underscores the potential that Annamycin has ‘pipeline in a product’ potential and represents a much-needed treatment option for other patients who otherwise have very poor outcomes. Annamycin’s performance in Phase 2 has outperformed the response rates seen in billion-dollar assets in the AML space and AML remains among the highest unmet needs in healthcare. Simply stated, the bar for approval is low, and the potential reward for shareholders is substantial and we have never been more excited about the prospects for Annamycin," commented Walter Klemp, Chairman and CEO of Moleculin.

Clinical Development Update

Relapsed or Refractory Acute Myeloid Leukemia (AML)

The Company is currently advancing the development of Annamycin in combination with Cytarabine (also known as "Ara-C" and for which the combination of Annamycin and Ara-C is referred to as "AnnAraC") to a Phase 3 pivotal trial for the treatment of AML patients who are refractory to or relapsed after induction therapy (R/R AML). This Phase 3 "MIRACLE" trial (derived from Moleculin R/R AML AnnAraC Clinical Evaluation) will be global, including sites in the US, Europe and the Middle East.

The MIRACLE study, subject to appropriate future filings with and potential additional feedback from the FDA and their foreign equivalents, utilizes an adaptive design whereby 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, which Annamycin doses 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 (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. This accelerated estimated timeline is due to the positive response the Company received in meetings during December with potential investigators regarding recruitment for the trial.

For Part B of the trial, approximately 244 additional subjects will be randomized 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. This increase from 240 to 244 subjects represents the statistical "cost" of the additional interim unblinding.

Important Development Program Highlights

Phase 3 MIRACLE trial builds off of positive results of Phase 1B/2 clinical trial evaluating AnnAraC for the treatment of subjects with AML as both first line therapy and for subjects who are refractory to or relapsed after induction therapy (MB-106):
Complete Remission (CR) rate was 50% and CRc (CR plus CRi (CR with incomplete recovery of blood counts)) rate was 60% for 2nd line subjects (n=10);
Median durability: ~8 months and increasing;
Median overall survival in MB-106 was 9.1 months for 0-6 prior lines of therapies (n=22) and 11.6 months for 2nd line subjects (n=10); and
Strong efficacy signal even where a prior venetoclax combination therapy has failed.
Received US Institutional Review Board (IRB) approval;
Leveraging expertise of Catalyst Clinical Research, a leading contract research organization (CRO), with our recent engagement with them to help conduct the MIRACLE trial; and
Accelerated planned unblinded data readout to H2 2025.
Expected Milestones for Annamycin AML Development Program

1Q – 3Q 2025 – Update on MIRACLE trial site selection/approvals by countries
1Q 2025 – First subject enrolled and treated in MIRACLE trial
2025 – Recruitment update for MIRACLE trial
2H 2025 – Data readout (n=45) unblinded efficacy/safety review
2H 2025 – 2026 – Impact of data readout (n=45) on regulatory pathway; Recruitment update
1H 2026 – Interim efficacy and safety data (n=~75-90) unblinded and Optimum Dose set for MIRACLE trial
2027 – Begin enrollment of 3rd line subjects in MIRACLE2
2027 – Enrollment ends in 2nd line subjects
2028 – Primary efficacy data for 2nd line subjects in MIRACLE
2028 – Begin 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
Soft Tissue Sarcoma (STS) Lung Metastases

As previously announced, the Company completed enrollment in the Phase 2 portion of its U.S. Phase 1B/2 clinical trial evaluating Annamycin as monotherapy for the treatment of soft tissue sarcoma lung metastases. Subjects who had stable disease at the time of study discontinuation were followed for progression free response and overall survival. The study database is locked, and the clinical study report is being written and should be completed in early 2025 and will be released in detail at that time.

Expected Milestones for Annamycin STS Lung Mets Development Program

2025 – Final MB-107 data readout
2025 – Identify next phase of development / pivotal IIT (investigator-initiated-trial) program
Annamycin currently has 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. Furthermore, Annamycin has Orphan Drug Designation for the treatment of relapsed or refractory acute myeloid leukemia from the European Medicines Agency (EMA).