Abstract published as part of the American
Society of Hematology (ASH) Annual Meeting
Study shows Annamycin effectively targets both
Cytarabine (Ara-C) and Venetoclax resistant acute myeloid leukemia
(AML) cell lines from heavily pretreated relapsed/refractory
primary AML patients in vitro
Lack of apparent cardiotoxicity, improved
organotropism, synergy with Ara-C, and possible immune-memory
reinforcing properties appear to contribute to the favorable
performance of Annamycin in clinical settings
Such preclinical data appear to correlate with
preliminary clinical data showing Annamycin in combination with
Ara-C achieving a 60% CRc rate in subjects who relapsed from or
were refractory to Venetoclax as a first line therapy
HOUSTON, Dec. 11,
2024 /PRNewswire/ -- 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, today announced the
online publication of its abstract titled, "Annamycin, a
non-cardiotoxic anthracycline, demonstrates unique organotropism
and activity against Ara-C and Venetoclax resistant
AML," as part of the ASH Annual Meeting held
December 7-10, 2024, in San Diego, CA.
For the preclinical study, subsets of parental, cytarabine
(Ara-C)-resistant, and Venetoclax (VEN)-resistant AML cell lines were treated
with Annamycin at 0-3000 nM in vitro, alone, or ±
VEN (1-1000 nM) and ± Ara-C
(1-3000 nM). Treatment of naïve and heavily pretreated
relapsed/refractory primary AML patient samples were also
evaluated. The impact of DOX and Annamycin was further tested on
established cultures of rat H9c2 cardiomyoblasts derived from
ventricular tissue of myocardium and on human cardiomyocytes
derived from induced pluripotent stem cells (iPSCs). RTCA CardioECR
was applied to probe-free determination of viability (cell index,
impedance), contractility, and electric potential. Finally,
anti-leukemic efficacy of Annamycin in combination with Ara-C was
evaluated in an aggressive, TP53 null FLT3-ITD mutated syngeneic
AML Turqoise2 model, with extensive evaluation of tumor burden in
bone marrow, spleen, lungs, and liver by fluorescence imaging. PK
and tissue-organ distribution of Annamycin were analyzed in naïve
mice and rats versus DOX.
Key Highlights
- Annamycin displayed synergy with Ara-C and VEN in reducing viability in parental
treatment naïve cell lines (10-20 nM) and in Ara-C-and VEN-resistant cell lines (30-350 nM).
- Annamycin showed no apparent toxicity in vivo. Parallel
comparison of Annamycin and DOX at 8 mg/kg for 7 weeks exhibited a
favorable toxicity profile for Annamycin, with no evidence of
cardiotoxicity ex vivo. DOX treated mice demonstrated
significant weight loss and increased levels of lactate
dehydrogenase (LDL) in blood serum. Histopathological evaluation of
heart tissue postmortem revealed mild cytoplasmic vacuolation of
cardiac myocytes only in DOX-treated cohorts. Evaluation of human
cardiomyocytes treated with Annamycin or DOX revealed a limited
impact of Annamycin on human cardiomyocyte contractility,
viability, and electric potential up to the highest tested dose of
1.5 uM as assessed by RTCA, in opposition to heavily perturbed
contractility induced by DOX at 0.5 uM.
- Annamycin's ability to extend survival was potentiated in
combination with Cytarabine (also known as "Ara-C" and for which
the combination of Annamycin and Ara-C is referred to as
"AnnAraC").
- Annamycin was well tolerated by the animals even at schedules
exceeding the therapeutic dosage of 4 mg/kg. Ex vivo
pathology examination confirmed no toxicity to the murine
heart/myocardium, similar to patients in clinical trials.
- PK and tissue-organ distribution of Annamycin revealed
significantly higher concentrations of Annamycin vs. DOX in
leukemia homing organs, suggesting conditions that might contribute
to increased therapeutic efficacy and reduced MRD.
- Assessment of Annamycin administration resulted in durable
disease eradication up to 150 days post treatment in 20% of mice.
Interestingly, rechallenging these animals with AML-Turq-2 cells
resulted in extended survival compared to naïve mice, suggesting
immune-memory inducing properties of Annamycin therapy and
warranting further examination.
Giovanni Martinelli, MD,
University of Bologna, Lead of the EU financed program IMPACT-AML,
and member of the Moleculin Scientific Advisory Board commented,
"The preliminary clinical activity of Annamycin in heavily
pretreated, relapsed/refractory AML patients who had progressive
disease following Ara-C and VEN is
very exciting and would provide a much needed treatment option for
other patients who otherwise have very poor outcomes. Since the
majority of our patients receive Ara-C or VEN in the front-line setting, having a drug
that can overcome these resistance pathways and provide a benefit
in these high-risk patients, while not doubling-up on toxicities
could truly be a game-changer. I look forward to seeing additional
clinical data on the combination of ANN and Ara-C from the
Company's Phase 3 MIRACLE study in 2025 and beyond."
"We believe these preclinical data correlate with what we saw in
our preliminary data in our clinical trial MB-106 with Annamycin in
combination with Ara-C (in combination called AnnAraC). Where
subjects relapsed from or were refractory to Venetoclax regimens as
first line therapy, we saw a 60% composite complete remission or
CRc rate (n=5) using AnnAraC as a second line treatment. When
subjects fail to respond to Venetoclax, the historical data show
they typically have dismal outcomes with traditional salvage
therapy, so this level of response is really unprecedented,"
concluded Walter V. Klemp, Chairman
and CEO.
The Company is advancing the development of Annamycin in a Phase
3 pivotal trial evaluating AnnAraC for the treatment of AML
patients who are refractory to or relapsed after induction therapy
(R/R AML) (MB-108). This Phase 3 "MIRACLE" trial (derived from
Moleculin R/R AML AnnAraC
Clinical Evaluation) will be a global trial,
including sites in the US. The Company remains on track to initiate
patient treatment in the first quarter of 2025.
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).
About Moleculin Biotech, Inc.
Moleculin Biotech, Inc. is a Phase 3 clinical stage
pharmaceutical company advancing a pipeline of therapeutic
candidates addressing hard-to-treat tumors and viruses. The
Company's lead program, Annamycin, is a next-generation
anthracycline designed to avoid multidrug resistance mechanisms and
to eliminate the cardiotoxicity common with currently prescribed
anthracyclines. Annamycin is currently in development for the
treatment of relapsed or refractory acute myeloid leukemia (AML)
and soft tissue sarcoma (STS) lung metastases.
The Company is initiating the MIRACLE (Moleculin
R/R AML AnnAraC Clinical Evaluation)
Trial (MB-108), a pivotal, adaptive design Phase 3 trial evaluating
Annamycin in combination with cytarabine, together referred to as
AnnAraC, for the treatment of relapsed or refractory acute myeloid
leukemia. Following a successful Phase 1B/2 study (MB-106), with input from the FDA, the
Company believes it has substantially de-risked the development
pathway towards a potential approval for Annamycin for the
treatment of AML. This study is subject to appropriate future
filings with potential additional feedback from the FDA and their
foreign equivalents.
Additionally, the Company is developing WP1066, an
Immune/Transcription Modulator capable of inhibiting p-STAT3 and
other oncogenic transcription factors while also stimulating a
natural immune response, targeting brain tumors, pancreatic and
other cancers. Moleculin is also engaged in the development of a
portfolio of antimetabolites, including WP1122 for the potential
treatment of pathogenic viruses, as well as certain cancer
indications.
For more information about the Company, please visit
www.moleculin.com and connect on X, LinkedIn and Facebook.
Forward-Looking Statements
Some of the statements in this release are forward-looking
statements within the meaning of Section 27A of the Securities Act
of 1933, Section 21E of the Securities Exchange Act of 1934 and the
Private Securities Litigation Reform Act of 1995, which involve
risks and uncertainties. Forward-looking statements in this press
release include, without limitation, the timing of the commencement
of enrollment of the MIRACLE trial. Although Moleculin
believes that the expectations reflected in such forward-looking
statements are reasonable as of the date made, expectations may
prove to have been materially different from the results expressed
or implied by such forward-looking statements. Moleculin has
attempted to identify forward-looking statements by terminology
including 'believes,' 'estimates,' 'anticipates,' 'expects,'
'plans,' 'projects,' 'intends,' 'potential,' 'may,' 'could,'
'might,' 'will,' 'should,' 'approximately' or other words that
convey uncertainty of future events or outcomes to identify these
forward-looking statements. These statements are only predictions
and involve known and unknown risks, uncertainties, and other
factors, including those discussed under Item 1A. "Risk Factors" in
our most recently filed Form 10-K filed with the Securities and
Exchange Commission (SEC) and updated from time to time in our Form
10-Q filings and in our other public filings with the SEC. Any
forward-looking statements contained in this release speak only as
of its date. We undertake no obligation to update any
forward-looking statements contained in this release to reflect
events or circumstances occurring after its date or to reflect the
occurrence of unanticipated events.
Investor Contact:
JTC Team, LLC
Jenene Thomas
(908) 824-0775
MBRX@jtcir.com
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SOURCE Moleculin Biotech, Inc.