Moleculin Announces Online Publication of Preclinical Data Demonstrating Significant Activity of Annamycin in Venetoclax Resistant AML Model
Moleculin Biotech announced the publication of preclinical data demonstrating the significant activity of Annamycin in treating venetoclax-resistant acute myeloid leukemia (AML) cell lines. The study, presented at the American Society of Hematology Annual Meeting, revealed that Annamycin effectively targets both Cytarabine (Ara-C) and Venetoclax resistant AML cell lines from heavily pretreated relapsed/refractory primary AML patients in vitro.
The data showed Annamycin's synergy with Ara-C and Venetoclax in reducing cell viability, a lack of cardiotoxicity, improved organotropism, and potential immune-memory reinforcing properties. These findings correlate with preliminary clinical data showing a 60% composite complete remission (CRc) rate in subjects using Annamycin and Ara-C (AnnAraC) as a second-line treatment.
Annamycin's favorable toxicity profile, as compared to DOX, and its ability to extend survival in combination with Ara-C, underscore its potential as a breakthrough treatment. Moleculin is advancing Annamycin in a Phase 3 trial, 'MIRACLE,' set to begin patient treatment in Q1 2025. Annamycin has Fast Track Status and Orphan Drug Designation from the FDA and EMA.
Moleculin Biotech ha annunciato la pubblicazione di dati preclinici che dimostrano l'attività significativa di Annamycin nel trattamento delle linee cellulari di leucemia mieloide acuta (AML) resistenti al venetoclax. Lo studio, presentato all'Annual Meeting della American Society of Hematology, ha rivelato che Annamycin colpisce efficacemente sia le linee cellulari resistenti ad Ara-C (Citarabina) che a Venetoclax, provenienti da pazienti con AML primaria in recidiva/riferimento pesantemente trattati in vitro.
I dati hanno mostrato la sinergia di Annamycin con Ara-C e Venetoclax nella riduzione della vitalità cellulare, l'assenza di cardiotossicità, un miglior organotropismo e potenziali proprietà di rinforzo della memoria immunitaria. Questi risultati sono correlati ai dati clinici preliminari che mostrano un tasso di remissione completa composita (CRc) del 60% nei soggetti che utilizzano Annamycin e Ara-C (AnnAraC) come trattamento di seconda linea.
Il profilo di tossicità favorevole di Annamycin, rispetto al DOX, e la sua capacità di prolungare la sopravvivenza in combinazione con Ara-C, evidenziano il suo potenziale come trattamento innovativo. Moleculin sta avanzando Annamycin in uno studio di Fase 3, 'MIRACLE', che prevede di iniziare il trattamento dei pazienti nel primo trimestre del 2025. Annamycin ha ricevuto lo Status di Fast Track e la Designazione di Farmaco Orfano dalla FDA e dall'EMA.
Moleculin Biotech anunció la publicación de datos preclínicos que demuestran la actividad significativa de Annamycin en el tratamiento de líneas celulares de leucemia mieloide aguda (LMA) resistentes a venetoclax. El estudio, presentado en la Reunión Anual de la Sociedad Americana de Hematología, reveló que Annamycin ataca eficazmente tanto las líneas celulares resistentes a Cytarabine (Ara-C) como a Venetoclax de pacientes de LMA primaria en recaída/resistente que habían sido tratados de forma intensiva in vitro.
Los datos mostraron la sinergia de Annamycin con Ara-C y Venetoclax en la reducción de la viabilidad celular, la ausencia de cardiotoxicidad, un mejor organotropismo y potenciales propiedades de refuerzo de la memoria inmunitaria. Estos hallazgos se correlacionan con datos clínicos preliminares que muestran una tasa de remisión completa compuesta (CRc) del 60% en sujetos que utilizan Annamycin y Ara-C (AnnAraC) como tratamiento de segunda línea.
El perfil de toxicidad favorable de Annamycin, en comparación con DOX, y su capacidad para extender la supervivencia en combinación con Ara-C, subrayan su potencial como un tratamiento innovador. Moleculin está avanzando Annamycin en un ensayo de Fase 3, 'MIRACLE', que se prevé comience el tratamiento de pacientes en el primer trimestre de 2025. Annamycin tiene el Estatus de Vía Rápida y Designación de Medicamento Huérfano de la FDA y la EMA.
몰레큘린 바이오텍(Moleculin Biotech)은 아나마이신(Annamycin)이 베네토클락스에 내성을 가진 급성 골수성 백혈병(AML) 세포주 치료에 있어 중요한 활성을 보여주는 전임상 데이터의 발표를 알렸습니다. 미국 혈액학회 연례 회의에서 발표된 이 연구는 아나마이신이 Ara-C(시타라빈) 및 베네토클락스에 내성을 가진 AML 세포주를 효과적으로 타겟팅한다고 밝혔습니다. 이 세포주들은 치료가 집약적으로 이루어진 재발/불응형 주요 AML 환자들로부터 인 비트로(in vitro)에서 얻어진 것입니다.
데이터는 아나마이신이 Ara-C 및 베네토클락스와 함께 세포 생존율을 줄이는 데 시너지를 발휘하고, 심장독성이 없으며, 장기 선호도가 개선되고 잠재적인 면역 기억 강화를 나타내는 특성을 가진다는 것을 보여주었습니다. 이러한 발견은 아나마이신과 Ara-C(AnnAraC)를 제2선 치료로 사용하는 피험자들에서 60%의 복합 완전 관해(CRc) 비율을 보여주는 초기 임상 데이터와 상관관계가 있습니다.
아나마이신은 DOX에 비해 유리한 독성 프로파일을 가지고 있으며, Ara-C와의 병용하여 생존을 연장할 수 있는 능력은 혁신적인 치료제로서의 잠재력을 강조합니다. 몰레큘린은 아나마이신을 Phase 3 시험인 'MIRACLE'에서 진행하고 있으며, 2025년 1분기부터 환자 치료를 시작할 예정입니다. 아나마이신은 FDA와 EMA에서 신속 심사 및 희귀의약품 지정을 받았습니다.
Moleculin Biotech a annoncé la publication de données précliniques démontrant l'activité significative de Annamycin dans le traitement des lignées cellulaires de leucémie myéloïde aiguë (LMA) résistantes au venetoclax. L'étude, présentée lors de la réunion annuelle de l'American Society of Hematology, a révélé qu'Annamycin cible efficacement à la fois les lignées cellulaires de LMA résistantes à la Cytarabine (Ara-C) et au Venetoclax provenant de patients atteints de LMA primaire en rechute/réfractaire ayant subi un traitement lourd in vitro.
Les données ont montré la synergie d'Annamycin avec Ara-C et Venetoclax pour réduire la viabilité cellulaire, l'absence de cardiotoxicité, un meilleur organotropisme et de potentielles propriétés de renforcement de la mémoire immunitaire. Ces résultats sont corrélés avec des données cliniques préliminaires montrant un taux de rémission complète composite (CRc) de 60 % chez des sujets utilisant Annamycin et Ara-C (AnnAraC) en tant que traitement de deuxième ligne.
Le profil de toxicité favorable d'Annamycin par rapport au DOX et sa capacité à prolonger la survie en association avec Ara-C soulignent son potentiel en tant que traitement innovant. Moleculin fait progresser Annamycin dans un essai de phase 3, 'MIRACLE', qui devrait commencer le traitement des patients au premier trimestre 2025. Annamycin a le statut de Fast Track et la désignation de médicament orphelin de la part de la FDA et de l'EMA.
Moleculin Biotech gab die Veröffentlichung präklinischer Daten bekannt, die die signifikante Aktivität von Annamycin bei der Behandlung von venetoclax-resistenten akuten myeloischen Leukämie (AML)-Zelllinien demonstrieren. Die Studie, die auf dem Jahresmeeting der American Society of Hematology präsentiert wurde, zeigte, dass Annamycin effektiv sowohl Cytarabin (Ara-C) als auch venetoclax-resistente AML-Zelllinien von stark vorbehandelten relapsierten/refraktären AML-Patienten in vitro angreift.
Die Daten zeigten die Synergie von Annamycin mit Ara-C und venetoclax bei der Reduzierung der Zellviabilität, das Fehlen von Kardiotoxizität, verbessertes Organotropismus und potenzielle immunologische Gedächtnisverstärkungs-Eigenschaften. Diese Ergebnisse korrelieren mit vorläufigen klinischen Daten, die eine 60%ige kumulative vollständige Remissionsrate (CRc) bei Probanden zeigen, die Annamycin und Ara-C (AnnAraC) als Zweitlinientherapie verwenden.
Das günstige Toxizitätsprofil von Annamycin im Vergleich zu DOX und seine Fähigkeit, in Kombination mit Ara-C die Überlebensdauer zu verlängern, unterstreichen sein Potenzial als bahnbrechende Therapie. Moleculin bringt Annamycin in einer Phase-3-Studie, 'MIRACLE', voran, die im ersten Quartal 2025 mit der Behandlung von Patienten beginnen soll. Annamycin hat den Status eines beschleunigten Verfahrens und die Orphan-Drug-Bezeichnung von der FDA und der EMA erhalten.
- Annamycin showed significant activity against Cytarabine and Venetoclax resistant AML cell lines.
- Preliminary clinical data indicates a 60% CRc rate in subjects using Annamycin and Ara-C (AnnAraC).
- Favorable toxicity profile with no apparent cardiotoxicity.
- Annamycin's potential immune-memory reinforcing properties.
- Advancement to a Phase 3 pivotal trial (MIRACLE) scheduled for Q1 2025.
- Fast Track Status and Orphan Drug Designations from FDA and EMA.
- None
Insights
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
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
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.
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