On December 12, 2024 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a clinical-stage biotechnology company developing novel LAG-3 immunotherapiesfor cancer and autoimmune disease, reported positive clinical resultsfrom Cohort B of the TACTI-003 (KEYNOTEC34) Phase IIb trial (Press release, Immutep, DEC 11, 2024, View Source [SID1234649054]). This study evaluates eftilagimod alpha (efti) in combination with MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy KEYTRUDA (pembrolizumab) in first line recurrent/metastatic head and neck squamous cell carcinoma (1L HNSCC) patients with negative PD-L1 expression.

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The new promising data presented by Martin Forster, M.D., Ph.D., at the ESMO (Free ESMO Whitepaper) Immuno-Oncology (IO) Annual Congress 2024 includes strong overall survival, progression-free survival, and durability. This adds to the high response rates and favourable safety data previously reported on 12 July 2024.

Prof. Martin Forster of the UCL Cancer Institute and University College London Hospital NHS Foundation Trust, London, UK, and TACTI-003 Investigator, stated, "The new survival and durability data, coupled with increasing complete responses, build on the strong response rates already established with this novel IO combination in head and neck squamous cell cancers with PD-L1 CPS <1. This difficult-to-treat disease places a high burden on patients who unfortunately have very limited treatment options that all include chemotherapy. Collectively, these impressive results build on the potential promise of efti to improve patient outcomes and expand populations that respond to anti-PD-1."

Results

Data as of the 31 October 2024 cut-off date in evaluable 1L HNSCC patients (N=31) whose tumours express PD-L1 below 1 (Combined Positive Score [CPS] <1) and who typically do not respond well to anti-PD-1 therapy alone shows:
• Positively, median overall survival (OS) has not yet been reached and the 12-month OS rate is 67%
• Promising progression-free survival (PFS) of 5.8 months
• Strong durability with interim median duration of response (DOR) of 9.3 months
• High 35.5% objective response rate (ORR) and 58.1% disease control rate (DCR), as reported on 12 July
• Complete response rate increases to 12.9% and 16.1%, according to RECIST 1.1 and iRECIST, respectively1
• Efti in combination with pembrolizumab continues to be well-tolerated with no new safety signals This data compares favourably to historical results from anti-PD-1 therapy alone in 1L HNSCC patients with PD-L1 CPS <1 including a 7.9-month median OS, 12-month OS rate of 39%, 2.1-month median PFS, 2.6-month median DOR, 5.4% ORR and 32.4% DCR with no complete responses

On December 11, 2024 Amplia Therapeutics Limited (ASX: ATX), ("Amplia" or the "Company"), reported updated data from Company’s ongoing Phase 2a clinical trial. This trial is investigating the Company’s FAK inhibitor narmafotinib in combination with standard-of-care chemotherapy of gemcitabine and Abraxane in the treatment of advanced pancreatic cancer (the ACCENT trial) (Press release, Amplia Therapeutics, DEC 11, 2024, View Source [SID1234649053]). This latest data analysis was conducted up to 6 December 2024 and expands on the previous interim data release1 which covered data up to 27 September 2024.

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Nine (9) confirmed partial responses (PRs) have now been recorded from the initial 26 patient cohort of the Phase 2a trial. This represents an objective response rate of ~35%, significantly better than the 23% reported for the historical trial2 being used as the benchmark for this study. A confirmed PR is recorded when there is at least a 30% decrease in the overall size of tumour lesions sustained for two or more months, with no new tumour lesions apparent.

Importantly, the median duration on trial for the 26 patients is currently 172 days which is a 47% improvement over the historical data of 117 days. The duration on trial is a measure of how effective the treatment is in inhibiting disease progression, as patients with progressive disease must leave the trial. Currently 11 patients from the initial 26 enrolled remain on trial.

Narmafotinib continues to be generally well tolerated by patients and no patients have withdrawn from study due to issues from narmafotinib.

The Company is now recruiting the second cohort of patients for the Phase 2a study to bring the total number of evaluable patients for the trial to 50. At this time 12 new patients have enrolled on the trial since reopening recruitment in October.

Amplia CEO and MD Dr Chris Burns commented: "Adding narmafotinib to the standard-of-care treatment continues to show promise in comparison to the historical data for standard-of-care alone. We’ve recruited over 75% of the trial at this time, and with ongoing positive support from clinicians involved in the study, we are well on track to fully recruit the trial by end of Q1 2025. In addition, we have been reassured by our clinical team in Korea that the recent political situation in the country is not impacting the trial sites located there in terms of recruitment and ongoing support of patients."

This ASX announcement was approved and authorised for release by the Board of Amplia Therapeutics.

About Narmafotinib

Narmafotinib (AMP945) is the company’s best-in-class inhibitor of the protein FAK, a protein overexpressed in pancreatic and other cancers, and a drug target gaining increasing attention for its role in solid tumours. The drug, which is a highly potent and selective inhibitor of FAK, has shown promising data in a range of preclinical cancer studies. The drug has successfully completed a healthy volunteer study, and is currently in an open-label Phase 2a trial in pancreatic cancer where a combination of narmafotinib and the chemotherapies gemcitabine and Abraxane is being assessed for safety, tolerability and efficacy.

About the ACCENT Trial

The ACCENT trial is entitled ‘A Phase 1b/2a, Multicentre, Open Label Study of the Pharmacokinetics, Safety and Efficacy of AMP945 in Combination with Nab-paclitaxel and Gemcitabine in Pancreatic Cancer Patients’.

The ACCENT trial explores the use of narmafotinib in combination with standard-of-care chemotherapy of gemcitabine and Abraxane in first-line patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. The firststage (Phase 1b), completed in November 2023, identified a 400 mg oral daily dose of narmafotinib, given in the days preceding regular chemotherapy infusion, as safe and well tolerated.

This second stage (Phase 2a), of the trial is designed to assess drug efficacy in combination with gemcitabine and Abraxane. The primary endpoints are Objective Response Rate (ORR) and Duration on Trial (DOT) with secondary endpoints being Progression Free Survival (PFS) and Overall Survival (OS). Safety and tolerability will continue to be assessed.

More information about the ACCENT trial, including a list of participating sites can be found via the ACCENT website, the Amplia Therapeutics website, and at ClinicalTrials.gov under the identifier NCT05355298.

On December 11, 2024 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, reported updated interim clinical data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα (Press release, Relay Therapeutics, DEC 11, 2024, View Source [SID1234649052]). The updated data show a median progression free survival (PFS) of 11.4 months in second line (2L) patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg twice daily (BID) + fulvestrant. These data are being presented today at the San Antonio Breast Cancer Symposium (SABCS) 2024.

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"These updated data help build on previously reported results that show a level of benefit that had not previously been seen with non-selective PI3Kα inhibitors," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "We are particularly encouraged to see even greater benefit observed in the patients in which we are working to start a pivotal study next year; in these 2L patients, RLY-2608 + fulvestrant demonstrated a median progression free survival that is more than twice that of the existing standards-of-care."

ReDiscover – RLY-2608 First-in-Human Study

RLY-2608 is currently being evaluated in ReDiscover, an ongoing first-in-human study, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of RLY-2608 in combination with fulvestrant, and in combination with fulvestrant and ribociclib or atirmociclib (Pfizer’s selective CDK4 inhibitor).

The RLY-2608 + fulvestrant arm of the study, as of the November 4, 2024 interim data cut-off for this arm, had enrolled 118 patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer across all doses in both the dose escalation and dose expansion portions of the study, including 64 patients at the company’s recommended Phase 2 dose (RP2D) of 600mg BID. Among these 64 patients, 31 had a kinase mutation and 33 had a non-kinase mutation. Twelve patients also had a PTEN or AKT co-mutation and were therefore excluded from the efficacy analysis, consistent with the planned pivotal population.

The RLY-2608 + ribociclib + fulvestrant arm of the study continues to enroll patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer in dose escalation. The RLY-2608 + atirmociclib + fulvestrant arm of the study has recently been initiated.

Patients were Heavily Pre-Treated

All RLY-2608 + fulvestrant patients across doses had received a significant level of prior therapy in the advanced setting, including at least one prior endocrine therapy and at least one prior CDK4/6 inhibitor. Among the 64 patients who received the RP2D:

•
41% of patients (n=26) had received two or more prior lines of therapy
•
52% of patients (n=33) had received a prior selective estrogen-receptor degrader (SERD), such as fulvestrant or a novel SERD
•
25% of patients (n=16) had received chemotherapy or an ADC
•
59% of patients (n=38) had visceral metastases
•
34% of patients (n=22) had a BMI of at least 30 and/or HbA1c of at least 5.7%

Promising Efficacy Data in Proposed Pivotal Population

Among the 52 RLY-2608 + fulvestrant patients who received the RP2D and did not have a PTEN or AKT co-mutation:

•
The median PFS was 9.2 months for all patients and 11.4 months for 2L patients
o
Median PFS was 11.4 months for patients with kinase mutations
•
Clinical benefit rate (CBR) was 67% across all patients (32 of 48 CBR-evaluable patients; CBR defined as the proportion of patients with complete response, partial response or stable disease for at least 24 weeks)
•
Among the 31 patients with measurable disease, 12 achieved a partial response (PR) (39% confirmed objective response rate, ORR)
o
Nearly three quarters of patients experienced tumor reductions (74%; n=23)
•
Among the 15 patients with measurable disease who had a kinase mutation, two thirds achieved a PR (67% confirmed ORR; n=10)
•
Median follow-up was 9.5 months

Maintained Meaningfully Differentiated Tolerability Profile

RLY-2608 + fulvestrant was generally well tolerated in the 118 patients treated across all doses as of the data cut-off date. The overall tolerability profile consisted of mostly low-grade treatment-related adverse events (TRAEs) that were manageable and reversible. Safety outcomes were generally as expected across dose levels based on exposure and consistent with mutant-selective PI3Kα inhibition. Among the 64 patients who received the RP2D:

•
The low rate of TRAE-related dose modifications allowed for 94% median dose intensity
•
Only two patients discontinued treatment due to TRAEs (Grade 1 pruritis; Grade 1 nausea, loss of appetite)
•
The majority of hyperglycemia was Grade 1; only two patients (3%) experienced Grade 3 hyperglycemia; no Grade 4-5 hyperglycemia
•
Only 31% of patients experienced a Grade 3 TRAE; no Grade 4-5 TRAEs

Continued Progression of Front-Line Breast Cancer Regimens

Two front-line triplet regimens are being progressed – one with the existing CDK4/6 standard-of-care ribociclib and one with Pfizer’s investigative selective-CDK4 inhibitor atirmociclib. RLY-2608 + ribociclib + fulvestrant dose escalation is ongoing with biologically active doses of RLY-2608. The RLY-2608 + atirmociclib + fulvestrant arm of the ReDiscover study has been initiated.

Anticipated RLY-2608 Next Steps

•
Breast Cancer:
o
Initiate 2L pivotal study of RLY-2608 + fulvestrant in 2025
o
Disclose complete Phase 1/2 data in 2025
•
Vascular Malformations:
o
Initiate vascular malformations study in the first quarter of 2025

Cash balance will be operationalized to preserve ability to complete 2L pivotal study

As of the end of the third quarter of 2024, cash, cash equivalents and investments were approximately $840 million.

Conference Call Information

Relay Therapeutics will host a conference call and live webcast today, December 11, 2024, at 7:00 a.m. ET (6:00 a.m. CT). Registration and dial-in for the conference call may be accessed through Relay Therapeutics’ website under Events in the News & Events section through the following link: View Source An archived replay of the webcast will be available following the event.

The data presentation from the San Antonio Breast Cancer Symposium is also available on the Relay Therapeutics website in the "Publications/Presentations" section through the following link: View Source

About RLY-2608

RLY-2608 is the lead program in Relay Therapeutics’ efforts to discover and develop mutant selective inhibitors of PI3Kα, the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 14% of patients with solid tumors. RLY-2608 has the potential, if approved, to address more than 300,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine.

Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor, designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608. RLY-2608 is currently being evaluated in a first-in-human study designed to treat patients with advanced solid tumors with a PIK3CA (PI3Kα) mutation. For more information on RLY-2608, please visit here.

On December 11, 2024 Prelude Therapeutics Incorporated (Nasdaq: PRLD) ("Prelude" or the "Company"), a clinical-stage precision oncology company, reported the presentation of the first interim clinical data from its ongoing open-label, dose-escalation trial of PRT2527, a potent and highly selective CDK9 inhibitor, as monotherapy and in combination with zanubrutinib in patients with relapsed/refractory lymphoid malignancies (Press release, Prelude Therapeutics, DEC 11, 2024, View Source [SID1234649051]). The data were presented at a poster session of the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California.

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The study investigators reported on the 46 patients that were enrolled, treated, and safety evaluable as of September 17, 2024. PRT2527 was generally well-tolerated through 4 dosing cohorts as monotherapy and 3 dosing cohorts in combination with zanubrutinib. PRT2527 monotherapy and in combination with zanubrutinib demonstrated an acceptable safety profile with evidence of preliminary activity in patients with relapsed/refractory lymphoid malignancies, including patients who received prior CAR-T therapy.

"CDK9 has long been considered a potential therapeutic approach for treating hematologic malignancies and a highly selective CDK9 inhibitor was sought to minimize off target toxicity," stated Jane Huang, M.D., President and Chief Medical Officer of Prelude. "We are encouraged by the results demonstrated to date by PRT2527 both as a monotherapy and particularly in combination with zanubrutinib resulting in an overall response rate of 38.5% including two patients with aggressive lymphomas who had received prior CAR-T therapy. These results represent a positive step for CDK9 inhibition as a possible future therapeutic approach for patients with aggressive hematologic cancers with limited treatment options."

PRT2527 Interim Phase 1 Results

PRT2527 is an investigational, potent and highly selective CDK9 inhibitor being evaluated in select relapsed/refractory (R/R) hematologic malignancies as monotherapy and in combination with zanubrutinib.

As of the cutoff date, 46 patients with relapsed/refractory lymphoid malignancies were treated with PRT2527. 29 patients were treated once weekly via intravenous infusion at four dose levels of PRT2527 monotherapy (9 mg/m2, 15 mg/m2, 18 mg/m2, 24 mg/m2) and 17 patients were treated once weekly at three dose levels of PRT2527 (9 mg/m2, 15 mg/m2, 18 mg/m2) in combination with zanubrutinib administered orally starting on C1D1 at 320 mg daily or 160 mg BID.

Initial Safety Data

The most frequent treatment emergent adverse events (TEAEs) observed in ≥20% of patients were neutropenia (48%) and nausea (33%), and the most frequent grade ≥3 TEAEs (≥10% of patients) were neutropenia (46%) and anemia (11%). Five patients discontinued treatment due to TEAEs in the monotherapy cohort; 3 TEAEs in 1 patient were treatment related: grade 3 hypotension, grade 3 diarrhea, and grade 4 neutropenia (n=1 each). No TEAEs led to treatment discontinuation in the combination therapy cohort.

PRT2527 dose interruptions due to TEAEs occurred in 17 patients (11 monotherapy; 6 combination therapy). Most dose interruptions were due to neutropenia and were managed with growth factor support. One DLT of grade 3 tumor lysis syndrome (TLS) occurred in a patient with primary cutaneous peripheral T cell lymphoma who had extensive disease at the 24 mg/m2 monotherapy dose level and did not receive ramp-up dosing. TLS was managed with rasburicase and IV fluids and resolved. The patient was able to resume study treatment as planned. No DLTs were observed in the combination therapy cohort.

Dose level 3 (18 mg/m2) was selected for dose confirmation for monotherapy and in combination with zanubrutinib due to higher rates of grade 3/4 neutropenia and of dose interruptions and reductions in the 24 mg/m2 dose level.

Analysis of Initial Clinical Activity

Of the 23 efficacy evaluable patients in the monotherapy cohort, complete responses (CRs) were observed in 1 patient (DLBCL) and 3 partial responses observed (TCL), with an overall response rate (ORR) of 17.4% (4 of 23). Of the 13 patients in the combination cohort who were evaluable for efficacy, complete responses (CRs) were observed in 3 patients (2 DLBCL, 1 MCL) and 2 partial responses (PRs) observed (DLBCL and CLL) with an overall response rate (ORR) of 38.5% (5 of 13).

The above-noted presentation can be found at Publications – Prelude Therapeutics (preludetx.com).

"We believe the clinical data presented today with PRT2527 confirm our hypothesis that a highly selective and potent inhibitor of CDK9 has the potential to offer meaningful clinical activity for patients with hematologic malignancies, while avoiding the off-target toxicities observed with less selective agents," stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude. "However, given the significant progress and potential of our SMARCA degrader programs that are currently advancing in the clinic, along with our productive discovery organization, we plan to focus our resources towards the continued advancement of those programs. As a result, we will only advance the CDK9 program with a partner beyond completion of the current ongoing Phase 1 study."

On December 11, 2024 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 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 (Free ASH Whitepaper) Annual Meeting held December 7-10, 2024, in San Diego, CA (Press release, Moleculin, DEC 11, 2024, View Source [SID1234649049]).

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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).