On December 11, 2024 The Menarini Group ("Menarini"), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group focused on bringing transformational oncology treatments to cancer patients, along with MEDSIR, a leading global independent clinical research company in oncology and part of Oncoclínicas & Co., the largest specialized oncology treatment group in Latin America, reported research on the pioneering clinical trial ADELA (Press release, Menarini, DEC 11, 2024, View Source [SID1234649063]). This important research addresses therapeutic resistance in advanced ER+/HER2- breast cancer. Presented at the San Antonio Breast Cancer Symposium 2024 (SABCS), the study represents a key milestone in the quest for more effective and personalized treatment options for patients with disease progression.

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The standard first-line treatment for advanced ER+/HER2- breast cancer combines endocrine therapy with CDK4/6 inhibitors. ESR1 mutations develop as a result of prior exposure to endocrine therapy during metastatic treatment, and up to 50% of ER+, HER2- advanced or metastatic breast cancers will develop these mutations. ESR1 mutations cause the tumors to become resistant to endocrine therapy, in turn causing the cancer to progress; therefore, it is important to test for ESR1 whenever mBC progresses. Longer exposure to endocrine therapy during first-line treatment increases the chance of a patient’s tumor developing an ESR1 mutation. With the goal of addressing this unmet medical need, the ADELA phase III clinical trial investigates a new therapeutic option combining elacestrant, a next generation, oral selective estrogen receptor degrader, with everolimus, an mTORC1 inhibitor.

This combination is being evaluated in patients with advanced ER+/HER2- breast cancer that harbors ESR1 mutations, and who have experienced progression after standard first-line treatment. Results from the phase III EMERALD study were the basis for elacestrant’s approval. Meanwhile, everolimus has shown efficacy in inhibiting other resistance mechanisms in this type of cancer. The elacestrant and everolimus combination has demonstrated preliminary efficacy with a manageable safety profile in the phase 1b/2 ELEVATE study (NCT05563220).

"We at Menarini Stemline are delighted to announce the collaboration with MEDSIR to continue advancing the clinical research to explore the combination therapy with elacestrant," said Nassir Habboubi, MD, Chief Medical Officer of Stemline Therapeutics. "We are committed to driving innovation in cancer treatment by delivering transformational therapies aiming to extend the lives of people living with cancer."

The primary objective of this international, randomized, double-blind trial is to evaluate whether the combination of elacestrant and everolimus offers greater efficacy in delaying disease progression compared to elacestrant monotherapy. Additionally, it investigates other crucial aspects, such as overall survival, toxicity profile, and the impact on patients’ quality of life.

The ADELA study represents a critical step in understanding how to overcome tumor resistance challenges in patients with ESR1 mutations, with the goal of advancing towards more effective and safer treatments.

"At MEDSIR, we understand innovation not only as achieving clinical results but as the ability to transform patients’ lives on a global scale. With ADELA, we take a decisive step toward accomplishing less invasive and more accessible treatments, aiming to offer new hope to those facing the most complex forms of the disease. This advancement reinforces our commitment to increasingly personalized and patient-centered medicine, a fundamental pillar in shaping the future of oncology," said Dr. Antonio Llombart-Cussac, Senior Scientific Leader at MEDSIR.

The phase III study not only has significant clinical objectives, but also holds the potential to pave the way for regulatory approval of this therapeutic combination, enabling its use in a broader population of patients with advanced breast cancer. Moreover, the international scope of the study, which includes participation from multiple countries, including Spain, Italy, France, Austria, the Czech Republic, Greece, Germany, and the United Kingdom, underscores the study’s global importance and relevance in the scientific community.

The presentation of the ADELA study at an event as prominent as SABCS 2024 reinforces MEDSIR’s leadership in excellence-driven oncology research and highlights its focus on addressing unmet needs in breast cancer treatment. The ADELA study is active and already recruiting patients.

About ORSERDU (elacestrant)

U.S. Indication: ORSERDU (elacestrant), 345 mg tablets, is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Full prescribing information for the U.S. can be found at www.orserdu.com.

Important Safety Information
Warning and Precautions

Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the final dose.

Adverse Reactions

Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).
The most common adverse reactions (≥10%), including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea(13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%).

Drug interactions

Concomitant use with CYP3A4 Inducers and/or inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU.

Use in specific populations

Lactation: Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose.
Hepatic Impairment: Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B).
The safety and effectiveness of ORSERDU in pediatric patients have not been established.

To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

On December 11, 2024 Beroni group reported that immune evasion has become one of the main obstacles in the development of tumor immunotherapy (Press release, Beroni Group, DEC 11, 2024, View Source [SID1234648997]). In the field of invariant natural killer T（iNKT） cell therapy, CD1d in cancer cells is the main tumor antigen presenting molecule that iNKT cells can recognize through its T cell receptor. The genetic and functional variability of CD1d in cancer cells has been considered an important factor in cancer immune evasion. In addition, the tumor specific proteins MUC4 and ITPRIPL1 expressed by refractory pancreatic cancer cells will also pose challenges such as protective immunity to iNKT cell therapy.

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In order to unravel the problem of the molecular mechanism of immune evasion of cancer cells during the treatment using iNKT cells and improve the therapeutic effect of iNKT cells, the research team of Beroni Pharmaceutical (Guangdong) Co., Ltd. adopted an adeno-associated virus (AAV) adjuvant strategy to continuously target, identify and label pancreatic cancer cells to express exogenous CD1D-like molecules using our unique pancreatic cancer tropism AAV variant capsid and pancreatic cancer specific gene regulatory elements. By overcoming the challenge of immune evasion mechanism, this innovative AAV adjuvant strategy may significantly improve the effect of iNKT cell therapy and improve the prognosis of pancreatic cancer patients.

In addition, the research team also found that the persistence and recognition killing efficacy of iNKT cells in solid tumors are often constrained by weakened immune suppression mechanisms and unfavorable metabolic environments in the tumor microenvironment. To address this challenge, the research team has developed a metabolic reprogramming strategy for iNKT cells, which optimizes the metabolic health of iNKT cells to better alleviate the immunosuppressive effects of solid tumors caused by the tumor microenvironment. This groundbreaking approach is expected to revolutionize traditional solid tumor immune adoptive therapy by significantly enhancing the metabolic health and tumor killing persistence of iNKT cells.

The research team of Beroni Pharmaceutical (Guangdong) Co., Ltd. is seeking patents for both technologies mentioned above, which marks an important step forward for Beroni Group in developing and improving effective iNKT cell therapy. This marks an important milestone for Beroni Group to continuously expand upon our existing anti-cancer product line. The combination of these two cutting-edge technology is expected to create a new treatment option for advanced solid tumor patients.

Beroni Group will strive to promote clinical application of iNKT cell therapy through unremitting research and clinical development, ultimately to improve prognosis and quality of life bring in cancer patients.

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).

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 Alpha Tau Medical Ltd. ("Alpha Tau", or the "Company") (NASDAQ: DRTS, DRTSW), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported that CEO Uzi Sofer and CFO Raphi Levy will present a corporate overview and update at the J.P. Morgan 43rd Annual Healthcare Conference on Thursday, January 16, 2025 at 9:45am PT / 12:45pm ET, in San Francisco, CA, and will host institutional investor meetings at the event (Press release, Alpha Tau Medical, DEC 11, 2024, View Source [SID1234649037]).

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Event: J.P. Morgan 43rd Annual Healthcare Conference
Format: Presentation and 1-on-1 Meetings
Date: January 16, 2025
Time: 9:45AM PT – 10:25AM PT
Location: Westin St. Francis, San Francisco, CA

Webcast: Link located on the "Events & Presentations" page in the Investor Relations section on the Company’s website at View Source

Please reach out to your J.P. Morgan representative to schedule 1-on-1 meetings with Mr. Sofer and Mr. Levy.