ENMD-2076 / CASI - LARVOL DELTA

WSB1-Mediated Degradation of PSMA Drives Neuroendocrine Differentiation in Early Prostate Cancer (AACR-NCI-EORTC 2025) - "Using patient-derived 3D spheroid cultures established from seven treatment-naïve prostate cancer biopsies, we modeled prolonged exposure to enzalutamide or abiraterone and observed progressive loss of prostate-specific membrane antigen (PSMA/FOLH1) accompanied by increased expression of neuroendocrine markers chromogranin A and synaptophysin...Consistent with this finding, t-NEPC spheroids derived from long-term drug-exposed patient samples exhibited pronounced sensitivity to the Aurora A inhibitors alisertib and ENMD-2076, independent of WSB1 expression levels but associated with impaired WSB1 E3 ligase activation...Targeting WSB1-dependent degradation pathways, either directly or through upstream Aurora A inhibition, may provide a rational therapeutic strategy to suppress or delay the emergence of t-NEPC in patients receiving AR-directed therapies. *These results were obtained after the regular abstract submission deadline and represent newly generated..."

Late-breaking abstract • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • AURKA • CHGA • FOLH1 • KLK3 • SYP • WSB1

Optimization of Novel Quinazolines as Potent Aurora Kinase Inhibitors for Triple-Negative Breast Cancer Treatment. (PubMed, J Med Chem) - "Mechanistic studies using immunoblotting, immunofluorescence staining, and flow cytometry showed that 9h outperforms ENMD-2076 in inhibiting Aurora A kinase activation, preventing spindle formation, arresting the cell cycle, and inducing cell apoptosis. Thus, 9h has the potential for further optimization and is a promising anticancer drug candidate."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKA

AURORA KINASE INHIBITOR ENMD-2076 INDUCED MITOCHONDRIAL DAMAGE BY REGULATING TFAM-MEDIATED MTDNA MAINTENANCE IN DLBCL (EBMT 2025) - "In summary, these results suggested that the Aurora A inhibitor ENMD-2076 inhibited the proliferation of DLBCL by arresting cell cycle at G2/M phase. In addition, ENMD-2076 induced mitochondrial dysfunction by inhibiting the expression of TFAM and downregulated the copy number and transcription level of mtDNA, which lead to the destroy of mitochondrial respiratory chain complex, and induced oxidative stress in DLBCL cells, thereby inhibiting the progression of DLBCL."

Clinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Metabolic Disorders • Oncology • AURKA • PLK1 • TFAM

Discovery of a first-in-class Aurora A covalent inhibitor for the treatment of triple negative breast cancer. (PubMed, Eur J Med Chem) - "11c displayed comparable therapeutic efficacy in an MDA-MB-231 xenograft mouse model relative to the positive control ENMD-2076, while requiring only half the dose of ENMD-2076. These results confirmed that 11c may be a promising drug candidate for the treatment of triple negative breast cancer (TNBC). Our work may provide a new perspective on the design of covalent inhibitors of Aurora kinase."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKA

Clinical safety and efficacy of the aurora and angiogenic kinase inhibitor ENMD-2076 in previously treated, locally advanced or metastatic triple-negative breast cancer (SABCS 2017) - "ENMD-2076 has durable clinical activity in a subset of patients with pretreated, advanced or metastatic triple-negative breast cancer. Predictive biomarker development using archival and fresh tumor tissue is underway. Exploration of lower doses of ENMD-2076 in future clinical trials may improve tolerability."

HER2 Breast Cancer • Hormone Receptor Breast Cancer • Triple Negative Breast Cancer

Phase II clinical and molecular trial of oral ENMD-2076 in clear cell ovarian cancer (CCOC): A study of the Princess Margaret phase II consortium. (ASCO 2017) - P2; "The PFS at 6 months was 20% for the evaluable patients, 31% in ARID1A loss and 12% in ARID1A positive patients. Loss of ARID1A, a known negative prognostic factor, was correlated with better PFS on ENMD-2076. Additional molecular profiling of the baseline biopsy material is underway."

Biomarker • Clinical • P2 data • Biosimilar • Cardiovascular • Ovarian Cancer

AML-377 A "Designed" High-Throughput Drug Screening Strategy Identifies Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML. (PubMed, Clin Lymphoma Myeloma Leuk) - "We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identification of promising lead compounds. Our study is the first to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML."

Journal • Preclinical • Acute Myelogenous Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • AURKA • NPM1

A “Designed” High-Throughput Drug Screening Strategy Identifi es Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML (SOHO 2022) - "In the validation assay, 2 compounds (MK-5108 and MK-8745) were confi rmed as more active against NPM1-mutated than NPM1–wild-type AML cells by either CyQUANT or apoptosis assay. Strikingly, we confi rmed selectivity for two additional AURKAi (Alisertib and ENMD-2076, both isoform-selective inhibitors of AURKA) that were not included in the screening library... We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identifi cation of promising lead compounds. Our study is the fi rst to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AURKA • NPM1

[VIRTUAL] Computational extraction and analysis of de-identified medical records to characterize hyperammonemia in patients with fibrolamellar carcinoma (FLC). (ASCO 2021) - "In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist . 2020 25(11):925-e1603), ENMD-2076 (Oncologist . 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies... NLP of large EMRs is a valuable tool to study FLC, a rare cancer . Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies . Further investigation may determine whether hyperammonemia is related to FLC tumor biology."

Clinical • CNS Disorders • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Failure • Oncology

A phase II study of ENMD-2076 in advanced soft tissue sarcoma (STS). (PubMed, Sci Rep) - "Although this study failed to meet its primary endpoint, occasional responses and prolonged stable disease was noted. ENMD-2076 evaluation in PTPRB mutated tumors and/or angiosarcoma is warranted."

Biomarker • Journal • P2 data • Hematological Malignancies • Hypertension • Leiomyosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats. (PubMed, Aging (Albany NY)) - "Our findings reveal that ENMD-2076 is a promising drug in dealing with glioblastoma and have a perspective application."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Antitumor activities of FGFR inhibitors in FGFR1-overexpressing hepatocellular carcinoma patient-derived xenograft tumor models (AACR 2014) - Presentation time: Monday, Apr 07, 2014, 1:00 PM - 5:00 PM; Abstract #2839; "...due to the multi-targeting mechanisms of these inhibitors, in vitro inhibitory effects of the compounds on FGFR1 enzyme and cell proliferation may not correlate with the in vivo anti-tumor activities. Overexpression of FGFR1 gene may serve as a predictive biomarker for therapeutic intervention of the FGF/FGFR pathway in HCC by using lenvatinib, dovitinib and ENMD-2076."

Biomarker • Hepatocellular Cancer • Oncology

CASI Pharmaceuticals: Annual Report 2014 (CASI Pharmaceuticals) - Anticipated initiation of P2 trial for advanced fibrolamellar carcinoma in 2015

Trial initiation date • Oncology

CASI Pharmaceuticals: CTOS 2015 (CASI Pharmaceuticals) - “ENMD-2076 has shown clinical activity in pts with advanced STS, with clinical benefits and side effects profile typical of this class of agent”; “Drug toxicities were of low grade and tolerable. High grade toxicities include hypertension (56%), ALT increase (35%) and diarrhea (17%)”; “All 4 patients who derived clinical benefit (2 PR and 2 SD > 6months) received ENMD-2076 in the first-line setting”; “Genetic variations in CCL11 and FLNB (FilaminB) are potentially associated with benefit from ENMD-2076 while gene variations in EGFR, and CYP4B1 polymorphism could be associated with lack of benefit. These findings warrant further investigation”

P2 data • Oncology • Sarcoma

ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer (Eur J Cancer) - P2, N=64; Study ID: 2076-CL-004; PFS rate at six months was 22% with a median TTP of 3.6 months; The median number of prior regimens was two; None of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples were predictive of greater benefit or resistance to ENMD-2076 treatment

P2 data • Oncology • Ovarian Cancer

A phase II study of oral ENMD-2076 administered to patients (pts) with advanced soft tissue sarcoma (STS) (ASCO 2013) - Presentation time: Saturday, Jun 1, 1:15 PM - 5:00 PM; Abstract #TPS10593; P2, N=3; NCT01719744; "PFSR at 6-months will be estimated using the Kaplan-Meier method. ORR will be estimated and 2-sided 95% exact binomial confidence interval will be provided. Study Progress: At deadline for abstract submission, 3 patients have been enrolled onto this study."

Clinical protocol • Oncology

A Multi-center, Open-label Study of Oral ENMD-2076 for the Treatment of Patients With Advanced Fibrolamellar Carcinoma (clinicaltrials.gov) - P2; N=29; Recruiting; Sponsor: CASI Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting; N=53 ➔ 29; Trial primary completion date: Apr 2019 ➔ Dec 2016

Enrollment change • Enrollment open • Trial primary completion date • Biosimilar • Hepatocellular Cancer • Oncology

Phase II study of oral ENMD-2076 administered to patients (pts) with advanced soft tissue sarcoma (STS) (ASCO 2014) - Presentation time: Tuesday, Jun 3; 8:00 AM - 11:00 AM; Abstract #10528; P2, N=10; NCT01719744; "2 pts had confirmed partial response (PR) and 1 pt with confirmed stable disease (SD) of > 6 months. Clinical benefit rate (PR+SD >6 months) was 30%. Median OS has not been reached. Median PFS at 1.8 months (95% CI: 1.2 – not reached). ENMD-2076 has generally been well tolerated with primarily grade 1 and 2 adverse events (AEs)."

P2 data • Oncology • Sarcoma

EntreMed: Corporate Presentation (Entremed) - "Phase 1 Data Demonstrated Good Safety Profile and Promising Preliminary Antitumor Activity in Multiple Types of Solid Tumors"; "Overall Response Rate - PR: 3%, - SD: 85% (30% reduction in tumor size)"

P1 data • Breast Cancer • Oncology • Ovarian Cancer

Data presented for ENMD-2076 in preclinical models of triple-negative breast cancer (Entremed Press Release) - “EntreMed, Inc…announced today the presentation of preclinical data from a study to assess the role of p53 family tumor suppressors in mediating response to ENMD-2076 in triple-negative breast cancer (TNBC).”

Preclinical • Breast Cancer • Oncology

A Dose-Escalation Study of ENMD-2076 Administered Orally to Patients With Advanced Cancer (clinicaltrials.gov) - P1; N=67; Completed; Sponsor: CASI Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Oncology

ENMD-2076: “Demonstrated durable clinical activity in a subset of patients with pretreated, advanced or metastatic triple-negative breast cancer” (CASI Pharmaceuticals) - ENMD-2076 Presentation: “Mechanism based adverse event profile was observed with hypertension and gi toxicity”

P2 data • Oncology • Triple Negative Breast Cancer

EntreMed announces publication of preclinical results for ENMD-2076 in triple-negative breast cancer (Entremed) - “ENMD-2076 demonstrated more robust activity against cell lines of the TNBC subtype compared to the luminal and HER2-amplified subtypes. This in vitro activity was confirmed in vivo, in MDA-MB-468 and MDA-MB-231 TNBC xenografts. Baseline gene expression profiling and pathway analysis of the panel revealed that p53 and G1/S cell cycle pathways were upregulated in the more sensitive cell lines. Within the TNBC subset itself, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and pro-apoptotic effects of ENMD-2076 exposure than cell lines with decreased p53 expression.”

Preclinical • Breast Cancer • Oncology

EntreMed: Corporate Presentation (Entremed) - "Phase 2 Trial Confirmed Safety and Antitumor Activity"; "Overall response rate - PR: 8%, - PR/SD: 58%, PFS 6: 22%"; "Stronger activities observed in clear cell ovarian cancer"; "Support further clinical trials in clear cell ovarian cancer"

P2 data • Oncology • Ovarian Cancer

CASI Pharmaceuticals receives EU orphan drug designation for the use of ENMD-2076 to treat hepatocellular carcinoma including fibrolamellar carcinoma (PRNewswire) - "The designation provides CASI with 10 years of market exclusivity in EU after ENMD-2076 receives marketing authorization there. The product was also granted Orphan Drug designation for the treatment of HCC by US Food and Drug Administration (FDA) in 2014, which provides CASI with a 7-year market exclusivity in the country after its New Drug Application approval."

European regulatory • Oncology