oprozomib (ONX 0912) / Amgen - LARVOL DELTA

A functional precision medicine clinical trial in Relapsed/Refractory multiple myeloma: Prospective study of a high throughput drug sensitivity assay on correlation of drug sensitivity scores with treatment response (ASH 2025) - P=N/A | "All patients (100%) had prior exposure to lenalidomide, 97.5% to bortezomib, 85% to carfilzomib, 82% to daratumumab, 77.5% to pomalidomide, and 12.5% BCMA CAR-T therapy...From Oncopanel2 v1, the top drugs by DSS included bortezomib (median DSS 47.7), carfilzomib (median DSS 47.3), panobinostat (median DSS 47), and romidepsin (median DSS 45.4). From Oncopanel2 v2, the top drugs by DSS were marizomib (an investigational PI, with median DSS 46.1), carfilzomib (median DSS 40.2), ixazomib (median DSS 37.2), and oprozomib (an investigational PI, with median DSS 31.6)... The use of a high throughput drug sensitivity assay was feasible among patients with relapsed/refractory MM. In our analysis of drug-specific DSS thresholds for bortezomib and Selinexor, DSS performance varied by agent, highlighting the need for drug-specific threshold optimization. In the patients who received Selinexor, there was a non-significant tendency toward higher DSS scores in responders,..."

Clinical • IO biomarker • Hematological Malignancies • Leukemia • Multiple Myeloma • Plasma Cell Leukemia • Plasmacytoma • SDC1

KRAS mutation derived PSMB8 activates MEK/ERK signaling to promote chemoresistance in pancreatic adenocarcinoma (EACR 2025) - "Functional validation included PSMB8 knockdown (siRNA) and pharmacological inhibition (oprozomib) in PAAD cell lines, with proliferation (CCK-8), metastasis (transwell), apoptosis (flow cytometry), and drug sensitivity assays (IC50). We established a robust KMUPSG signature for prognostic stratification and chemotherapy response prediction in PAAD. PSMB8 emerged as a central effector of KRAS-mediated chemoresistance, operating through MEK/ERK signaling. Targeting PSMB8 represents a promising strategy to overcome gemcitabine resistance, offering actionable insights for precision therapy in KRAS-mutant PAAD."

Tumor mutational burden • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Targeted Protein Degradation • KRAS • MAP2K1 • PSMB8 • TMB

INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=61 | Completed | Sponsor: Amgen | Phase classification: P1b ➔ P1

Combination therapy • Phase classification • Hematological Malignancies • Multiple Myeloma • Oncology

Tissue-, region-, and gene-specific induction of microsomal epoxide hydrolase expression and activity in the mouse intestine by arsenic in drinking water. (PubMed, Drug Metab Dispos) - "The induction of intestinal mEH was accompanied by increases in microsomal enzymatic activities toward a model mEH substrate, cis-stilbene oxide, and an epoxide-containing drug, oprozomib, in vitro, and by increases in the levels of PR-176, the main hydrolysis metabolite of oprozomib, in the proximal small intestine of oprozomib-treated mice...The small intestinal epithelial cells are the main site of absorption of ingested arsenic, but they are not well characterized for arsenic exposure-related changes. This study identified gene expression changes in the small intestine that may be mechanistically linked to the adverse effects of arsenic exposure and possible interactions between arsenic ingestion and the pharmacokinetics of epoxide-containing drugs in vivo."

Journal • Preclinical • Diabetes • Metabolic Disorders • EPHX1

Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sjögren's Syndrome: A public databases-based study. (PubMed, PLoS One) - "Other drugs, such as bortezomib, carfilzomib, oprozomib, cyclosporine and zidovudine, may be ideal drugs for the future treatment of RA patients with pSS. In conclusion, we identified commom targets as potential biomarkers in RA and pSS from publicly available databases and predicted potential drugs based on the targets. A new understanding of the molecular mechanisms associated with RA and pSS is provided according to the miRNA-gene network."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • CXCL10 • GZMA • ITGA4 • MIR21 • PSMB9

Proteasome inhibitors as anticancer agents. (PubMed, Expert Opin Ther Pat) - "This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood-brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic 'working on' aspect for the near future."

Journal • Review • Brain Cancer • CNS Tumor • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • Targeted Protein Degradation

A Reliable and Effective UPLC-MS/MS Method for the Determination of Oprozomib in Rat Plasma. (PubMed, J Anal Methods Chem) - "Using the selective reaction monitoring (SRM) method, the measurement was finished with the ion transitions of m/z 533.18 ⟶ 199.01 for oprozomib and m/z 493.03 ⟶ 112.03 for tepotinib (internal standard, IS), respectively. Moreover, the recovery was determined to be from 85.1% to 96.1%, and the values of matrix effect were no more than 110.4%. The optimized UPLC-MS/MS method was also suitable for the pharmacokinetic study of rats after a single oral administration of 21 mg/kg oprozomib."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Effect of optimized new Shengmai powder on exercise tolerance in rats with heart failure by regulating the ubiquitin-proteasome signaling pathway. (PubMed, Front Cardiovasc Med) - "Rats (left ventricular ejection fraction ≤ 45%) were randomly divided into the following groups: model group, YHXSMS group, Benazepril group, and proteasome inhibitor Oprozomib group, and they were administered the corresponding drugs by gavage for 4 weeks. Our study suggested that optimized new Shengmai powder could exert antiapoptotic effects on myocardial and skeletal muscle cells and improve myocardial contractility and exercise tolerance by inhibiting the overactivation of the UPS pathway, downregulating MAFbx, and Murf-1 overexpression, inhibiting the activation of the JNK signaling pathway, upregulating bcl-2 expression, and decreasing bax and caspase-3 levels. The study showed that the optimized new Shengmai powder could improve cardiac function and exercise tolerance in rats with heart failure through the UPS pathway."

IO biomarker • Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Targeted Protein Degradation • BAX • BCL2 • CASP3

Proteasome inhibition in combination with immunotherapies: State-of-the-Art in multiple myeloma. (PubMed, Blood Rev) - "In this paper we briefly highlight essential clinical elements relating to proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib. A high number of patients develop PI resistance. Thus, we also review new generation PIs, such as marizomib, oprozomib (ONX0912) and delanzomib (CEP-18770) and their combinations with immunotherapies."

Combination therapy • Journal • Review • Bone Marrow Transplantation • Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology • Transplantation

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials? (PubMed, Front Endocrinol (Lausanne)) - "We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance..."

Journal • Review • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Rare Diseases • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Clinical Predictors of T Cell Fitness for CAR T Cell Manufacturing and Efficacy in Multiple Myeloma (ASH 2018) - P1, P1/2, P2; "...In an accompanying abstract (Cohen et al.), we report that higher percentage of early-mem T cells and CD4/CD8 ratio within the leukapheresis product are associated with favorable clinical response to anti-BCMA CAR T cells (CART-BCMA) in relapsed/refractory MM...Results : The post-ind cohort includes 38 patients with median age 55y (range 41-68) and prior exposure to lenalidomide (22), bortezomib (21), dexamethasone (38), cyclophosphamide (8), vincristine (2), thalidomide (8), and doxorubicin (4); median time from first systemic therapy to leukapheresis was 152 days (range 53-1886) with a median of 1 prior line of therapy (range 1-4). The rel/ref cohort included 25 patients with median age 58y (range 44-75), median 7 prior lines of therapy (range 3-13), and previously exposed to lenalidomide (25), bortezomib (25), pomalidomide (23), carfilzomib/oprozomib (24), daratumumab (19), cyclophosphamide (25), autologous SCT (23), allogeneic SCT (1), and anti-PD1...

CAR T-Cell Therapy • Clinical • PD(L)-1 Biomarker • Biosimilar • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia. (PubMed, Am J Clin Oncol) - "Once validated, it is proposed that a combination of selected drugs can be evaluated in the laboratory to treat WM."

Journal • PK/PD data • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia

Bendamustine with ixazomib and dexamethasone (BID) for double refractory relapsed multiple myeloma (RRMM): Phase I safety and dosing results. (ASCO 2017) - P1/2; "Prior therapies included bortezomib (100%), lenalidomide (100%), carfilzomib (47%), oprozomib (7%), thalidomide (7%), pomalidomide (7%) and 87% autotransplant. BID has an acceptable safety profile and a promising ORR of 45% and CBR of 73% in pts. with advanced double refractory MM."

Clinical • P1 data • Biosimilar • Immunology • Multiple Myeloma • Venous Thromboembolism

INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b | N=61 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Determination of Tropifexor in Beagle Dog Plasma by UPLC-MS/MS and Its Application in Pharmacokinetics. (PubMed, J Anal Methods Chem) - "The chromatographic separation of tropifexor and oprozomib (internal standard, ISTD) on the column, with the addition of acetonitrile for rapid precipitation and protein extraction, was achieved with 0.1% formic acid aqueous solution-acetonitrile for the mobile phase. The stability met the requirements for the quantification of plasma samples under various conditions. Finally, the pharmacokinetic profile of tropifexor in beagle dog plasma following oral administration of 0.33 mg/kg tropifexor was determined by using the method facilitated in this work."

Journal • PK/PD data

INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b; N=61; Active, not recruiting; Sponsor: Amgen; Trial completion date: Dec 2021 ➔ Dec 2022; Trial primary completion date: Dec 2021 ➔ Dec 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Phase 1b Study of Oprozomib with Dexamethasone or Pomalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (ASH 2018) - "...Methods : Adult patients with RRMM who had received at least 2 prior lines of therapy and whose prior treatment included both lenalidomide and a proteasome inhibitor were eligible for inclusion...Fourteen patients (41%) received prior carfilzomib, and 10 of these were carfilzomib-refractory; 27 patients (79%) received prior bortezomib and 14 were bortezomib-refractory...The most common AEs observed were gastrointestinal disorders, and most of these were grade 1–2 with no gastrointestinal bleeding reported. Furthermore, OPomD therapy showed promising efficacy, with an objective response rate of 67% for patients in the IR 200-mg/day cohort."

Clinical • P1 data • Biosimilar • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Neutropenia • Oncology • Renal Disease

Research progress in proteasome inhibitor resistance to multiple myeloma. (PubMed, Zhong Nan Da Xue Xue Bao Yi Xue Ban) - "Bortezomib, ixazomib, and carfilzomib are also widely used for MM. Marizomib, oprozomib, and KZR-616 are in clinical trials. However, the drug resistance of PIs in MM is still a problem. The mechanisms for PIs resistance to MM include ubiquitin-proteasome pathway, autophagy lysosome pathway, endoplasmic reticulum stress pathway, cell survival signal pathway, exosome-mediated resistance, and bone marrow microenvironment-mediated resistance."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner. (PubMed, Cancer Lett) - "Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition."

Journal • Acute Myelogenous Leukemia • Adenoid Cystic Carcinoma • Hematological Malignancies • Leukemia • Oncology

Ubiquitin-proteasome System Is a Promising Target for Killing Cisplatin-resistant Bladder Cancer Cells. (PubMed, Anticancer Res) - "Targeting the UPS could be an effective strategy for treating cisplatin-resistant bladder cancer."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Urothelial Cancer

The new-generation proteasome inhibitor oprozomib increases the sensitivity of cervical cancer cells to cisplatin-induced apoptosis. (PubMed, J Biol Regul Homeost Agents) - "Moreover, OPZ promoted the phosphorylation of the apoptosis signaling pathway JNK that was activated by cisplatin, thereby inducing tumor cell apoptosis. These findings provide a theoretical basis for the clinical use of OPZ alone and in combination with cisplatin in the treatment of cervical cancer."

Journal • Cervical Cancer • Oncology • Solid Tumor • CASP3 • PARP1

A Study of Oprozomib, Pomalidomide, and Dexamethasone in Adults With Primary Refractory or Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1b; N=33; Terminated; Sponsor: Amgen; Completed ➔ Terminated; A program evaluation identified that the safety profile and pharmacokinetic (PK) characteristics of the formulation used in all oprozomib studies required further optimization and thus enrollment in OPZ007 was halted during dose-expansion.

Clinical • Trial termination • Hematological Malignancies • Multiple Myeloma • Neutropenia • Oncology

Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting 2018. (PubMed, Clin Lymphoma Myeloma Leuk) - "Maintenance with ixazomib results in prolonged progression-free survival (PFS) compared with placebo. Regarding transplant-ineligible NDMM patients, large phase III studies showed that the additional use of daratumumab in backbone first-line regimens provides deep responses and PFS prolongation, whereas dose-/schedule-adjusted lenalidomide-dexamethasone has similar efficacy and is more tolerable than continuous lenalidomide-dexamethasone. In the relapsed/refractory setting carfilzomib- and daratumumab-based regimens remain highly effective and safe treatments, whereas the introduction of venetoclax, isatuximab, atezolizumab, and oprozomib broadens the therapeutic options. Among heavily pretreated MM patients, selinexor and melflufen showed particularly encouraging results. Novel immunotherapeutic approaches including chimeric antigen receptor T cells against B-cell maturation antigen and bispecific antibodies constitute a promising alternative that remains to be..."

Clinical • Journal • Review • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation

Clinical Efficacy of Intracellular Molecular Inhibitors for Relapsed, Refractory Multiple Myeloma: A Systematic Review of Early Clinical Data (ASH 2018) - "...Forty-eight patients were quad-refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) while 31 patients were penta-refractory (including isatuximab/daratumumab)...The best response was seen when selinexor was used in combination with bortezomib (V) and dexamethasone (d) i.e. 77%...The best response was seen when vorinostat was used in combination with V, doxorubicin (DX) and d i.e. 67%...Conclusion : In RRMM patients, vorinostat and selinexor when used in combination regimens demonstrated a weak efficacy with a pooled ORR of 43% and 36% respectively...The data on other intracellular molecular inhibitors (ricolinostat, oprozomib, marizomib, filanesib, dinaciclib, and palbociclib) when used either as single agents or in combination regimens, suggested a poor efficacy with an ORR of < 35%. However, future randomized well designed prospective clinical trials involving a larger population are required to further explore the efficacy of these..."

Clinical • Review • Biosimilar • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Oprozomib and Dexamethasone,in Combination With Lenalidomide or Oral Cyclophosphamide to Treat Newly Diagnosed Multiple Myeloma (clinicaltrials.gov) - P1b/2; N=22; Terminated; Sponsor: Amgen; Completed ➔ Terminated; A program evaluation identified that the safety profile and pharmacokinetic (PK) characteristics of the formulation used in all oprozomib studies required further optimization and thus enrollment in OPZ003 was halted during dose-escalation.

Clinical • Combination therapy • Trial termination • Hematological Malignancies • Multiple Myeloma • Neutropenia • Oncology