GSK's BCMA-Targeted ADC Belantamab Mafodotin Achieves Pivotal Clinical Success in Relapsed/Refractory Multiple Myeloma, BLA Submission Underway
Dec 18, 2019 09:31
CST Updated
09:31
GSK
Pharmaceutical R&D Manufacturer
December 18, 2019 /BioValleyBIOON/ -- British pharmaceutical giantGlaxoSmithKline(GSK) recently announced that the full results of the pivotal clinical study DREAMM-2 (NCT03525678), evaluating belantamab mafodotin (GSK2857916), a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC), as monotherapy for relapsed or refractory multiple myeloma (R/R MM), have been published online in The Lancet.TumorThe Lancet Oncology
DREAMM-2 was a randomized, open-label, two-arm phase II study that enrolled 196 patients with relapsed/refractory multiple myeloma (R/R MM) whose disease had progressed despite current standard of care, who had received a median of 7 prior lines of therapy, and who were refractory to immunomodulatory drugs and proteasome inhibitors, as well as refractory and/or intolerant to anti-CD38 antibodies. In the study, patients were randomized into two groups to receive belantamab mafodotin at a dose of 2.5 mg/kg or 3.4 mg/kg once every three weeks.
The results showed that the study met its primary endpoint: in this refractory patient population, the overall response rate (ORR) for belantamab mafodotin (2.5 mg/kg) monotherapy was 31% (n=30/97), which is clinically meaningful. Among the 30 patients who responded, 18 achieved a very good partial response or better, including 3 who attained a stringent complete response. With a median follow-up of 6 months, the median duration of response (DoR) had not been reached, and overall survival (OS) had also not been reached.
In this study, the safety and tolerability of belantamab mafodotin were consistent with those observed in the first-in-human clinical study DREAMM-1; the most common grade 3 or 4 adverse events in the 2.5 mg/kg groupAdverse Reactionsfor corneal lesions (27%), thrombocytopenia (20%), andAnemia(20%). Overall, patients in the DREAMM-2 study had more severe disease, poorer prognosis, and worse performance status compared with those in the DREAMM-1 study. Moreover, patients in the DREAMM-2 study had received a greater number of prior treatment regimens than those in the DREAMM-1 study. The results of the DREAMM-2 study were consistent with those observed in the comparable patient subset from the DREAMM-1 study.
Based on these data, GSK is preparing to submit an application to the U.S. Food and Drug Administration (FDA) Submit a Biologics License Application (BLA) seeking approval of belantamab mafodotin at a dose of 2.5 mg/kg for patients with relapsed or refractory multiple myeloma (R/R MM) who have received prior therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. If approved, belantamab mafodotin would become the first anti-BCMA therapy in the United States.
Dr. Hal Barron, Chief Scientific Officer and President of Research and Development at GSK, stated, “Patients with multiple myeloma whose disease progresses despite currently available treatments have limited therapeutic options and a poor prognosis. Data from the DREAMM-2 study show that, if approved, belantamab mafodotin could provide an important new treatment option for these patients.”
The DREAMM-1 and DREAMM-2 studies are part of the DREAMM clinical development program, which comprises 10 clinical trials (DREAMM-1 through DREAMM-10) evaluating the efficacy and safety of belantamab mafodotin as monotherapy and in combination regimens for first-line, second-line, and multi-line treatment of multiple myeloma (MM).
In March this year, GSK announced updated data from the DREAMM-1 study, which is the first human clinical trial evaluating belantamab mafodotin. The purpose of the study was to investigate the drug's efficacy in patients with relapsed/refractory multiple myeloma (R/R MM) and other advanced hematologic malignancies expressing BCMA.TumorEfficacy and Safety in Patients. The results showed that the overall response rate (ORR) of belantamab mafodotin treatment reached 60% in BCMA-positive R/R MM patients.
Multiple Myeloma (MM) is the second most common hematologic malignancy, after non-Hodgkin lymphoma.Tumor. In recent years, despite significant advances in chemotherapy, proteasome inhibitors, immunomodulatory thalidomide derivatives, and CD38-targeted antibodies, nearly all patients eventually experience relapse. Therefore, there is an urgent need for new therapeutic regimens. The multiple myeloma (MM) market was valued at nearly $14 billion in 2017 and is projected to reach approximately $29 billion by 2027.
BCMA is an extremely important B-cellBiomarkers, widely expressed on the surface of MM cells, has become a focus in recent years for MM and other hematologic malignanciesTumora highly popular immunotherapy target. Currently, there are more than 20 immunotherapies developed against BCMA, mainly divided into three categories: chimeric antigen receptor T-cell therapy (CAR-T, Celgene/Bluebird Bio,Novartisrepresented by), bispecific antibodies (BsAbs, represented by Amgen), antibody-drug conjugates (ADCs,GlaxoSmithKlineas a representative).
Belantamab mafodotin is a novel humanized Fc-engineered anti-BCMA monoclonal antibody conjugated to the cytotoxic agent MMAF (monomethyl auristatin-F) via a non-cleavable linker (drug-linker technology from SeattleGeneticsan ADC drug formed by conjugation (upon obtaining authorization). Belantamab mafodotin targets and binds to BCMA on the surface of multiple myeloma (MM) cells via an anti-BCMA monoclonal antibody, is rapidly internalized by MM cells, degraded in lysosomes, and releases non-permeable MMAF within MM cells to exert its therapeutic effect. MMAF is a mitotic inhibitor and an anti-tubulin agent that suppresses cell division by blocking microtubule polymerization, thereby enablingTumorCells arrested at the G2/M phase and induced caspase-3-dependentApoptosis。
Furthermore, belantamab mafodotin can induce NK cell-mediated ADCC (antibody-dependent cellular cytotoxicity) and simultaneously induce macrophage-mediated ADCP (antibody-dependent cellular phagocytosis). By selectively targeting MM cells through multiple cytotoxic mechanisms, belantamab mafodotin holds promise as a highly potential next-generation immunotherapy option for this type of cancer.
Currently, belantamab mafodotin is under clinical development for the treatment of relapsed/refractory multiple myeloma (R/R MM) and other advanced hematologic malignancies expressing BCMA.TumorTreatment of patients. In 2017, belantamab mafodotin received U.S.FDAGranted Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) designation by the European Medicines Agency (EMA), becoming the first BCMA-targeted therapy to receive both BTD and PRIME. These designations aim to facilitate the development of investigational drugs with clinical potential in areas of significant unmet medical needs. (Bioon.com)