GSK’s Belantamab Mafodotin Set to Become First BCMA-Targeted Therapy Approved in US and EU

July 26, 2020 News /Bio ValleyBIOON/ --GlaxoSmithKline(GSK) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending approval of Blenrep (belantamab mafodotin, GSK2857916), an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA), for the following indication: as monotherapy for the treatment of adult patients with multiple myeloma (MM) who have received at least four prior therapies and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 antibody, and who demonstrated disease progression during or after their last line of therapy. The CHMP’s positive opinion will now be reviewed by the European Commission (EC), which typically renders a final decision within two months.

In terms of U.S. regulation, mid-month this month,FDATumorThe Oncologic Drugs Advisory Committee (ODAC) voted 12-0 that the clinical benefits of belantamab mafodotin outweigh its risks, supporting its approval as a monotherapy for the treatment of patients with relapsed or refractory multiple myeloma (MM) who have previously received at least four prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Notably, at the ODAC meetingConferencePreviously, FDA internal reviewers expressed concerns about belantamab mafodotin-related ocular adverse events.FDAThe ODAC’s recommendations will be considered in making the final review decision, although they are not binding.

Currently, belantamab mafodotin is undergoing priority review by the U.S. FDA and accelerated assessment by the European EMA. If approved, this drug will become the first BCMA-targeted therapy to be marketed. In 2017, belantamab mafodotin received U.S.FDAGranted Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) designation by the European Medicines Agency (EMA), this drug is also the first BCMA-targeted therapy to receive both BTD and PRIME designations. These designations are intended to facilitate the development of investigational drugs with clinical potential in areas of significant unmet medical needs.

GlaxoSmithKlineSenior Vice President andTumorDr. Axel Hoos, Head of R&D, stated: “The CHMP’s positive opinion today marks an important step in helping patients with relapsed or refractory multiple myeloma who have limited treatment options and a poor prognosis. If approved, belantamab mafodotin will provide a first-in-class anti-BCMA therapy for patients and physicians in Europe, offering a mechanism of action distinct from other currently available treatments.”

CHMP’s Positive Opinion, Based on DREAMMClinical TrialThe project data include the pivotal DREAMM-2 study. This was a randomized, open-label, two-arm Phase II study that enrolled 196 patients with relapsed/refractory multiple myeloma (R/R MM) who had been heavily pretreated. These patients experienced disease progression despite receiving current standard of care, had received a median of seven prior lines of therapy, were refractory to immunomodulatory drugs and proteasome inhibitors, and were 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 six-month preliminary results of this study were published in The Lancet in December 2019.TumorStudies》, and serve as the basis for regulatory submissions in the United States and Europe.

In late May this year, GSK at the 2020 American ClinicalTumorThe 13-month follow-up data from this study were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting virtual conference. The results showed that the median duration of response (DoR) for belantamab mafodotin monotherapy (2.5 mg/kg every 3 weeks [Q3W]) was 11 months (95% CI: 4.2–not reached), the median overall survival (OS) was 14.9 months (95% CI: 9.9–not reached), and the objective response rate (ORR) was consistent with the 6-month data (ORR = 32%). Among these patients, the majority (58%) achieved a very good partial response (VGPR) or better (≥ VGPR), including 2 cases of stringent complete response (sCR) and 5 cases of complete response (CR). The proportion of patients who achieved clinical benefit was 36% (95% CI: 26.6–46.5).

During long-term follow-up, no new safety signals were identified. Among patients receiving the 2.5 mg/kg dose, the most common Grade ≥3 adverse events (occurring in more than 10% of patients) were keratopathy/microcystic epithelial changes (MEC; 46%) and thrombocytopenia (22%),Anemia(21%), decreased lymphocyte count (13%), and neutropenia (11%). The first case of microcystic epithelial keratopathy (MEC) is characterized by changes in corneal epithelial cells observed during ocular examination, which may be symptomatic or asymptomatic. At the data cutoff, 77% of patients in the 2.5 mg/kg dose group had resolution, and no cases of permanent vision loss have been reported to date.

For patients with relapsed/refractory multiple myeloma (R/R MM) whose disease continues to progress despite currently available therapies, treatment options are very limited and the prognosis is poor. The latest results from the DREAMM-2 study further demonstrate the potential of belantamab mafodotin. If approved, belantamab mafodotin will provide an important new treatment option for these patients, helping to address a significant unmet medical need.

Mechanism of Action of Belantamab Mafodotin (Image source: DOI: https://doi.org/10.1016/S1470-2045(19)30788-0)

The DREAMM clinical development program comprises 10 clinical studies (DREAMM-1 to DREAMM-10), which are evaluating the efficacy and safety of belantamab mafodotin as a monotherapy and in combination regimens for first-line, second-line, and later-line treatment of multiple myeloma (MM). Previously reported updated data from the first-in-human DREAMM-1 study demonstrated that belantamab mafodotin achieved an overall response rate (ORR) of 60% in patients with BCMA-positive relapsed/refractory multiple myeloma (R/R MM).

At the ASCO Annual Meeting, GSK also presented data from the DREAMM-6 study. This study evaluated the efficacy and safety of belantamab mafodotin (2.5 mg/kg every 3 weeks [Q3W]) in combination with bortezomib/dexamethasone (BorDex) in patients with relapsed/refractory multiple myeloma (R/R MM) who were refractory to or had relapsed after one or more prior therapies.

Preliminary results showed that the overall response rate (ORR) for belantamab mafodotin combined with BorDex (B-Vd) reached 78% (n=14/18; 95% CI: 52.4–93.6), with 50% achieving very good partial response (VGPR) and 28% achieving partial response (PR). The proportion of patients who achieved clinical benefit (minimal response or better) was 83% (95% CI: 58.6–96.4). At a median treatment duration of 18.2 weeks, the median duration of response (DoR) had not yet been reached. Grade 3 or higher adverse events included microcystic epithelial changes (MEC; 56%) and thrombocytopenia (61%). There were no cases of grade 4 MEC. These preliminary results confirm the potential of belantamab mafodotin combination therapy in patients with early-stage multiple myeloma.

BCMA-Targeted Investigational Immunotherapies for Multiple Myeloma (Source: PMID: 31277554)

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 Amgen), bispecific antibodies (BsAb, represented by Amgen), and antibody-drug conjugates (ADC, represented by GlaxoSmithKline).

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 SeattleHeredityan ADC drug formed by conjugation (with authorization obtained). 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 arrest at the G2/M phase and induce caspase-3-dependentApoptosis. Furthermore, belantamab mafodotin can induce NK cell-mediated ADCC (antibody-dependent cellular cytotoxicity) while simultaneously inducing macrophage-mediated ADCP (antibody-dependent cellular phagocytosis).

Belantamab mafodotin selectively targets multiple myeloma (MM) cells through multiple cytotoxic mechanisms, holding promise as a highly potential next-generation immunotherapy option for this type of cancer. Currently, belantamab mafodotin is in clinical development for the treatment of relapsed/refractory MM and other advanced hematologic malignancies expressing BCMA.TumorPatient Treatment. (Bioon.com)

Original Source:GSK receives positive CHMP opinion recommending approval of belantamab mafodotin for the treatment of relapsed and refractory multiple myeloma