The sequencing of the human genome and the elucidation of many molecular pathways that are important in disease have provided unprecedented opportunities for the development of new therapeutics. The types of molecule in development are increasingly varied, and include antisense oligonucleotides and ribozymes. Antisense technology and catalytic nucleic-acid enzymes are important tools for blocking the expression of abnormal genes. One FDA-approved antisense drug is already in the clinic for the treatment of cytomegalovirus retinitis, and other nucleic-acid therapies are undergoing clinical trials. This article reviews different strategies for modulating gene expression, and discusses the successes and problems that are associated with this type of therapy.
Background:
B-cell maturation antigen (BCMA) is a tumour necrosis superfamily cell-surface receptor required for plasma cell survival. This study evaluated safety, tolerability and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin-F, in patients with relapsed/refractory multiple myeloma (MM).
Methods:
This international, multicentre, open-label, first-in-human Phase 1 study comprised dose escalation (Part 1) and dose expansion (Part 2) phases. Adults with histologically or cytologically confirmed MM, Eastern Cooperative Oncology Group performance status 0/1, and progressive disease following stem cell transplant, alkylators, proteasome inhibitors and immunomodulators were recruited. In Part 1, patients received GSK2857916 (0 03–4 6 mg/kg) via 1-hour intravenous infusion. In Part 2, patients received the selected dose of GSK2857916 (3 4 mg/kg) every 3 weeks. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). All patients who received ≥1 dose were included in this prespecified administrative interim analysis (cut-off: 26 June 2017), which was performed for internal purposes. The study is ongoing (NCT02064387).
Findings:
Between July 2014 and February 2017, 73 patients were treated (Part 1 n=38; Part 2 n=35). No MTD was identified in Part 1. Based on safety/clinical activity, 3 4 mg/kg was selected as RP2D. Corneal events were common (42/73; 58%); most (37/42) were Grade 1/2 and did not result in treatment discontinuation in Part 2. The other most common Grade 3/4 events were thrombocytopenia (25/73; 34%) and anaemia (11/73; 15%). There were 12 treatmentrelated serious adverse events and no treatment-related deaths. Overall response rate at 3 4 mg/kg in Part 2 was 60% (21/35; 95% confidence interval: 42 1%–76 1%).
Interpretation:
At the identified RP2D, GSK2857916 is well tolerated and data suggest it has good clinical activity in heavily pretreated patients, thereby indicating that this may be a promising candidate for the treatment of relapsed/refractory MM.
Funding:
GlaxoSmithKline plc
Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) represent an unmet clinical need. Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class antibody-drug conjugate (ADC; or immunoconjugate) that delivers a cytotoxic payload, monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study (NCT03525678), single-agent belamaf (2.5 mg/kg) demonstrated clinically meaningful anti-myeloma activity (overall response rate 32%) in patients with heavily pretreated disease. Microcyst-like epithelial changes (MECs) were common, consistent with reports from other MMAFcontaining ADCs. Methods: Corneal examination findings from patients in DREAMM-2 were reviewed, and the clinical descriptions and accompanying images (slit lamp microscopy and in vivo confocal microscopy [IVCM]) of representative events were selected. A literature review on corneal
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