Biosimilar ranibizumab (Epruvy)

Reappraisal of Comparison of the Efficacy and Safety of Biosimilar Adalimumab with Innovator Adalimumab in Ankylosing Spondylitis.

Gawari Nitin Chintaman NC, Naik Tanvi T, Shingare Sujata Prakash SP, Hassan Yasir Y

Doping Control Analysis of Darbepoetin Alfa Biosimilars in Human Urine, Serum, Plasma, and Dried Blood Spots.

Akiyama Kentaro K, Sakurai Hikaru H, Sato Mitsuhiko M, Momobayashi Atsushi A et al.

Following the patent expiration of the originator darbepoetin alfa, three biosimilar products have been marketed in Japan; however, their detectability by current anti-doping methods has not yet been verified. The present study assessed whether these biosimilars can be detected in human urine, serum, plasma, and dried blood spots (DBS) using the established initial testing procedure and confirmation analysis for erythropoietin-receptor agonists. The originator product and three biosimilars (5 μg, i.v.) were administered to healthy male volunteers. Samples collected up to 72 h postdose were subjected to immunopurification followed by sodium N-lauroyl sarcosinate polyacrylamide-gel electrophoresis (SAR-PAGE) as the initial testing procedure. Confirmation was performed by SAR-PAGE with double blotting for serum and plasma. DBS and urine samples were confirmed by SAR-PAGE using an alternative antibody, and urine samples were further examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). SAR-PAGE analysis of the pharmaceutical preparations revealed product-specific electrophoretic profiles: two biosimilars migrated slightly above one originator product as diffused smears, whereas the third produced a sharp band comparable to that of another originator product. Similar profiles were observed in postdose samples from all biological matrices, and all biosimilars remained detectable in urine, serum, plasma, and DBS for at least 72 h. Although some biosimilars showed distinct SAR-PAGE banding patterns, product attribution remained limited. LC-MS/MS confirmed administered darbepoetin alfa in the 24 h urine samples but did not detect analyte in lower concentration samples, indicating that its performance was concentration-dependent. Accordingly, SAR-PAGE should incorporate reference standards beyond the originator product, particularly those with different band morphologies.

Molecular predictors of minimal residual disease in newly diagnosed multiple myeloma treated with quadruplet therapy.

Magrangeas Florence F, Cherkaoui Mia M, Bessonneau-Gaborit Victor V, Derrien Jennifer J et al.

Quadruplet therapy, combining anti-CD38 antibodies, immunomodulatory drugs, proteasome inhibitors and dexamethasone, is now the standard induction treatment for newly diagnosed multiple myeloma (NDMM). However, treatment response is heterogeneous and molecular predictors are needed to guide early therapeutic decisions. We performed integrated genomic, transcriptomic and epigenomic profiling of 423 tumor samples from patients with NDMM from the MIDAS cohort to characterize molecular heterogeneity and its association with measurable residual disease (MRD) after quadruplet induction with isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd). Postinduction MRD-negativity rates varied significantly across gene expression subtypes, with HP1/HP3 and MS groups showing superior responses compared to the MF and CD2 subtypes. B cell differentiation was associated with MRD positivity, while proliferation and MYC programs were associated with MRD negativity. These MRD-associated transcriptomic features were independently validated in the CASSIOPEIA cohort. Whole-genome sequencing revealed both known (APOBEC mutagenesis, chromothripsis) and new genomic instability phenotypes validated in the MMRF cohort. New driver alterations were identified with independent validation across three external cohorts with multiple myeloma (MMRF, MANHATTAN and CASSIOPEIA; 1,451 cases). Genomic instability features and driver genes such as CCND1 and MYC correlated with differential MRD outcomes. DNA methylation profiling identified nine MRD-linked subgroups distinguished by the extent of hypomethylation in quiescent chromatin and cis/trans signatures of driver translocations. A multimodal random forest model integrating genomic, transcriptomic and epigenomic features predicted MRD status after induction, with an area under the curve of 0.77, outperforming clinical and genomic models, while providing comparable discrimination and improved calibration relative to the transcriptomic and epigenomic models. These findings define a multiomic classification of NDMM linked to Isa-KRd response. ClinicalTrials.gov identifier: NCT04934475 .

Mastering the Eye: Clinical Paradigm Shifts from Optical Restoration to Genomic Correction.

Zhang Xiulan X, Li Fei F, Huang David D, Yu-Wai-Man Patrick P et al.

Historically, the main operation for cataract was couching, and the interior of the living eye could not be examined until Hermann von Helmholtz introduced the ophthalmoscope in 1851. Since the mid-twentieth century, seven advances have reshaped ophthalmic care. Harold Ridley implanted the first intraocular lens in 1949, and the ophthalmologist Charles Kelman and the engineer Anton Banko developed phacoemulsification, reported in 1967. Robert Machemer performed the first pars plana vitrectomy in 1970, while David Huang and colleagues described optical coherence tomography in 1991. Endothelial keratoplasty, developed by Gerrit Melles and others between 1998 and 2006, replaced only the failing corneal endothelium instead of the full thickness of the cornea. Anti-VEGF therapy followed the purification of VEGF by Napoleone Ferrara and colleagues in 1989 and the approval of ranibizumab in 2006. Minimally invasive glaucoma surgery has spread since 2012, and in 2017 voretigene neparvovec became the first approved gene therapy for an inherited retinal disease. Five of these advances enabled a new type of intervention, whereas endothelial keratoplasty and minimally invasive glaucoma surgery made existing operations safer. For each advance we summarize the best available evidence of benefit to patients and its certainty, which is high for some, such as anti-VEGF therapy, and low for others, such as the effect of imaging on patient outcomes. Each advance created new burdens, from chronic injections to dependence on donor tissue, and routine adoption depended on manufacturing, regulation, cost, reimbursement, and health-system capacity.