Objective
Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.
Methods
Subjects included patients with SMA aged 2 months–60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age‐appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD‐OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2–6 months depending on study and assessment. SD‐OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study.
Results
A total of 245 patients receiving risdiplam were assessed. Comprehensive, high‐quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD‐OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam‐induced toxicity and resolved with ongoing treatment.
Interpretation
Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.
Introduction.Much of what we know about the functioning of human T lymphocytes is based on the experiments carried out at atmospheric oxygen (O 2 ) concentrations, which are significantly higher than those maintained in blood. Interestingly, the gender differences in the activity of T cells and their susceptibility to apoptosis under different O 2 conditions have not yet been described. The aim of the study was to compare two main markers of lymphocyte function: proliferation capacity and ability to produce cytokines as well as their susceptibility to apoptosis under two different O 2 concentrations, between men and women. Material and methods. 25 healthy volunteers, both males (13) and females (12) were recruited to the study (mean age 25.48 ± 5.51). By using cytometry proliferation parameters of human CD4 + CD28+ cells or CD8 + CD28 + cells in response to polyclonal stimulation of the TCR/CD3 complex at atmospheric (21%) and physiological (10%) O 2 concentrations using our modified dividing cell tracking technique (DCT) were analyzed as well as the percentages of apoptotic cells. We also determined the levels of IFN-g, IL-2, IL-10 and IL-17A using Cytometric Bead Array Flex system in cell culture supernatants.
Results. CD4+ CD28 + and CD8 + CD28 + cells from the whole study group were characterized by shorter time required to enter the first (G1) phase of the first cell cycle at 21% compared to 10% O 2 . Both T cell populations performed significantly more divisions at 21% O 2 . The percentages of dividing cells were also significantly higher at atmospheric O 2 . Interestingly, data analysis by gender showed that male lymphocytes had similar proliferative parameters at both O 2 concentrations while female lymphocytes proliferate more efficiently at 21% oxygen. Compared to males, the female CD4 + cells showed increased susceptibility to apoptosis at both O 2 concentrations. No differences in the levels of cytokines regardless of gender and oxygen conditions were found. Conclusions. We showed that in vitro female T cells (both CD4 + and CD8 + cells) are more sensitive than male lymphocytes to low O 2 concentration as demonstrated by the decrease in their proliferation dynamics. The effect does not depend on increased apoptosis of female T cells under low O 2 because percentage of apoptotic cells was similar at both O
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