ABSTRACT
Background: ABX464 (obefazimod) is a small molecule that upregulates a single microRNA (miR-124) in immune cells and reduces the production of various inflammatory cytokines and chemokines. Objective: We assessed the efficacy and safety of the standard of care (SoC) plus oral obefazimod (SoC plus ABX464), 50 mg once daily, versus the SoC plus placebo for prevention of severe acute respiratory syndrome in patients with coronavirus disease 2019 (COVID-19) who are at risk for severe disease. Methods: Eligible patients for this phase 2/3 double-blind, placebo-controlled miR-AGE study were randomized (2:1) into 2 groups: SoC-ABX464 (n = 339) and SoC-placebo (n = 170). The primary end point was the percentage of patients who did not require use of high-flow oxygen or invasive or noninvasive mechanical ventilation within 28 days. The safety analyses included patients who had been randomly assigned and had received at least 1 dose of the study treatment. Results: At the time of the interim analysis, obefazimod showed no benefit over placebo when added to the SoC; the study enrollment was stopped for futility. The evaluation of the safety of obefazimod in 505 patients showed significantly more treatment-emergent adverse events in the SoC-ABX464 group than in the SoC-placebo group (P = .007). Frequently reported AEs in the SoC-ABX464 group included headache (14.6%), abdominal pain (9.6%), diarrhea (9.0%), back pain (6.9%), and nausea (6.0%). No treatment-related changes in laboratory parameters were reported. Conclusion: For patients who have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and are at risk for severe COVID-19, obefazimod, 50 mg, provided no benefit over placebo when added to the SoC, although it did have a good safety profile (comparable to that reported in many therapeutic areas).
ABSTRACT
OBJECTIVES: Treatment of HIV-infected patients is associated with early onset of aging-related comorbidities. Some of the adverse effects of antiretroviral therapy have been attributed to the mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI), and it is of note that mitochondrial dysfunction and oxidative stress are involved in the aging processes. In this regard, we examined whether NRTIs could accelerate the senescence of cultured cells. METHODS: Human fibroblasts were exposed to NRTIs from culture passage 1 to 14. Cytochrome c-oxidase (COX) subunits 2 and 4, mitochondrial potential and mass, and reactive oxygen species (ROS) were quantified at each passage. Proliferation, cell-cycle arrest, senescence-associated beta-galactosidase activity, and morphology were assessed in parallel. Mitochondrial and senescence markers were assessed in cultured murine preadipocytes and in fat samples from lipodystrophic HIV-infected patients. RESULTS: Stavudine and zidovudine induced mitochondrial dysfunction and increased ROS levels in fibroblasts at early culture passages, while cell division gradually slowed. At passages 8-12, fibroblasts exposed to stavudine or zidovudine but not abacavir, didanosine, lamivudine and tenofovir were senescent, on the basis of p16(INK4) and p21(WAF-1) protein expression, cell morphology and senescence-associated-beta-galactosidase activity. Senescence markers and COX2 underexpression were also found in 3T3-F442A preadipocytes exposed for 7 weeks to stavudine or zidovudine, but not lamivudine, and in adipose tissue samples from lipodystrophic HIV-infected patients on antiretroviral regimens containing stavudine or zidovudine. CONCLUSIONS: Mitochondrial changes and oxidative damage could partly explain the premature senescence of fibroblasts and adipose cells induced by stavudine and zidovudine. This suggests that thymidine analogues might be involved in the early aging-related diseases observed in some HIV-infected patients taking antiretroviral drugs.