Browsing by Subject "Quinolones"

Now showing 1 - 4 of 4
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    Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy
    (ACS Publications, 2017-06-08) Rietz, Anne; Li, Hongxia; Quist, Kevin M.; Cherry, Jonathan J.; Lorson, Christian L.; Burnett, Barrington; Kern, Nicholas L.; Calder, Alyssa N.; Fritsche, Melanie; Lusic, Hrvoje; Boaler, Patrick J.; Choi, Sungwoon; Xing, Xuechao; Glicksman, Marcie A.; Cuny, Gregory D.; Androphy, Elliot J.; Hodgetts, Kevin J.; Dermatology, School of Medicine
    Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.
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    Elexacaftor/Tezacaftor/Ivacaftor Improved Clinical Outcomes in a Patient with N1303K-CFTR Based on In Vitro Experimental Evidence
    (American Thoracic Society, 2021) Huang, Yunjie; Paul, Grace; Lee, Jesun; Yarlagadda, Sunitha; McCoy, Karen; Naren, Anjaparavanda P.; Pediatrics, School of Medicine
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    Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study
    (Elsevier, 2021) Flume, Patrick A.; Biner, Reta Fischer; Downey, Damian G.; Brown, Cynthia; Jain, Manu; Fischer, Rainald; De Boeck, Kris; Sawicki, Gregory S.; Chang, Philip; Paz-Diaz, Hildegarde; Rubin, Jaime L.; Yang, Yoojung; Hu, Xingdi; Pasta, David J.; Millar, Stefanie J.; Campbell, Daniel; Wang, Xin; Ahluwalia, Neil; Owen, Caroline A.; Wainwright, Claire E.; VX14-661-110 study group; Medicine, School of Medicine
    Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes.
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    Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2016-04-15) Pozniak, Anton; Arribas, Jose R.; Gathe, Joseph; Gupta, Samir K.; Post, Frank A.; Bloch, Mark; Avihingsanon, Anchalee; Crofoot, Gordon; Benson, Paul; Lichtenstein, Kenneth; Ramgopal, Moti; Chetchotisakd, Ploenchan; Custodio, Joseph M.; Abram, Michael E.; Wei, Xuelian; Cheng, Andrew; McCallister, Scott; SenGupta, Devi; Fordyce, Marshall W.; Department of Medicine, IU School of Medicine
    BACKGROUND: Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved renal and bone safety compared with TDF-containing regimens. We report the 48 week safety and efficacy of a once-daily single tablet regimen of elvitegravir 150 mg (E), cobicistat 150 mg (C), emtricitabine 200 mg (F), and TAF 10 mg (E/C/F/TAF) in HIV-1-infected patients with mild to moderate renal impairment. METHODS: We enrolled virologically suppressed HIV-1-infected subjects with estimated creatinine clearance (CrCl) 30-69 mL/min in a single-arm, open-label study to switch regimens to E/C/F/TAF. The primary endpoint was the change from baseline in glomerular filtration rate estimated using various formulae. This study is registered with ClinicalTrials.gov, number NCT01818596. FINDINGS: We enrolled and treated 242 patients with mean age 58 years, 18% Black, 39% hypertension, 14% diabetes. Through week 48, no significant change in estimated CrCl was observed. Two patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had significant improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001 for all). Hip and spine bone mineral density significantly increased from baseline to week 48 (mean percent change +1.47 and +2.29, respectively, P < 0.05). Ninety-two percent (222 patients) maintained HIV-1 RNA <50 copies per milliliter at week 48. INTERPRETATION: Switch to E/C/F/TAF was associated with minimal change in GFR. Proteinuria, albuminuria and bone mineral density significantly improved. These data support the efficacy and safety of once daily E/C/F/TAF in HIV+ patients with mild or moderate renal impairment without dose adjustment.