Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata.

Background: Janus kinase (JAK) activation is suggested to have a pathological role in alopecia areata (AA). CTP-543, a deuterated compound that selectively inhibits JAK1 and JAK2, is being developed as an oral treatment for AA.

Objective: To assess the safety and efficacy of a 24-week regimen of CTP-543 in patients with chronic, moderate-to-severe AA.

Altering Metabolic Profiles of Drugs by Precision Deuteration 2: Discovery of a Deuterated Analog of Ivacaftor with Differentiated Pharmacokinetics for Clinical Development.

Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, whereas Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (-ivacaftor) and -ivacaftor.

A First-in-Patient, Multicenter, Double-Blind, 2-Arm, Placebo-Controlled, Randomized Safety and Tolerability Study of a Novel Oral Drug Candidate, CTP-499, in Chronic Kidney Disease.

The prevalence of chronic kidney disease (CKD) related to type 2 diabetes is increasing worldwide. In addition to standard of care, treatment with anti-inflammatory and antifibrotic agents such as CTP-499, a novel oral, multisubtype selective inhibitor of phosphodiesterases, may be important in CKD treatment. A phase 1b randomized, double-blind, placebo-controlled clinical trial of CTP-499 in CKD patients (25 active, 8 placebo) with an estimated glomerular filtration rate of 30-59 mL/min/1.

Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis.

CTP-499 is a novel oral multi-subtype selective inhibitor of PDEs that is currently in clinical testing, in combination with angiotensin modulators, as a potentially first-in-class treatment for diabetic kidney disease. The compound was discovered and developed by using Concert's proprietary DCE Platform(®) in which deuterium was incorporated at select positions of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX). CTP-499 metabolizes to five major metabolites: C-21256, D-M2, D-M3, D-M4 and M5, of which all contains deuterium except M5.

Revealing the metabolic sites of atazanavir in human by parallel administrations of D-atazanavir analogs.

Atazanavir (Reyataz(®)) is an important member of the HIV protease inhibitor class. Because of the complexity of its chemical structure, metabolite identification and structural elucidation face serious challenges. So far, only seven non-conjugated metabolites in human plasma have been reported, and their structural elucidation is not complete, especially for the major metabolites produced by oxidations.

A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy.

To determine maximum tolerated dose and food effect for CTP-499, a novel agent being studied for the treatment of diabetic kidney disease. CTP-499 has demonstrated anti-inflammatory, anti-fibrotic and anti-oxidative activities in vitro as well as anti-inflammatory and renoprotective effects in a diabetic nephropathy (DN) model. Two studies were performed.

Relationship of quality of life scores with baseline characteristics and outcomes in the African-American heart failure trial.

Background: To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known.

Evidence for the continued safety and tolerability of fixed-dose isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American Heart Failure Trial).

The benefits of fixed-dose combination isosorbide dinitrate plus hydralazine (ID/H) in African-Americans with heart failure (HF) were established by the African-American Heart Failure Trial (A-HeFT), which was terminated early because of a significant survival benefit of ID/H. The Extension to A-HeFT trial (X-A-HeFT), designed to make ID/H available for ethical reasons after A-HeFT termination, afforded an opportunity to further observe responsiveness and compliance with ID/H. In total 198 patients completing the A-HeFT took ID/H for an additional 209 +/- 116 days.

Clinical and microbial evaluation of a histatin-containing mouthrinse in humans with experimental gingivitis: a phase-2 multi-center study.

Objective: P-113, a 12 amino acid histatin-based peptide, was evaluated in a mouthrinse formulation for safety and efficacy in a phase 2 multi-center clinical study.

Method: 294 healthy subjects abstained from oral hygiene procedures and self-administered either 0.01% P-113, 0.