Dona Fleishaker

Linezolid for the treatment of methicillin-resistant Staphylococcus aureus infections in children.

Background. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly prevalent. Linezolid is effective and well-tolerated in the treatment of adults with MRSA infections. Objective. To evaluate the clinical efficacy and safety of iv/oral linezolid in children with MRSA infections. Methods. Data were obtained from two independent clinical trials. In an outpatient trial children (5 to 17 years of age) with uncomplicated skin and skin structure infections (SSSIs) were treated with linezolid or cefadroxil. In an inpatient trial hospitalized children (0 to 11 years of age) with pneumonia, bacteremia or complicated SSSI caused by resistant Gram-positive pathogens were administered iv linezolid with the option to switch to oral suspension (patients >90 days of age) or iv vancomycin. A subset of patients with MRSA infections from the two clinical trials is analyzed herein. Results. In the outpatient trial children with skin infections caused by MRSA were treated with linezolid (15 patients) and cefadroxil (10 patients). In the microbiologically evaluable population, the clinical cure rate was 92.3% in the linezolid group and 85.7% in the cefadroxil group (P = 0.64). The pathogen eradication rate for MRSA was 92.3 and 85.7% in the linezolid and cefadroxil groups, respectively (P = 0.64). There were very few adverse events or drug-related adverse events and no serious adverse events in the outpatient trial. In the inpatient trial 20 children treated with linezolid and 14 treated with vancomycin had infections caused by MRSA. In the microbiologically evaluable population, the clinical cure rate was 94.1% in the linezolid group and 90.0% in the vancomycin group (P = 0.69). Pathogen eradication rates were 88.2 and 90.0% for the linezolid and vancomycin groups, respectively (P = 0.89). Susceptibility patterns of the MRSA isolates showed distinct patterns between the outpatient and inpatient trials. In the inpatient trial fewer patients in the linezolid group had drug-related adverse events than did those in the vancomycin group (20%vs. 43%; P = 0.15). Conclusions. Intravenous/oral linezolid is effective and well-tolerated in children with MRSA infections.

Linezolid versus cefadroxil in the treatment of skin and skin structure infections in children

Background. Skin and skin structure infections are common reasons for visits to pediatricians, accounting for up to 18%. Staphylococcus aureus and Streptococcus pyogenes are the most frequently isolated Gram-positive pathogens in uncomplicated skin infections. Increasingly outpatient infections involve antibiotic-resistant Gram-positive pathogens including methicillin-resistant S. aureus. Methods. This randomized, blinded, comparator-controlled, multinational trial compared the efficacy and safety of linezolid and cefadroxil for treatment of uncomplicated skin/skin structure infections in pediatric patients. Children ages 5 to 11 years were to receive linezolid suspension [10 mg/kg (up to 600 mg)] or cefadroxil suspension [15 mg/kg (up to 500 mg)] every 12 h. Patients ages 12 to 17 years were to receive linezolid tablets (600 mg) or cefadroxil capsules (500 mg) every 12 h. Therapy lasted 10 to 21 consecutive days with a follow-up visit 10 to 21 days posttherapy. Results. Linezolid and cefadroxil were consistently effective treatments across all primary and secondary efficacy assessments. At follow-up cure rates were 88.7% (205 of 231) for linezolid-treated and 86.2% (193 of 224) for cefadroxil-treated intent-to-treat patients; cure rates were 91.0% (201 of 221) for linezolid-treated and 90.0% (189 of 210) for cefadroxil-treated clinically evaluable patients. S. aureus was eradicated in 89.6% (120 of 134) linezolid-treated and 88.8% (111 of 125) cefadroxil-treated microbiologically evaluable patients. Gastrointestinal complaints were the most common adverse events reported, without significant differences between treatment groups, and myelosuppression was not observed in this study Conclusions. Linezolid is well-tolerated and as effective as cefadroxil in treating uncomplicated skin infections in pediatric patients. Linezolid effectively treated infections caused by S. aureus, methicillin-resistant S. aureus and S. pyogenes.

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study

Objectives To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis). Methods In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored. Results Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16. Conclusions Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications. Trial registration number NCT01786668.

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial

IntroductionThe purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX).MethodsThis phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.ResultsSixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).ConclusionsMaraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.Trial RegistrationClinicalTrials.gov: NCT00427934

Improved disease activity with fosdagrocorat (PF-04171327), a partial agonist of the glucocorticoid receptor, in patients with rheumatoid arthritis: a Phase 2 randomized study

To assess efficacy and safety of fosdagrocorat (PF‐04171327), a potential dissociated agonist of the glucocorticoid receptor, in rheumatoid arthritis (RA) patients.

Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients

Abstract Objectives Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ⩾2.5 for SI joint and ⩾5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS treated with tofacitinib or placebo, and correlation with clinical responses. Methods Adult AS patients in a 12-week phase 2 study (n = 207) were randomized 1: 1: 1: 1 to tofacitinib 2, 5 or 10 mg twice daily (BID) or placebo. MIC in SPARCC SI joint and spine scores were assessed for patients with available MRI data (N = 164; 79%). Clinical endpoints at week 12, including Assessment of SpondyloArthritis international Society 20% improvement (ASAS20), were compared between patients achieving/not achieving MIC. Results A greater proportion of patients achieved MIC with tofacitinib 2, 5 and 10 mg BID vs placebo for SI joint (28.6, 38.6, 29.6 vs 11.8%) and spine scores (29.3, 36.4, 40.9 vs 11.8%). Generally, a greater proportion of patients treated with tofacitinib 2, 5 and 10 mg BID or placebo, respectively, who achieved MIC for SI joint and spine scores achieved ASAS20 (SI joint: 75.0, 88.2, 69.2, 75.0%; spine: 91.7, 85.7, 72.2, 75.0%) vs patients who did not achieve MIC (SI joint: 51.7, 84.0, 58.1, 48.3%; spine: 46.4, 85.7, 53.8, 48.3%). Numerically greater responses were seen in those patients achieving vs not achieving MIC across a range of other efficacy assessments. Conclusion Approximately one-third of tofacitinib-treated AS patients experienced clinically meaningful reductions in spinal MRI inflammation at week 12. Patients achieving MIC for MRI inflammation had greater clinical response.

In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251802 (Dagrocorat), a Novel Dissociated Agonist of the Glucocorticoid Receptor

The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF‐04171327 (fosdagrocorat) is a phosphate ester prodrug of PF‐00251802 (dagrocorat), a selective high‐affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF‐04015475. This study evaluated the cytochrome P450 (CYP)–mediated drug–drug interaction (DDI) potential of PF‐00251802 and PF‐04015475 in vitro and used model‐based prediction approaches to estimate clinical impact. PF‐00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF‐00251802 and PF‐04015475 are time‐dependent inhibitors and inducers of CYP3A in vitro; PF‐00251802 is also a time‐dependent inhibitor of CYP2D6. Model‐based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open‐label, multiple‐dose study evaluated the effect of PF‐04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF‐04171327 resulted in equivalent pharmacokinetic profiles (AUCinf, 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF‐04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF‐00251802 and PF‐04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).

SAT0293 Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, up to 36 months in patients with active psoriatic arthritis: data from the third interim analysis of opal balance, an open-label, long-term extension study

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). Objectives To report the safety, tolerability and efficacy of tofacitinib in patients (pts) with active PsA from an ongoing, open-label, long-term extension (LTE) study (OPAL Balance, NCT01976364; November 2017 data-cut; database not locked). Methods Eligible pts from 2 Phase (P)3 tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered a 3 year LTE ≤3 months after completing the P3 study or discontinuing for reasons unrelated to study drug. Pts received tofacitinib 5 mg BID to Month (M)1, after which dose adjustments between 5 and 10 mg BID were permitted to improve efficacy, or for safety reasons. Pts receiving a csDMARD at P3 study entry continued the same csDMARD in the LTE. Primary endpoints were incidence and severity of adverse events (AEs) and changes from baseline (Δ) in laboratory values. Safety data are reported up to M36. Efficacy was evaluated up to M30 (when n>50) as a secondary endpoint. Results 686 pts were treated in OPAL Balance; 468 (68.2%) remained in the study at data cut-off. Mean (range) LTE tofacitinib exposure was 614 (1–1032) days. On Day 1, 675 pts (98.4%) received a csDMARD, which was discontinued in 86 pts (12.7%). To M36, 2189 AEs were reported in 546 pts (79.6%), 95 pts (13.8%) had serious AEs and 59 pts (8.6%) discontinued due to AEs. Serious infections occurred in 12 pts (1.7%), herpes zoster (HZ) in 20 pts (2.9%; 1 serious event), major adverse cardiovascular events in 5 pts (0.7%), malignancies in 24 pts (3.5%; including 12 pts with NMSC) and uveitis in 2 pts (0.3%). No AEs of gastrointestinal perforation or inflammatory bowel disease were reported. There were 5 deaths (not attributed to treatment, as assessed by the investigator) due to metastatic pancreatic carcinoma, acute cardiac failure/hypertensive heart disease, chronic obstructive pulmonary disease, pulmonary embolism and cardiovascular insufficiency. Four AEs of latent tuberculosis were reported in pts whose previously negative QuantiFERON response became positive. ALT was elevated ≥3 x ULN in 27 pts (4.0%), and AST≥3 x ULN in 15 pts (2.2%). Changes in laboratory values observed in P3 studies were generally stable in the LTE, except for a modest decrease in absolute lymphocyte count over time. Eight pts (1.2%) discontinued (protocol-mandated) due to laboratory value changes. ACR responses, ΔHAQ-DI, PASI75 response, ΔLeeds Enthesitis Index, ΔDactylitis Severity Score and ΔPain were maintained up to M30. Conclusions Over 36 months in the LTE, the safety profile of tofacitinib in active PsA pts was generally similar to that of the P3 studies. No new safety risks were identified. Efficacy across various PsA disease domains was maintained over time. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest P. Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, L. Coates Grant/research support from: AbbVie, Janssen, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer Inc, Sun Pharma, UCB, A. Kivitz Consultant for: AbbVie, Celgene, Genentech, Genzyme, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, Speakers bureau: AbbVie, Celgene, Genentech, Genzyme, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer Inc, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, J. Covarrubias-Cobos Grant/research support from: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, D. Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Kudlacz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc