ObjectiveAURORA 2 evaluated the long‐term safety, tolerability, and efficacy of voclosporin compared to placebo in patients with lupus nephritis (LN) receiving an additional two years of treatment following completion of the one‐year... more
ObjectiveAURORA 2 evaluated the long‐term safety, tolerability, and efficacy of voclosporin compared to placebo in patients with lupus nephritis (LN) receiving an additional two years of treatment following completion of the one‐year AURORA 1 study.MethodsEnrolled patients continued their double‐blinded treatment of voclosporin or placebo randomly assigned in AURORA 1, in combination with mycophenolate mofetil and low‐dose glucocorticoids. The primary objective was safety assessed with adverse events (AEs) and biochemical and hematological assessments. Efficacy was measured by renal response.ResultsA total of 216 patients enrolled in AURORA 2. Treatment was well tolerated with 86.1% completing the study and no unexpected safety signals. AEs occurred in 86% and 80% of patients in the voclosporin and control groups, respectively, with an AE profile similar to that seen in AURORA 1, albeit with reduced frequency. Investigator reported AEs of both glomerular filtration rate (GFR) decrea...
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Background and Aims The calcineurin inhibitors (CNI) cyclosporine (CSA) and tacrolimus (TAC) were revolutionary immunosuppressants when first introduced for solid organ transplantation in the 1980s. Voclosporin (VCS), a novel CNI,... more
Background and Aims The calcineurin inhibitors (CNI) cyclosporine (CSA) and tacrolimus (TAC) were revolutionary immunosuppressants when first introduced for solid organ transplantation in the 1980s. Voclosporin (VCS), a novel CNI, recently became the first oral therapy approved in the United States, Great Britain, and Europe for the treatment of active lupus nephritis based on positive results from Phase 2 and 3 clinical trials. Unlike CSA and TAC, VCS has demonstrated a consistent pharmacokinetic and pharmacodynamic profile, eliminating the need for therapeutic drug monitoring. Further, VCS is associated with a more favorable metabolic profile and has not been associated with electrolyte disturbances. Emerging evidence indicates small molecule therapeutics may display differential disposition within organ tissues. This suggests that CNIs may be differentially distributed and retained in the kidney, potentially explaining the difference in their efficacy and safety profiles. To eval...
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ObjectiveThis integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN)... more
ObjectiveThis integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN) using pooled data from two large phase II and phase III clinical trials. The purpose was to expand the pool of patients for safety analyses and to increase power for efficacy analyses in patient subpopulations.MethodsAurinia Urinary Protein Reduction in Active Lupus with Voclosporin (AURA‐LV) (phase II) and Aurinia Renal Response in Active Lupus With Voclosporin (AURORA 1) (phase III) were randomized, placebo‐controlled, double‐blind trials with similar designs and end points comparing voclosporin to control in combination with MMF and oral glucocorticoids for the treatment of LN. The primary efficacy outcome of the integrated analysis was complete renal response (CRR) at approximately one year (Week 48 data from AURA‐LV and Week 52 from AURORA 1). Saf...
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Background. An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MPAG,... more
Background. An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MPAG, the pharmacologically inactive metabolite of MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination. Methods. MMF was orally administered at a dose of 1 g twice a day for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg twice a day for 7 consecutive days (Days 1–7), starting on the evening of Day 1 and ending with the morning dose on Day 7. Dense pharmacokinetic blood samples were collected pre-dose in the morning and from 0.25 to 12 h after the morning doses. Analyses were derived by noncompartmental methods. Results. In 24 patients, MPA exposure [maximum serum concentration (Cmax) and area ...
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Background: Psoriasis is a chronic skin condition that can negatively affect a patient’s quality of life (QoL), often hindering social functioning. ISA247, a novel psoriatic agent, has shown clinical efficacy in moderate to severe... more
Background: Psoriasis is a chronic skin condition that can negatively affect a patient’s quality of life (QoL), often hindering social functioning. ISA247, a novel psoriatic agent, has shown clinical efficacy in moderate to severe psoriasis sufferers, but its effect on QoL is currently not reported. Objective: The objective of this study was to assess the effect of ISA247 on the QoL in patients with stable, plaque-type psoriasis. Methods: A phase II, randomized, double-blind, placebo-controlled, parallel-group, multicenter study assessed the effects of ISA247 doses of 0.5 mg/kg/d (n 5 77) or 1.5 mg/kg/d (n 5 83) compared with placebo (n 5 41) for 12 weeks. QoL was assessed using the Dermatology Life Quality Index (DLQI) and Psoriasis Disability Index (PDI) scales. Results: ISA247 treatment (pooled groups) significantly improved QoL scores as assessed by both the DLQI and the PDI compared with those receiving placebo (p,.05). Treatment with the higher dose of 1.5 mg/kg/d demonstrated...
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lacebo in achieving remission in patients with active lupus nephritis Brad H. Rovin, Neil Solomons, William F. Pendergraft III, Mary Anne Dooley, James Tumlin, Juanita Romero-Diaz, Lidia Lysenko, Sandra V. Navarra and Robert B. Huizinga;... more
lacebo in achieving remission in patients with active lupus nephritis Brad H. Rovin, Neil Solomons, William F. Pendergraft III, Mary Anne Dooley, James Tumlin, Juanita Romero-Diaz, Lidia Lysenko, Sandra V. Navarra and Robert B. Huizinga; for the AURA-LV Study Group Department of Internal Medicine–Nephrology, Ohio State University, Columbus, Ohio, USA; Aurinia Pharmaceuticals, Victoria, Canada; University of North Carolina Kidney Center, Chapel Hill, North Carolina, USA; GA Nephrology, Atlanta, Georgia, USA; Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; First Moscow State Medical University, Moscow, Russia; and St. Luke’s Medical Center and University of Santo Tomas Hospital, Philippines
From the days of Aristotle, the use of metaphor to describe our world has attracted more interest than any other traditionally recognized figures of speech. It is seen in Aristotle’s writings, Egyptian hieroglyphics, Western European cave... more
From the days of Aristotle, the use of metaphor to describe our world has attracted more interest than any other traditionally recognized figures of speech. It is seen in Aristotle’s writings, Egyptian hieroglyphics, Western European cave paintings, Christian scriptures, and even in the stock market’s use of raging bulls and angry bears. Metaphors are easily understood, are powerful, and add texture and beauty to dialogue. By comparing two things that appear dissimilar, metaphors evoke a comprehension of an event or situation. As theories of organization are based upon metaphors, the expansion of both our understanding of metaphor and the limitation of metaphors is helpful in understanding organizational trust, organizational performance, and even organizational longevity. It is worth noting that using metaphors can lead to an oversimplification of phenomena, subjectivity, and even a distortion of the organizational view. However, if properly used, metaphors help us in interpreting ...
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Background An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MPAG,... more
Background An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MPAG, the pharmacologically inactive metabolite of MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination. Methods MMF was orally administered at a dose of 1 g twice a day for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg twice a day for 7 consecutive days (Days 1–7), starting on the evening of Day 1 and ending with the morning dose on Day 7. Dense pharmacokinetic blood samples were collected pre-dose in the morning and from 0.25 to 12 h after the morning doses. Analyses were derived by non-compartmental methods. Results In 24 patients, MPA exposure [maximum serum concentration (Cmax) and area un...
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Background and Aims Voclosporin (VCS) is a novel high potency calcineurin inhibitor (CNI) with a favorable metabolic profile and a consistent predictable dose response potentially eliminating the need for therapeutic drug monitoring. The... more
Background and Aims Voclosporin (VCS) is a novel high potency calcineurin inhibitor (CNI) with a favorable metabolic profile and a consistent predictable dose response potentially eliminating the need for therapeutic drug monitoring. The Aurinia Renal Response in Active Lupus with Voclosporin (AURORA) study, involving 357 patients with active LN, was a Phase 3 global, double-blind, placebo-controlled RCT designed to evaluate the efficacy and safety of VCS (23.7mg BID) vs placebo in combination with mycophenolate (MMF, 2 g/day) and rapidly tapered low dose oral steroids. Method The primary endpoint was renal response (RR) at 52 weeks. RR was defined as UPCR of ≤ 0.5 mg/mg, eGFR ≥ 60 mL/min, or no confirmed decrease from baseline in eGFR of > 20%, presence of sustained, low dose steroids and no administration of rescue medication. Results AURORA met its primary endpoint, achieving statistically superior RR rates of 40.8% for voclosporin vs. 22.5% for the control (OR 2.65, 95% CI; p...
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ContextThe incidence of new onset diabetes after transplant (NODAT) has increased over the past decade. It has been suggested that NODAT is caused by exposure to calcineurin inhibitors, particularly tacrolimus (TAC). Voclosporin (VCS), a... more
ContextThe incidence of new onset diabetes after transplant (NODAT) has increased over the past decade. It has been suggested that NODAT is caused by exposure to calcineurin inhibitors, particularly tacrolimus (TAC). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT.ObjectiveWhilst calcineurin plays important roles in pancreatic β-cell survival, proliferation, and function, the effects of calcineurin inhibitors on human β-cells remain understudied. In particular, we do not understand why some inhibitors have more profound effects on the incidence of NODAT.DesignHere, we compared the effects of TAC and VCS on the dynamics of insulin secretory function, the programmed cell death rate, and the transcriptomic profile of human islets. We studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the clinical trough and peak concentrations.ResultsTAC, but not VCS, caused a sig...
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With the decrease in donor quality and the increase in recipient co-morbidities, transplantation immunosuppression is changing. New paradigms in transplantation include co-stimulation, lymphocyte retrafficking, and inhibiting antibody... more
With the decrease in donor quality and the increase in recipient co-morbidities, transplantation immunosuppression is changing. New paradigms in transplantation include co-stimulation, lymphocyte retrafficking, and inhibiting antibody production. With these new paradigms come new immunosuppressive agents. While these new agents show great promise, their use in day-to-day clinical transplantation remains to be seen.
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This article briefly reviews the current status of renal transplantation and the current focus of immunosuppression in the prevention of chronic rejection. Four paradigms involved in the understanding of the immune system and their role... more
This article briefly reviews the current status of renal transplantation and the current focus of immunosuppression in the prevention of chronic rejection. Four paradigms involved in the understanding of the immune system and their role in rejection are discussed. The paradigms are co-stimulation, quantifying immunosuppression, changing the direction of lymphocytes, and inhibition of antibody. Examples of each of these paradigms are given.
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Research Interests: Quality of life, Adolescent, Medicine, Activities of Daily Living, Humans, and 15 moreInternal Medicine, Placebo, Female, Male, Psoriasis, Cyclosporine, Aged, Middle Aged, Questionnaires, Adult, Randomized Controlled Trial, Leisure Activities, Disability Evaluation, Dermatology Life Quality Index, and Dermatologic agents
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Research Interests: Urology, Kidney transplantation, Pharmacokinetics, Clinical Pharmacology, Medicine, and 14 morePopulation, Humans, Female, Male, Cyclosporine, Clearance, Middle Aged, Adult, Pharmacodynamics, Calcineurin, Calcineurin inhibitors, Immunosuppressive Agents, Dosing, and Pharmacology and pharmaceutical sciences
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Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the effect of renal or hepatic impairment on pharmacokinetics of voclosporin.... more
Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the effect of renal or hepatic impairment on pharmacokinetics of voclosporin. Thirty-three subjects were enrolled into 1 of 4 groups based on renal function as defined by creatinine clearance and 18 subjects were enrolled into 1 of 3 groups based on hepatic function defined by Child-Pugh classes. Voclosporin 0.4 mg/kg was administered orally. Geometric mean ratios (renal/hepatic impairment-to-normal) and 90% confidence intervals for Cmax and AUC were calculated. A default no-effect interval of 80-125% was set. Although 90% confidence intervals exceeded the no-effect intervals for both parameters, individual Cmax and AUC plots indicate almost complete overlapping range of values for mild and moderate renal impairment and normal subjects. Severe renal impairment resulted in a 1.5-fold increase in AUC without an increase in Cmax . Mild to moderate hepatic impairment resulted in a 1.5- to 2-fold increase in voclosporin exposure. Voclosporin can be administered safely to patients with mild to moderate renal impairment without dose modification. Appropriate safety monitoring with concentration-based adjustments in transplantation are recommended for patients with severe renal impairment, and for patients with hepatic impairment.
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Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium... more
Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.